Cystic Fibrosis Survival Gap Closing Between US and Canada: Don't Leave Anyone Behind!

Am J Respir Crit Care Med. 2017 Nov 28;:

Authors: Schultz A, Sly PD

PMID: 29182890 [PubMed - as supplied by publisher]

Improved Lung Function after Sinus Surgery in Cystic Fibrosis Patients with Moderate Obstruction.

Otolaryngol Head Neck Surg. 2017 Nov 01;:194599817739284

Authors: Khalfoun S, Tumin D, Ghossein M, Lind M, Hayes D, Kirkby AS

Abstract
Objectives Cystic fibrosis (CF) is characterized by infection and inflammation of the sinorespiratory tract. Functional endoscopic sinus surgery (FESS) is an option for patients with severe sinusitis. We sought to evaluate pulmonary function testing after FESS in pediatric and adult patients with CF. Study Design Retrospective chart review using data from all patients with CF who underwent FESS from January 2009 to July 2014. Setting Patients were from a single institution. Subjects and Methods Data were extracted for 181 patients and 320 surgeries. Lung function data, including the forced expiratory volume in one second (FEV1), forced vital capacity (FVC), and FEV1/FVC, were retrieved within 1 year before and after surgery. Mixed-effects regression was used to compare FEV1 trajectories before and after surgery. The effect of surgery was stratified by presurgery FEV1 to compare patients with mild/no lung disease (FEV1 >80%) and moderate/severe lung disease (FEV1 <80%). Results Of the 181 patients reviewed, 131 with primary FESS had FEV1 data. Presurgery average age was 16 years (95% confidence interval [CI], 14.27-17.73), and FEV1 mean was 85% (95% CI, 81.02-88.98). There were 88 patients with FEV1 >80% and 43 patients with FEV1 <80%. For the entire cohort, lung function did not change related to FESS. Among patients with FEV1 <80%, FEV1 declined presurgery by 3.5% per year (95% CI, -6.1% to -0.8%; P = .010), which halted after surgery with these patients, then showing no subsequent change in FEV1 (95% CI, 0.9%-3.7%; P = .240). No benefit was identified for patients with FEV1 >80%. Conclusion Pulmonary function testing improved in patients with moderate/severe lung disease 1 year following FESS. This suggests FESS may benefit pulmonary outcomes.

PMID: 29182491 [PubMed - as supplied by publisher]

The role of basal cells in producing persistent lentivirus-mediated airway gene expression.

Hum Gene Ther. 2017 Nov 27;:

Authors: Farrow NR, Donnelley M, Cmielewski P, Roscioli E, Rout-Pitt N, McIntyre C, Bertoncello I, Parsons D

Abstract
RATIONALE: Cystic Fibrosis (CF) lung disease is an ideal candidate for a genetic therapy. We have previously shown that pre-conditioning with lysophosphatidylcholine (LPC) prior to lentiviral (LV) vector delivery results in long-term in vivo gene expression in the airway epithelium of CF mice. We hypothesise that this outcome is largely due to transduction of airway basal cells that in turn pass the transgene onto their progeny.
OBJECTIVES: The aim of these studies was to confirm if the in vivo delivery of a HIV-1 VSV-G pseudotyped LV vector following LPC airway conditioning results in transduction of mouse airway basal cells in situ and if the transgene is passed onto their progeny. Additionally, we sought to determine the efficiency of in vitro transduction of human airway basal cells.
METHODS AND MAIN RESULTS: Firstly, normal mouse nasal airways were pre-treated with LPC prior to delivery of a HIV-1 VSV-G pseudotyped LV vector carrying a LacZ marker gene. An epithelial ablation model utilising polidocanol was then used to demonstrate that clonal outgrowth of linear and spotted clusters of transgene expressing ciliated, basal, and goblet cells occurs following transduction of basal cells. Secondly, human basal cells were cultured from primary bronchial epithelial cells, with identity confirmed by Keratin 5 staining. High levels of transgene expression were found following LV-LacZ transduction.
CONCLUSIONS: This study demonstrates the ability of our vector delivery protocol to transduce mouse airway basal cells, the LV vector to transduce human basal cells, and the likely role of these cells in maintaining long-term gene expression. These findings support and further develop the potential of LV gene transfer for persistent correction of CF airway disease.

PMID: 29179571 [PubMed - as supplied by publisher]

Rare cause for hemoptysis in an adolescent: Bronchial capillary hemangioma.

Pediatr Pulmonol. 2017 Jul;52(7):E40-E42

Authors: Hämmerling S, Becker S, Mall MA

Abstract
Hemoptysis is rare in children and adolescents. We describe an 11-year-old girl who presented with hemoptysis, cough, and exertional dyspnea. Radiologic and bronchoscopic assessment revealed a pedunculated mass in the right main stem bronchus with a ball valve effect. Carcinoid or hemangioma was suspected as cause of the mass. The tumor could be excised bronchoscopically, and histologic examination showed a capillary hemangioma. In the literature, bronchial hemangiomas are described in infants and adults. This case demonstrates that bronchial hemangioma should also be taken into consideration as a cause of hemoptysis in adolescents.

PMID: 28165678 [PubMed - indexed for MEDLINE]

Cilia and Mucociliary Clearance.

Cold Spring Harb Perspect Biol. 2017 Apr 03;9(4):

Authors: Bustamante-Marin XM, Ostrowski LE

Abstract
Mucociliary clearance (MCC) is the primary innate defense mechanism of the lung. The functional components are the protective mucous layer, the airway surface liquid layer, and the cilia on the surface of ciliated cells. The cilia are specialized organelles that beat in metachronal waves to propel pathogens and inhaled particles trapped in the mucous layer out of the airways. In health this clearance mechanism is effective, but in patients with primary cilia dyskinesia (PCD) the cilia are abnormal, resulting in deficient MCC and chronic lung disease. This demonstrates the critical importance of the cilia for human health. In this review, we summarize the current knowledge of the components of the MCC apparatus, focusing on the role of cilia in MCC.

PMID: 27864314 [PubMed - indexed for MEDLINE]

In vitro tests for drug hypersensitivity reactions: an ENDA/EAACI Drug Allergy Interest Group position paper.

Allergy. 2016 Aug;71(8):1103-34

Authors: Mayorga C, Celik G, Rouzaire P, Whitaker P, Bonadonna P, Rodrigues-Cernadas J, Vultaggio A, Brockow K, Caubet JC, Makowska J, Nakonechna A, Romano A, Montañez MI, Laguna JJ, Zanoni G, Gueant JL, Oude Elberink H, Fernandez J, Viel S, Demoly P, Torres MJ, In vitro tests for Drug Allergy Task Force of EAACI Drug Interest Group

Abstract
Drug hypersensitivity reactions (DHRs) are a matter of great concern, both for outpatient and in hospital care. The evaluation of these patients is complex, because in vivo tests have a suboptimal sensitivity and can be time-consuming, expensive and potentially risky, especially drug provocation tests. There are several currently available in vitro methods that can be classified into two main groups: those that help to characterize the active phase of the reaction and those that help to identify the culprit drug. The utility of these in vitro methods depends on the mechanisms involved, meaning that they cannot be used for the evaluation of all types of DHRs. Moreover, their effectiveness has not been defined by a consensus agreement between experts in the field. Thus, the European Network on Drug Allergy and Drug Allergy Interest Group of the European Academy of Allergy and Clinical Immunology has organized a task force to provide data and recommendations regarding the available in vitro methods for DHR diagnosis. We have found that although there are many in vitro tests, few of them can be given a recommendation of grade B or above mainly because there is a lack of well-controlled studies, most information comes from small studies with few subjects and results are not always confirmed in later studies. Therefore, it is necessary to validate the currently available in vitro tests in a large series of well-characterized patients with DHR and to develop new tests for diagnosis.

PMID: 26991315 [PubMed - indexed for MEDLINE]

Naringenin Regulates CFTR Activation and Expression in Airway Epithelial Cells.

Cell Physiol Biochem. 2017 Nov 27;44(3):1146-1160

Authors: Shi R, Xiao ZT, Zheng YJ, Zhang YL, Xu JW, Huang JH, Zhou WL, Li PB, Su WW

Abstract
BACKGROUND/AIMS: Sputum symptoms are commonly seen in the elderly. This study aimed to identify an efficacious expectorant treatment stratagem through evaluating the secretion-promoting activation and cystic fibrosis transmembrane conductance regulator (CFTR) expression of the bioactive herbal monomer naringenin.
METHODS: Vectorial Cl- transport was determined by measuring short-circuit current (ISC) in rat airway epithelium. cAMP content was measured by ELISA in primary cultured epithelial cells and Calu-3 cells. CFTR expression in Calu-3 cells was determined by qPCR.
RESULTS: Addition of naringenin to the basolateral side of the rat airway led to a concentration-dependent sustained increase in ISC. The current was suppressed when exposed to Cl--free solution or by bumetanide, BaCl2, and DPC but not by DIDS and IBMX. Forskolin-induced ISC increase and CFTRinh-172/MDL-12330A-induced ISC inhibition were not altered by naringenin. Intracellular cAMP content was significantly increased by naringenin. With lipopolysaccharide stimulation, CFTR expression was significantly reduced, and naringenin dose-dependently enhanced CFTR mRNA expression.
CONCLUSION: These results demonstrate that naringenin has the ability to stimulate Cl- secretion, which is mediated by CFTR through a signaling pathway by increasing cAMP content. Moreover, naringenin can increase CFTR expression when organism CFTR expression is seriously hampered. Our data suggest a potentially effective treatment strategy for sputum.

PMID: 29179179 [PubMed - as supplied by publisher]

Spectrum of CFTR gene mutations in Ecuadorian cystic fibrosis patients: the second report of the p.H609R mutation.

Mol Genet Genomic Med. 2017 Nov;5(6):751-757

Authors: Ortiz SC, Aguirre SJ, Flores S, Maldonado C, Mejía J, Salinas L

Abstract
BACKGROUND: High heterogeneity in the CFTR gene mutations disturbs the molecular diagnosis of cystic fibrosis (CF). In order to improve the diagnosis of CF in our country, the present study aims to define a panel of common CFTR gene mutations by sequencing 27 exons of the gene in Ecuadorian Cystic Fibrosis patients.
METHODS: Forty-eight Ecuadorian individuals with suspected/confirmed CF diagnosis were included. Twenty-seven exons of CFTR gene were sequenced to find sequence variations. Prevalence of pathogenic variations were determined and compared with other countries' data.
RESULTS: We found 70 sequence variations. Eight of these are CF-causing mutations: p.F508del, p.G85E, p.G330E, p.A455E, p.G970S, W1098X, R1162X, and N1303K. Also this study is the second report of p.H609R in Ecuadorian population. Mutation prevalence differences between Ecuadorian population and other Latin America countries were found.
CONCLUSION: The panel of mutations suggested as an initial screening for the Ecuadorian population with cystic fibrosis should contain the mutations: p.F508del, p.G85E, p.G330E, p.A455E, p.G970S, W1098X, R1162X, and N1303K.

PMID: 29178639 [PubMed - in process]

Quorum Sensing Down-Regulation Counteracts the Negative Impact of Pseudomonas aeruginosa on CFTR Channel Expression, Function and Rescue in Human Airway Epithelial Cells.

Front Cell Infect Microbiol. 2017;7:470

Authors: Maillé É, Ruffin M, Adam D, Messaoud H, Lafayette SL, McKay G, Nguyen D, Brochiero E

Abstract
The function of cystic fibrosis transmembrane conductance regulator (CFTR) channels is crucial in human airways. However unfortunately, chronic Pseudomonas aeruginosa infection has been shown to impair CFTR proteins in non-CF airway epithelial cells (AEC) and to alter the efficiency of new treatments with CFTR modulators designed to correct the basic CFTR default in AEC from cystic fibrosis (CF) patients carrying the F508del mutation. Our aim was first to compare the effect of laboratory strains, clinical isolates, engineered and natural mutants to determine the role of the LasR quorum sensing system in CFTR impairment, and second, to test the efficiency of a quorum sensing inhibitor to counteract the deleterious impact of P. aeruginosa both on wt-CFTR and on the rescue of F508del-CFTR by correctors. We first report that exoproducts from either the laboratory PAO1 strain or a clinical ≪Early≫ isolate (from an early stage of infection) altered CFTR expression, localization and function in AEC expressing wt-CFTR. Genetic inactivation of the quorum-sensing LasR in PAO1 (PAO1ΔlasR) or in a natural clinical mutant (≪Late≫ CF-adapted clinical isolate) abolished wt-CFTR impairment. PAO1 exoproducts also dampened F508del-CFTR rescue by VRT-325 or Vx-809 correctors in CF cells, whereas PAO1ΔlasR had no impact. Importantly, treatment of P. aeruginosa cultures with a quorum sensing inhibitor (HDMF) prevented the negative effect of P. aeruginosa exoproducts on wt-CFTR and preserved CFTR rescue by correctors in CF AEC. These findings indicate that LasR-interfering strategies could be of benefits to counteract the deleterious effect of P. aeruginosa in infected patients.

PMID: 29177135 [PubMed - in process]

Supine posture changes lung volumes and increases ventilation heterogeneity in cystic fibrosis.

PLoS One. 2017;12(11):e0188275

Authors: Smith LJ, Macleod KA, Collier GJ, Horn FC, Sheridan H, Aldag I, Taylor CJ, Cunningham S, Wild JM, Horsley A

Abstract
INTRODUCTION: Lung Clearance Index (LCI) is recognised as an early marker of cystic fibrosis (CF) lung disease. The effect of posture on LCI however is important when considering longitudinal measurements from infancy and when comparing LCI to imaging studies.
METHODS: 35 children with CF and 28 healthy controls (HC) were assessed. Multiple breath washout (MBW) was performed both sitting and supine in triplicate and analysed for LCI, Scond, Sacin, and lung volumes. These values were also corrected for the Fowler dead-space to create 'alveolar' indices.
RESULTS: From sitting to supine there was a significant increase in LCI and a significant decrease in FRC for both CF and HC (p<0.01). LCI, when adjusted to estimate 'alveolar' LCI (LCIalv), increased the magnitude of change with posture for both LCIalv and FRCalv in both groups, with a greater effect of change in lung volume in HC compared with children with CF. The % change in LCIalv for all subjects correlated significantly with lung volume % changes, most notably tidal volume/functional residual capacity (Vtalv/FRCalv (r = 0.54,p<0.001)).
CONCLUSION: There is a significant increase in LCI from sitting to supine, which we believe to be in part due to changes in lung volume and also increasing ventilation heterogeneity related to posture. This may have implications in longitudinal measurements from infancy to older childhood and for studies comparing supine imaging methods to LCI.

PMID: 29176899 [PubMed - in process]

Pseudomonas aeruginosa exoproducts determine antibiotic efficacy against Staphylococcus aureus.

PLoS Biol. 2017 Nov 27;15(11):e2003981

Authors: Radlinski L, Rowe SE, Kartchner LB, Maile R, Cairns BA, Vitko NP, Gode CJ, Lachiewicz AM, Wolfgang MC, Conlon BP

Abstract
Chronic coinfections of Staphylococcus aureus and Pseudomonas aeruginosa frequently fail to respond to antibiotic treatment, leading to significant patient morbidity and mortality. Currently, the impact of interspecies interaction on S. aureus antibiotic susceptibility remains poorly understood. In this study, we utilize a panel of P. aeruginosa burn wound and cystic fibrosis (CF) lung isolates to demonstrate that P. aeruginosa alters S. aureus susceptibility to bactericidal antibiotics in a variable, strain-dependent manner and further identify 3 independent interactions responsible for antagonizing or potentiating antibiotic activity against S. aureus. We find that P. aeruginosa LasA endopeptidase potentiates lysis of S. aureus by vancomycin, rhamnolipids facilitate proton-motive force-independent tobramycin uptake, and 2-heptyl-4-hydroxyquinoline N-oxide (HQNO) induces multidrug tolerance in S. aureus through respiratory inhibition and reduction of cellular ATP. We find that the production of each of these factors varies between clinical isolates and corresponds to the capacity of each isolate to alter S. aureus antibiotic susceptibility. Furthermore, we demonstrate that vancomycin treatment of a S. aureus mouse burn infection is potentiated by the presence of a LasA-producing P. aeruginosa population. These findings demonstrate that antibiotic susceptibility is complex and dependent not only upon the genotype of the pathogen being targeted, but also on interactions with other microorganisms in the infection environment. Consideration of these interactions will improve the treatment of polymicrobial infections.

PMID: 29176757 [PubMed - as supplied by publisher]

Chemoattractants and cytokines in primary ciliary dyskinesia and cystic fibrosis: key players in chronic respiratory diseases.

Cell Mol Immunol. 2017 Nov 27;:

Authors: Cockx M, Gouwy M, Van Damme J, Struyf S

Abstract
Patients with primary ciliary dyskinesia (PCD) and cystic fibrosis (CF), two inherited disorders, suffer from recurrent airway infections characterized by persistent bacterial colonization and uncontrollable inflammation. Although present in high counts, neutrophils fail to clear infection in the airways. High levels of C-X-C motif chemokine ligand 8/interleukin-8 (CXCL8/IL-8), the most potent chemokine to attract neutrophils to sites of infection, are detected in the sputum of both patient groups and might cause the high neutrophil influx in the airways. Furthermore, in CF, airway neutrophils are highly activated because of the genetic defect and the high levels of proinflammatory chemoattractants and cytokines (e.g., CXCL8/IL-8, tumor necrosis factor-α and IL-17). The overactive state of neutrophils leads to lung damage and fuels the vicious circle of infection, excessive inflammation and tissue damage. The inflammatory process in CF airways is well characterized, whereas the lung pathology in PCD is far less studied. The knowledge of CF lung pathology could be useful to guide molecular investigations of the inflammatory processes in PCD lungs. Current available therapies can not completely remedy the chronic airway infections in these diseases. This review gives an overview of the role that chemoattractants and cytokines play in these neutrophil-dominated lung pathologies. Finally, the most frequently applied treatments in CF and PCD and new experimental therapies to reduce neutrophil-dominated airway inflammation are described.Cellular and Molecular Immunology advance online publication, 27 November 2017; doi:10.1038/cmi.2017.118.

PMID: 29176750 [PubMed - as supplied by publisher]

Pancreatic Enzyme Replacement Therapy use in infants with Cystic Fibrosis Diagnosed by Newborn Screening.

J Pediatr Gastroenterol Nutr. 2017 Nov 15;:

Authors: Gelfond D, Heltshe SL, Skalland M, Heubi JE, Kloster M, Leung DH, Ramsey BW, Borowitz D, BONUS Study Investigators

Abstract
OBJECTIVES: To describe pancreatic enzyme practices during the first year of life in infants with cystic fibrosis (CF) and evaluate associations between dosing and outcomes, including growth and gastrointestinal symptoms.
METHODS: We analyzed data from a subset of infants who were in a prospective cohort study conducted at 28 US CF centers. Anthropometric measurements and medications were recorded at each visit. Diaries with infant diet, pancreatic enzyme replacement therapy (PERT) dosing, stool frequency and consistency and pain were completed by a parent/guardian for three days prior to each visit.
RESULTS: 231 infants were enrolled in the main study; 205 of these met criteria for pancreatic insufficiency. PERT dose between birth and 6 months was on average 1882 LU/kg/meal (range: 492-3727) and was similar between 6 months and 12 months (mean: 1842 LU/kg/mean, range: 313-3612). PERT dose had a weak, negative association with weight z-score at 3 and 6 months (r = -0.16, 95% CI = -0.29, -0.02 and r = -0.18, 95% CI = -0.31, -0.04, respectively) but not at 12 months. There was not a clear relationship between PERT dosing and number of stools/day, stool consistency or pain. 144 infants (70%) were placed on acid suppression medication. Weight z-score mean was 0.37 higher in infants using proton pump inhibitors exclusively vs those using histamine-2 blockers exclusively (95% CI = -0.02, 0.76, p = 0.06).
CONCLUSIONS: We did not observe that centers with a higher PERT dosing strategy yielded greater clinical benefit than dosing at the lower end of the recommended range.

PMID: 29176494 [PubMed - as supplied by publisher]

rpoB gene sequencing highlights the prevalence of an E. miricola cluster over other Elizabethkingia species among UK cystic fibrosis patients.

Diagn Microbiol Infect Dis. 2017 Oct 26;:

Authors: Kenna DTD, Fuller A, Martin K, Perry C, Pike R, Burns PJ, Narayan O, Wilkinson S, Hill R, Woodford N, Logan JMJ, Turton JF

Abstract
Difficulties in distinguishing species of the Elizabethkingia genus by MALDI-TOF prompted use of rpoB sequencing to investigate species distribution among 44 isolates from cystic fibrosis (CF) patients. Forty-three isolates from 38 patients formed a cluster comprising E. miricola and proposed novel species E. bruuniana sp. nov., the exception clustering with proposed species E. ursingii sp. nov., also part of this wider cluster. All 44 isolates were PCR-positive for urease gene ureG, whereas only one of 23 E. anophelis isolates from non-CF patients was positive, suggesting that this gene is largely associated with the E. miricola cluster. Antibiotic susceptibilities of 12 CF isolates revealed all were resistant to beta-lactams with the exception of piperacillin-tazobactam, and were only susceptible to minocycline and co-trimoxazole. Pulsed-field gel electrophoresis analysis revealed 4 shared strains among 17 CF patients in one pediatric clinic, but epidemiological investigations did not support patient-to-patient transmission except between one sibling pair.

PMID: 29174734 [PubMed - as supplied by publisher]

Multiple reaction monitoring mass spectrometry to identify novel plasma protein biomarkers of treatment response in cystic fibrosis pulmonary exacerbations.

J Cyst Fibros. 2017 Nov 21;:

Authors: Roberts JM, Dai DLY, Hollander Z, Ng RT, Tebbutt SJ, Wilcox PG, Sin DD, Quon BS

Abstract
BACKGROUND: Systemic inflammation decreases with IV antibiotics during the treatment of CF pulmonary exacerbations (PEx). We used multiple reaction monitoring mass spectrometry and immunoassays to monitor blood proteins during PEx treatment to determine if early changes could be used to predict PEx outcomes following treatment.
METHODS: Blood samples from 25 PEx (22 unique adults) were collected within 24h of admission, day 5, day 10, and at IV antibiotic completion. Ninety-two blood proteins involved in host immunity and inflammation were measured.
RESULTS: Levels of several blood proteins changed from admission to end of IV antibiotics, most increasing with treatment. Early changes (admission to day 5) in fibrinogen levels had the strongest correlation with overall improvement in CFRSD-CRISS and FEV1% predicted by the end of treatment.
CONCLUSIONS: Several plasma proteins changed significantly with IV antibiotics. Future studies will evaluate fibrinogen as an early biomarker of PEx treatment response in CF.

PMID: 29174082 [PubMed - as supplied by publisher]

Guidelines for the clinical management and follow-up of infants with inconclusive cystic fibrosis diagnosis through newborn screening.

Arch Pediatr. 2017 Nov 21;:

Authors: Sermet-Gaudelus I, Brouard J, Audrézet MP, Couderc Kohen L, Weiss L, Wizla N, Vrielynck S, LLerena K, Le Bourgeois M, Deneuville E, Remus N, Nguyen-Khoa T, Raynal C, Roussey M, Girodon E

Abstract
Neonatal screening for cystic fibrosis (CF) can detect infants with elevated immunoreactive trypsinogen (IRT) levels and inconclusive sweat tests and/or CFTR DNA results. These cases of uncertain diagnosis are defined by (1) either the presence of at most one CF-associated cystic fibrosis transmembrane conductance regulator (CFTR) mutation with sweat chloride values between 30 and 59mmol/L or (2) two CFTR mutations with at least one of unknown pathogenic potential and a sweat chloride concentration below 60mmol/L. This encompasses various clinical situations whose progression cannot be predicted. In these cases, a sweat chloride test has to be repeated at 12 months, and if possible at 6 and 24 months of life along with extended CFTR sequencing to detect rare mutations. When the diagnosis is not definite, CFTR functional explorations may provide a better understanding of CFTR dysfunction. The initial evaluation of these infants must be conducted in dedicated CF reference centers and should include bacteriological sputum analysis, chest radiology, and fecal elastase assay. The primary care physicians in charge of these patients should be familiar with the current management of CF and should work in collaboration with CF centers. A follow-up should be performed in a CF reference center at 3, 6, and 12 months of life and every year thereafter. Any symptom indicative of CF requires immediate reevaluation of the diagnosis. These guidelines were established by the "neonatal screening and difficult diagnoses" working group of the French CF society. Their objective is to standardize the management of infants with unclear diagnosis.

PMID: 29174009 [PubMed - as supplied by publisher]

Omalizumab treatment for allergic bronchopulmonary aspergillosis in young patients with cystic fibrosis.

Respir Med. 2017 Dec;133:12-15

Authors: Perisson C, Destruys L, Grenet D, Bassinet L, Derelle J, Sermet-Gaudelus I, Thumerelle C, Prevotat A, Rosner V, Clement A, Corvol H

Abstract
BACKGROUND: Allergic bronchopulmonary aspergillosis (ABPA) is a severe lung disease complication caused by an Aspergillus fumigatus-induced hypersensitivity that affects 2-15% of patients with cystic fibrosis (CF). The mainstay treatment consists of a combination of corticosteroids and antifungals. However, repeated or long-term corticosteroid therapies can lead to serious side effects. The monoclonal anti-IgE antibody, omalizumab, has demonstrated its efficacy in allergic asthma. As ABPA results from a hypersensitivity to a specific allergen, omalizumab might benefit CF patients with ABPA. Therefore, we conducted a retrospective study to investigate the effects of omalizumab on ABPA in CF patients.
METHODS: We retrospectively analyzed the clinical records of young patients with CF treated with omalizumab for an ABPA in several French CF centers. The clinical data were collected 3 months before the start of omalizumab treatment, at initiation, and every 3 months up to 12 following initiation. These data comprised clinical, biological, nutritional, and functional parameters.
RESULTS: Eighteen patients were included (mean age: 17.1 ± 5.2 yrs). Under omalizumab was observed a stabilization of the lung function decline associated with a significant decrease in the corticosteroid daily dose (p = 0.0007) and an improvement in the nutritional status (p = 0.01). No serious side effect of omalizumab was reported.
CONCLUSIONS: This study suggests that omalizumab might be an interesting therapeutic strategy in ABPA, associated with less side effects compared to long-term corticosteroids. Further randomized-controlled trials are needed to ascertain the efficacy of omalizumab in CF patients with ABPA.

PMID: 29173443 [PubMed - in process]

Targeted Gene Next-Generation Sequencing in Chinese Children with Chronic Pancreatitis and Acute Recurrent Pancreatitis.

J Pediatr. 2017 Dec;191:158-163.e3

Authors: Xiao Y, Yuan W, Yu B, Guo Y, Xu X, Wang X, Yu Y, Yu Y, Gong B, Xu C

Abstract
OBJECTIVE: To identify causal mutations in certain genes in children with acute recurrent pancreatitis (ARP) or chronic pancreatitis (CP).
STUDY DESIGN: After patients were enrolled (CP, 55; ARP, 14) and their clinical characteristics were investigated, we performed next-generation sequencing to detect nucleotide variations among the following 10 genes: cationic trypsinogen protease serine 1 (PRSS1), serine protease inhibitor, Kazal type 1 (SPINK1), cystic fibrosis transmembrane conductance regulator gene (CFTR), chymotrypsin C (CTRC), calcium-sensing receptor (CASR), cathepsin B (CTSB), keratin 8 (KRT8), CLAUDIN 2 (CLDN2), carboxypeptidase A1 (CPA1), and ATPase type 8B member 1 (ATP8B1). Mutations were searched against online databases to obtain information on the cause of the diseases. Certain novel mutations were analyzed using the SIFT2 and Polyphen-2 to predict the effect on protein function.
RESULTS: There were 45 patients with CP and 10 patients with ARP who harbored 1 or more mutations in these genes; 45 patients had at least 1 mutation related to pancreatitis. Mutations were observed in the PRSS1, SPINK1, and CFTR genes in 17 patients, the CASR gene in 5 patients, and the CTSB, CTRC, and KRT8 genes in 1 patient. Mutations were not found in the CLDN, CPA1, or ATP8B1 genes. We found that mutations in SPINK1 may increase the risk of pancreatic duct stones (OR, 11.07; P = .003). The patients with CFTR mutations had a higher level of serum amylase (316.0 U/L vs 92.5 U/L; P = .026).
CONCLUSION: Mutations, especially those in PRSS1, SPINK1, and CFTR, accounted for the major etiologies in Chinese children with CP or ARP. Children presenting mutations in the SPINK1 gene may have a higher risk of developing pancreatic duct stones.

PMID: 29173301 [PubMed - in process]

A Homogeneous Cell-Based Halide-Sensitive Yellow Fluorescence Protein Assay to Identify Modulators of the Cystic Fibrosis Transmembrane Conductance Regulator Ion Channel.

Assay Drug Dev Technol. 2017 Nov 27;:

Authors: Smith E, Giuliano KA, Shumate J, Baillargeon P, McEwan B, Cullen MD, Miller JP, Drew L, Scampavia L, Spicer TP

Abstract
Cystic fibrosis (CF), an inherited genetic disease, is caused by mutation of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene, which encodes an ion channel involved in hydration maintenance by anion homeostasis. Ninety percent of CF patients possess one or more copies of the F508del CFTR mutation. This mutation disrupts trafficking of the protein to the plasma membrane and diminishes function of mature CFTR. Identifying small molecule modulators of mutant CFTR activity or biosynthesis may yield new tools for discovering novel CF treatments. One strategy utilizes a 384-well, cell-based fluorescence-quenching assay, which requires extensive wash steps, but reports sensitive changes in fluorescence-quenching kinetic rates. In this study, we describe the methods of adapting the protocol to a homogeneous, miniaturized 1,536-well format and further optimization of this functional F508del CFTR assay. The assay utilizes a cystic fibrosis bronchial epithelial (CFBE41o-) cell line, which was engineered to report CFTR-mediated intracellular flux of iodide by a halide-sensitive yellow fluorescence protein (YFP) reporter. We also describe the limitations of quench rate analysis and the subsequent incorporation of a novel, kinetic data analysis modality to quickly and efficiently find active CFTR modulators. This format yields a Z' value interval of 0.61 ± 0.05. As further evidence of high-throughput screen suitability, we subsequently completed a screening campaign of >645,000 compounds, identifying 2,811 initial hits. After completing secondary and tertiary follow-up assays, we identified 187 potential CFTR modulators, which EC50's < 5 μM. Thus, the assay has integrated the advantages of a phenotypic screen with high-throughput scalability to discover new small-molecule CFTR modulators.

PMID: 29172645 [PubMed - as supplied by publisher]

Oxidative stress-driven pulmonary inflammation and fibrosis in a mouse model of human ataxia-telangiectasia.

Redox Biol. 2017 Nov 10;14:645-655

Authors: Duecker R, Baer P, Eickmeier O, Strecker M, Kurz J, Schaible A, Henrich D, Zielen S, Schubert R

Abstract
Lung failure is responsible for significant morbidity and is a frequent cause of death in ataxia-telangiectasia (A-T). Disturbance in the redox balance of alveolar epithelial cells must be considered as a causal factor for respiratory disease in A-T. To investigate bronchoalveolar sensitivity to reactive oxygen species (ROS) and ROS-induced DNA damage, we used bleomycin (BLM) to induce experimental inflammation and fibrotic changes in the Atm-deficient mouse model. BLM or saline was administered by oropharyngeal instillation into the lung of Atm-deficient mice and wild-type mice. Mice underwent pulmonary function testing at days 0, 9, and 28, and bronchoalveolar lavage (BAL) was analysed for cell distribution and cytokines. Lung tissue was analysed by histochemistry. BLM administration resulted in a tremendous increase in lung inflammation and fibrotic changes in the lung tissue of Atm-deficient mice and was accompanied by irreversible deterioration of lung function. ATM (ataxia telangiectasia mutated) deficiency resulted in reduced cell viability, a delay in the resolution of γH2AX expression and a significant increase in intracellular ROS in pulmonary epithelial cells after BLM treatment. This was confirmed in the human epithelial cell line A549 treated with the ATM-kinase inhibitor KU55933. Our results demonstrate high bronchoalveolar sensitivity to ROS and ROS-induced DNA damage in the Atm-deficient mouse model and support the hypothesis that ATM plays a pivotal role in the control of oxidative stress-driven lung inflammation and fibrosis.

PMID: 29172151 [PubMed - as supplied by publisher]