Nutritional Status in Childhood as a Prognostic Factor in Patients with Cystic Fibrosis.

Lung. 2019 Mar 18;:

Authors: Ashkenazi M, Nathan N, Sarouk I, Aluma BEB, Dagan A, Bezalel Y, Keler S, Vilozni D, Efrati O

Abstract
INTRODUCTION: There is a strong association between cystic fibrosis and malnutrition, mainly because of the higher energy needs combined with lower intake. There is also a well-established correlation between good nutritional status and better lung function. To date, however, there are no studies examining nutritional status in childhood and adult lung function. To respond to this need, this innovative study explored the long-term correlations between nutritional status in childhood and lung function in adulthood for the same patient population.
METHODS: A retrospective patient file study was conducted to identify putative correlations between nutritional status in childhood and lung function in adulthood. The medical archives at Sheba Medical Center were examined for a period of 31 years between 1986 and 2017 for age, gender, mutations, pancreatic sufficiency or insufficiency (PI/PS), sputum cultures, cystic fibrosis related diabetes, body mass index (BMI) at the age of 10, and FEV1 at 20 and 30 in patients who underwent or did not undergo lung transplantation.
RESULTS: The database was composed of the records of sixty-five patients, thirteen of whom underwent lung transplantation. The correlations (R²) between BMI at age of 10 years and FEV1 at the age of 20 and 30 years were 0.35 and 0.28, respectively, p < 0.001. A BMI of lower than - 0.75 at the age of 10 emerged as a risk factor for lung transplantation (OR 3.42 p = 0.023) and had a negative predictive value of 90%. Kaplan-Meier survival curve showed significant lower lung transplantation rate in the group of BMI z score higher than - 0.75 at the age of 10 years. Logistic regression found nutritional at the age of 10 years as a dominant risk factor for lung transplantation.
CONCLUSIONS: This study reports a clear, significant and important correlation for the first time between nutritional status in childhood and lung function for the same patients at adulthood. Hence, nutritional status sets a clear trajectory and should be treated aggressively. The findings emphasize the importance of new-born screening and early implementation of nutritional guidelines for cystic fibrosis patients.

PMID: 30887107 [PubMed - as supplied by publisher]

The Yin and Yang of Streptococcus Lung Infections in Cystic Fibrosis: A Model for Studying Polymicrobial Interactions.

J Bacteriol. 2019 Mar 18;:

Authors: Scott JE, O'Toole GA

Abstract
The streptococci are increasingly recognized as a core component of the cystic fibrosis (CF) lung microbiome, yet the role that they play in CF lung disease is unclear. The presence of Streptococcus milleri group (SMG, also known as the anginosus group streptococci, AGS) correlates with exacerbation when these microbes are the predominant species in the lung. In contrast, microbiome studies have indicated that increased relative abundance of streptococci in the lung, including members of the oral microflora, correlates with less severe impacts on lung disease compared to other CF-associated microflora, indicating a complex role for this genus in the context of CF. Recent findings suggest that streptococci in the CF lung microenvironment may influence the growth and/or virulence of other CF pathogens as evidenced by increased virulence factor production by Pseudomonas aeruginosa when grown in coculture with oral streptococci. Conversely, the presence of P. aeruginosa can enhance the growth of streptococci, including members of the SMG, a phenomenon that could be exacerbated by the fact that streptococci are not susceptible to some of the front-line antibiotics used to treat P. aeruginosa Collectively, these studies indicate the necessity for further investigation into the role of streptococci in the CF airway to determine how these microbes, alone or via interactions with other CF-associated pathogens, might influence CF lung disease, for better or for worse. We also propose that studying the interactions of streptococci with other CF pathogens is an ideal model to study clinically relevant microbial interactions.

PMID: 30885933 [PubMed - as supplied by publisher]

Diagnostic accuracy of MRI with MRCP and B-Mode-sonography with elastography of the pancreas in patients with cystic fibrosis: a point-to-point comparison.

BMC Res Notes. 2019 Mar 18;12(1):150

Authors: Kloth C, Fabricius D, Wendlik I, Schmidt SA, Pfahler M, Lormes E, Beer M, Kratzer W, Schmidberger J

Abstract
OBJECTIVE: For patients with cystic fibrosis, the imaging of the pancreas is of crucial importance for the early detection of pancreatic carcinoma. Comparative studies between Magnetic Resonance Imaging (MRI) and sonographic pancreas sonography are not yet available. The aim of the study was to compare MRI, sonography and point-shearwave elastography (pSWE). A total of 19 patients were included (10 male, 9 female; age 29.7 ± 14.3 years) in the study. Ultrasonography with pSWE and contrast enhanced MRI with MRCP were performed.
RESULTS: Significant differences between measurements of pancreatic body were registered in MRI with 1.4 ± 0.6 cm vs 1.0 ± 0.4 cm in ultrasound (p = 0.049), however not for pancreatic head and tail. In 10/19 patients (52.6%) pancreatic parenchyma did not show in MRI because of complete lipomatous transformation, but could be detected in ultrasound. pSWE-values showed no significant differences between the full and partial fatty transformation in pancreatic head (p = 0.968), body (p = 0.657) and tail (p = 0.840). pSWE-values did not correlate with measured signal intensity in T1w flash (p = 0.930, r = 0.025) and T2w HASTE sequences (p = 0.152, r = - 0.375). In patients with CF ultrasound is superior to MRI for displaying full fibro-fatty parenchymal transformation, pancreatic duct. Ultrasound elastography did not provide additional clinical relevant information.

PMID: 30885270 [PubMed - in process]

Computed Tomography Description of the Uncinate Process Angulation in Patients With Cystic Fibrosis and Comparison With Primary Ciliary Dyskinesia, Nasal Polyposis, and Controls.

Ear Nose Throat J. 2019 Feb;98(2):89-93

Authors: Hervochon R, Teissier N, Blondeau JR, Remus N, Bassinet L, Canoui-Poitrine F, Van Den Abbeele T, Prulière-Escabasse V

Abstract
BACKGROUND:: There is a medial bulging of the lateral nasal wall in patients with cystic fibrosis (CF).
AIMS:: Uncinate process (UP) angulation measurements in patients and controls to objectify this bulging.
MATERIALS AND METHODS:: Thirty CF, 17 primary ciliary dyskinesia (PCD), 13 chronic rhinosinusitis with polyps (CRSwp), and 30 controls were included. Angles were measured bilaterally on computed tomography (CT) scans: A, B, C on coronal sections, D and E on axial sections. Angle A was between the UP and the orbit inner wall, whereas the others were between UP and midline.
RESULTS:: There was no significant difference between controls, PCD, and CRSwp. However, CF had 3 statistically different angles with controls, 5 with CRSwp, and 4 with PCD. Angle A average value was 126° (±16°) in patients with CF, 138° (±19°) in controls ( P = .007), 145° (±15°) in PCD ( P = .001), and 138° (±14°) in CRSwp ( P = .001). Angle E average value was 35° (±10°) in patients with CF, 20° (±6°) in controls ( P < .001), 21° (±4°) in PCD ( P < .001), and 22° (±6°) in CRSwp ( P < .001).
CONCLUSION:: Uncinate process's anatomy is only modified in CF: Angle between UP and inner wall of orbit is closed, and angles between UP and midline are opened.
SIGNIFICANCE:: These measures quantify the medial bulging of lateral nasal wall and support nasofibroscopic observations.

PMID: 30884997 [PubMed - in process]

Aerosolized agents for airway clearance in cystic fibrosis.

Pediatr Pulmonol. 2019 Mar 18;:

Authors: Southern KW, Clancy JP, Ranganathan S

Abstract
The outlook for people with cystic fibrosis (CF) has improved considerably as a result of conventional therapies including aerosolized agents for airway clearance. These will continue to play a significant role in maintaining well-being and improving survival, even as newer agents emerge that correct the underlying CF defect. In this review, we explore the evidence supporting the use of dornase alfa, hypertonic saline, and mannitol in improving mucus clearance in patients with CF from different age groups with differing disease severity. We also discuss the clinical use of these agents in the context of available international guidelines as well as practical considerations in the clinic, highlighting the importance of a multidisciplinary approach and shared decision-making. Unanswered questions regarding the optimal use of these agents are highlighted.

PMID: 30884217 [PubMed - as supplied by publisher]

Pulmonary Mycobacterium abscessus complex in children with cystic fibrosis: A practical management guideline.

J Paediatr Child Health. 2019 Mar 18;:

Authors: Andrew EC, Connell T, Robinson P, Curtis N, Massie J, Robertson C, Harrison J, Shanthikumar S, Bryant PA, Starr M, Steer A, Ranganathan S, Gwee A

Abstract
The treatment of Mycobacterium abscessus complex (MABSC) pulmonary infections is an emerging challenge in patients with cystic fibrosis (CF). Multidrug therapy for prolonged durations is required and carries the significant burden of drug-related toxicity, cost and selective pressure for multiresistant bacteria. International guidelines acknowledge that clinical and in vitro data to support treatment regimens are limited, particularly in children. As part of a collaboration between the infectious diseases and respiratory units at our institution, we have developed a modified treatment guideline that aims to balance the aims of MABSC eradication and slowing disease progression with minimising drug toxicity and resistance. The outcomes of this treatment approach will be monitored and reported. In this manuscript, we discuss the available evidence for treatment choices and present our treatment guideline for paediatric patients with CF and MABSC infection.

PMID: 30884016 [PubMed - as supplied by publisher]

Hydroxyurea (hydroxycarbamide) for transfusion-dependent β-thalassaemia.

Cochrane Database Syst Rev. 2019 Mar 16;3:CD012064

Authors: Ansari SH, Lassi ZS, Khowaja SM, Adil SO, Shamsi TS

Abstract
BACKGROUND: Hydroxyurea (hydroxycarbamide) promotes the production of foetal haemoglobin (HbF) by reactivating gamma-genes. Evidence has shown clinical benefits of hydroxyurea in people with sickle cell anemia; however, only a few studies have assessed this treatment in people with beta (β)-thalassaemia.
OBJECTIVES: The primary objective is to review the efficacy of hydroxyurea in reducing or ameliorating the requirement of blood transfusions in people with transfusion-dependent β-thalassaemia. The second objective is to review the safety of hydroxyurea with regards to severe adverse effects in this population.
SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register, compiled from electronic database searches and hand searching of journals and conference abstract books. We also searched electronic databases and trial registries, including ClinicalTrials.gov, the WHO ICTRP and PubMed (09 October 2018).Date of last search of the Group's haemoglobinopathies trials register: 04 March 2019.
SELECTION CRITERIA: Randomised controlled trials of hydroxyurea in people with transfusion-dependent β-thalassaemia, compared with placebo or standard treatment or comparing different doses of hydroxyurea.
DATA COLLECTION AND ANALYSIS: Two authors independently assessed trials for inclusion in the review, which was verified by a third author.
MAIN RESULTS: No trials were eligible for inclusion in this review.
AUTHORS' CONCLUSIONS: Currently, there is no high-quality evidence to support or challenge the continued use of hydroxyurea for managing people with transfusion-dependent β-thalassaemia. Multicentre, randomised controlled trials (compared to placebo or other available treatment, i.e. blood transfusion and iron chelation) are needed in order to assess the efficacy and safety of hydroxyurea for reducing the need for blood transfusion, for maintaining or improving mean haemoglobin levels, as well as for determining its cost-effectiveness.

PMID: 30882896 [PubMed - as supplied by publisher]

Nebulized Amikacin and Fosfomycin for Severe Pseudomonas aeruginosa Pneumonia: An Experimental Study.

Crit Care Med. 2019 Mar 15;:

Authors: Li Bassi G, Motos A, Fernandez-Barat L, Aguilera Xiol E, Chiurazzi C, Senussi T, Saco MA, Fuster C, Carbonara M, Bobi J, Amaro R, De Rosa F, Comaru T, Yang H, Ranzani OT, Marti JD, Rinaudo M, Comino Trinidad O, Rigol M, Bringué J, Ramirez J, Nicolau DP, Pelosi P, Antonelli M, Blasi F, Artigas A, Montgomery AB, Torres A

Abstract
OBJECTIVES: Latest trials failed to confirm merits of nebulized amikacin for critically ill patients with nosocomial pneumonia. We studied various nebulized and IV antibiotic regimens in a porcine model of severe Pseudomonas aeruginosa pneumonia, resistant to amikacin, fosfomycin, and susceptible to meropenem.
DESIGN: Prospective randomized animal study.
SETTING: Animal Research, University of Barcelona, Spain.
SUBJECTS: Thirty female pigs.
INTERVENTIONS: The animals were randomized to receive nebulized saline solution (CONTROL); nebulized amikacin every 6 hours; nebulized fosfomycin every 6 hours; IV meropenem alone every 8 hours; nebulized amikacin and fosfomycin every 6 hours; amikacin and fosfomycin every 6 hours, with IV meropenem every 8 hours. Nebulization was performed through a vibrating mesh nebulizer. The primary outcome was lung tissue bacterial concentration. Secondary outcomes were tracheal secretions P. aeruginosa concentration, clinical variables, lung histology, and development of meropenem resistance.
MEASUREMENTS AND MAIN RESULTS: We included five animals into each group. Lung P. aeruginosa burden varied among groups (p < 0.001). In particular, IV meropenem and amikacin and fosfomycin + IV meropenem groups presented lower P. aeruginosa concentrations versus amikacin and fosfomycin, amikacin, CONTROL, and fosfomycin groups (p < 0.05), without significant difference between these two groups undergoing IV meropenem treatment. The sole use of nebulized antibiotics resulted in dense P. aeruginosa accumulation at the edges of the interlobular septa. Amikacin, amikacin and fosfomycin, and amikacin and fosfomycin + IV meropenem effectively reduced P. aeruginosa in tracheal secretions (p < 0.001). Pathognomonic clinical variables of respiratory infection did not differ among groups. Resistance to meropenem increased in IV meropenem group versus amikacin and fosfomycin + meropenem (p = 0.004).
CONCLUSIONS: Our findings corroborate that amikacin and fosfomycin alone efficiently reduced P. aeruginosa in tracheal secretions, with negligible effects in pulmonary tissue. Combination of amikacin and fosfomycin with IV meropenem does not increase antipseudomonal pulmonary tissue activity, but it does reduce development of meropenem-resistant P. aeruginosa, in comparison with the sole use of IV meropenem. Our findings imply potential merits for preemptive use of nebulized antibiotics in order to reduce resistance to IV meropenem.

PMID: 30882478 [PubMed - as supplied by publisher]

Aerosol Transmission of Aspergillus fumigatus in Cystic Fibrosis Patients in the Netherlands.

Emerg Infect Dis. 2019 Apr;25(4):797-799

Authors: Engel TGP, Erren E, Vanden Driessche KSJ, Melchers WJG, Reijers MH, Merkus P, Verweij PE

Abstract
We collected sputum samples and cough plates from 15 cystic fibrosis patients in the Netherlands who were colonized with Aspergillus fumigatus; we recovered A. fumigatus of the same genotype in cough aerosols and sputum samples from 2 patients. The belief that transmission of A. fumigatus from cystic fibrosis patients does not occur should be reconsidered.

PMID: 30882308 [PubMed - in process]

Pore-forming small molecules offer a promising way to tackle cystic fibrosis.

Nature. 2019 Mar;567(7748):315-317

Authors: Sheppard DN, Davis AP

Abstract

PMID: 30880331 [PubMed - in process]

Accuracy of Transient Elastography Data Combined With APRI in Detection and Staging of Liver Disease in Pediatric Patients With Cystic Fibrosis.

Clin Gastroenterol Hepatol. 2019 Mar 14;:

Authors: Lewindon PJ, Puertolas-Lopez MV, Ramm LE, Noble C, Pereira TN, Wixey JA, Hartel GF, Calvopina DA, Leung DH, Ramm GA

Abstract
BACKGROUND & AIMS: Liver disease develops in 15%-72% of patients with cystic fibrosis, and 5%-10% develop cirrhosis or portal hypertension, usually during childhood. Transient elastography (TE) is a noninvasive method to measure liver stiffness. We aimed to validate its accuracy in detection of liver disease and assessment of fibrosis in children with cystic fibrosis.
METHODS: We performed a cross-sectional study to evaluate the accuracy of TE in analysis of liver fibrosis in 160 consecutive children who presented with cystic fibrosis (9.0±0.4 years old, 53% male) at a tertiary referral pediatric center in Australia, from 2011 through 2016. Patients were classified as having cystic fibrosis-associated liver disease (CFLD) or cystic fibrosis without liver disease (CFnoLD) based on clinical, biochemical, and imaging features. Fibrosis severity was determined from histologic analysis of dual-pass liver biopsies from children with CFLD, as the reference standard. Data from healthy children without cystic fibrosis (n=64, controls) were obtained from a separate study. Liver stiffness measurements (LSMs) were made by Fibroscan analysis, using the inter-quartile range/median ≤30% of 10 valid measurements. Children with macronodularity or portal hypertension with heterogeneous changes on ultrasound without available biopsy were assigned to the category of stage F3-F4 fibrosis.
RESULTS: LSM was made reliably in 86% of children; accuracy increased with age. LSMs were significantly higher in children with CFLD (10.7±2.4 kPa, n=33) than with CFnoLD (4.6±0.1 kPa, n=105) (P<.0001) or controls (4.1±0.1kPa) (P<.0001); LSMs were higher in children with CFnoLD than controls (P<.05). At a cut-off value of 5.55kPa, LSM identified children with CFLD with an area under the receiver operating characteristic (AUROC) curve of 0.82, 70% sensitivity, and 82% specificity (P<.0001). Classification and regression tree models that combined LSM and aspartate aminotransferase to platelet ratio index (APRI) identified children with CFLD with an AUROC curve of 0.89, 87% sensitivity, and 74% specificity (odds ratio, 18.6). LSMs correlated with fibrosis stage in patients with CFLD (r=0.67, P=.0001). A cut-off value of 8.7kPa differentiated patients with stage F3-F4 fibrosis from patients with stage F1-F2 fibrosis (AUROC, 0.87; 75% sensitivity; 100% specificity, P=.0002). The combination of LSMs and APRI improved the differentiation of patients with F3-F4 fibrosis vs F1-F2 fibrosis (AUROC, 0.92; 83% sensitivity; and 100% specificity (P<.01).
CONCLUSIONS: LSMs made by TE accurately detect liver disease in children with cystic fibrosis; diagnostic accuracy increases when LSMs are combined with APRI. LSMs also differentiate between children with cystic fibrosis with mild-moderate fibrosis vs advanced fibrosis.

PMID: 30880274 [PubMed - as supplied by publisher]

Effects of Lumacaftor/Ivacaftor on physical activity and exercise tolerance in three adults with cystic fibrosis.

J Cyst Fibros. 2019 Mar 14;:

Authors: Savi D, Schiavetto S, Simmonds NJ, Righelli D, Palange P

Abstract
The combination of the corrector lumacaftor with the potentiator ivacaftor has been approved for treatment of cystic fibrosis (CF) patients homozygous for the Phe508del CFTR mutation. There are no reports detailing the effect of lumacaftor-ivacaftor on physical activity (PA) and exercise tolerance. We performed incremental cardiopulmonary exercise testing (CPET) and we assessed PA pre- and post 2 years initiation of lumacaftor-ivacaftor in three CF adults. PA of mild intensity improved by +13% in patient 1, + 84% in patients 2 and + 89% in patient 3. Oxygen uptake increased both at anaerobic threshold and at peak exercise (patient 1 + 33%, patient 2 + 42% and patient 3 + 20%). Daily physical activities and exercise tolerance improved after two years of lumacaftor-ivacaftor therapy.

PMID: 30879989 [PubMed - as supplied by publisher]

Challenges and safety of beta lactam desensitization during extracorporeal membrane oxygenation.

Ann Allergy Asthma Immunol. 2019 Mar 13;:

Authors: Foer D, Marquis K, Romero N, Castells MC

PMID: 30878628 [PubMed - as supplied by publisher]

Posaconazole therapy in children with cystic fibrosis and Aspergillus-related lung disease.

Med Mycol. 2019 Mar 16;:

Authors: Patel D, Popple S, Claydon A, Modha DE, Gaillard EA

Abstract
There is emerging evidence for the role of posaconazole in the management of Aspergillus-related cystic fibrosis (CF) lung disease. The tolerability and efficacy of posaconazole in paediatric CF is not well established. We report a prospective study over a fifty-three month period evaluating the safety, tolerability, and efficacy of posaconazole in pediatric CF. Fourteen children (seven males, median age 13 years, range 3-17 years) received a total of twenty-three courses of posaconazole (13 oral suspension and 10 tablet formulation). Of these patient episodes, nine received posaconazole for emerging or active allergic bronchopulmonary aspergillosis (ABPA) and two required a combination of posaconazole and systemic corticosteroids for difficult-to-treat ABPA. A subgroup of patients (n = 12) with persistent isolates of Aspergillus fumigatus, in the absence of serological markers of ABPA, received posaconazole monotherapy for pulmonary exacerbations not responding to conventional broad-spectrum antibiotic treatment. Posaconazole levels, full blood count, electrolytes, and liver function were monitored on day 7 of treatment and then monthly. Posaconazole was well tolerated in all but three patients. Therapeutic plasma levels >1 mg/l were achieved in all receiving the tablet formulation in comparison to 60% on the liquid preparation. There was a modest but significant improvement in FEV1 (% predicted) demonstrated for the cohort as a whole (p = 0.015) following posaconazole therapy. Posaconazole is well tolerated in children as young as six years old, improvements in lung function are observed, and therapeutic plasma levels are readily achieved in patients taking the tablet formulation and in adherent patients taking the liquid formulation.

PMID: 30877757 [PubMed - as supplied by publisher]

Biochemistry of very-long-chain and long-chain ceramides in cystic fibrosis and other diseases: The importance of side chain.

Prog Lipid Res. 2019 Mar 12;:

Authors: Garić D, De Sanctis JB, Shah J, Dumut DC, Radzioch D

Abstract
Ceramides, the principal building blocks of all sphingolipids, have attracted the attention of many scientists around the world interested in developing treatments for cystic fibrosis, the most common genetic disease of Caucasians. Many years of fruitful research in this field have produced some fundamentally important, yet controversial results. Here, we aimed to summarize the current knowledge on the role of long- and very-long- chain ceramides, the most abundant species of ceramides in animal cells, in cystic fibrosis and other diseases. We also aim to explain the importance of the length of their side chain in the context of stability of transmembrane proteins through a concise synthesis of their biophysical chemistry, cell biology, and physiology. This review also addresses several remaining riddles in this field. Finally, we discuss the technical challenges associated with the analysis and quantification of ceramides. We provide the evaluation of the antibodies used for ceramide quantification and we demonstrate their lack of specificity. Results and discussion presented here will be of interest to anyone studying these enigmatic lipids.

PMID: 30876862 [PubMed - as supplied by publisher]

Lentiviral Vectors for the Treatment and Prevention of Cystic Fibrosis Lung Disease.

Genes (Basel). 2019 Mar 14;10(3):

Authors: Marquez Loza LI, Yuen EC, McCray PB

Abstract
Despite the continued development of cystic fibrosis transmembrane conductance regulator (CFTR) modulator drugs for the treatment of cystic fibrosis (CF), the need for mutation agnostic treatments remains. In a sub-group of CF individuals with mutations that may not respond to modulators, such as those with nonsense mutations, CFTR gene transfer to airway epithelia offers the potential for an effective treatment. Lentiviral vectors are well-suited for this purpose because they transduce nondividing cells, and provide long-term transgene expression. Studies in primary cultures of human CF airway epithelia and CF animal models demonstrate the long-term correction of CF phenotypes and low immunogenicity using lentiviral vectors. Further development of CF gene therapy requires the investigation of optimal CFTR expression in the airways. Lentiviral vectors with improved safety features have minimized insertional mutagenesis safety concerns raised in early clinical trials for severe combined immunodeficiency using γ-retroviral vectors. Recent clinical trials using improved lentiviral vectors support the feasibility and safety of lentiviral gene therapy for monogenetic diseases. While work remains to be done before CF gene therapy reaches the bedside, recent advances in lentiviral vector development reviewed here are encouraging and suggest it could be tested in clinical studies in the near future.

PMID: 30875857 [PubMed]

Mid-Term Reproducibility of Chest MRI in Adults with Clinically Stable Cystic Fibrosis and Chronic Obstructive Pulmonary Disease.

Am J Respir Crit Care Med. 2019 Mar 15;:

Authors: Wielpütz MO, Eichinger M, Wege S, Eberhardt R, Mall MA, Kauczor HU, Puderbach MU, Risse F, Heußel CP, Heußel G

PMID: 30875236 [PubMed - as supplied by publisher]

Shifting Landscape of Airway Infection in Early Cystic Fibrosis.

Am J Respir Crit Care Med. 2019 Mar 15;:

Authors: Hoppe JE, Sagel SD

PMID: 30875233 [PubMed - as supplied by publisher]

Autophagy suppresses the pathogenic immune response to dietary antigens in cystic fibrosis.

Cell Death Dis. 2019 Mar 15;10(4):258

Authors: Villella VR, Esposito S, Ferrari E, Monzani R, Tosco A, Rossin F, Castaldo A, Silano M, Marseglia GL, Romani L, Barlev NA, Piacentini M, Raia V, Kroemer G, Maiuri L

Abstract
Under physiological conditions, a finely tuned system of cellular adaptation allows the intestinal mucosa to maintain the gut barrier function while avoiding excessive immune responses to non-self-antigens from dietary origin or from commensal microbes. This homeostatic function is compromised in cystic fibrosis (CF) due to loss-of-function mutations in the CF transmembrane conductance regulator (CFTR). Recently, we reported that mice bearing defective CFTR are abnormally susceptible to a celiac disease-like enteropathy, in thus far that oral challenge with the gluten derivative gliadin elicits an inflammatory response. However, the mechanisms through which CFTR malfunction drives such an exaggerated response to dietary protein remains elusive. Here we demonstrate that the proteostasis regulator/transglutaminase 2 (TGM2) inhibitor cysteamine restores reduced Beclin 1 (BECN1) protein levels in mice bearing cysteamine-rescuable F508del-CFTR mutant, either in homozygosis or in compound heterozygosis with a null allele, but not in knock-out CFTR mice. When cysteamine restored BECN1 expression, autophagy was increased and gliadin-induced inflammation was reduced. The beneficial effects of cysteamine on F508del-CFTR mice were lost when these mice were backcrossed into a Becn1 haploinsufficient/autophagy-deficient background. Conversely, the transfection-enforced expression of BECN1 in human intestinal epithelial Caco-2 cells mitigated the pro-inflammatory cellular stress response elicited by the gliadin-derived P31-43 peptide. In conclusion, our data provide the proof-of-concept that autophagy stimulation may mitigate the intestinal malfunction of CF patients.

PMID: 30874543 [PubMed - in process]

Erratum: Azithromycin for Early Pseudomonas Infection in Cystic Fibrosis. The OPTIMIZE Randomized Trial.

Am J Respir Crit Care Med. 2019 Mar 15;199(6):809

Authors:

PMID: 30874457 [PubMed - in process]