"Switching partners": Piperacillin-avibactam is a highly potent combination against multidrug-resistant Burkholderia cepacia Complex and Burkholderia gladioli Cystic Fibrosis isolates.

J Clin Microbiol. 2019 Jun 05;:

Authors: Zeiser ET, Becka SA, Wilson BM, Barnes MD, LiPuma JJ, Papp-Wallace KM

Abstract
Background: In persons with cystic fibrosis (CF), airway infection with Burkholderia cepacia complex (Bcc) species or Burkholderia gladioli presents a significant challenge due to inherent resistance to multiple antibiotics. Two chromosomally-encoded inducible β-lactamases, a Pen-like class A and AmpC are produced in Bcc and B gladioli Previously, ceftazidime-avibactam demonstrated significant potency against Bcc and B gladioli isolated from the sputum of individuals with CF; however, 10% of the isolates tested resistant to ceftazidime-avibactam. Herein, we describe an alternative antibiotic combination to overcome ceftazidime-avibactam resistance.Methods: Antimicrobial susceptibility testing was performed on Bcc and B gladioli clinical and control isolates. Biochemical analysis was conducted on purified PenA1 and AmpC1 β-lactamases from Burkholderia multivorans ATCC 17616. Analytic isoelectric focusing and immunoblotting were conducted on cellular extracts of B. multivorans induced by various β-lactams or β-lactam-β-lactamase inhibitor combinations.Results: The combinations of piperacillin-avibactam as well as piperacillin-tazobactam plus ceftazidime-avibactam (the clinically available counterpart) were tested against a panel of ceftazidime-avibactam non-susceptible Bcc and B gladioli The piperacillin-avibactam and piperacillin-tazobactam-ceftazidime-avibactam combinations restored susceptibly to 99% of the isolates tested. Avibactam is a potent inhibitor of PenA1 (K i app = 0.5 μM), while piperacillin was found to inhibit AmpC1 (K i app = 2.6 μM). Moreover, piperacillin, tazobactam, ceftazidime, and avibactam as well as combinations thereof did not induce expression of bla penA1 and bla ampC1 in the B multivorans ATCC 17616 background.Conclusions: When ceftazidime-avibactam is combined with piperacillin-tazobactam, the susceptibility of Bcc and B gladioli to ceftazidime and piperacillin is restored in vitro Lack of bla penA1 induction as well as potent inactivation of PenA1 by avibactam likely provide the major contributions towards susceptibility. With in vivo validation, piperacillin-tazobactam-ceftazidime-avibactam may represent salvage therapy for individuals with CF and highly drug-resistant Bcc and B gladioli infections.

PMID: 31167848 [PubMed - as supplied by publisher]

Microbiological contamination of nebulizers used by cystic fibrosis patients: an underestimated problem.

J Bras Pneumol. 2019 May 30;45(3):e20170351

Authors: Riquena B, Monte LFV, Lopes AJ, Silva-Filho LVRFD, Damaceno N, Aquino EDS, Marostica PJC, Ribeiro JD

Abstract
OBJECTIVE: Home nebulizers are routinely used in the treatment of patients with cystic fibrosis (CF). This study aims to evaluate the contamination of nebulizers used for CF patients, that are chronically colonized by Pseudomonas aeruginosa, and the association of nebulizer contamination with cleaning, decontamination and drying practices.
METHODS: A cross-sectional, observational, multicenter study was conducted in seven CF reference centers in Brazil to obtain data from medical records, structured interviews with patients/caregivers were performed, and nebulizer's parts (interface and cup) were collected for microbiological culture.
RESULTS: overall, 77 CF patients were included. The frequency of nebulizer contamination was 71.6%. Candida spp. (52.9%), Stenotrophomonas maltophilia (11.9%), non-mucoid P. aeruginosa (4.8%), Staphylococcus aureus (4.8%) and Burkholderia cepacia complex (2.4%) were the most common isolated pathogens. The frequency of nebulizers' hygiene was 97.4%, and 70.3% of patients reported cleaning, disinfection and drying the nebulizers. The use of tap water in cleaning method and outdoor drying of the parts significantly increased (9.10 times) the chance of nebulizers' contamination.
CONCLUSION: Despite the high frequency hygiene of the nebulizers reported, the cleaning and disinfection methods used were often inadequate. A significant proportion of nebulizers was contaminated with potentially pathogenic microorganisms for CF patients. These findings support the need to include patients/caregivers in educational programs and / or new strategies for delivering inhaled antibiotics.

PMID: 31166553 [PubMed - in process]

Cigarette and ENDS preparations differentially regulate ion channels and mucociliary clearance in primary normal human bronchial 3D cultures.

Am J Physiol Lung Cell Mol Physiol. 2019 Jun 05;:

Authors: Rayner RE, Makena P, Prasad GL, Cormet-Boyaka E

Abstract
Cigarette smoking is known to disrupt the normal mucociliary function of the lungs, whereas the effect of electronic nicotine delivery systems (ENDS) is not completely understood. This study aimed to compare the effects of acute exposure of primary normal human bronchial epithelial (NHBE) 3D cultures at air-liquid interface to combustible cigarette and ENDS preparations on mucociliary function including ion channel function, ciliary beat frequency (CBF) and airway surface liquid (ASL) height. Differentiated NHBE cultures were exposed to whole smoke conditioned media (WS-CM) or total particulate matter (TPM) prepared from 3R4F reference cigarettes, whole aerosol conditioned media (ACM) or e-TPM generated from a marketed ENDS product, or nicotine alone. We found that a dose of 7µg/ml equi-nicotine units of cigarette TPM and WS-CM significantly decreased cystic fibrosis transmembrane conductance regulator (CFTR) and the epithelial sodium channel (ENaC) function, which regulate fluid homeostasis in the lung. Conversely, higher (56µg/mL) equi-nicotine units of ENDS preparations or nicotine alone had no effect on CFTR and ENaC function. Despite a significant decrease in ion channel function, cigarette smoke preparations did not alter CBF and ASL. Similarly, ENDS preparations and nicotine alone had no effect on ASL and CBF. This study demonstrates that acute exposures of cigarette smoke preparations exert a notable inhibitory effect on CFTR and ENaC function compared to ENDS preparations. In summary, the functional assays described herein are potentially useful for tobacco product evaluations.

PMID: 31166129 [PubMed - as supplied by publisher]

Pathobiology of inherited biliary diseases: a roadmap to understand acquired liver diseases.

Nat Rev Gastroenterol Hepatol. 2019 Jun 05;:

Authors: Fabris L, Fiorotto R, Spirli C, Cadamuro M, Mariotti V, Perugorria MJ, Banales JM, Strazzabosco M

Abstract
Bile duct epithelial cells, also known as cholangiocytes, regulate the composition of bile and its flow. Acquired, congenital and genetic dysfunctions in these cells give rise to a set of diverse and complex diseases, often of unknown aetiology, called cholangiopathies. New knowledge has been steadily acquired about genetic and congenital cholangiopathies, and this has led to a better understanding of the mechanisms of acquired cholangiopathies. This Review focuses on findings from studies on Alagille syndrome, polycystic liver diseases, fibropolycystic liver diseases (Caroli disease and congenital hepatic fibrosis) and cystic fibrosis-related liver disease. In particular, knowledge on the role of Notch signalling in biliary repair and tubulogenesis has been advanced by work on Alagille syndrome, and investigations in polycystic liver diseases have highlighted the role of primary cilia in biliary pathophysiology and the concept of biliary angiogenic signalling and its role in cyst growth and biliary repair. In fibropolycystic liver disease, research has shown that loss of fibrocystin generates a signalling cascade that increases β-catenin signalling, activates the NOD-, LRR- and pyrin domain-containing 3 inflammasome, and promotes production of IL-1β and other chemokines that attract macrophages and orchestrate the process of pericystic and portal fibrosis, which are the main mechanisms of progression in cholangiopathies. In cystic fibrosis-related liver disease, lack of cystic fibrosis transmembrane conductance regulator increases the sensitivity of epithelial Toll-like receptor 4 that sustains the secretion of nuclear factor-κB-dependent cytokines and peribiliary inflammation in response to gut-derived products, providing a model for primary sclerosing cholangitis. These signalling mechanisms may be targeted therapeutically and they offer a possibility for the development of novel treatments for acquired cholangiopathies.

PMID: 31165788 [PubMed - as supplied by publisher]

Human epididymis protein 4 (HE4) protects against cystic pulmonary fibrosis associated-inflammation through inhibition of NF-κB and MAPK singnaling.

Genes Genomics. 2019 Jun 04;:

Authors: Wang J, Zhao H, Xu F, Zhang P, Zheng Y, Jia N

Abstract
BACKGROUND: Cystic pulmonary fibrosis (CF) affects mostly the lung of the newborns. Chronic infection and inflammation become the major causes of morbidity and mortality in CF. However, the underlying molecular mechanisms causing CF still remain unclear.
METHODS: ELISA assay was used to examine the expression of HE4 and pro-inflammatory cytokines in W126VA4 cells supernatant fluid. qRT-PCR was applicable to determine the mRNA level of HE4, α-SMA, collagen 1, MMP2, MMP9 and various interleukins. Immunofluorescent assay was used to test the expression of HE4 in WI-26 VA4 cells. Major elements of MAPK and NF-κB signals pathways were examined by western blot.
RESULTS: We found higher expression of HE4 in CF patients serum and lung biopsy. Interestingly, HE4 expression was positively correlated with fibrosis markers expression. In addition,HE4 overexpression increased inflammatory cytokines secretion and fibrosis markers expression in WI-26 VA4 cells. And NF-κB pathways were responsible for elevated inflammation. In addition, HE4/MAPK/MMPs signaling cascades destroyed the normal extracellular matrix (ECM) and promoted fibrosis.
CONCLUSIONS: Overall, we first identified that HE4 promoted CF-associated inflammation. Additionally, NF-κB and MAPK signalings were further validated to be responsible for CF-associated inflammation and ECM destruction. Characterization of lumacaftor/ivacaftor in CF-associated inflammation may provide a novel insight into clinical CF treatment.

PMID: 31165362 [PubMed - as supplied by publisher]

Is the Potable Water System an Advantageous Preinfection Niche for Bacteria Colonizing the Cystic Fibrosis Lung?

MBio. 2019 Jun 04;10(3):

Authors: Wargo MJ

Abstract
People with cystic fibrosis are susceptible to lung infections from a variety of bacteria, a number of which also reside in the potable water system, including Pseudomonas aeruginosa, Stenotrophomonas maltophilia, Achromobacter xylosoxidans, Burkholderia cepacia complex, and nontuberculosis Mycobacteria Here, I propose chemical and physical aspects of the potable water system along with bacterial lifestyle strategies in this system that may enhance successful colonization of cystic fibrosis lungs by these bacteria, including iron and copper levels, lipids, and low growth rates within low-oxygen biofilms.

PMID: 31164466 [PubMed - in process]

Temperate Bacteriophages from Chronic Pseudomonas aeruginosa Lung Infections Show Disease-Specific Changes in Host Range and Modulate Antimicrobial Susceptibility.

mSystems. 2019 Jun 04;4(4):

Authors: Tariq MA, Everest FLC, Cowley LA, Wright R, Holt GS, Ingram H, Duignan LAM, Nelson A, Lanyon CV, Perry A, Perry JD, Bourke S, Brockhurst MA, Bridge SH, De Soyza A, Smith DL

Abstract
Temperate bacteriophages are a common feature of Pseudomonas aeruginosa genomes, but their role in chronic lung infections is poorly understood. This study was designed to identify the diverse communities of mobile P. aeruginosa phages by employing novel metagenomic methods, to determine cross infectivity, and to demonstrate the influence of phage infection on antimicrobial susceptibility. Mixed temperate phage populations were chemically mobilized from individual P. aeruginosa, isolated from patients with cystic fibrosis (CF) or bronchiectasis (BR). The infectivity phenotype of each temperate phage lysate was evaluated by performing a cross-infection screen against all bacterial isolates and tested for associations with clinical variables. We utilized metagenomic sequencing data generated for each phage lysate and developed a novel bioinformatic approach allowing resolution of individual temperate phage genomes. Finally, we used a subset of the temperate phages to infect P. aeruginosa PAO1 and tested the resulting lysogens for their susceptibility to antibiotics. Here, we resolved 105 temperate phage genomes from 94 lysates that phylogenetically clustered into 8 groups. We observed disease-specific phage infectivity profiles and found that phages induced from bacteria isolated from more advanced disease infected broader ranges of P. aeruginosa isolates. Importantly, when infecting PAO1 in vitro with 20 different phages, 8 influenced antimicrobial susceptibility. This study shows that P. aeruginosa isolated from CF and BR patients harbors diverse communities of inducible phages, with hierarchical infectivity profiles that relate to the progression of the disease. Temperate phage infection altered the antimicrobial susceptibility of PAO1 at subinhibitory concentrations of antibiotics, suggesting they may be precursory to antimicrobial resistance.IMPORTANCE Pseudomonas aeruginosa is a key opportunistic respiratory pathogen in patients with cystic fibrosis and non-cystic fibrosis bronchiectasis. The genomes of these pathogens are enriched with mobile genetic elements including diverse temperate phages. While the temperate phages of the Liverpool epidemic strain have been shown to be active in the human lung and enhance fitness in a rat lung infection model, little is known about their mobilization more broadly across P. aeruginosa in chronic respiratory infection. Using a novel metagenomic approach, we identified eight groups of temperate phages that were mobilized from 94 clinical P. aeruginosa isolates. Temperate phages from P. aeruginosa isolated from more advanced disease showed high infectivity rates across a wide range of P. aeruginosa genotypes. Furthermore, we showed that multiple phages altered the susceptibility of PAO1 to antibiotics at subinhibitory concentrations.

PMID: 31164451 [PubMed]

Identifying the molecular target sites for CFTR potentiators GLPG1837 and VX-770.

J Gen Physiol. 2019 Jun 04;:

Authors: Yeh HI, Qiu L, Sohma Y, Conrath K, Zou X, Hwang TC

Abstract
The past two decades have witnessed major breakthroughs in developing compounds that target the chloride channel CFTR for the treatment of patients with cystic fibrosis. However, further improvement in affinity and efficacy for these CFTR modulators will require insights into the molecular interactions between CFTR modulators and their binding targets. In this study, we use in silico molecular docking to identify potential binding sites for GLPG1837, a CFTR potentiator that may share a common mechanism and binding site with VX-770, the FDA-approved drug for patients carrying mutations with gating defects. Among the five binding sites predicted by docking, the two top-scoring sites are located at the interface between CFTR's two transmembrane domains: site I consists of D924, N1138, and S1141, and site IIN includes F229, F236, Y304, F312, and F931. Using mutagenesis to probe the importance of these sites for GLPG187 binding, we find that disruption of predicted hydrogen-bonding interactions by mutation of D924 decreases apparent affinity, while hydrophobic amino acids substitutions at N1138 and introduction of positively charged amino acids at S1141 improve the apparent affinity for GLPG1837. Alanine substitutions at Y304, F312, and F931 (site IIN) decrease the affinity for GLPG1837, whereas alanine substitutions at F229 and F236 (also site IIN), or at residues in the other three lower-scoring sites, have little effect. In addition, current relaxation analysis to assess the apparent dissociation rate of VX-770 yields results consistent with the dose-response experiments for GLPG8137, with the dissociation rate of VX-770 accelerated by D924N, F236A, Y304A, and F312A, but decelerated by N1138L and S1141K mutations. Collectively, these data identify two potential binding sites for GLPG1837 and VX-770 in CFTR. We discuss the pros and cons of evidence for these two loci and the implications for future drug design.

PMID: 31164398 [PubMed - as supplied by publisher]

Atypical presentation of cystic fibrosis at 70 years of age.

BMJ Case Rep. 2019 Jun 03;12(6):

Authors: Saleem MA, Phillips A, Ganaie MB

Abstract
Cystic fibrosis (CF) is an autosomal recessive condition, mostly diagnosed in infancy. It is uncommon for adults to be diagnosed with CF, especially after the age of 65. Individuals, who are diagnosed later in life, usually have milder disease and single organ involvement which can be challenging for clinicians to diagnose. Adult CF patients are more likely to be pancreatic sufficient. They have predominantly upper lobe bronchiectasis, lower incidence of Pseudomonas aeruginosa compared with Staphylococcus aureus and are more likely to have mutations other than ΔF508.

PMID: 31164380 [PubMed - in process]

Influence of frequency and amplitude on the mucus viscoelasticity of the novel mechano-acoustic Frequencer™.

Respir Med. 2019 May 27;153:52-59

Authors: Schieppati D, Germon R, Galli F, Rigamonti MG, Stucchi M, Boffito DC

Abstract
BACKGROUND: Cystic fibrosis affects 1/3200 Caucasians. This genetic disease disturbs the ion and water homeostasis across epithelia, thus rendering mucus more viscous and harder to expel. Conventional treatments rely on the clapping method coupled with postural drainage. Despite the effectiveness of these procedures, they are invasive and enervating.
METHODS: Here we study a new mechano-acoustic treatment device to help patients expectorate excess mucus, the Frequencer™. We test both normal and pathological synthetic mucin solutions (1 % and 4 % by weight) in vitro. We varied the frequency applied (from 20 Hz to 60 Hz) as well as the amplitude (from 50 % to 100 % intensity). Moreover, we assessed the effect of NaCl on mucus rehydration.
RESULTS: A frequency of 40 Hz coupled with a 0.5 gL-1NaCl solution provokes partial mucus rehydration, regardless of the amplitude selected, as the work of adhesion measurements evidenced.
CONCLUSIONS: Mechanical solicitation is fundamental to help patients affected by cystic fibrosis expectorate mucus. With an operating frequency of 20 Hz to 65 Hz, the Frequencer™ provides a gentler therapy than traditional methods (conventional chest physiotherapy). The Frequencer™ proved to be effective in the homogenization of synthetic mucin solutions in vitro in 20 min and elicited improved effectiveness in a mucin-rich environment.

PMID: 31163350 [PubMed - as supplied by publisher]

Clinical predictors of cystic fibrosis chronic rhinosinusitis severity.

Int Forum Allergy Rhinol. 2019 Jun 04;:

Authors: Zemke AC, Nouraie SM, Moore J, Gaston JR, Rowan NR, Pilewski JM, Bomberger JM, Lee SE

Abstract
BACKGROUND: Chronic rhinosinusitis (CRS) is a significant manifestation of cystic fibrosis (CF) with wide-ranging symptom and disease severity. The goal of the study was to determine clinical variables that correlate with outcome measures of disease severity.
METHODS: A prospective, longitudinal, observational study of 33 adults with symptomatic CRS treated in a CF-focused otolaryngology clinic was performed. Symptom severity, the presence of rhinosinusitis exacerbations, and endoscopic appearance were assessed, and regression analysis was used to determine clinical predictors of disease outcome.
RESULTS: Thirty-three adults with CF-CRS were included in the study and followed for a mean of 15 months. Rhinosinusitis exacerbations occurred in 61% of participants during the study, and female sex increased the odds of presenting with an exacerbation visit. Sinus disease exacerbations were associated with an odds ratio of 2.07 for presenting with a pulmonary exacerbation at the next visit. CF-related diabetes was found to be associated with worse symptoms and endoscopic appearance. Infection with Staphylococcus aureus predicted worsening of symptoms, whereas infections with Pseudomonas aeruginosa improved over time. Allergic rhinitis was associated with worse endoscopic appearance, and nasal steroid use was associated with improved endoscopic appearance.
CONCLUSION: Sex, CF-related diabetes, sinonasal infection status, allergic rhinitis, and nasal steroid use may all modulate severity of CF-CRS in adults. Sinusitis exacerbation may be a precursor to pulmonary exacerbation.

PMID: 31162888 [PubMed - as supplied by publisher]

Look at the wood and not at the tree: The Microbiome in Chronic Osxtructive Lung Disease and Cystic Fibrosis.

Arch Bronconeumol. 2019 May 31;:

Authors: Monsó E

PMID: 31160069 [PubMed - as supplied by publisher]

Outcomes of Lung Transplantation for Cystic Fibrosis in the Setting of Extensively Drug-Resistant Organisms.

Prog Transplant. 2019 Jun 03;:1526924819853830

Authors: Winstead RJ, Waldman G, Autry EB, Evans RA, Schadler A, Kays L, Baz M, Anstead MI, Shafii A, Goetz ME

Abstract
INTRODUCTION: Since the largest study on extensively drug-resistant organisms and lung transplantation in patients with cystic fibrosis, there have been innovations and advancements in the treatment of Pseudomonas aeruginosa.
RESEARCH QUESTION: What differences exist for patients with cystic fibrosis with a history of extensively drug-resistant infections who undergo lung transplantation despite treatment advances with antimicrobial therapy?
STUDY DESIGN: Two-center, retrospective, cohort study conducted in 44 patients with cystic fibrosis chronically infected with extensively drug-resistant organisms who received a lung transplant from January 2008 through August 2016. Patients in the resistant cohort were chronically infected with pan-resistant P aeruginosa, polymyxin-sensitive only, or sensitive to 2 antibiotic classes (polymyxin plus one other); remaining patients with more susceptible P aeruginosa or no P aeruginosa remained in the control cohort. The primary outcome is a composite of patient survival, retransplantation, chronic lung allograft dysfunction, and acute rejection 12 months posttransplant. Categorical variables were analyzed using χ2 testing. The independent samples t test was utilized for continuous variables.
RESULTS: There was no difference in the primary outcome (40% vs 37%, P = .831). Differences between patient survival (84% vs 95%, P = .487), the incidence of acute rejection (20% vs 33%, P = .323), and the incidence of chronic lung allograft rejection (12% vs 5%, P = .441) were not different between groups.
DISCUSSION: Recipients chronically infected with an extensively resistant P aeruginosa had similar outcomes compared to those infected with more sensitive organisms.

PMID: 31159656 [PubMed - as supplied by publisher]

Phenotypic Stability of Staphylococcus Aureus Small Colony Variants (SCV) Isolates from Cystic Fibrosis (CF) Patients.

Int J Environ Res Public Health. 2019 May 31;16(11):

Authors: Kittinger C, Toplitsch D, Folli B, Masoud Landgraf L, Zarfel G

Abstract
One of the most interesting features of Staphylococcus aureus is its ability to switch to a small colony variant (SCV). This switch allows the pathogen to survive periods of antibiotic treatment or pressure from the immune system of the host and further enables it to start the infection once again after the environmental stress declines. However, so far only little is known about this reversion back to the more virulent wild type phenotype. Therefore, this study aimed to analyze the frequency of reversion to the wild type phenotype of thymidine auxotroph S. aureus SCV isolates (TD-SCVs) obtained from patients with cystic fibrosis (CF). With the use of single cell starting cultures, the occurrence of the thymidine prototroph revertants was monitored. The underlying mutational cause of the SCVs and subsequent revertants were analyzed by sequencing the gene coding for thymidylate synthase (ThyA), whose mutations are known to produce thymidine auxotroph S. aureus SCV. In our study, the underlying mutational cause for the switch to the TD-SCV phenotype was primarily point mutations. Out of twelve isolates, seven isolates showed an occurrence of revertants with a frequency ranging from 90.06% to 0.16%. This high variability in the frequency of reversion to the wild type was not expected. However, this variability in the frequency of reversion may also be the key to successful re-infection of the host. Sometimes quick reversion to the wild type proves necessary for survival, whereas other times, staying hidden for a bit longer leads to success in re-colonization of the host.

PMID: 31159295 [PubMed - in process]

Colistin methanesulfonate infusion solutions are stable over time and suitable for home administration.

Eur J Hosp Pharm Sci Pract. 2018 Nov;25(6):337-339

Authors: Post TE, Kamerling IMC, van Rossen RCJM, Burggraaf J, Stevens J, Dijkmans AC, Heijerman HGM, Touw DJ, van Velzen AJ, Wilms EB

Abstract
The stability of colistin methanesulfonate (CMS) was determined in quadruplicate in elastomeric home infusion pumps containing 1, 2 or 3 MU CMS and in infusion bags with 2 MU CMS all in 100 mL normal saline. Infusions were stored at room temperature (20°C-24°C) with or without exposure to natural light or refrigerated (4°C-8°C) and protected from light up to 2 weeks. In the initial solution of 2 MU CMS in 100 mL saline sampled immediately after reconstitution and dilution, 1.5% of CMS was hydrolysed to colistin. When stored at room temperature and exposed to natural light, colistin concentration in elastomeric infusion pumps increased to 2.6% in 8 days and to 2.1% when stored at 4°C. CMS stability increases at lower temperatures and higher concentrations. Based on the current data, chemical stability of CMS infusion solution is sufficient for a shelf life of 7 days refrigerated plus 1 day at room temperature.

PMID: 31157054 [PubMed]

Evolution of sinonasal clinical features in children with cystic fibrosis.

Int J Pediatr Otorhinolaryngol. 2019 May 25;124:47-53

Authors: Suy P, Coudert A, Vrielynck S, Truy E, Hermann R, Ayari-Khalfallah S

Abstract
OBJECTIVE: to assess the evolution of sinonasal manifestations in children with cystic fibrosis, since the improvement of their prognosis over the last decades.
METHODS: an observational, monocentric study with a retrospective cohort. We included 173 children (from 4 to 18 years old) with cystic fibrosis followed at the pediatric cystic fibrosis center of lyon, france. We collected respiratory, infectious and nutritional data, sinonasal complaints and physical examination at the onset of sinonasal symptoms (t-0), at the most severe of evolution (t-max) and at the end of followup (t-end).
RESULTS: sinonasal symptomatology appeared early around 5.4 years old, then rapidly reached the maximum at 6.9 years and finally improved during childhood (p < 0.0001), reaching scores at t-end significantly better than at t-0 (p < 0.0001). This evolution was significant for nasal obstruction, rhinorrhea and snoring. The other symptoms were rarer, with no significant 38,7% at t-max (p < 0.0001), and 29,5% at t-end (p = 0.52). The lildholdt score, turbinate hypertrophy and medial bulging of medial wall of the maxillary sinus followed the same evolution (p < 0.003). There was no association between sinonasal evolution and cystic fibrosis disease at infectious, respiratory or nutritional level.
CONCLUSION: it is the only recent study evaluating the evolution of each sinonasal manifestations in children with cystic fibrosis. Rhinosinusitis improved during childhood, reaching better scores than at the beginning of management. This particular improvement may be related to good effectiveness to ent management, but also to a positive effect of nasal cavity growth, independently to extra-ent manifestations.

PMID: 31158571 [PubMed - as supplied by publisher]

The anti-sigma factor MucA of Pseudomonas aeruginosa: Dramatic differences of a mucA22 vs. a ΔmucA mutant in anaerobic acidified nitrite sensitivity of planktonic and biofilm bacteria in vitro and during chronic murine lung infection.

PLoS One. 2019;14(6):e0216401

Authors: Panmanee W, Su S, Schurr MJ, Lau GW, Zhu X, Ren Z, McDaniel CT, Lu LJ, Ohman DE, Muruve DA, Panos RJ, Yu HD, Thompson TB, Tseng BS, Hassett DJ

Abstract
Mucoid mucA22 Pseudomonas aeruginosa (PA) is an opportunistic lung pathogen of cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) patients that is highly sensitive to acidified nitrite (A-NO2-). In this study, we first screened PA mutant strains for sensitivity or resistance to 20 mM A-NO2- under anaerobic conditions that represent the chronic stages of the aforementioned diseases. Mutants found to be sensitive to A-NO2- included PA0964 (pmpR, PQS biosynthesis), PA4455 (probable ABC transporter permease), katA (major catalase, KatA) and rhlR (quorum sensing regulator). In contrast, mutants lacking PA0450 (a putative phosphate transporter) and PA1505 (moaA2) were A-NO2- resistant. However, we were puzzled when we discovered that mucA22 mutant bacteria, a frequently isolated mucA allele in CF and to a lesser extent COPD, were more sensitive to A-NO2- than a truncated ΔmucA deletion (Δ157-194) mutant in planktonic and biofilm culture, as well as during a chronic murine lung infection. Subsequent transcriptional profiling of anaerobic, A-NO2--treated bacteria revealed restoration of near wild-type transcript levels of protective NO2- and nitric oxide (NO) reductase (nirS and norCB, respectively) in the ΔmucA mutant in contrast to extremely low levels in the A-NO2--sensitive mucA22 mutant. Proteins that were S-nitrosylated by NO derived from A-NO2- reduction in the sensitive mucA22 strain were those involved in anaerobic respiration (NirQ, NirS), pyruvate fermentation (UspK), global gene regulation (Vfr), the TCA cycle (succinate dehydrogenase, SdhB) and several double mutants were even more sensitive to A-NO2-. Bioinformatic-based data point to future studies designed to elucidate potential cellular binding partners for MucA and MucA22. Given that A-NO2- is a potentially viable treatment strategy to combat PA and other infections, this study offers novel developments as to how clinicians might better treat problematic PA infections in COPD and CF airway diseases.

PMID: 31158231 [PubMed - in process]

Past, Present, and Future Research on the Lung Microbiome in Inflammatory Airway Disease.

Chest. 2019 May 30;:

Authors: Caverly LJ, Huang YJ, Sze MA

Abstract
Chronic obstructive pulmonary disease (COPD), asthma, and cystic fibrosis (CF) are obstructive lung diseases with distinct pathophysiologies and clinical phenotypes. In this review article we highlight recent advances in our understanding of relationships between clinical phenotypes, host inflammatory response, and lung microbiota in these diseases. Although COPD, asthma, and CF largely have distinct lung microbiota and inflammatory profiles, certain commonalities exist. In all three of these lung diseases, and in healthy persons, anaerobic taxa that are typically associated with oral microbiota (e.g. Prevotella and Veillonella) are present in the airways and associated with increased host inflammatory response. Similarly, across all three diseases, members of the Proteobacteria phylum are associated with more advanced disease. Finally, we highlight challenges in translating these findings into advances in clinical care, including continued knowledge gaps regarding the causal relationships between host inflammatory response, lung microbiota, medication effects, and clinical phenotypes.

PMID: 31154042 [PubMed - as supplied by publisher]

Microbiological evaluation of UV disinfection effectiveness in a specialist cystic fibrosis clinic.

J Cyst Fibros. 2019 May 29;:

Authors: Allen O, Haworth CS, Jadkauskaite L, Shafi NT, Jackson A, Athithan V, Chiu YD, Ies E, Floto RA

Abstract
The aim of the study was to evaluate the impact of manual cleaning and manual cleaning followed by Ultraviolet-C disinfection on the colony forming units of bacteria retrievable from equipment and surfaces within clinic rooms following a CF outpatient encounter. While UV disinfection has proven to be effective within general healthcare settings, it has not been evaluated in a CF centre. Microbiological sampling was performed following outpatient encounters involving 11 adult patients with CF and chronic infection with P.aeruginosa, MRSA or E. coli ESBL. The results of this study suggest that manual cleaning followed by UV-C disinfection is more effective than manual cleaning alone at reducing environmental contamination within a CF clinic and that UV-C isinfection is likely to reduce the risk of fomite transmission in the CF outpatient setting.

PMID: 31153817 [PubMed - as supplied by publisher]

Detecting respiratory infection in children with cystic fibrosis: Cough swab, sputum induction or bronchoalveolar lavage.

Paediatr Respir Rev. 2019 Mar 13;:

Authors: Forton JT

Abstract
Young children with cystic fibrosis (CF) are generally very well, cough free and non-productive, and are often incapable of spontaneously expectorating sputum even if actively coughing during an exacerbation. Obtaining a meaningful airway sample for microbiological analysis is therefore problematic, yet essential if lower airway infection is to be detected and adequately treated. Recently there has been increasing interest in the use of sputum-induction in young children with CF, as a simple, cost effective, well tolerated and frequently repeatable approach to sampling the lower airway, and the relative merits of this approach to bacterial sampling are discussed. Culture-independent microbiology has increased our understanding of the respiratory microbiota and has challenged the current paradigm of "single pathogen causes disease". Understanding how to diagnose infection using these new, highly sensitive technologies will be important. How we should best intervene to optimise, manipulate and prevent disruption of the respiratory microbiota is likely to greatly influence how we manage infection in the future.

PMID: 31153794 [PubMed - as supplied by publisher]