Efficacy and safety of infliximab in very early onset inflammatory bowel disease: a national comparative retrospective study.

United European Gastroenterol J. 2019 Jul;7(6):759-766

Authors: Bramuzzo M, Arrigo S, Romano C, Filardi MC, Lionetti P, Agrusti A, Dipasquale V, Paci M, Zuin G, Aloi M, Strisciuglio C, Miele E, Pastore M, Martelossi S, Alvisi P, SIGENP IBD Working Group

Abstract
Background: Very few data regarding the use of infliximab in children with very early-onset inflammatory bowel disease (VEO-IBD) have been reported.
Objective: We aimed to assess the efficacy and the safety of infliximab in children with VEO-IBD compared with older children.
Methods: Children treated with infliximab were identified within the Italian IBD registry. The primary outcome was the rate of clinical remission at weeks 14 and 54. Secondary outcomes included the proportion of partial clinical response, treatment duration, and incidence of adverse events.
Results: Forty-two children with VEO-IBD were compared with 130 children with IBD. Despite significantly higher infliximab withdrawals in VEO-IBD patients during induction (42.9% vs 7.7% p < 0.01), remission rates at week 14 were similar (28.6% vs 43.8%, p = 0.10). At week 54 fewer VEO-IBD children were in remission (15.8% vs 54.3%, p < 0.01). The treatment duration was shorter in VEO-IBD (median 12.0 vs 18.4 months, p < 0.01). During the induction phase, adverse events were more common in the VEO-IBD group (p < 0.01).
Conclusion: Compared with older children, VEO-IBD patients have higher rates of infliximab failures, lower remission rates at one year, and more often experience adverse events during induction.

PMID: 31316780 [PubMed]

Establishment and equilibrium levels of deleterious mutations in large populations.

Sci Rep. 2019 Jul 17;9(1):10384

Authors: Viljoen JW, de Villiers JP, van Zyl AJ, Mezzavilla M, Pepper MS

Abstract
Analytical and statistical stochastic approaches are used to model the dispersion of monogenic variants through large populations. These approaches are used to quantify the magnitude of the selective advantage of a monogenic heterozygous variant in the presence of a homozygous disadvantage. Dunbar's results regarding the cognitive upper limit of the number of stable social relationships that humans can maintain are used to determine a realistic effective community size from which an individual can select mates. By envisaging human community structure as a network where social proximity rather than physical geography predominates, a significant simplification is achieved, implicitly accounting for the effects of migration and consanguinity, and with population structure and genetic drift becoming emergent features of the model. Effective community size has a dramatic effect on the probability of establishing beneficial alleles. It also affects the eventual equilibrium values that are reached in the case of variants conferring a heterozygous selective advantage, but a homozygous disadvantage, as in the case of cystic fibrosis and sickle cell disease. The magnitude of this selective advantage can then be estimated based on observed occurrence levels of a specific allele in a population, without requiring prior information regarding its phenotypic manifestation.

PMID: 31316137 [PubMed - in process]

Comparing clinical characteristics of pediatric patients with pancreatic diabetes to patients with type 1 diabetes - a matched case-control study.

Pediatr Diabetes. 2019 Jul 17;:

Authors: Lanzinger S, Welters A, Thon A, Konrad K, Kapellen T, Grulich-Henn J, Raddatz D, Holl RW

Abstract
BACKGROUND: Only few studies have been conducted on pancreatic diabetes and data from large epidemiological studies are missing. Our main objective was to study the most important differences and similarities between pediatric individuals with pancreatic diabetes and type 1 diabetes.
METHODS: Patients <20 years of age were identified from the diabetes patient follow-up registry (DPV). Data of the most recent treatment year between January 2000 and March 2018 was aggregated. Propensity score was used to match individuals with pancreatic diabetes to individuals with type 1 diabetes. Matching was conducted one to one by sex, age, diabetes duration, BMI-SDS and migration background.
RESULTS: We studied 731 individuals with pancreatic diabetes and 74,460 with type 1 diabetes. In the matched cohort of 631 pairs, HbA1c was significantly lower in pancreatic diabetes (7.4% [95%-confidence interval: 7.2; 7.5%]) compared to type 1 diabetes patients (8.7% [8.5; 8.8%]). Daily insulin dose (0.80 IU/kg [0.77; 0.84] vs. 0.86 IU/kg [0.82; 0.90]) and insulin pump use (13.3% [10.7; 16.4] vs. 22.1% [19.0; 25.6%]) were lower in patients with pancreatic diabetes. However, event rates of severe hypoglycemia were similar between pancreatic and type 1 diabetes patients (8.8 [5.4; 14.2] vs. 9.6 [5.9; 15.6] events per 100 patient years).
CONCLUSIONS: With the use of robust epidemiological data our study improves the knowledge on clinical characteristics in pediatric individuals with pancreatic diabetes. Moreover, our results serve as a basis to reconsider treatment options and for discussing clinical practice guidelines for patients with this rare medical condition. This article is protected by copyright. All rights reserved.

PMID: 31314155 [PubMed - as supplied by publisher]

What is the recommended amikacin dosing for cystic fibrosis patients with acute pulmonary exacerbations?

Pediatr Pulmonol. 2019 Jul 16;:

Authors: Thirion DJG, Pasche V, Marsot A

PMID: 31313524 [PubMed - as supplied by publisher]

Prevalence, risk factors and outcomes of patients coming from the community with sepsis due to multidrug resistant bacteria.

Multidiscip Respir Med. 2019;14:23

Authors: Capsoni N, Bellone P, Aliberti S, Sotgiu G, Pavanello D, Visintin B, Callisto E, Saderi L, Soldini D, Lardera L, Monzani V, Brambilla AM

Abstract
Background: Although previous studies showed an increasing prevalence of infections due to multi-drug resistant (MDR) bacteria in the community, specific data on sepsis are lacking. We aimed to assess prevalence, risk factors and outcomes of patients with sepsis due to MDR bacteria.
Methods: An observational, retrospective study was conducted on consecutive adult patients coming from the community and admitted to the Policlinico Hospital, Milan, Italy, with a diagnosis of sepsis between January 2011 and December 2015. Primary study outcome was in-hospital mortality.
Results: Among 518 patients, at least one MDR bacteria was isolated in 88 (17%). ESBL+ Enterobacteriaceae were the most prevalent MDR bacteria (9.7%) followed by MRSA (3.9%). Independent risk factors for sepsis due to MDR bacteria were septic shock (OR: 2.2; p = 0.002) and hospitalization in the previous 90 days (OR: 2.3; p = 0.003). Independent risk factors for sepsis due to ESBL+ bacteria were hospitalization in the previous 90 days (OR: 2.1; p = 0.02) and stroke (OR: 2.1; p = 0.04). A significantly higher mortality was detected among patients with vs. without MDR bacteria (40.2% vs. 23.1% respectively, p = 0.001). Independent risk factors for mortality among patients with sepsis were coagulation dysfunction (OR: 3.2; p = 0.03), septic shock (OR: 3.2; p = 0.003), and isolation of a MDR bacteria (OR: 4.6; p < 0.001).
Conclusion: In light of the prevalence and impact of MDR bacteria causing sepsis in patients coming from the community, physicians should consider ESBL coverage when starting an empiric antibiotic therapy in patients with specific risk factors, especially in the presence of septic shock.

PMID: 31312449 [PubMed]

HDAC6 depletion improves cystic fibrosis mouse airway responses to bacterial challenge.

Sci Rep. 2019 Jul 16;9(1):10282

Authors: Rosenjack J, Hodges CA, Darrah RJ, Kelley TJ

Abstract
The hypothesis of this study was that Hdac6 depletion would restore cystic fibrosis (CF) responses to bacterial challenge to more wild type profiles using a CF mouse model. CF mice harboring the F508del Cftr mutation respond to bacterial challenge with 25,000 CFU Pseudomonas aeruginosa embedded into agarose beads to slow clearance. CF mice respond significantly more aggressively to this challenge compared to WT mice with respect to bacterial clearance, weight loss, neutrophil recruitment, and MIP-2 production. Depletion of Hdac6 expression in the CF mice (CF/Hdac6) significantly improves these responses to more WT levels. Weight loss in response to infection is most severe in CF mice and significantly attenuated in CF/Hdac6 mice. Bacterial levels are reduced at a faster rate in CF/Hdac6 mice compared to CF mice where infection persists. Percent neutrophils in lung lavage fluid post-infection are significantly higher in CF mice, but returned to WT levels with CF/Hdac6 mice. Similarly, CF Mip-2 levels are restored to WT levels in the absence of Hdac6 expression. These data demonstrate that Hdac6 depletion restores CF responses to bacterial challenge to WT-like profiles and offer a potential therapeutic avenue for addressing inflammation and infection in CF airways independently of Cftr correction.

PMID: 31311988 [PubMed - in process]

Bioactive Thymosin Alpha-1 Does Not Influence F508del-CFTR Maturation and Activity.

Sci Rep. 2019 Jul 16;9(1):10310

Authors: Armirotti A, Tomati V, Matthes E, Veit G, Cholon DM, Phuan PW, Braccia C, Guidone D, Gentzsch M, Lukacs GL, Verkman AS, Galietta LJV, Hanrahan JW, Pedemonte N

Abstract
Deletion of phenylalanine 508 (F508del) in the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel is the most frequent mutation causing cystic fibrosis (CF). F508del-CFTR is misfolded and prematurely degraded. Recently thymosin a-1 (Tα-1) was proposed as a single molecule-based therapy for CF, improving both F508del-CFTR maturation and function by restoring defective autophagy. However, three independent laboratories failed to reproduce these results. Lack of reproducibility has been ascribed by the authors of the original paper to the use of DMSO and to improper handling. Here, we address these potential issues by demonstrating that Tα-1 changes induced by DMSO are fully reversible and that Tα-1 peptides prepared from different stock solutions have equivalent biological activity. Considering the negative results here reported, six independent laboratories failed to demonstrate F508del-CFTR correction by Tα-1. This study also calls into question the autophagy modulator cysteamine, since no rescue of mutant CFTR function was detected following treatment with cysteamine, while deleterious effects were observed when bronchial epithelia were exposed to cysteamine plus the antioxidant food supplement EGCG. Although these studies do not exclude the possibility of beneficial immunomodulatory effects of thymosin α-1, they do not support its utility as a corrector of F508del-CFTR.

PMID: 31311979 [PubMed - in process]

Patient-derived pancreas-on-a-chip to model cystic fibrosis-related disorders.

Nat Commun. 2019 Jul 16;10(1):3124

Authors: Shik Mun K, Arora K, Huang Y, Yang F, Yarlagadda S, Ramananda Y, Abu-El-Haija M, Palermo JJ, Appakalai BN, Nathan JD, Naren AP

Abstract
Cystic fibrosis (CF) is a genetic disorder caused by defective CF Transmembrane Conductance Regulator (CFTR) function. Insulin producing pancreatic islets are located in close proximity to the pancreatic duct and there is a possibility of impaired cell-cell signaling between pancreatic ductal epithelial cells (PDECs) and islet cells as causative in CF. To study this possibility, we present an in vitro co-culturing system, pancreas-on-a-chip. Furthermore, we present an efficient method to micro dissect patient-derived human pancreatic ducts from pancreatic remnant cell pellets, followed by the isolation of PDECs. Here we show that defective CFTR function in PDECs directly reduced insulin secretion in islet cells significantly. This uniquely developed pancreatic function monitoring tool will help to study CF-related disorders in vitro, as a system to monitor cell-cell functional interaction of PDECs and pancreatic islets, characterize appropriate therapeutic measures and further our understanding of pancreatic function.

PMID: 31311920 [PubMed - in process]

Side lying during nebulisation can significantly improve apical deposition in healthy adults and adults with mild cystic fibrosis lung disease: a randomised crossover trial.

BMC Pulm Med. 2019 Jul 16;19(1):128

Authors: Dentice RL, Elkins MR, Verschuer J, Eberl S, Dwyer G, Bye PTP

Abstract
BACKGROUND: In people with and without Cystic Fibrosis (CF), does side lying during nebulisation change: the proportion of the dose loaded in the nebuliser that is deposited in the lungs; the uniformity of deposition throughout the lungs; or the apical drug density as a percentage of the drug density in the remaining lung? Do these effects differ depending on the degree of lung disease present?
METHODS: A randomised crossover trial with concealed allocation, intention-to-treat analysis and blinded assessors, involving 39 adults: 13 healthy, 13 with mild CF lung disease (FEV1 > 80%pred), and 13 with more advanced CF lung disease (FEV1 < 80%pred). In random order, 4 mL of nebulised radioaerosol was inhaled in upright sitting and in alternate right and left side lying at 2-min intervals, for 20 min.
RESULTS: Compared to sitting upright, lung deposition and the uniformity of deposition were not significantly altered by side lying in any of the three groups. In sitting, the density of the deposition was significantly less in the apical regions than in the rest of the lung in all participants. Side lying significantly improved apical deposition in healthy adults (MD, 13%; 95% CI, 7 to 19), and in minimal CF lung disease (MD, 4%; 95% CI, 1 to 7) but not in advanced disease (MD, 4%; 95% CI, - 2 to 9).
CONCLUSION: Alternating between right and left side lying during nebulisation significantly improves apical deposition in healthy adults and in adults with mild CF lung disease, without substantial detriment to overall deposition.
TRIAL REGISTRATION: ACTRN12611000674932 (Healthy), ACTRN12611000672954 (CF) Retrospectively registered 4/7/2011.

PMID: 31311524 [PubMed - in process]

CFTRgene variants:A predisposition factor to aquagenic palmoplantar keratoderma.

Br J Dermatol. 2019 Jul 16;:

Authors: Raynal C, Girodon E, Audrezet MP, Cabet F, Pagin A, Reboul MP, Dufernez F, Fergelot P, Bergougnoux A, Fanen P, Ferec C, Bienvenu T

Abstract
Aquagenic palmoplantar keratoderma (APK) is a rare skin disorder characterized by skin wrinkling with oedema and whitish papules on the palms and/or soles, pruritus, burning, and pain after contact with water. 1 Most cases are sporadic, but familial cases also have been reported, and APK pathogenesis is poorly understood. In 1974, Elliot first described APK in patients with cystic fibrosis (CF). This article is protected by copyright. All rights reserved.

PMID: 31310009 [PubMed - as supplied by publisher]

High-dose or Multi-day Praziquantel for Imported Schistosomiasis? A Systematic Review.

J Travel Med. 2019 Jul 16;:

Authors: Cucchetto G, Buonfrate D, Marchese V, Rodari P, Ferrari A, Zanotti P, Bottieau E, Silva R, Bisoffi Z, Gobbi F

Abstract
BACKGROUND: Schistosomiasis affects more than 260 million people worldwide, mostly in sub-Saharan Africa, where more than 280.000 deaths per year are estimated. In the last few years, the increasing flow of migrants from endemic areas and the upward number of international travels have caused the emergence of the disease also in non-endemic areas. A single course of praziquantel (PZQ) 40 mg/kg is the first-line treatment recommended by the World Health Organization, mainly based on clinical trials conducted in endemic countries. No trials have been performed in non-endemic areas.
METHODS: We carried out a systematic review of case reports and case series published between 1956 and August 2017 on cases of chronic schistosomiasis (infection acquired more than 3 months before) diagnosed in non-endemic areas and treated with PZQ. Primary outcome was to assess the number of different therapeutic regimens deployed and their frequency of use, calculated as the number of reports for each regimen over the total number of included cases.
RESULTS: The final database included 99 case reports and 51 case series, for a total of 1433 patients. In 57 of the 150 records (38%) the administered treatment was different from the one recommended by the World Health Organization. The proportion of "alternative" regimens included increased doses of PZQ (up to 80 mg/kg) and/or prolonged duration of treatment and/or doses repeated some days/weeks apart. About 50% of the records regarding Western short-term travellers reported a non-standard treatment.
CONCLUSIONS: This is the first complete catalogue of the published experience with PZQ outside of endemic areas in the situation where reinfection is not an issue. We found a wide heterogeneity of the therapeutic regimens reported. Multicenter clinical trials conducted in non-endemic areas and guidelines specifically addressing the treatment of imported cases of chronic schistosomiasis are needed.

PMID: 31309979 [PubMed - as supplied by publisher]

Dynamics of cheater invasion in a cooperating population of Pseudomonas aeruginosa.

Sci Rep. 2019 Jul 15;9(1):10190

Authors: Feng X, Kostylev M, Dandekar AA, Greenberg EP

Abstract
Pseudomonas aeruginosa quorum sensing (QS) regulates expression of dozens of genes in a cell density-dependent manner. Many QS-regulated genes code for production of extracellular factors, "public goods" that can benefit the entire population. This cooperation encourages individuals to cheat by using but not producing public goods. QS also controls expression of a limited number of genes encoding "private" cellular enzymes like Nuh, an enzyme involved in adenosine catabolism. Growth of P. aeruginosa on casein requires QS-regulated production of an extracellular protease and is an example of cooperative behavior. When P. aeruginosa is transferred daily on casein, QS mutants emerge. These cheaters have mutations in lasR, which encodes the primary QS transcription factor. When growth is on casein and adenosine, cheater emergence is constrained. Here, we report the dynamics of LasR mutant invasion during growth on casein or casein plus adenosine. We show that LasR mutants have the greatest advantage during early to mid-logarithmic growth on casein. Addition of adenosine to casein medium constrains cheaters throughout growth. Our data support the view that co-regulation of the public protease and the private nucleosidase by QS stabilizes cooperation, and the data are not consistent with other proposed alternate hypotheses.

PMID: 31308401 [PubMed - in process]

Assessing cell-specific effects of genetic variations using tRNA microarrays.

BMC Genomics. 2019 Jul 16;20(Suppl 8):549

Authors: Polte C, Wedemeyer D, Oliver KE, Wagner J, Bijvelds MJC, Mahoney J, de Jonge HR, Sorscher EJ, Ignatova Z

Abstract
BACKGROUND: By definition, effect of synonymous single-nucleotide variants (SNVs) on protein folding and function are neutral, as they alter the codon and not the encoded amino acid. Recent examples indicate tissue-specific and transfer RNA (tRNA)-dependent effects of some genetic variations arguing against neutrality of synonymous SNVs for protein biogenesis.
RESULTS: We performed systematic analysis of tRNA abunandance across in various models used in cystic fibrosis (CF) research and drug development, including Fischer rat thyroid (FRT) cells, patient-derived primary human bronchial epithelia (HBE) from lung biopsies, primary human nasal epithelia (HNE) from nasal curettage, intestinal organoids, and airway progenitor-directed differentiation of human induced pluripotent stem cells (iPSCs). These were compared to an immortalized CF bronchial cell model (CFBE41o-) and two widely used laboratory cell lines, HeLa and HEK293. We discovered that specific synonymous SNVs exhibited differential effects which correlated with variable concentrations of cognate tRNAs.
CONCLUSIONS: Our results highlight ways in which the presence of synonymous SNVs may alter local kinetics of mRNA translation; and thus, impact protein biogenesis and function. This effect is likely to influence results from mechansistic analysis and/or drug screeining efforts, and establishes importance of cereful model system selection based on genetic variation profile.

PMID: 31307398 [PubMed - in process]

β-Lactam hypersensitivity involves expansion of circulating and skin-resident TH22 cells.

J Allergy Clin Immunol. 2018 01;141(1):235-249.e8

Authors: Sullivan A, Wang E, Farrell J, Whitaker P, Faulkner L, Peckham D, Park BK, Naisbitt DJ

Abstract
BACKGROUND: β-Lactam hypersensitivity has been classified according to the phenotype and function of drug-specific T cells. However, new T-cell subsets have not been considered.
OBJECTIVE: The objective of this study was to use piperacillin as a model of β-lactam hypersensitivity to study the nature of the drug-specific T-cell response induced in the blood and skin of hypersensitive patients and healthy volunteers.
METHODS: Drug-specific T cells were cloned from blood and inflamed skin, and cellular phenotype and function were explored. Naive T cells from healthy volunteers were primed to piperacillin, cloned, and subjected to the similar analyses.
RESULTS: PBMC and T-cell clones (n = 570, 84% CD4+) from blood of piperacillin-hypersensitive patients proliferated and secreted TH1/TH2 cytokines alongside IL-22 after drug stimulation. IL-17A secretion was not detected. Drug-specific clones from inflamed skin (n = 96, 83% CD4+) secreted a similar profile of cytokines but displayed greater cytolytic activity, secreting perforin, granzyme B, and Fas ligand when activated. Blood- and skin-derived clones expressed high levels of skin-homing chemokine receptors and migrated in the presence of the ligands CCL17 and CCL27. Piperacillin-primed naive T cells from healthy volunteers also secreted IFN-γ, IL-13, IL-22, and cytolytic molecules. Aryl hydrocarbon receptor blockade prevented differentiation of the naive T cells into antigen-specific IL-22-secreting cells.
CONCLUSION: Together, our results reveal that circulating and skin-resident, antigen-specific, IL-22-secreting T cells are detectable in patients with β-lactam hypersensitivity. Furthermore, differentiation of naive T cells into antigen-specific TH22 cells is dependent on aryl hydrocarbon receptor signaling.

PMID: 28219704 [PubMed - indexed for MEDLINE]

Factors associated with outpatient follow-up after a pediatric inpatient stay at a community hospital.

Int J Pediatr Adolesc Med. 2019 Mar;6(1):6-11

Authors: Jani S, Fogel J, Kelly C

Abstract
Background and objectives: Pediatric settings often use a patient-centered medical home model in caring for patients in the outpatient setting and for attempting to connect inpatient care with outpatient follow-up. This medical home model has proven to be beneficial in many aspects of patient care, but there needs to be a good transition between inpatient and outpatient services. Our goal in this study is to determine the association of particular variables with adherence to outpatient follow-up after a general inpatient stay, in the pediatric population.
Methods: In a retrospective sample of 221 patients, we study the association of variables such as demographics, medical history, hospital discharge and appointments, and caregiver information, with patient adherence to outpatient appointments after discharge from pediatric inpatient treatment.
Results: We found that increased length of hospital stay and a non English-speaking caregiver were each associated with increased odds for adherence. Discharge diagnosis of respiratory illness and that of neurology/psychiatry/toxicology were associated with decreased odds for adherence. None of the demographic and medical history variables were associated with adherence.
Conclusions: Our findings offer guidance to clinicians for the types of patients who may need closer follow-up and interventions set in place to remind these patients of the importance of attending an outpatient appointment.

PMID: 31304221 [PubMed]

Community analysis and co-occurrence patterns in airway microbial communities during health and disease.

ERJ Open Res. 2019 Jul;5(3):

Authors: Einarsson GG, Zhao J, LiPuma JJ, Downey DG, Tunney MM, Elborn JS

Abstract
Ecological relationships between bacteria are important when considering variation in bacterial communities in humans, with such variation playing an important role in both health and disease. Using high-throughput sequence data of the 16S rRNA marker-gene, we analysed the prevalence of taxa in the airways of a number of health- and disease-associated cohorts and determined the main drivers of community variance and bacterial co-occurrence. A number of facultative and obligately anaerobic bacterial taxa are commonly associated with the upper airways, forming the main "core" microbiota, e.g. Streptococcus spp., Veillonella spp., Prevotella spp., Granulicatella spp. and Fusobacterium spp. Opportunistic pathogenic bacteria associated with chronic airways disease, such as Pseudomonas spp. (Pseudomonas aeruginosa), Burkholderia spp. (Burkholderia cepacia complex) and Haemophilus spp. (Haemophilus influenzae) demonstrated poor correlation with other members of their respective communities (ρ<0.5; p>0.005), indicating probable independent acquisition and colonisation. Furthermore, our findings suggest that intra-genus variation between health and disease may affect community assemblies. Improved understanding of how bacteria assemble in time and space during health and disease will enable the future development of tailored treatment according to the patient's own signature microbiota, potentially providing benefit to patients suffering from airway diseases characterised by chronic infection.

PMID: 31304176 [PubMed]

How does Pseudomonas aeruginosa affect the progression of bronchiectasis?

Clin Microbiol Infect. 2019 Jul 12;:

Authors: Chai YH, Xu JF

Abstract
BACKGROUND: Pseudomonas aeruginosa is one of the most common pathogens isolated from respiratory tract specimen in patients with bronchiectasis which is considered highly responsible for pathogenicity, progression and clinical outcomes of bronchiectasis.
AIMS: This narrative review aims to summarize existing evidence on how different factors of Pseudomonas aeruginosa affect the pathogenicity, progression and clinical outcomes of bronchiectasis, as to provide possible insights for clinical practice and related research in the future.
SOURCES: PubMed was searched for studies pertaining to bronchiectasis and Pseudomonas aeruginosa, published up to now, with no specific inclusion/exclusion criteria set. Reference lists of retrieved reviews were searched for additional articles.
CONTENT: This review focused on non-cystic fibrosis bronchiectasis and also provided some data on cystic fibrosis when studies in bronchiectasis were limited. We discussed various factors in relation to Pseudomonas aeruginosa: virulence factors, drug-resistance, regulatory systems, genomic diversity and transmission of Pseudomonas aeruginosa as well as treatment for Pseudomonas aeruginosa. Their impacts on bronchiectasis and its management were discussed.
IMPLICATIONS: Impact of Pseudomonas aeruginosa on bronchiectasis is definite although conclusions in some aspects are still vague. Faced with the worrying drug-resistance status and treatment bottleneck, individualized management and novel therapies beyond classic pathway are most likely to be a future trend. To confirm the independent or integrated impact of various factors of Pseudomonas aeruginosa on bronchiectasis and figure out all the problems mentioned, larger randomized control trials are truly needed in the future.

PMID: 31306794 [PubMed - as supplied by publisher]

Patient-reported outcomes of dual bronchodilator fixed-dose combination versus bronchodilator monotherapy in individuals with COPD.

Int J Chron Obstruct Pulmon Dis. 2019;14:1377-1388

Authors: Strange C, Walker V, DePietro M, Tong J, Kurlander J, Carlyle M, Millette LA, Wittbrodt E

Abstract
Background: This study compared real-world patient-reported outcomes (PROs) measured by the Clinical COPD Questionnaire (CCQ), the London Chest Activities of Daily Living (LCADL) scale, and the Work Productivity and Activity Impairment (WPAI) questionnaire between individuals with COPD initiating LAMA/LABA fixed-dose combination (FDC) dual therapy versus either long-acting muscarinic antagonist (LAMA) or long-acting beta2-agonist (LABA) monotherapy. Methods: Individuals with COPD aged ≥40 years initiating a LAMA/LABA FDC dual therapy or a LAMA or LABA monotherapy (index date = first prescription date) between January 1, 2016 and December 31, 2016 were identified from a large US administrative claims database. Individuals were excluded if they were prescribed an inhaled corticosteroid (ICS) or ICS/LABA two months prior to the index date or were diagnosed with cystic fibrosis, idiopathic pulmonary fibrosis, or asthma. The cohorts were propensity score matched (PSM) 1:1 for COPD severity using baseline measures. Each participant completed a survey. Results: Surveys were completed by 399 participants in the dual therapy cohort, and 718 participants in the monotherapy cohort. Following PSM, 379 participants remained in each cohort for analysis (monotherapy: 369 LAMA and 10 LABA). The dual therapy cohort reported fewer COPD-related symptoms (CCQ symptom score 2.75 vs 2.97, respectively, P=0.023), and, fewer limitations in leisure activities (LCADL leisure score 4.78 vs 5.17, respectively, P=0.021) versus the monotherapy cohort. No significant differences were found in the WPAI. A greater percentage of participants in the dual therapy cohort stayed on index therapy (63.1%) when compared with the monotherapy cohort (30.3%, P<0.0001). Conclusions: Only 30% of the participants prescribed monotherapy, usually with a LAMA, remained on index therapy alone at the time of survey administration. In the dual therapy cohort, 63% of the participants remained on the index medication and had fewer COPD-related symptoms and fewer limitations in leisure activities compared with participants in the monotherapy cohort.

PMID: 31303751 [PubMed - in process]

Lung Transplantation for Cystic Fibrosis and Non-cystic Fibrosis Bronchiectasis: A Single-Center Experience.

Transplant Proc. 2019 Jul 11;:

Authors: Rusanov V, Fridman V, Wille K, Kramer MR

Abstract
OBJECTIVES: Lung transplantation is a well-established treatment for selected patients with advanced cystic fibrosis (CF)- and non-cystic fibrosis (non-CF)--related bronchiectasis. Because the number of lung transplants performed for patients with non-CF bronchiectasis is much smaller than for patients with CF, little data is available regarding patient selection, choice of procedure, and outcomes.
METHODS: Between November 1997 and December 2013, 42 patients with CF and 33 patients with non-CF bronchiectasis underwent lung transplantation at the Rabin Medical Center, Israel. We analyzed and compared pretransplant evaluation data and short- and long-term results in both groups.
RESULTS: Median survival for the CF group in our study was 8.4 years, compared with 7.1 years for the non-CF group (P = .098), similarly to that reported by the International Society for Heart and Lung Transplantation Registry data. The main survival difference between groups was in the early postoperative period. Both groups achieved similar peak forced expiratory volume in 1 second values and had stable lung function at the 3-year follow-up. Biopsy-proven rates of acute cellular rejection were low for both groups. Rates of chronic lung allograft dysfunction development did not differ between CF and non-CF recipients.
CONCLUSION: Our institutional experience confirms that lung transplantation is feasible for non-CF bronchiectasis, and results are comparable to our CF cohort. The increased early mortality in this study occurred from 1999 to 2008 and was probably related to surgical techniques used at the time. Overall, 3-year and 5-year survival were comparable with the International Society for Heart and Lung Transplantation Registry data. Non-CF bronchiectasis patients achieved and maintained satisfactory lung function.

PMID: 31303417 [PubMed - as supplied by publisher]

Speeding up access to new drugs for CF: Considerations for clinical trial design and delivery.

J Cyst Fibros. 2019 Jul 11;:

Authors: Davies JC, Drevinek P, Elborn JS, Kerem E, Lee T, European CF Society (ECFS) Strategic Planning Task Force on ‘Speeding up access to new 4 drugs for CF’, Amaral MD, de Boeck K, Davies JC, Drevinek P, Elborn JS, Kerem E, Lee T

Abstract
The last decade has witnessed developments in the CF drug pipeline which are both exciting and unprecedented, bringing with them previously unconsidered challenges. The Task Force group was brought together to consider these challenges and possible strategies to address them. Over the last 18 months, we have discussed internally and gathered views from a broad range of individuals representing patient organisations, clinical and research teams, the pharmaceutical industry and regulatory agencies. In this and the accompanying article, we discuss two main areas of focus: i) optimising trial design and delivery for speed and efficiency; ii) drug development for patients with rare CFTR mutations. We propose some strategies to tackle the challenges ahead and highlight areas where further thought is needed. We see this as the start of a process rather than the end and hope herewith to engage the wider community in seeking solutions to improved treatments for all patients with CF.

PMID: 31303382 [PubMed - as supplied by publisher]