The Association of Area Deprivation and State Child Health with Respiratory Outcomes of Pediatric Patients with Cystic Fibrosis in the United States.

Pediatr Pulmonol. 2020 Dec 01;:

Authors: Oates G, Rutland S, Juarez L, Friedman A, Schechter MS

Abstract
BACKGROUND: Differences in socio-environmental exposures influence overall child health, but their association with pediatric CF outcomes is less clear. This observational study investigated the relationship between area-level socioeconomic deprivation, state child health, and CF respiratory outcomes in a national cohort.
METHODS: We assessed relationships between 2015 Area Deprivation Index, a composite measure of socioeconomic disadvantage; 2016 Child Health Index, a state-specific measure of overall child health; and CF respiratory outcomes in the 2016 CF Foundation Patient Registry.
RESULTS: The sample included 9,934 individuals with CF, aged 6-18 years. In multiple regression analysis adjusted for demographic and clinical covariates, those residing in the worst tertile for area deprivation had 2.8% lower ppFEV1 (95% CI -4.1 to -1.5), 1.2 more IV treatment nights (CI 0.1-2.4), and 20% higher odds of ≥2 pulmonary exacerbations (OR 1.2, CI 1.0-1.5) than best-tertile counterparts. Children with CF in states at the worst tertile for child health had 2.3% lower ppFEV1 (CI -4.5 to -0.2), 2.2 more IV treatment nights (CI 0.5-3.6), and 40% higher odds of ≥2 exacerbations (OR 1.4, CI 1.1-1.8) than best-tertile counterparts. State child health accounted for the association between area deprivation and multiple exacerbations and more IV treatment nights.
CONCLUSIONS: Both area socioeconomic characteristics and state child health play a role in pediatric CF outcomes. The residual association of the state child health with CF outcomes after controlling for area deprivation reflects the ability of state programs to mitigate the effect of poverty. This article is protected by copyright. All rights reserved.

PMID: 33258546 [PubMed - as supplied by publisher]

IgA autoantibodies directed against self DNA are elevated in cystic fibrosis and associated with more severe lung dysfunction.

Autoimmunity. 2020 Dec;53(8):476-484

Authors: Yadav R, Linnemann RW, Kahlenberg JM, Bridges LS, Stecenko AA, Rada B

Abstract
Although extracellular host DNA (ecDNA) levels in CF airways were linked to airflow obstruction and recombinant DNAse therapy is beneficial for CF patients, it remains incompletely understood whether ecDNA also leads to an autoimmune response. Here we hypothesized that chronic presence of DNA in CF airways triggers the production of autoantibodies targeting host human DNA. We measured the levels of IgA autoantibodies recognising host double-stranded (ds) DNA in the blood and sputum samples of CF patients and only sera of controls subjects and patients suffering from rheumatoid arthritis and systemic lupus erythematosus (SLE) that served as non-CF, autoimmune disease cohorts. We found that concentrations of anti-dsDNA IgA, but not IgG, autoantibodies in the circulation were significantly elevated in adult CF patients compared to age-matched, control subjects. Systemic levels of anti-dsDNA IgA antibodies negatively correlated with FEV1% predicted, a measure of lung function, in CF patients. Anti-dsDNA IgA autoantibodies were also detected in CF sputa but sputum levels did not correlate with the degree of airway obstruction or sputum levels of DNA. We also found elevated autoantibody levels in CF children as 76.5% of CF patients younger than 10 years and 87.5% of CF patients 10-21 years had higher blood anti-dsDNA IgA levels than the highest value found in healthy control adults. Overall, our results detect elevated systemic anti-dsDNA IgA autoantibody levels in CF adults, teenagers and young children. We speculate that the appearance of an autoimmune response against host DNA in CF is an early event potentially contributing to disease pathogenesis. Highlights CF serum contains elevated levels of anti-dsDNA IgA, but not anti-dsDNA IgG, autoantibodies Anti-dsDNA IgA autoantibody levels in serum correlate with airflow obstruction in CF Anti-dsDNA IgA autoantibodies are detected in CF sputum but do not correlate with airflow obstruction Anti-dsDNA IgA autoantibodies are also elevated in the blood of the majority of CF toddlers and youth.

PMID: 33258386 [PubMed - in process]

Updated guidance on the management of children with cystic fibrosis transmembrane conductance regulator-related metabolic syndrome/cystic fibrosis screen positive, inconclusive diagnosis (CRMS/CFSPID).

J Cyst Fibros. 2020 Nov 27;:

Authors: Barben J, Castellani C, Munck A, Davies JC, deWinter K, Gartner S, Kashirskaya N, Linnane B, Mayell SJ, McColley S, Ooi CY, Proesmans M, Ren CL, Salinas D, Sands D, Sermet-Gaudelus I, Sommerburg O, Southern KW, European CF Society Neonatal Screening Working Group (ECFS NSWG)

Abstract
Over the past two decades there has been considerable progress with the evaluation and management of infants with an inconclusive diagnosis following Newborn Screening (NBS) for cystic Fibrosis (CF). In addition, we have an increasing amount of evidence on which to base guidance on the management of these infants and, importantly, we have a consistent designation being used across the globe of CRMS/CFSPID. There is still work to be undertaken and research questions to answer, but these infants now receive more consistent and appropriate care pathways than previously. It is clear that the majority of these infants remain healthy, do not convert to a diagnosis of CF in childhood, and advice on management should reflect this. However, it is also clear that some will convert to a CF diagnosis and monitoring of these infants should facilitate their early recognition. Those infants that do not convert to a CF diagnosis have some potential of developing a CFTR-RD later in life. At present, it is not possible to quantify this risk, but families need to be provided with clear information of what to look out for. This paper contains a number of changes from previous guidance in light of developing evidence, but the major change is the recommendation of a detailed assessment of the child with CRMS/CFSPID in the sixth year of age, including respiratory function assessment and imaging. With these data, the CF team can discuss future care arrangements with the family and come to a shared decision on the best way forward, which may include discharge to primary care with appropriate information. Information is key for these families, and we recommend consideration of a further appointment when the individual is a young adult to directly communicate the implications of the CRMS/CFSPID designation.

PMID: 33257262 [PubMed - as supplied by publisher]

Right Ventricle Dysfunction in Patients With Adult Cystic Fibrosis Enlisted for Lung Transplant.

Transplant Proc. 2020 Nov 27;:

Authors: Scaravilli V, Scansani S, Grasso A, Guzzardella A, Vicenzi M, Rota I, Nosotti M, Zanella A, Blasi F, Pesenti A, Grasselli G

Abstract
Knowledge of preoperative right heart function of adult patients with cystic fibrosis (CF) awaiting lung transplant (LUTX) is limited. The echocardiography of adult patients with CF enlisted for LUTX was retrospectively analyzed and compared with standards and invasive analyses (right heart catheterization, multigated radionuclide ventriculography). We included 49 patients (reported as mean ± standard deviation; 29 ± 9 years of age; forced expiratory volume in first second of expiration, 31% ± 11% predicted; lung allocation score, 36 ± 5; invasive mean pulmonary artery pressure, 17 ± 5 mm Hg; multigated radionuclide ventriculography right ventricle [RV] ejection fraction, 50% ± 9%). Patients had increased RV end-diastolic area, RV wall thickness, and increased pulmonary artery acceleration time with subnormal tricuspid annular plane systolic excursion, tissue Doppler positive peak systolic velocity, and fraction area change. Subnormal tricuspid annular plane systolic excursion (< 23 mm), tissue Doppler positive peak systolic velocity (< 14 cm/s), and fraction area change (< 49%) had high sensitivity and negative predictive value in predicting impaired RV. EJECTION FRACTION: A good correlation between echocardiographic estimated and invasively measured systolic pulmonary artery pressure was observed (R2 = 0.554, P < .001). Adults with CF awaiting LUTX have morphologic alterations of the right heart, with subclinical impairment of RV systolic function. Echocardiography may be used as a bedside, repeatable, and reliable noninvasive test to screen further deterioration in RV function while on the waiting list for LUTX. More prospective follow-up echocardiographic studies are necessary to confirm such a hypothesis.

PMID: 33257002 [PubMed - as supplied by publisher]

Azithromycin potentiates avian IgY effect against Pseudomonas aeruginosa in a murine pulmonary infection model.

Int J Antimicrob Agents. 2020 Oct 23;:106213

Authors: Thomsen K, Christophersen L, Lerche CJ, Holmgaard DB, Calum H, Høiby N, Moser C

Abstract
Cystic fibrosis (CF) patients are at risk of acquiring chronic Pseudomonas aeruginosa lung infections. The biofilm mode of growth of P. aeruginosa induces tolerance to antibiotics and the host response; accordingly, treatment failure occurs. Supplemental azithromycin has proven beneficial in CF owing to potential immunomodulatory mechanisms. Clinical studies have demonstrated a reduction in exacerbations in CF patients by avian IgY anti-Pseudomonas immunotherapy. We hypothesise that azithromycin pre-treatment could potentiate the observed anti-Pseudomonas effect of IgY opsonisation in vivo. Evaluation of phagocytic cell capacity was performed using in vitro exposure of azithromycin pre-treated human polymorphonuclear neutrophils to IgY opsonised P. aeruginosa PAO3. A murine lung infection model using nasal planktonic P. aeruginosa inoculation and successive evaluation 24 h post-infection was used to determine lung bacteriology and subsequent pulmonary inflammation. Combined azithromycin treatment and IgY opsonisation significantly increased bacterial killing compared with the two single-treated groups and controls. In vivo, significantly increased bacterial pulmonary elimination was revealed by combining azithromycin and IgY. A reduction in the inflammatory markers mobiliser granulocyte colony-stimulating factor (G-CSF), macrophage inflammatory protein 2 (MIP-2) and interleukin 1 beta (IL-1β) paralleled this effect. Combination of azithromycin and anti-Pseudomonas IgY potentiated the killing and pulmonary elimination of P. aeruginosa in vitro and in vivo. The augmented effect of combinatory treatment with azithromycin and IgY constitutes a potential clinical application for improving anti-Pseudomonas strategies.

PMID: 33256950 [PubMed - as supplied by publisher]

Molecular Characterization of the Burkholderia cenocepacia dcw Operon and FtsZ Interactors as New Targets for Novel Antimicrobial Design.

Antibiotics (Basel). 2020 Nov 24;9(12):

Authors: Trespidi G, Scoffone VC, Barbieri G, Riccardi G, De Rossi E, Buroni S

Abstract
The worldwide spread of antimicrobial resistance highlights the need of new druggable cellular targets. The increasing knowledge of bacterial cell division suggested the potentiality of this pathway as a pool of alternative drug targets, mainly based on the essentiality of these proteins, as well as on the divergence from their eukaryotic counterparts. People suffering from cystic fibrosis are particularly challenged by the lack of antibiotic alternatives. Among the opportunistic pathogens that colonize the lungs of these patients, Burkholderia cenocepacia is a well-known multi-drug resistant bacterium, particularly difficult to treat. Here we describe the organization of its division cell wall (dcw) cluster: we found that 15 genes of the dcw operon can be transcribed as a polycistronic mRNA from mraZ to ftsZ and that its transcription is under the control of a strong promoter regulated by MraZ. B. cenocepacia J2315 FtsZ was also shown to interact with the other components of the divisome machinery, with a few differences respect to other bacteria, such as the direct interaction with FtsQ. Using an in vitro sedimentation assay, we validated the role of SulA as FtsZ inhibitor, and the roles of FtsA and ZipA as tethers of FtsZ polymers. Together our results pave the way for future antimicrobial design based on the divisome as pool of antibiotic cellular targets.

PMID: 33255486 [PubMed]

Local and Systemic Alterations of the L-Arginine/Nitric Oxide Pathway in Sputum, Blood, and Urine of Pediatric Cystic Fibrosis Patients and Effects of Antibiotic Treatment.

J Clin Med. 2020 Nov 24;9(12):

Authors: Hanusch B, Brinkmann F, Mayorandan S, Chobanyan-Jürgens K, Wiemers A, Jansen K, Ballmann M, Schmidt-Choudhury A, Bollenbach A, Derichs N, Tsikas D, Lücke T

Abstract
Alterations in the L-arginine (Arg)/nitric oxide (NO) pathway have been reported in cystic fibrosis (CF; OMIM 219700) as the result of various factors including systemic and local inflammatory activity in the airways. The aim of the present study was to evaluate the Arg/NO metabolism in pediatric CF patients with special emphasis on lung impairment and antibiotic treatment. Seventy CF patients and 78 healthy controls were included in the study. CF patients (43% male, median age 11.8 years) showed moderately impaired lung functions (FEV1 90.5 ± 19.1% (mean ± SD); 21 (30%) had a chronic Pseudomonas aeruginosa (PSA) infection, and 24 (33%) had an acute exacerbation). Plasma, urinary, and sputum concentrations of the main Arg/NO metabolites, nitrate, nitrite, Arg, homoarginine (hArg), and asymmetric dimethylarginine (ADMA) were determined in pediatric CF patients and in healthy age-matched controls. Clinical parameters in CF patients included lung function and infection with PSA. Additionally, the Arg/NO pathway in sputum samples of five CF patients was analyzed before and after routine antibiotic therapy. CF patients with low fractionally exhaled NO (FENO) showed lower plasma Arg and nitrate concentrations. During acute exacerbation, sputum Arg and hArg levels were high and dropped after antibiotic treatment: Arg: pre-antibiotics: 4.14 nmol/25 mg sputum vs. post-antibiotics: 2.33 nmol/25 mg sputum, p = 0.008; hArg: pre-antibiotics: 0.042 nmol/25 mg sputum vs. post-antibiotics: 0.029 nmol/25 mg sputum, p = 0.035. The activated Arg/NO metabolism in stable CF patients may be a result of chronic inflammation. PSA infection did not play a major role regarding these differences. Exacerbation increased and antibiotic therapy decreased sputum Arg concentrations.

PMID: 33255369 [PubMed]

Impact of Pseudomonas aeruginosa Infection on Patients with Chronic Inflammatory Airway Diseases.

J Clin Med. 2020 Nov 24;9(12):

Authors: Garcia-Clemente M, de la Rosa D, Máiz L, Girón R, Blanco M, Olveira C, Canton R, Martinez-García MA

Abstract
Pseudomonas aeruginosa (P. aeruginosa) is a ubiquitous and opportunistic microorganism and is considered one of the most significant pathogens that produce chronic colonization and infection of the lower respiratory tract, especially in people with chronic inflammatory airway diseases such as asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), and bronchiectasis. From a microbiological viewpoint, the presence and persistence of P. aeruginosa over time are characterized by adaptation within the host that precludes any rapid, devastating injury to the host. Moreover, this microorganism usually develops antibiotic resistance, which is accelerated in chronic infections especially in those situations where the frequent use of antimicrobials facilitates the selection of "hypermutator P. aeruginosa strain". This phenomenon has been observed in people with bronchiectasis, CF, and the "exacerbator" COPD phenotype. From a clinical point of view, a chronic bronchial infection of P. aeruginosa has been related to more severity and poor prognosis in people with CF, bronchiectasis, and probably in COPD, but little is known on the effect of this microorganism infection in people with asthma. The relationship between the impact and treatment of P. aeruginosa infection in people with airway diseases emerges as an important future challenge and it is the most important objective of this review.

PMID: 33255354 [PubMed]

Correction: Effects of the SARS-CoV2-Lockdown on Pediatric Care in the Rhine-Main Area.

Klin Padiatr. 2020 Nov 30;:

Authors: Donath H, Zielen S, Wittekindt B, Klingebiel T, Graf J, Eckrich M, Walter C, Blümchen K

PMID: 33254244 [PubMed - as supplied by publisher]

Mining GWAS and eQTL data for CF lung disease modifiers by gene expression imputation.

PLoS One. 2020;15(11):e0239189

Authors: Dang H, Polineni D, Pace RG, Stonebraker JR, Corvol H, Cutting GR, Drumm ML, Strug LJ, O'Neal WK, Knowles MR

Abstract
Genome wide association studies (GWAS) have identified several genomic loci with candidate modifiers of cystic fibrosis (CF) lung disease, but only a small proportion of the expected genetic contribution is accounted for at these loci. We leveraged expression data from CF cohorts, and Genotype-Tissue Expression (GTEx) reference data sets from multiple human tissues to generate predictive models, which were used to impute transcriptional regulation from genetic variance in our GWAS population. The imputed gene expression was tested for association with CF lung disease severity. By comparing and combining results from alternative approaches, we identified 379 candidate modifier genes. We delved into 52 modifier candidates that showed consensus between approaches, and 28 of them were near known GWAS loci. A number of these genes are implicated in the pathophysiology of CF lung disease (e.g., immunity, infection, inflammation, HLA pathways, glycosylation, and mucociliary clearance) and the CFTR protein biology (e.g., cytoskeleton, microtubule, mitochondrial function, lipid metabolism, endoplasmic reticulum/Golgi, and ubiquitination). Gene set enrichment results are consistent with current knowledge of CF lung disease pathogenesis. HLA Class II genes on chr6, and CEP72, EXOC3, and TPPP near the GWAS peak on chr5 are most consistently associated with CF lung disease severity across the tissues tested. The results help to prioritize genes in the GWAS regions, predict direction of gene expression regulation, and identify new candidate modifiers throughout the genome for potential therapeutic development.

PMID: 33253230 [PubMed - as supplied by publisher]

Effect of host-mimicking medium and biofilm growth on the ability of colistin to kill Pseudomonas aeruginosa.

Microbiology (Reading). 2020 Nov 30;:

Authors: Sweeney E, Sabnis A, Edwards AM, Harrison F

Abstract
In vivo biofilms cause recalcitrant infections with extensive and unpredictable antibiotic tolerance. Here, we demonstrate increased tolerance of colistin by Pseudomonas aeruginosa when grown in medium that mimics cystic fibrosis (CF) sputum versus standard medium in in vitro biofilm assays, and drastically increased tolerance when grown in an ex vivo CF model versus the in vitro assay. We used colistin conjugated to the fluorescent dye BODIPY to assess the penetration of the antibiotic into ex vivo biofilms and showed that poor penetration partly explains the high doses of drug necessary to kill bacteria in these biofilms. The ability of antibiotics to penetrate the biofilm matrix is key to their clinical success, but hard to measure. Our results demonstrate both the importance of reduced entry into the matrix in in vivo-like biofilm, and the tractability of using a fluorescent tag and benchtop fluorimeter to assess antibiotic entry into biofilms. This method could be a relatively quick, cheap and useful addition to diagnostic and drug development pipelines, allowing the assessment of drug entry into biofilms, in in vivo-like conditions, prior to more detailed tests of biofilm killing.

PMID: 33253080 [PubMed - as supplied by publisher]

Trypsin Detection Strategies: A Review.

Crit Rev Anal Chem. 2020 Nov 30;:1-19

Authors: Kaur J, Singh PK

Abstract
Trypsin, a pancreatic serine protease, due to its narrow specificity and selectivity, has been tremendously used in food technology, proteome analysis, modulating soy protein allergenicity, antihypertensive peptide production, as well as, a biomarker in diseases such as pancreatitis, cystic fibrosis etc. Therefore, simple, sensitive and selective biosensors, for trypsin evaluation, are strongly recommended. This review provides, for the first time, an overview of various sensing systems, developed for the detection of trypsin. We have categorized various sensors, developed in the last ten years, according to their signal output as optical (fluorescence, colorimeter, surface plasmon resonance, liquid crystals), electrochemical (photo-electrochemical, nanopore sensors), piezoelectric and enzyme linked immunosorbant assay based sensors. Under each section, further subsections explain, construction of biosensors on the basis of various natural proteins acting as substrate unit and nucleic acids, nanoparticles, inorganic dyes, polymers etc. as participant interacting units. Their working principles and strategies along with salient features, such as, limit of detection, linearity range, time etc. have been critically analyzed to highlight their comparative merits and demerits. The most sensitive biosensors for trypsin detection is a photo-electrochemical anti-trypsin based immunosensor, with a lowest limit of detection 0.02 ng mL-1; linearity 0.10-100 ng mL-1.

PMID: 33252991 [PubMed - as supplied by publisher]

Gene therapy for sickle cell disease.

Cochrane Database Syst Rev. 2020 Nov 30;11:CD007652

Authors: Olowoyeye A, Okwundu CI

Abstract
BACKGROUND: Sickle cell disease encompasses a group of genetic disorders characterized by the presence of at least one hemoglobin S (Hb S) allele, and a second abnormal allele that could allow abnormal haemoglobin polymerisation leading to a symptomatic disorder. Autosomal recessive disorders (such as sickle cell disease) are good candidates for gene therapy because a normal phenotype can be restored in diseased cells with only a single normal copy of the mutant gene. This is an update of a previously published Cochrane Review.
OBJECTIVES: The objectives of this review are: - to determine whether gene therapy can improve survival and prevent symptoms and complications associated with sickle cell disease; - to examine the risks of gene therapy against the potential long-term gain for people with sickle cell disease.
SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register, which comprises of references identified from comprehensive electronic database searches and searching relevant journals and abstract books of conference proceedings. We also searched online trial registries, Date of the most recent search of the Group's Haemoglobinopathies Trials Register: 21 September 2020.
SELECTION CRITERIA: All randomised or quasi-randomised clinical trials (including any relevant phase 1, 2 or 3 trials) of gene therapy for all individuals with sickle cell disease, regardless of age or setting.
DATA COLLECTION AND ANALYSIS: No trials of gene therapy for sickle cell disease were found.
MAIN RESULTS: No trials of gene therapy for sickle cell disease were reported.
AUTHORS' CONCLUSIONS: No randomised or quasi-randomised clinical trials of gene therapy for sickle cell disease were reported. Thus, no objective conclusions or recommendations in practice can be made on gene therapy for sickle cell disease. This systematic review has identified the need for well-designed, randomised controlled trials to assess the benefits and risks of gene therapy for sickle cell disease.

PMID: 33251574 [PubMed - in process]

Peptidorhamnomannans From Scedosporium and Lomentospora Species Display Microbicidal Activity Against Bacteria Commonly Present in Cystic Fibrosis Patients.

Front Cell Infect Microbiol. 2020;10:598823

Authors: de Oliveira EB, Xisto MIDDS, Rollin-Pinheiro R, Rochetti VP, Barreto-Bergter E

Abstract
Scedosporium and Lomentospora species are filamentous fungi that cause a wide range of infections in humans. They are usually found in the lungs of cystic fibrosis (CF) patients and are the second most frequent fungal genus after Aspergillus species. Several studies have been recently performed in order to understand how fungi and bacteria interact in CF lungs, since both can be isolated simultaneously from patients. In this context, many bacterial molecules were shown to inhibit fungal growth, but little is known about how fungi could interfere in bacterial development in CF lungs. Scedosporium and Lomentospora species present peptidorhamnomannans (PRMs) in their cell wall that play crucial roles in fungal adhesion and interaction with host epithelial cells and the immune system. The present study aimed to analyze whether PRMs extracted from Lomentospora prolificans, Scedosporium apiospermum, Scedosporium boydii, and Scedosporium aurantiacum block bacterial growth and biofilm formation in vitro. PRM from L. prolificans and S. boydii displayed the best bactericidal effect against methicillin resistant Staphylococcus aureus (MRSA), Burkholderia cepacia, and Escherichia coli, but not Pseudomonas aeruginosa, all of which are the most frequently found bacteria in CF lungs. In addition, biofilm formation was inhibited in all bacteria tested using PRMs at minimal inhibitory concentration (MIC). These results suggest that PRMs from the Scedosporium and Lomentospora surface seem to play an important role in Scedosporium colonization in CF patients, helping to clarify how these pathogens interact to each other in CF lungs.

PMID: 33251161 [PubMed - in process]

A Scientific Rationale for Using Cystic Fibrosis Transmembrane Conductance Regulator Therapeutics in COVID-19 Patients.

Front Physiol. 2020;11:583862

Authors: Lidington D, Bolz SS

Abstract
Several pathological manifestations in coronavirus disease 2019 (COVID-19), including thick mucus, poor mucociliary clearance, and bronchial wall thickening, overlap with cystic fibrosis disease patterns and may be indicative of "acquired" cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction. Indeed, tumor necrosis factor (TNF), a key cytokine driving COVID-19 pathogenesis, downregulates lung CFTR protein expression, providing a strong rationale that acquired CFTR dysfunction arises in the context of COVID-19 infection. In this perspective, we propose that CFTR therapeutics, which are safe and generally well-tolerated, may provide benefit to COVID-19 patients. Although CFTR therapeutics are currently only approved for treating cystic fibrosis, there are efforts to repurpose them for conditions with "acquired" CFTR dysfunction, for example, chronic obstructive pulmonary disease. In addition to targeting the primary lung pathology, CFTR therapeutics may possess value-added effects: their anti-inflammatory properties may dampen exaggerated immune cell responses and promote cerebrovascular dilation; the latter aspect may offer some protection against COVID-19 related stroke.

PMID: 33250777 [PubMed]

Prostaglandin E2 and phagocytosis of inhaled particulate matter by airway macrophages in cystic fibrosis.

J Cyst Fibros. 2020 Nov 26;:

Authors: Liu NM, Miyashita L, Sanak M, Barratt B, Grigg J

Abstract
BACKGROUND: Exposure to particulate matter (PM) air pollution is associated with adverse health outcomes in children with cystic fibrosis (CF). Airway macrophages (AM) phagocytose and retain inhaled PM in vivo, and the area of carbon in AM reflects both inhaled PM dose and phagocytic function. Since airway prostaglandin-E2 (PGE2) is increased in CF, and PGE2 suppresses AM phagocytosis, we sought evidence for PGE2-mediated suppression of AM phagocytosis of inhaled carbonaceous PM in CF.
METHODS: After informed consent, urine was obtained from 20 controls and 24 CF children. In the subgroup of older children, at least one induced sputum was done in 20 controls and 19 CF children. Urinary tetranor PGEM, the major metabolite of PGE2, and sputum PGE2 were measured by mass spectrometry. The area of carbon in AM was determined by image analysis. Exposure to PM was assessed by modelling and personal monitoring. The effect of either PGE2 or CF sputum supernatant on phagocytosis of diesel exhaust particle (DEP) by AM was assessed in vitro. Data were analysed by t-test.
RESULTS: Both urinary tetranor PGEM (P<0.05), and sputum PGE2 (P<0.05) were increased in CF . Despite no difference in PM exposure between groups, the area of phagocytosed carbon by AM was decreased in children with CF (P<0.01). PGE2 suppressed phagocytosis of DEP by AM from both controls and CF (P<0.0001). CF sputum supernatant suppressed phagocytosis of DEP by AM (P<0.0001) in a PGE2-dependent manner.
CONCLUSION: Increased PGE2 in the CF airway suppresses phagocytosis of inhaled PM by AM.

PMID: 33250436 [PubMed - as supplied by publisher]

The cystic fibrosis gut as a potential source of multidrug resistant pathogens.

J Cyst Fibros. 2020 Nov 26;:

Authors: Taylor SL, Leong LEX, Sims SK, Keating RL, Papanicolas LE, Richard A, Mobegi FM, Wesselingh S, Burr LD, Rogers GB

Abstract
BACKGROUND: The emergence of multidrug resistant (MDR) pathogens represents a profound threat to global health. Individuals with CF have amongst the highest cumulative antibiotic exposure of any patient group, including to critically-important last-line agents. While there is little evidence that antibiotic resistance in airway pathogens results in worse clinical outcomes for CF patients, the potential emergence of MDR pathogens in non-respiratory systems, as a consequence of CF care, represents a potential health threat to the wider population, including family and carers.
METHODS: Stool from 19 adults with CF and 16 healthy adult controls was subjected to metagenomic sequencing, to assess faecal resistome, and culture-based analysis. Resistant isolates were identified phenotypically, and genetic determinants of resistance characterised by whole genome sequencing.
RESULTS: CF and control faecal resistomes differed significantly (P = 0.0003). The proportion of reads that mapped to mobile genetic elements was significantly higher in CF (P = 0.014) and the composition was significantly different (P = 0.0001). Notably, CF patients displayed higher carriage of plasmid-mediated aminoglycoside-modifying genes ant(6)-Ib, aac(6')-Ip, and aph(3')-IIIa (P < 0.01). Culture-based analysis supported higher aminoglycoside resistance, with a higher proportion of aminoglycoside-resistant, Gram-negative bacteria (P < 0.0001). Isolated extended spectrum beta lactamase (ESBL)-positive Escherichia coli from CF stool exhibited phenotypic resistance to tobramycin and gentamicin. Genomic analysis showed co-localisation of both aminoglycoside resistance and ESBL genes, consistent with MDR emergence through horizontal gene transfer.
CONCLUSIONS: The carriage of potentially transmissible resistance within the adult CF gut microbiome is considerably greater than in healthy individuals and could contribute to the emergence and dissemination of MDR pathogens.

PMID: 33250435 [PubMed - as supplied by publisher]

Development of elexacaftor - tezacaftor - ivacaftor: highly effective CFTR modulation for the majority of people with cystic fibrosis.

Expert Rev Respir Med. 2020 Nov 29;:

Authors: Middleton PG, Taylor-Cousar JL

Abstract
INTRODUCTION: Cystic Fibrosis (CF), the most common life-shortening inherited disorder in people of European descent, also occurs in other ethnicities. The identification of the disease, the isolation of the causative gene, termed the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) and the improved survival from comprehensive multidisciplinary treatment is one of the success stories of modern medicine. Survival has increased dramatically over the last 50 years, from 10 years in the 1960s to 30 years in the 1990s and approximately 50 years currently.
AREAS COVERED: This review will examine the development of highly effective modulators for CF which will revolutionise therapy for more than 90% of people with CF. This review summarises the development of triple combination CFTR modulator elexacaftor - tezacaftor - ivacaftor.
EXPERT OPINION: The development of this highly effective CFTR modulator for the majority of people with CF will likely change the landscape of CF care. The challenge is to now find highly effective therapy for the remaining 10% of people with CF who may need other therapeutic agents to correct their primary defect.

PMID: 33249928 [PubMed - as supplied by publisher]

Physiotherapy: At what cost? Parents experience of performing chest physiotherapy for infants with cystic fibrosis.

J Child Health Care. 2020 Nov 30;:1367493520976481

Authors: Andrews K, Smith M, Cox NS

Abstract
Physiotherapy is one of the most burdensome aspects of cystic fibrosis (CF) care. Healthcare requirements for older children with CF are reported to impact parental quality of life and physiotherapy adherence. How parents of infants experience performing chest physiotherapy as a part of CF care is unknown. This study aimed to explore the experience of performing chest physiotherapy for parents of infants with CF. In this study, 13 parents of infants (aged 1-2 years) with CF participated in one in-depth semi-structured interview and completed a daily diary for five days. Principles of hermeneutic phenomenology guided interpretation of interview transcripts, diary entries, and field notes. For these parents, being responsible for performing chest physiotherapy was an ever-present experience of pressure, doubt, and guilt. Managing chest physiotherapy resulted in sacrifices that were perceived by parents as an expected and necessary part of meeting the healthcare needs of their child. Despite perceived sacrifices, performing chest physiotherapy was also experienced by parents as an opportunity to positively impact the health of their child. Awareness of parental perceptions and experiences of chest physiotherapy in CF may enhance the personalization of physiotherapy and minimize burden.

PMID: 33249885 [PubMed - as supplied by publisher]

"Adenosine an old player with new possibilities in kidney diseases": Preclinical evidences and clinical perspectives.

Life Sci. 2020 Nov 26;:118834

Authors: Pandey S, Aggarwal D, Gupta K, Kumari A, Sen P, Singh R, Joshi JC, Sharma VV, Mehra K, Singh G

Abstract
Renal injury might originate from multiple factors like ischemia reperfusion (I/R), drug toxicity, cystic fibrosis, radio contrast agent etc. The four adenosine receptor subtypes have been identified and found to show diverse physiological and pathological roles in kidney diseases. The activation of A1 adenosine receptor (A1) protects against acute kidney injury by improving renal hemodynamic alterations, decreasing tubular necrosis and its inhibition might facilitate removal of toxin or drug metabolite in chronic kidney disease models. Furthermore, recent findings revealed that A2A receptor subtype activation regulates macrophage phenotype in experimental models of nephritis. Interestingly the emerging role of adenosine kinase inhibitors in kidney diseases has been discussed which act by increasing adenosine availability at target sites and thereby promote A2A receptor stimulation. In addition, the least explored adenosine receptor subtype A3 inhibition was observed to exert anti- oxidant, immunosuppressive and anti-fibrotic effects, but more studies are required to confirm its benefits in other renal injury models. The clinical studies targeting A1 receptor in patients with pre-existing kidney disease have yielded disappointing results, perhaps owing to the origin of unexpected neurological complications during the course of trial. Importantly, conducting well designed clinical trials and testing adenosine modulators with lesser brain penetrability could clear the way for clinical approval of these agents for patients with renal functional impairments.

PMID: 33249096 [PubMed - as supplied by publisher]