Synergistic meropenem-tobramycin combination dosage regimens against clinical hypermutable Pseudomonas aeruginosa at simulated epithelial lining fluid concentrations in a dynamic biofilm model.

Antimicrob Agents Chemother. 2019 Aug 19;:

Authors: Bilal H, Bergen PJ, Kim TH, Chung SE, Peleg AY, Oliver A, Nation RL, Landersdorfer CB

Abstract
Exacerbations of chronic Pseudomonas aeruginosa infections are a major treatment challenge in cystic fibrosis due to biofilm formation and hypermutation. We aimed to evaluate different dosage regimens of meropenem and tobramycin in monotherapies and combination against hypermutable carbapenem-resistant P. aeruginosa A hypermutable P. aeruginosa isolate (MICmeropenem and MICtobramycin 8 mg/L) was investigated in the dynamic CDC biofilm reactor over 120 h. Regimens were meropenem as standard (2 g 8-hourly, 30% epithelial lining fluid (ELF) penetration) and continuous infusion (CI, 6 g/day, 30% and 60% ELF penetration), and tobramycin 10 mg/kg 24-hourly (50% ELF penetration). The time-courses of total and less-susceptible bacteria and MICs were determined and antibiotic concentrations quantified by LC-MS/MS. All monotherapies failed with substantial regrowth of planktonic (>6 log10 CFU/mL) and biofilm (≥6 log10 CFU/cm2) bacteria. Except for meropenem CI (60% ELF penetration) all monotherapies amplified less-susceptible planktonic and biofilm bacteria by 120 h. The meropenem standard regimen with tobramycin caused initial killing followed by considerable regrowth with resistance (MICmeropenem 64 mg/L, MICtobramycin 32 mg/L) for planktonic and biofilm bacteria. The combination containing the meropenem CI, at both levels of ELF penetration, synergistically suppressed regrowth of total planktonic bacteria and resistance of planktonic and biofilm bacteria. The combination with meropenem CI at 60% ELF penetration in addition synergistically suppressed regrowth of total biofilm bacteria. Standard regimens of meropenem and tobramycin were ineffective against planktonic and biofilm bacteria. The combination with meropenem CI exhibited enhanced bacterial killing and resistance suppression of carbapenem-resistant hypermutable P. aeruginosa.

PMID: 31427301 [PubMed - as supplied by publisher]

Efficacy of oral amoxicillin-clavulanate or azithromycin for non-severe respiratory exacerbations in children with bronchiectasis (BEST-1): a multicentre, three-arm, double-blind, randomised placebo-controlled trial.

Lancet Respir Med. 2019 Aug 16;:

Authors: Goyal V, Grimwood K, Ware RS, Byrnes CA, Morris PS, Masters IB, McCallum GB, Binks MJ, Smith-Vaughan H, O'Grady KF, Champion A, Buntain HM, Schultz A, Chatfield M, Torzillo PJ, Chang AB

Abstract
BACKGROUND: Bronchiectasis guidelines recommend antibiotics for the treatment of acute respiratory exacerbations, but randomised placebo-controlled trials in children are lacking. We hypothesised that oral amoxicillin-clavulanate and azithromycin would each be superior to placebo in achieving symptom resolution of non-severe exacerbations in children by day 14 of treatment.
METHODS: In this multicentre, three-arm, parallel, double-dummy, double-blind, randomised placebo-controlled trial at four paediatric centres in Australia and New Zealand, we enrolled children aged 1-18 years with CT-confirmed bronchiectasis unrelated to cystic fibrosis, who were under the care of a respiratory physician and who had had at least two respiratory exacerbations in the 18 months before study entry. Participants were allocated (1:1:1) at exacerbation onset to receive oral suspensions of amoxicillin-clavulanate (45 mg/kg per day) plus placebo azithromycin, azithromycin (5 mg/kg per day) plus placebo amoxicillin-clavulanate, or both placebos for 14 days. An independent statistician prepared a computer-generated, permuted-block (size 2-8) randomisation sequence, stratified by centre, age, and cause. Participants, caregivers, study coordinators, and investigators were masked to treatment assignment until data analysis was completed. The primary outcome was the proportion of children with exacerbation resolution by day 14 in the intention-to-treat population. Treatment groups were compared using generalised linear models. Statistical significance was set at p<0·0245 to account for multiple comparisons. This trial is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12612000011886) and is completed.
FINDINGS: Between April 17, 2012, and March 1, 2017, 604 children were screened and 252 were enrolled. Between July 31, 2012, and June 26, 2017, 197 children were allocated at the start of an exacerbation (63 to the amoxicillin-clavulanate group, 67 to the azithromycin group, and 67 to the placebo group). Respiratory viruses were identified in 82 (53%) of 154 children with available nasal swabs on day 1 of treatment. Primary outcome data were available for 196 (99%) children (one child with missing data [placebo group] was recorded as non-resolved according to criteria defined a priori). By day 14, exacerbations had resolved in 41 (65%) children in the amoxicillin-clavulanate group, 41 (61%) in the azithromycin group, and 29 (43%) in the placebo group. Compared with placebo, relative risk for resolution by day 14 was 1·50 (95% CI 1·08-2·09, p=0·015; number-needed-to-treat [NNT] 5 [95% CI 3-20]) in the amoxicillin-clavulanate group and 1·41 (1·01-1·97, p=0·042; NNT 6 [3-79]) in the azithromycin group. Adverse events were recorded in 19 (30%) children in the amoxicillin-clavulanate group, 20 (30%) in the azithromycin group, and 14 (21%) in the placebo group, but no events were severe or life-threatening.
INTERPRETATION: Amoxicillin-clavulanate treatment is beneficial in terms of resolution of non-severe exacerbations of bronchiectasis in children, and should remain the first-line oral antibiotic in this setting.
FUNDING: National Health and Medical Research Council (Australia), Cure Kids (New Zealand).

PMID: 31427252 [PubMed - as supplied by publisher]

What's BEST for children with non-cystic fibrosis bronchiectasis?

Lancet Respir Med. 2019 Aug 16;:

Authors: O'Sullivan B

PMID: 31427251 [PubMed - as supplied by publisher]

Basic and translational science advances in congenital diaphragmatic hernia.

Semin Perinatol. 2019 Jul 30;:151170

Authors: Wagner R, Montalva L, Zani A, Keijzer R

Abstract
Congenital Diaphragmatic Hernia (CDH) is a birth defect that is characterized by lung hypoplasia, pulmonary hypertension and a diaphragmatic defect that allows herniation of abdominal organs into the thoracic cavity. Although widely unknown to the public, it occurs as frequently as cystic fibrosis (1:2500). There is no monogenetic cause, but different animal models revealed various biological processes and epigenetic factors involved in the pathogenesis. However, the pathobiology of CDH is not sufficiently understood and its mortality still ranges between 30 and 50%. Future collaborative initiatives are required to improve our basic knowledge and advance novel strategies to (prenatally) treat the abnormal lung development. This review focusses on the genetic, epigenetic and protein background and the latest advances in basic and translational aspects of CDH research.

PMID: 31427115 [PubMed - as supplied by publisher]

Feedback of airborne bacterial consortia to haze pollution with different PM2.5 levels in typical mountainous terrain of Jinan, China.

Sci Total Environ. 2019 Aug 13;695:133912

Authors: Ji L, Zhang Q, Fu X, Zheng L, Dong J, Wang J, Guo S

Abstract
Polluted air is as harmful as polluted water sources to public health. As air living organisms, the research on microbial consortia under haze stress with different PM2.5 levels in a mountainous environment remains very limited. This study investigated the dynamic changes in bacterial cell counts, apoptosis, human pathogens, consortia characteristics, metabolic pathways, and the biochemical functions under haze conditions with various degrees of pollution (leading pollutant PM2.5) from August to December 2017 in a typical mountainous terrain of Jinan, China. Samples were evaluated with flow cytometry and 16S rRNA gene amplicon sequencing. Results indicated that cell counts ranged from 6.83 × 105 ± 1.27 × 104 (non-polluted air, NP) to 2.32 × 106 ± 3.56 × 104 (heavily polluted air, HP) cell m-3 air. The proportion of viable apoptotic and necrotic cells were positively correlated to PM2.5. Burkholderia cenocepacia (36.6%) was the most abundant human pathogen found in HP; this gram-negative bacterium is associated with potentially lethal respiratory infections in cystic fibrosis patients. The relative abundance of the phylum Proteobacteria (63.8%) in NP first decreased in lightly polluted (LP) (41.3%) and moderately polluted air (MP) (26.3%) then increased in HP (81.0%). Cupriavidus (22.9%) and BTEX-degrading bacteria (0.6%, Pseudomonas) were found in HP. Metabolic pathways with significant differences included cell motility and endocrine and immune diseases that exhibited increasing relative abundance as pollution levels increased. The diversity of biochemical functions was found to be decreased in hazy air.

PMID: 31425993 [PubMed - as supplied by publisher]

Treatment of dental and orthodontic complications in thalassaemia.

Cochrane Database Syst Rev. 2019 Aug 02;8:CD012969

Authors: Mulimani P, Abas AB, Karanth L, Colombatti R, Kulkarni P

Abstract
BACKGROUND: Thalassaemia is a quantitative abnormality of haemoglobin caused by mutations in genes controlling production of alpha or beta globins. Abnormally unpaired globin chains cause haemolytic anaemia by causing membrane damage and cell death within organ systems and destruction of erythroid precursors in the bone marrow. The life-long management of the general health effects of thalassaemia in affected individuals is a highly challenging issue in and of itself; and failure to deal with dental and orthodontic complications in people with thalassaemia exacerbates the public health, financial and personal burden posed by the condition. There exists a lack of evidence-based guidelines for care-seekers and providers to best deal with such dental and orthodontic complications in thalassaemia, which this review seeks to address.
OBJECTIVES: The main objective of this review was to assess different methods to treat dental and orthodontic complications in people with thalassaemia.
SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We searched the reference lists of relevant articles and reviews.Date of last search: 01 August 2019.We also searched nine online databases (PubMed, Google Scholar, ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, Literature in the Health Sciences in Latin America and the Caribbean database, African Index Medicus, Index Medicus for South East Asia Region, Index Medicus for the Eastern Mediterranean Region, Indexing of Indian Medical Journals). We searched the reference lists of relevant articles and reviews and contacted haematologists, experts in fields of dentistry, organizations, pharmaceutical companies and researchers working in this field.Date of last search: 22 July 2019.
SELECTION CRITERIA: We searched for published or unpublished randomised controlled trials for treatment of dental and orthodontic complications in individuals diagnosed with thalassaemia, irrespective of phenotype, severity, age, gender and ethnic origin.
DATA COLLECTION AND ANALYSIS: Two review authors independently screened 35,202 titles from search results. We identified four unique randomised controlled trials, of which one seemed potentially relevant. Based on closer inspection, the trial was found not to be eligible for inclusion.
MAIN RESULTS: We did not find any relevant trials for inclusion in the review.
AUTHORS' CONCLUSIONS: We were unable to draw any conclusions due to the lack of available data and trials. This review highlights the need for conducting and appropriate reporting, of high-quality randomised controlled trials investigating the effectiveness of various treatment modalities for dental and orthodontic complications in people with thalassaemia.

PMID: 31425614 [PubMed - as supplied by publisher]

Singing as an adjunct therapy for children and adults with cystic fibrosis.

Cochrane Database Syst Rev. 2019 Jul 12;7:CD008036

Authors: Irons JY, Petocz P, Kenny DT, Chang AB

Abstract
BACKGROUND: Cystic fibrosis is a genetically inherited, life-threatening condition that affects major organs. The management of cystic fibrosis involves a multi-faceted daily treatment regimen that includes airway clearance techniques, pancreatic enzymes and other medications. Previous studies have found that compliance with this intensive treatment is poor, especially among adolescents. Because of both the nature and consequences of the illness and the relentless demands of the treatment, many individuals with cystic fibrosis have a poor quality of life. Anecdotal reports suggest that singing may provide both appropriate exercise for the whole respiratory system and a means of emotional expression which may enhance quality of life. This is an update of a previously published review.
OBJECTIVES: To evaluate the effects of singing as an adjunct therapy to standard treatment on the quality of life, morbidity, respiratory muscle strength and pulmonary function of children and adults with cystic fibrosis.
SEARCH METHODS: We searched the Group's Cystic Fibrosis Trials Register and the Cochrane Central Register of Controlled Trials. Date of latest search: 07 January 2019.We also searched major allied complementary data bases, and clinical trial registers. Additionally, we handsearched relevant conference proceedings and journals. Date of latest search: 28 March 2019.
SELECTION CRITERIA: Randomised controlled trials in which singing (as an adjunct intervention) is compared with either a control intervention (for example, playing computer games or doing craft activities) or no singing in people with cystic fibrosis.
DATA COLLECTION AND ANALYSIS: Results of searches were reviewed against pre-determined criteria for inclusion. Only one eligible trial was available for analysis.
MAIN RESULTS: Since only one small study (n = 40) was included, no meta-analysis could be performed. The included randomised controlled study was of parallel design and undertaken at two paediatric hospitals in Australia. The study evaluated the effects of a singing program on the quality of life and respiratory muscle strength of hospitalised children with cystic fibrosis (mean age 11.6 years, 35% male). While the singing group received eight individual singing sessions, the control group participated in preferred recreational activities, such as playing computer games or watching movies. This study was limited by a small sample size (51 participants) and a high drop-out rate (21%). There were no differences between the groups at either post-intervention or follow-up; although by the end of treatment there were some improvements in some of the domains of the quality of life questionnaire Cystic Fibrosis Questionnaire-Revised (e.g. emotional, social and vitality domains) for both singing and control groups. For the respiratory muscle strength indices, maximal expiratory pressure at follow-up (six to eight weeks post-intervention) was higher in the singing group, mean difference 25.80 (95% confidence interval 5.94 to 45.66). There was no difference between groups for any of the other respiratory function parameters (maximal inspiratory pressure, spirometry) at either post-intervention or follow-up. No adverse effects were observed in the singing group; adverse events for the control group were not reported in the paper.
AUTHORS' CONCLUSIONS: There is insufficient evidence to determine the effects of singing on quality of life or on the respiratory parameters in people with cystic fibrosis. However, there is growing interest in non-medical treatments for cystic fibrosis and researchers may wish to investigate the impact of this inexpensive therapy on respiratory function and psychosocial well-being further in the future.

PMID: 31425607 [PubMed - as supplied by publisher]

Controlled evaluation of a transition clinic for Dutch young people with cystic fibrosis.

Pediatr Pulmonol. 2019 Aug 19;:

Authors: Peeters MAC, Sattoe JNT, van Staa A, Versteeg SE, Heeres I, Rutjes NW, Janssens HM

Abstract
BACKGROUND: Transition clinics (TCs) are advocated as best practice to support young people with cystic fibrosis (CF) during transition to adulthood and adult care. We aimed to research the functioning of a TC for young people with CF compared with direct hand-over care and to evaluate whether those treated at the TC have better transfer experiences and outcomes compared with the control group.
METHODS: Mixed-methods retrospective controlled design, including interviews with professionals, observations of clinics, chart reviews (at four measurement moments), and patient surveys. Qualitative data analysis focused on organization and daily routines, and barriers and facilitators experienced. Young people's transfer experiences, self-management, health care use, and clinical outcomes were assessed quantitatively.
RESULTS: The most notable feature distinguishing the TC and direct hand-over care comprised joint consultations between pediatric and adult care professionals in the former. A transition coordinator was considered essential for the success of the TC. The main barriers were lack of time, planning, and reimbursement issues. Young people treated at the TC tended to have better transfer experiences and were more satisfied. They reported significantly more trust in their adult care professionals. Their self-management-related outcomes were less favorable.
CONCLUSIONS: The TC had several perceived benefits and showed positive trends in transfer experiences and satisfaction, but no differences in health-related outcomes. Structured preparation of young people, joint consultations with pediatric and adult care professionals, and better coordination were perceived as facilitating elements. Further improvement demands solutions for organizational and financial barriers, and better embedding of self-management interventions in CF care.

PMID: 31424181 [PubMed - as supplied by publisher]

c.753_754delAG, a novel CFTR mutation found in a Chinese patient with cystic fibrosis: A case report and review of the literature.

World J Clin Cases. 2019 Aug 06;7(15):2110-2119

Authors: Wang YQ, Hao CL, Jiang WJ, Lu YH, Sun HQ, Gao CY, Wu M

Abstract
BACKGROUND: Cystic fibrosis (CF) is rare in Asian populations relative to the Caucasian population. In this paper, we report the cystic fibrosis transmembrane conductance regulator (CFTR) variation in a family of Chinese CF patients, and systematically review the previous literature.
CASE SUMMARY: Here we report a 30-month-old Chinese girl who was diagnosed with CF based on her history and symptoms such as recurrent productive cough, wheezing with repeated infection of Pseudomonas aeruginosa, and parasinusitis. Chest computed tomography (CT) scanning revealed obvious exudative lesions and bilateral bronchiectasis. Liver CT scanning revealed a low-density lesion in the left lobe of the liver. A diagnosis of CF was made based upon CFTR gene tests. The CFTR gene was sequenced using the blood samples of her and her parents and showed a heterozygous novel missense mutation of c.753_754delAG in exon 7. In addition, a heterozygous c.1240 C>T mutation was found in exon 10 of the CFTR. The mutation c.753_754delAG was verified to have been inherited from her mother, and the c.1240 C>T mutation was from her father who was diagnosed with congenital absence of vas deferens.
CONCLUSION: A novel mutation of CFTR, c.753_754delAG, was found in a Chinese CF child. c.2909G>A is the most common mutation among Chinese CF patients.

PMID: 31423445 [PubMed]

CNS imaging studies in cystic fibrosis patients presenting with sudden neurological events.

BMJ Open Respir Res. 2019;6(1):e000456

Authors: Ellis S, Rang C, Kotsimbos T, Keating D, Finlayson F, Stark R, Thyagarajan D, Wilson J

Abstract
Background: Acute neurological events may present as an extrapulmonary complication in patients with cystic fibrosis (CF). These events can be secondary to a range of different aetiologies.
Methods: A retrospective analysis of 476 medical records of CF patients attending a large teaching hospital between 2000 and 2018 was performed. Patients presenting with acute neurological events who had MRI brain imaging were evaluated. Patients who had headaches without associated neurological symptoms were excluded from this analysis.
Results: Acute neurological presentations, excluding headaches without associated neurological symptoms, were reported in 27 index patients out of the 476 patients. Of these, 16 patients had MRI brain imaging for review. Three patients suffered pathology secondary to vascular events, both ischaemic and haemorrhagic; four patients had evidence of ischaemia or infarction not consistent with a vascular territory stroke and the remaining patients experienced a range of different neurological events. The most common presentation among these patients was seizure activity, followed by a transient motor or sensory deficit.
Conclusions: Neurological complications are recognised among individuals with CF. Although rare, they can be secondary to a range of different aetiologies, including dysfunctional cell energetics. Additional studies are required to further evaluate this association.

PMID: 31423315 [PubMed]

Metabolite Profiling of the Antisense Oligonucleotide Eluforsen Using Liquid Chromatography-Mass Spectrometry.

Mol Ther Nucleic Acids. 2019 Jul 22;17:714-725

Authors: Kim J, Basiri B, Hassan C, Punt C, van der Hage E, den Besten C, Bartlett MG

Abstract
Eluforsen (previously known as QR-010) is a 33-mer 2'-O-methyl modified phosphorothioate antisense oligonucleotide targeting the F508del mutation in the gene encoding CFTR protein of cystic fibrosis patients. In this study, eluforsen was incubated with endo- and exonucleases and mouse liver homogenates to elucidate its in vitro metabolism. Mice and monkeys were used to determine in vivo liver and lung metabolism of eluforsen following inhalation. We developed a liquid chromatography-mass spectrometry method for the identification and semi-quantitation of the metabolites of eluforsen and then applied the method for in vitro and in vivo metabolism studies. Solid-phase extraction was used following proteinase K digestion for sample preparation. Chain-shortened metabolites of eluforsen by 3' exonuclease were observed in mouse liver in an in vitro incubation system and by either 3' exonuclease or 5' exonuclease in liver and lung samples from an in vivo mouse and monkey study. This study provides approaches for further metabolite characterization of 2'-ribose-modified phosphorothioate oligonucleotides in in vitro and in vivo studies to support the development of oligonucleotide therapeutics.

PMID: 31422288 [PubMed - as supplied by publisher]

Luminescent nanosensors for ratiometric monitoring of three-dimensional oxygen gradients in lab and clinical Pseudomonas aeruginosa biofilms.

Appl Environ Microbiol. 2019 Aug 16;:

Authors: Jewell MP, Galyean AA, Harris JK, Zemanick ET, Cash KJ

Abstract
Bacterial biofilms can form persistent infections on wounds, on implanted medical devices, and are associated with many chronic diseases, such as cystic fibrosis. These infections are medically difficult to treat as biofilms are more resistant to antibiotic attack compared to their planktonic counterparts. The understanding of spatial and temporal variation in metabolism of biofilms is a critical component toward improved biofilm treatments. To this end, we developed oxygen-sensitive luminescent nanosensors to measure 3D oxygen gradients, an application of which is demonstrated here with Pseudomonas aeruginosa biofilms. The method was applied here and improves on traditional 1D methods of measuring oxygen profiles by investigating the spatial and temporal variation of oxygen concentration when biofilms are challenged with antibiotic attack. We observed increased oxygenation of biofilms that were consistent with cell death from comparisons with antibiotic kill curves for PAO1. Due to the spatial and temporal nature of our approach, we also identified spatial and temporal inhomogeneities in the biofilm metabolism that are consistent with previous observations. Clinical strains of P. aeruginosa subjected to similar interrogation showed variations in resistance to colistin and tobramycin, two antibiotics commonly used to treat P. aeruginosa infections in cystic fibrosis patients.Importance. Biofilm infections are more difficult to treat compared to planktonic infections for a variety of reasons such as decreased antibiotic penetration. Their complex structure makes biofilms challenging to study without disruption. To address this limitation, we developed and demonstrated oxygen-sensitive luminescent nanosensors that can be incorporated into biofilms for studying oxygen penetration, distribution, and antibiotic efficacy - demonstrated here with our sensors monitoring antibiotic impacts on metabolism in biofilms formed from clinical isolates. The significance of our research is not only in demonstrating a non-disruptive method for imaging and measuring oxygen in biofilms, but also that this nanoparticle-based sensing platform can be modified to measure many different ions and small molecule analytes.

PMID: 31420335 [PubMed - as supplied by publisher]

Automated glycemic control with the bionic pancreas in cystic fibrosis-related diabetes: A pilot study.

J Cyst Fibros. 2019 Aug 13;:

Authors: Sherwood JS, Jafri RZ, Balliro CA, Zheng H, El-Khatib FH, Damiano ER, Russell SJ, Putman MS

Abstract
Cystic fibrosis-related diabetes (CFRD) is the most common extrapulmonary manifestation of cystic fibrosis. The current standard of care for CFRD involves treatment with insulin, typically via multiple daily injections. We conducted a small pilot study comparing usual care with automated glycemic control using the bihormonal (insulin and glucagon) and insulin-only configurations of the bionic pancreas. Both configurations of the bionic pancreas achieved good glycemic control, with mean glucose levels <150 mg/dl and minimal hypoglycemia. Subjects reported improved treatment satisfaction and reduced burden of diabetes management with the bionic pancreas. Further investigation of automated glycemic control in the treatment of CFRD is warranted.

PMID: 31420176 [PubMed - as supplied by publisher]

Total pancreatectomy with islet autotransplantation in a pancreatic-sufficient cystic fibrosis patient.

J Cyst Fibros. 2019 Aug 13;:

Authors: St Onge I, Nathan JD, Abu-El-Haija M, Chini BA

Abstract
For children with Cystic Fibrosis (CF) suffering from acute recurrent pancreatitis (ARP), abdominal pain can be severe, difficult to treat, impair their quality of life, affect participation at school, and can lead to chronic opioid dependence. Total pancreatectomy with islet autotransplantation (TPIAT) is an uncommon treatment that is reserved for refractory cases of ARP. We present a case of a 4 year old female with pancreatic-sufficient CF, refractory ARP, frequent hospital admissions for abdominal pain, and continued growth failure despite gastrostomy tube and parenteral nutrition. One year after successful TPIAT, the patient is insulin-independent, growing well, and has not been re-hospitalized for abdominal pain. To our knowledge, this is the youngest patient with CF to undergo TPIAT for debilitating ARP. With CFTR modulators restoring some pancreatic function, CF clinicians should have increased vigilance for the development of ARP.

PMID: 31420175 [PubMed - as supplied by publisher]

Characterization of the "Frequent Exacerbator Phenotype" in Bronchiectasis.

Am J Respir Crit Care Med. 2018 06 01;197(11):1410-1420

Authors: Chalmers JD, Aliberti S, Filonenko A, Shteinberg M, Goeminne PC, Hill AT, Fardon TC, Obradovic D, Gerlinger C, Sotgiu G, Operschall E, Rutherford RM, Dimakou K, Polverino E, De Soyza A, McDonnell MJ

Abstract
RATIONALE: Exacerbations are key events in the natural history of bronchiectasis, but clinical predictors and outcomes of patients with frequently exacerbating disease are not well described.
OBJECTIVES: To establish if there is a "frequent exacerbator phenotype" in bronchiectasis and the impact of exacerbations on long-term clinical outcomes.
METHODS: We studied patients with bronchiectasis enrolled from 10 clinical centers in Europe and Israel, with up to 5 years of follow-up. Patients were categorized by baseline exacerbation frequency (zero, one, two, or three or more per year). The repeatability of exacerbation status was assessed, as well as the independent impact of exacerbation history on hospitalizations, quality of life, and mortality.
MEASUREMENTS AND MAIN RESULTS: A total of 2,572 patients were included. Frequent exacerbations were the strongest predictor of future exacerbation frequency, suggesting a consistent phenotype. The incident rate ratios for future exacerbations were 1.73 (95% confidence interval [CI], 1.47-2.02; P < 0.0001) for one exacerbation per year, 3.14 (95% CI, 2.70-3.66; P < 0.0001) for two exacerbations, and 5.97 (95% CI, 5.27-6.78; P < 0.0001) for patients with three or more exacerbations per year at baseline. Additional independent predictors of future exacerbation frequency were Haemophilus influenzae and Pseudomonas aeruginosa infection, FEV1, radiological severity of disease, and coexisting chronic obstructive pulmonary disease. Patients with frequently exacerbating disease had worse quality of life and were more likely to be hospitalized during follow-up. Mortality over up to 5 years of follow-up increased with increasing exacerbation frequency.
CONCLUSIONS: The frequent exacerbator phenotype in bronchiectasis is consistent over time and shows high disease severity, poor quality of life, and increased mortality during follow-up.

PMID: 29357265 [PubMed - indexed for MEDLINE]

StatPearls

Book. 2019 01

Authors:

Abstract
Cystic fibrosis-related diabetes (CFRD) is an extrapulmonary complication of cystic fibrosis (CF) and is associated with increased morbidity and mortality in affected individuals. Cystic fibrosis-related diabetes is the result of abnormal glucose metabolism primarily characterized by insulin deficiency, intermittently exacerbated by insulin resistance. It is crucial to recognize the early signs of abnormal glucose metabolism in individuals with CF to make the diagnosis of CFRD. Early diagnosis and treatment correlate with slower rates of pulmonary decline and improved growth. This activity will provide an overview of CFRD. 

PMID: 31424776

StatPearls

Book. 2019 01

Authors:

Abstract
Ion channels are used by cells to regulate many cellular functions, from action potential conduction to water balance, which is sometimes achieved by using a single ion in the setting of different channels types. Although ion channels are described as transmembrane proteins that have a “pore” which allows for the diffusion of specific ions across a concentration gradient, other channels involved in ion transport include antiporters (exchange), symporters (cotransport in the same direction) and pumps (use energy from hydrolysis of ATP). Chloride channels are a remarkable example of this since they are involved in the control of transepithelial transport, membrane excitability, and the regulation of cell volume and intracellular and intraorganelle pH. All of this is achievable by the use of the many different types of chloride channels, of which there are three major families: the voltage-gated chloride channels, the cystic fibrosis transmembrane conductance regulator (CFTR) and related channels, and the ligand-gated channels activated by gamma-aminobutyric acid (GABA) and glycine.[1][2]

PMID: 31424722

Anti-PcrV titers in non-cystic fibrosis patients with Pseudomonas aeruginosa respiratory tract infection.

Int J Infect Dis. 2019 Aug 13;:

Authors: Nagaoka K, Yamashita Y, Kimura H, Kimura H, Suzuki M, Fukumoto T, Hayasaka K, Yoshida M, Hara T, Maki H, Ohkawa T, Konno S

Abstract
OBJECTIVE: The epidemiology and role of anti-PcrV titer in non-cystic fibrosis patients ofPseudomonas aeruginosa (PA)-airway tract infection is not fully understood. Here, we compared anti-PcrV titers of patients with and without PA respiratory tract infection.
METHODS: We conducted a prospective cohort study at Hokkaido University Hospital in Japan. Participants had blood and sputum specimens collected on admission. They were divided into two groups based on their sputum culture results. Those with PA infection were assigned to the PA group, and those without PA infection were assigned to the non-PA group. Serum anti-PcrV titers were measured using a validated ELISA.
RESULTS: Of the 44 participants, 15 were assigned to the PA group and 29 were assigned to the non-PA group. In the PA group, 10/15 participants (66.7%) had an anti-PcrV titer >1000 ng/mL compared to 3/29 participants (10.3%) in the non-PA group (p < 0.001). In the PA group two of the five participants with an anti-PcrV titer <1000 ng/mL, died of recurrentP. aeruginosa pneumonia, but the other three participants did not develop pneumonia.
CONCLUSION: The anti-PcrV titers in participants withP. aeruginosa infection varied considerably. Patients with low anti-PcrV titers and refractory P. aeruginosa infection need to be closely monitored.

PMID: 31419482 [PubMed - as supplied by publisher]

Burkholderia cepacia Complex Species Differ in the Frequency of Variation of the Lipopolysaccharide O-Antigen Expression During Cystic Fibrosis Chronic Respiratory Infection.

Front Cell Infect Microbiol. 2019;9:273

Authors: Hassan AA, Coutinho CP, Sá-Correia I

Abstract
Burkholderia cepacia complex (Bcc) bacteria can adapt to the lung environment of cystic fibrosis (CF) patients resulting in the emergence of a very difficult to eradicate heterogeneous population leading to chronic infections associated with rapid lung function loss and increased mortality. Among the important phenotypic modifications is the variation of the lipopolysaccharide (LPS) structure at level of the O-antigen (OAg) presence, influencing adherence, colonization and the ability to evade the host defense mechanisms. The present study was performed to understand whether the loss of OAg expression during CF infection can be considered a general phenomenon in different Bcc species favoring its chronicity. In fact, it is still not clear why different Bcc species/strains differ in their ability to persist in the CF lung and pathogenic potential. The systematic two-decade-retrospective-longitudinal-screening conducted covered 357 isolates retrieved from 19 chronically infected patients receiving care at a central hospital in Lisbon. The study involved 21 Bcc strains of six/seven Bcc species/lineages, frequently or rarely isolated from CF patients worldwide. Different strains/clonal variants obtained during infection gave rise to characteristic OAg-banding patterns. The two most prevalent and feared species, B. cenocepacia and B. multivorans, showed a tendency to lose the OAg along chronic infection. B. cenocepacia recA lineage IIIA strains known to lead to particularly destructive infections exhibit the most frequent OAg loss, compared with lineage IIIB. The switch frequency increased with the duration of infection and the level of lung function deterioration. For the first time, it is shown that the rarely found B. cepacia and B. contaminans, whose representation in the cohort of patients examined is abnormally high, keep the OAg even during 10- or 15-year infections. Data from co-infections with different Bcc species reinforced these conclusions. Concerning the two other rarely found species examined, B. stabilis exhibited a stable OAg expression phenotype over the infection period while for the single clone of the more distantly related B. dolosa species, the OAg-chain was absent from the beginning of the 5.5-year infection until the patient dead. This work reinforces the relevance attributed to the OAg-expression switch suggesting marked differences in the various Bcc species.

PMID: 31417878 [PubMed - in process]

The CXCL12/CXCR4 Signaling Axis Retains Neutrophils at Inflammatory Sites in Zebrafish.

Front Immunol. 2019;10:1784

Authors: Isles HM, Herman KD, Robertson AL, Loynes CA, Prince LR, Elks PM, Renshaw SA

Abstract
The inappropriate retention of neutrophils at inflammatory sites is a major driver of the excessive tissue damage characteristic of respiratory inflammatory diseases including COPD, ARDS, and cystic fibrosis. The molecular programmes which orchestrate neutrophil recruitment to inflammatory sites through chemotactic guidance have been well-studied. However, how neutrophil sensitivity to these cues is modulated during inflammation resolution is not understood. The identification of neutrophil reverse migration as a mechanism of inflammation resolution and the ability to modulate this therapeutically has identified a new target to treat inflammatory disease. Here we investigate the role of the CXCL12/CXCR4 signaling axis in modulating neutrophil retention at inflammatory sites. We used an in vivo tissue injury model to study neutrophilic inflammation using transgenic zebrafish larvae. Expression of cxcl12a and cxcr4b during the tissue damage response was assessed using in situ hybridization and analysis of RNA sequencing data. CRISPR/Cas9 was used to knockdown cxcl12a and cxcr4b in zebrafish larvae. The CXCR4 antagonist AMD3100 was used to block the Cxcl12/Cxcr4 signaling axis pharmacologically. We identified that cxcr4b and cxcl12a are expressed at the wound site in zebrafish larvae during the inflammatory response. Following tail-fin transection, removal of neutrophils from inflammatory sites is significantly increased in cxcr4b and cxcl12a CRISPR knockdown larvae. Pharmacological inhibition of the Cxcl12/Cxcr4 signaling axis accelerated resolution of the neutrophil component of inflammation, an effect caused by an increase in neutrophil reverse migration. The findings of this study suggest that CXCR4/CXCL12 signaling may play an important role in neutrophil retention at inflammatory sites, identifying a potential new target for the therapeutic removal of neutrophils from the lung in chronic inflammatory disease.

PMID: 31417560 [PubMed - in process]