Cystic Fibrosis Presenting as Pseudo-Bartter Syndrome: An Important Diagnosis that is Missed!

Indian J Pediatr. 2020 Jun 05;:

Authors: Mantoo MR, Kabra M, Kabra SK

Abstract
Cystic fibrosis (CF), an autosomal recessive disorder, occurs due to mutations in CFTR gene resulting in impaired cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel function in various epithelia. In addition to the well-known pulmonary and pancreatic morbidities, CF is characterized by electrolyte and acid-base abnormalities- hypochloremia, hyponatremia, hypokalemia and metabolic alkalosis. These are collectively known as Pseudo-Bartter syndrome, as similar abnormalities are seen in Bartter syndrome- an inherited tubulopathy affecting thick ascending limb of loop of Henle. There may be a significant clinical overlap between the Classic Bartter syndrome, Gitelman syndrome and CF presenting as Pseudo-Bartter syndrome, especially in early childhood. This review focuses on Pseudo-Bartter syndrome in CF, its pathogenesis and differentiation from Bartter/Gitelman syndrome. Other causes of metabolic abnormalities resembling Bartter syndrome are also highlighted.

PMID: 32504456 [PubMed - as supplied by publisher]

Management of initial colonisations with Burkholderia species in France, with retrospective analysis in five cystic fibrosis Centres: a pilot study.

BMC Pulm Med. 2020 Jun 05;20(1):159

Authors: Gruzelle V, Guet-Revillet H, Segonds C, Bui S, Macey J, Chiron R, Michelet M, Murris-Espin M, Mittaine M

Abstract
BACKGROUND: Whereas Burkholderia infections are recognized to impair prognosis in cystic fibrosis (CF) patients, there is no recommendation to date for early eradication therapy. The aim of our study was to analyse the current management of initial colonisations with Burkholderia cepacia complex (BCC) or B. gladioli in French CF Centres and its impact on bacterial clearance and clinical outcome.
METHODS: We performed a retrospective review of the primary colonisations (PC), defined as newly positive sputum cultures, observed between 2010 and 2018 in five CF Centres. Treatment regimens, microbiological and clinical data were collected.
RESULTS: Seventeen patients (14 with BCC, and 3 with B. gladioli) were included. Eradication therapy, using heterogeneous combinations of intravenous, oral or nebulised antibiotics, was attempted in 11 patients. Six out of the 11 treated patients, and 4 out of the 6 untreated patients cleared the bacterium. Though not statistically significant, higher forced expiratory volume in 1 second and forced vital capacity at PC and consistency of treatment with in vitro antibiotic susceptibility tended to be associated with eradication. The management of PC was shown to be heterogeneous, thus impairing the statistical power of our study. Large prospective studies are needed to define whom to treat, when, and how.
CONCLUSIONS: Pending these studies, we propose, due to possible spontaneous clearance, to check the presence of Burkholderia 1 month after PC before starting antibiotics, at least in the milder cases, and to evaluate a combination of intravenous beta-lactam + oral or intravenous fluoroquinolone + inhaled aminoglycoside.

PMID: 32503487 [PubMed - as supplied by publisher]

Release mechanisms and molecular interactions of Pseudomonas aeruginosa extracellular DNA.

Appl Microbiol Biotechnol. 2020 Jun 04;:

Authors: Sarkar S

Abstract
Pseudomonas aeruginosa infection is a significant threat for clinicians. Increasing incidents of resistant biofilm infection result in high mortality rates worldwide. There is a considerable current interest in the field of extracellular DNA (eDNA)-mediated P. aeruginosa biofilm formation. eDNA acts as a glue to make biofilm more stable. This review focuses on the diverse mechanisms and factors, which enhance the eDNA release into the extracellular milieu. Furthermore, eDNA-mediated molecular interactions within the biofilm are emphasized. In addition, drug resistance mechanisms due to the versatility of eDNA are discussed. Spatial physiological diversity is expected due to different metabolic activity of bacterial subpopulation present in P. aeruginosa biofilm layers. In P. aeruginosa, eDNA release is accomplished by cell lysis and OMVs (outer membrane vesicles). eDNA release is a spontaneous and multifactorial process, which may be accomplished by PQS, pyocyanin, and lambda prophage induction. Hydrogen peroxide and pyocin trigger cell death, which may facilitate eDNA release. Lung mucosa of cystic fibrosis patients is enriched with eDNA, which acidifies biofilm and develops P. aeruginosa resistance to aminoglycosides. Further studies on spatial and molecular characterization of bacterial subpopulation in biofilm will shed light on eDNA-biofilm interaction more precisely.Key Points • Extracellular DNA (eDNA) is a key component of Pseudomonas aeruginosa biofilm.• P. aeruginosa eDNA acts as a glue to make biofilm more stronger.• Bacterial cell death or lysis may be the potential way to release P. aeruginosa eDNA into extracellular milieu.• P. aeruginosa eDNA contributes to develop resistance to antimicrobials.

PMID: 32500267 [PubMed - as supplied by publisher]

CRISPRi-mediated functional analysis of lung disease-associated loci at non-coding regions.

NAR Genom Bioinform. 2020 Jun;2(2):lqaa036

Authors: Stuart WD, Guo M, Fink-Baldauf IM, Coleman AM, Clancy JP, Mall MA, Lim FY, Brewington JJ, Maeda Y

Abstract
Genome-wide association studies have identified lung disease-associated loci; however, the functions of such loci are not well understood in part because the majority of such loci are located at non-coding regions. Hi-C, ChIP-seq and eQTL data predict potential roles (e.g. enhancer) of such loci; however, they do not elucidate the molecular function. To determine whether these loci function as gene-regulatory regions, CRISPR interference (CRISPRi; CRISPR/dCas9-KRAB) has been recently used. Here, we applied CRISPRi along with Hi-C, ChIP-seq and eQTL to determine the functional roles of loci established as highly associated with asthma, cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). Notably, Hi-C, ChIP-seq and eQTL predicted that non-coding regions located at chromosome 19q13 or chromosome 17q21 harboring single-nucleotide polymorphisms (SNPs) linked to asthma/CF/COPD and chromosome 11p15 harboring an SNP linked to IPF interact with nearby genes and function as enhancers; however, CRISPRi indicated that the regions with rs1800469, rs2241712, rs12603332 and rs35705950, but not others, regulate the expression of nearby genes (single or multiple genes). These data indicate that CRISPRi is useful to precisely determine the roles of non-coding regions harboring lung disease-associated loci as to whether they function as gene-regulatory regions at a genomic level.

PMID: 32500120 [PubMed]

Sputum Neutrophil Elastase associates with microbiota and P. aeruginosa in bronchiectasis.

Eur Respir J. 2020 Jun 04;:

Authors: Oriano M, Gramegna A, Terranova L, Sotgiu G, Sulaiman I, Ruggiero L, Saderi L, Wu B, Chalmers JD, Segal LN, Marchisio P, Blasi F, Aliberti S

Abstract
INTRODUCTION: Neutrophilic inflammation is a major driver of bronchiectasis pathophysiology, and neutrophil elastase activity is the most promising biomarker evaluated in sputum to date. How active neutrophil elastase correlates with lung microbiome in bronchiectasis is still unexplored. We aimed at understanding if active neutrophil elastase is associated with low microbial diversity and distinct microbiome characteristics.
METHODS: An observational, cross-sectional study was conducted at the Bronchiectasis Program of the Policlinico Hospital in Milan, Italy, where adults with bronchiectasis were enrolled between March 2017 and March 2019. Active neutrophil elastase was measured on sputum collected during stable state, microbiota analysed through 16S rRNA gene sequencing, molecular assessment of respiratory pathogens through real time PCR and clinical data collected.
MEASUREMENTS AND MAIN RESULTS: Among 185 patients enrolled, decreasing alpha diversity, evaluated through the Shannon entropy (rho: -0.37; p-value <0.00001), Pielou' evenness (rho: -0.36, p<0.00001) and richness (rho: -0.33; p<0.00001), was significantly correlated with increasing elastase. A significant difference in median levels of Shannon was detected between patients with neutrophil elastase ≥20 µg·mL-1 [3.82 (2.20-4.96)] versus neutrophil elastase <20 µg·mL-1 [4.88 (3.68-5.80)], p<0.0001. A distinct microbiome was found in these two groups, mainly characterised by enrichment with Pseudomonas in the high and with Streptococcus in the low elastase group. Further confirmation of the association of P. aeruginosa with elevated active neutrophil elastase was found based on standard culture and targeted real-time PCR.
CONCLUSIONS: High levels of active neutrophil elastase are associated to low microbiome diversity and specifically to P. aeruginosa infection.

PMID: 32499333 [PubMed - as supplied by publisher]

Clinical effects of the three CFTR potentiator treatments curcumin, genistein and ivacaftor in patients with the CFTR-S1251N gating mutation.

J Cyst Fibros. 2020 Jun 01;:

Authors: Berkers G, van der Meer R, van Mourik P, Vonk AM, Kruisselbrink E, Suen SW, Heijerman HG, Majoor CJ, Koppelman GH, Roukema J, Janssens HM, de Rijke YB, Kemper EM, Beekman JM, van der Ent CK, de Jonge HR

Abstract
BACKGROUND: The natural food supplements curcumin and genistein, and the drug ivacaftor were found effective as CFTR potentiators in the organoids of individuals carrying a S1251N gating mutation, possibly in a synergistic fashion. Based on these in vitro findings, we evaluated the clinical efficacy of a treatment with curcumin, genistein and ivacaftor, in different combinations.
METHODS: In three multi-center trials people with CF carrying the S1251N mutation were treated for 8 weeks with curcumin+genistein, ivacaftor and ivacaftor+genistein. We evaluated change in lung function, sweat chloride concentration, CFQ-r, BMI and fecal elastase to determine the clinical effect. We evaluated the pharmacokinetic properties of the compounds by evaluating the concentration in plasma collected after treatment and the effect of the same plasma on the intestinal organoids.
RESULTS: A clear clinical effect of treatment with ivacaftor was observed, evidenced by a significant improvement in clinical parameters. In contrast we observed no clear clinical effect of curcumin and/or genistein, except for a small but significant reduction in sweat chloride and airway resistance. Plasma concentrations of the food supplements were low, as was the response of the organoids to this plasma.
CONCLUSIONS: We observed a clear clinical effect of treatment with ivacaftor, which is in line with the high responsiveness of the intestinal organoids to this drug. No clear clinical effect was observed of the treatment with curcumin and/or genistein, the low plasma concentration of these compounds emphasizes that pharmacokinetic properties of a compound have to be considered when in vitro experiments are performed.

PMID: 32499204 [PubMed - as supplied by publisher]

Vitamin K supplementation for cystic fibrosis.

Cochrane Database Syst Rev. 2020 Jun 04;6:CD008482

Authors: Jagannath VA, Thaker V, Chang AB, Price AI

Abstract
BACKGROUND: Malabsorption and deficiency of fat-soluble vitamins K may occur in cystic fibrosis, a genetic disorder affecting multiple organs. Vitamin K is known to play an important role in both blood coagulation and bone formation, hence the role of supplementation of vitamin K in this category needs to be reviewed. This is an updated version of the review.
OBJECTIVES: To assess the effects of vitamin K supplementation in people with cystic fibrosis and to investigate the hypotheses that vitamin K will decrease deficiency-related coagulopathy, increase bone mineral density, decrease risk of fractures and improve quality of life in people with CF. Also to determine the optimal dose and route of administration of vitamin K for people with CF (for both routine and therapeutic use).
SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. Most recent search: 12 August 2019.
SELECTION CRITERIA: Randomised controlled trials of all preparations of vitamin K used as a supplement compared to either no supplementation (or placebo) at any dose or route and for any duration, in patients with cystic fibrosis.
DATA COLLECTION AND ANALYSIS: Two authors independently screened papers, extracted trial details and assessed their risk of bias. The quality of the evidence was assessed using the GRADE criteria.
MAIN RESULTS: Three trials (total 70 participants, aged 8 to 46 years) assessed as having a moderate risk of bias were included. One trial compared vitamin K to placebo, a second to no supplementation and the third compared two doses of vitamin K. No trial in either comparison reported our primary outcomes of coagulation and quality of life or the secondary outcomes of nutritional parameters and adverse events. Vitamin K versus control Two trials compared vitamin K to control, but data were not available for analysis. One 12-month trial (n = 38) compared 10 mg vitamin K daily or placebo in a parallel design and one trial (n = 18) was of cross-over design with no washout period and compared 5 mg vitamin K/week for four-weeks to no supplementation for four-weeks. Only the 12-month trial reported on the primary outcome of bone formation; we are very uncertain whether vitamin K supplementation has any effect on bone mineral density at the femoral hip or lumbar spine (very low-quality evidence). Both trials reported an increase in serum vitamin K levels and a decrease in undercarboxylated osteocalcin levels. The cross-over trial also reported that levels of proteins induced by vitamin K absence (PIVKA) showed a decrease and a return to normal following supplementation, but due to the very low-quality evidence we are not certain that this is due to the intervention. High-dose versus low-dose vitamin K One parallel trial (n = 14) compared 1 mg vitamin K/day to 5 mg vitamin K/day for four weeks. The trial did report that there did not appear to be any difference in serum undercarboxylated osteocalcin or vitamin K levels (very low-quality evidence). While the trial reported that serum vitamin K levels improved with supplementation, there was no difference between the high-dose and low-dose groups.
AUTHORS' CONCLUSIONS: There is very low-quality evidence of any effect of vitamin K in people with cystic fibrosis. While there is no evidence of harm, until better evidence is available the ongoing recommendations by national CF guidelines should be followed.

PMID: 32497260 [PubMed - as supplied by publisher]

[News drugs and evolution towards personalized treatment for cystic fibrosis].

Rev Med Liege. 2020 May;75(5-6):410-414

Authors: Boboli H, Pirson J, Kempenners C, Seghaye MC

Abstract
Cystic fibrosis is a genetic disorder responsible for the production of a defective transmembrane protein. In recent years, new protein modulators have been developed. They aim to treat the underlying cause of the disease. The results on the biomarkers of the function of the CFTR protein and on the clinical outcomes are very encouraging. However, there is an individual heterogeneity in the response to modulators within a same genotype. Furthermore, clinical trials focus on the most common mutations in the CFTR gene, in particular DF508. Intestinal organoids, a new model of ex vivo study, could offer a quick approach to increase access to effective treatment for all patients with cystic fibrosis regardless of their CFTR genotype. Organoids could enable personalized treatment of cystic fibrosis.

PMID: 32496689 [PubMed - as supplied by publisher]

Prevention of severe respiratory syncytial virus infection in the pediatric population in Mexico: position of a group of experts.

Bol Med Hosp Infant Mex. 2020;77(3):100-111

Authors: Moreno-Espinosa S, Estrada-Ruelas I, Sánchez-Miranda Y, Flores-Arizmendi RA, Macías-Avilés HA, Ruiz-Gutiérrez HH, Lima-Rogel V, Gutiérrez-Padilla JA, González-Gómez LA

Abstract
Respiratory syncytial virus (RSV) is the agent that causes more hospitalizations and deaths due to lower acute respiratory infection. Its distribution is widespread, and almost every child has been infected by the age of two years. Different risk populations have been identified: preterm newborns (NB), children with congenital heart disease, bronchopulmonary dysplasia, Down syndrome, cystic fibrosis, asthmatics, neuromuscular diseases, among others. However, preterm NBs, children with congenital heart disease or bronchopulmonary dysplasia show higher rates of hospitalization and death from RSV. In the late 90s, monoclonal antibodies against RSV were developed, with demonstrated efficacy and safety for the prevention of RSV hospitalizations in these populations. Currently, the American Academy of Pediatrics recommends this therapy for the prevention of severe infection in the population at higher risk. Economic evaluations have been conducted to determine the effectiveness of immunization, resulting favorable for palivizumab. Immunization in Mexico has resulted cost-effective in NBs under 32 gestation weeks. Mexican authorities should discuss the inclusion of palivizumab in their clinical guidelines.

PMID: 32496469 [PubMed - as supplied by publisher]

[Abdominal imaging in cystic fibrosis].

Radiologe. 2020 Jun 03;:

Authors: Mentzel HJ, Renz DM

Abstract
CLINICAL ISSUE: Abdominal complications are often the first indications for cystic fibrosis (CF), a multiorgan disease. A broad range of abdominal manifestations are associated with the disease, including gastrointestinal abnormalities (such as meconium ileus in newborns and distal intestinal obstruction syndrome in older children) and hepatobiliary alterations (e.g., cholelithiasis, microgallbladder, hepatosteatosis, biliary cirrhosis). A characteristic finding is pancreatic involvement, which leads to exocrine and over the course of time to endocrine insufficiency.
STANDARD RADIOLOGICAL METHODS: Ultrasonography is the preferred and often sole modality for a precise diagnosis of abdominal CF manifestations. However, all imaging modalities can be used, depending on the pathology: X‑ray, fluoroscopic examinations, computed tomography, magnetic resonance imaging (also with application of magnetic resonance cholangiopancreatography).
METHODICAL INNOVATIONS/PERFORMANCE: Scoring systems are useful for standardized diagnostics. Sonographic findings, described using a scoring system, correlate with clinical symptoms, such as pancreatic lipomatosis with abdominal pain (p = 0.018), flatulence (p = 0.006), and gastroesophageal reflux (p = 0.006).
EVALUATION/PRACTICAL RECOMMENDATIONS: A standardized approach with structured reporting is important due to the numerous abdominal CF manifestations. To enable precise follow-up analyses, scoring systems based on sonographic findings are excellent.

PMID: 32495009 [PubMed - as supplied by publisher]

Pharmacological modulation of mitochondrial calcium uniporter controls lung inflammation in cystic fibrosis.

Sci Adv. 2020 May;6(19):eaax9093

Authors: Rimessi A, Pozzato C, Carparelli L, Rossi A, Ranucci S, De Fino I, Cigana C, Talarico A, Wieckowski MR, Ribeiro CMP, Trapella C, Rossi G, Cabrini G, Bragonzi A, Pinton P

Abstract
Mitochondria physically associate with the endoplasmic reticulum to coordinate interorganelle calcium transfer and regulate fundamental cellular processes, including inflammation. Deregulated endoplasmic reticulum-mitochondria cross-talk can occur in cystic fibrosis, contributing to hyperinflammation and disease progression. We demonstrate that Pseudomonas aeruginosa infection increases endoplasmic reticulum-mitochondria associations in cystic fibrosis bronchial cells by stabilizing VAPB-PTPIP51 (vesicle-associated membrane protein-associated protein B-protein tyrosine phosphatase interacting protein 51) tethers, affecting autophagy. Impaired autophagy induced mitochondrial unfolding protein response and NLRP3 inflammasome activation, contributing to hyperinflammation. The mechanism by which VAPB-PTPIP51 tethers regulate autophagy in cystic fibrosis involves calcium transfer via mitochondrial calcium uniporter. Mitochondrial calcium uniporter inhibition rectified autophagy and alleviated the inflammatory response in vitro and in vivo, resulting in a valid therapeutic strategy for cystic fibrosis pulmonary disease.

PMID: 32494695 [PubMed - in process]

Intrinsic Abnormalities of Cystic Fibrosis Airway Connective Tissue Revealed by an In Vitro 3D Stromal Model.

Cells. 2020 Jun 01;9(6):

Authors: Mazio C, Scognamiglio LS, Cegli R, Galietta LJV, Bernardo DD, Casale C, Urciuolo F, Imparato G, Netti PA

Abstract
Cystic fibrosis is characterized by lung dysfunction involving mucus hypersecretion, bacterial infections, and inflammatory response. Inflammation triggers pro-fibrotic signals that compromise lung structure and function. At present, several in vitro cystic fibrosis models have been developed to study epithelial dysfunction but none of these focuses on stromal alterations. Here we show a new cystic fibrosis 3D stromal lung model made up of primary fibroblasts embedded in their own extracellular matrix and investigate its morphological and transcriptomic features. Cystic fibrosis fibroblasts showed a high proliferation rate and produced an abundant and chaotic matrix with increased protein content and elastic modulus. More interesting, they had enhanced pro-fibrotic markers and genes involved in epithelial function and inflammatory response. In conclusion, our study reveals that cystic fibrosis fibroblasts maintain in vitro an activated pro-fibrotic state. This abnormality may play in vivo a role in the modulation of epithelial and inflammatory cell behavior and lung remodeling. We argue that the proposed bioengineered model may provide new insights on epithelial/stromal/inflammatory cells crosstalk in cystic fibrosis, paving the way for novel therapeutic strategies.

PMID: 32492951 [PubMed - in process]

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Provision of information on transplantation to cystic fibrosis patients and their relatives: Overview of French practices and recommendations.

Respir Med Res. 2020 Jan 23;77:79-88

Authors: David V, Perrin A, Le Rhun A, Pougheon-Bertrand D, Kanaan R, Grenet D, Moret L

Abstract
BACKGROUND: How health-care professionals inform cystic fibrosis patients and their relatives about transplantation is not well known. Such information may not be provided in a timely or satisfactory manner. We conducted a survey about patient information practices among professionals from all French cystic fibrosis centers and transplant centers, to determine how they might be improved.
METHODS: This was a national, retrospective, multicenter, descriptive assessment of practices involving health-care professionals, transplant recipients and their relatives, and peer patients who are themselves transplant recipients. Questionnaires were developed by the French working group on cystic fibrosis patient education (GETHEM: Groupe éducation thérapeutique et mucoviscidose). At the end of the questionnaires, respondents were invited to suggest ways to improve the current process.
RESULTS: In all, 216 professionals, 55 patients, 30 relatives of these patients, and 17 peer patients responded to the questionnaires, which addressed topics in chronological order, from neonatal screening or later diagnosis of the illness to the time of the transplant, if one was performed.
CONCLUSIONS: Study findings have allowed us to draft nine recommendations for professionals to improve patient information practices. A booklet now being prepared aims to facilitate the process for professionals, and e-learning modules are also forthcoming.

PMID: 32492649 [PubMed - as supplied by publisher]

Inactivation of Rho GTPases by Burkholderia cenocepacia Induces a WASH-Mediated Actin Polymerization that Delays Phagosome Maturation.

Cell Rep. 2020 Jun 02;31(9):107721

Authors: Walpole GFW, Plumb JD, Chung D, Tang B, Boulay B, Osborne DG, Piotrowski JT, Catz SD, Billadeau DD, Grinstein S, Jaumouillé V

Abstract
Burkholderia cenocepacia is an opportunistic bacterial pathogen that causes severe pulmonary infections in cystic fibrosis and chronic granulomatous disease patients. B. cenocepacia can survive inside infected macrophages within the B. cenocepacia-containing vacuole (BcCV) and to elicit a severe inflammatory response. By inactivating the host macrophage Rho GTPases, the bacterial effector TecA causes depolymerization of the cortical actin cytoskeleton. In this study, we find that B. cenocepacia induces the formation of large cytosolic F-actin clusters in infected macrophages. Cluster formation requires the nucleation-promoting factor WASH, the Arp2/3 complex, and TecA. Inactivation of Rho GTPases by bacterial toxins is necessary and sufficient to induce the formation of the cytosolic actin clusters. By hijacking WASH and Arp2/3 activity, B. cenocepacia disrupts interactions with the endolysosomal system, thereby delaying the maturation of the BcCV.

PMID: 32492429 [PubMed - as supplied by publisher]

Cardiac and Pulmonary Disorders and the Nervous System.

Continuum (Minneap Minn). 2020 Jun;26(3):556-576

Authors: Weathered NR

Abstract
PURPOSE OF REVIEW: This article reviews the neurologic complications encountered with cardiac and pulmonary disorders, specifically focusing on endocarditis, cardiac arrest, heart failure, hypercapnia, hypoxia, and cystic fibrosis. As neurologic dysfunction is one of the most frequent complications of these diseases and may even be the presenting symptom, it is important to be familiar with these complications to foster early recognition and intervention.
RECENT FINDINGS: Advances have been made in the identification of which patients can safely undergo valvular surgery for treatment of infective endocarditis in the setting of stroke, which, ideally, will minimize the risk of recurrent stroke in these patients. Additionally, technologic advances are improving our ability to use a multimodal approach for prognostication after cardiac arrest.
SUMMARY: The neurologic complications from the described disorders range from cerebrovascular complications to encephalitis, cognitive impairment, sleep-disordered breathing, headache, and increased intracranial pressure leading to coma or even death. Given the severity of these symptoms, it is paramount that neurologists be closely involved in the care of patients with neurologic complications from cardiac and pulmonary disorders.

PMID: 32487896 [PubMed - in process]

TMEM16A deficiency: a potentially fatal neonatal disease resulting from impaired chloride currents.

J Med Genet. 2020 Jun 02;:

Authors: Park JH, Ousingsawat J, Cabrita I, Bettels RE, Große-Onnebrink J, Schmalstieg C, Biskup S, Reunert J, Rust S, Schreiber R, Kunzelmann K, Marquardt T

Abstract
INTRODUCTION: TMEM16A is a calcium-activated chloride channel expressed in various secretory epithelia. Two siblings presented in early infancy with reduced intestinal peristalsis and recurrent episodes of haemorrhagic diarrhoea. In one of them, the episodes were characterised by hepatic pneumatosis with gas bubbles in the portal vein similar to necrotising enterocolitis of the newborn.
METHODS: Exome sequencing identified a homozygous truncating pathogenic variant in ANO1. Expression analysis was performed using reverse transcription PCR, western blot and immunohistochemistry. Electrophysiological and cell biological studies were employed to characterise the effects on ion transport both in patient respiratory epithelial cells and in transfected HEK293 cells.
RESULTS: The identified variant led to TMEM16A dysfunction, which resulted in abolished calcium-activated Cl- currents. Secondarily, CFTR function is affected due to the close interplay between both channels without inducing cystic fibrosis (CF).
CONCLUSION: TMEM16A deficiency is a potentially fatal disorder caused by abolished calcium-activated Cl- currents in secretory epithelia. Secondary impairment of CFTR function did not cause a CF phenotyp, which may have implications for CF treatment.

PMID: 32487539 [PubMed - as supplied by publisher]

Development of the gut microbiota in early life: The impact of cystic fibrosis and antibiotic treatment.

J Cyst Fibros. 2020 May 30;:

Authors: Kristensen M, Prevaes SMPJ, Kalkman G, Tramper-Stranders GA, Hasrat R, de Winter-de Groot KM, Janssens HM, Tiddens HA, van Westreenen M, Sanders EAM, Arets B, Keijser B, van der Ent CK, Bogaert D

Abstract
OBJECTIVES: Patients with Cystic Fibrosis (CF) suffer from pancreatic insufficiency, lipid malabsorption and gastrointestinal complaints, next to progressive pulmonary disease. Altered mucosal homoeostasis due to malfunctioning chloride channels results in an adapted microbial composition of the gastrointestinal and the respiratory tract. Additionally, antibiotic treatment has the potential to distort resident microbial communities dramatically. This study aims to investigate early life development of the gut microbial community composition of children with CF compared to healthy infants and to study the independent effects of antibiotics taking into account other clinical and lifestyle factors.
STUDY DESIGN: Faecal samples from 20 infants with CF and 45 healthy infants were collected regularly during the first 18 months of life and microbial composition was determined using 16S rRNA based sequencing.
RESULTS: We observed significant differences in the overall microbiota composition between infants with CF and healthy infants (p<0.001). Akkermansia and Anaerostipes were significantly more abundant in control infants, whereas Streptococci and E. coli were significantly more abundant in infants with CF, also after correction for several clinical factors (p<0.05). Antibiotic use in infants with CF was associated with a lower alpha diversity, a reduced abundance of Bifidobacterium and Bacteroides, and a higher abundance of Enterococcus.
CONCLUSION: Microbial development of the gut is different in infants with CF compared to healthy infants from the first months of life on, and further deviates over time, in part as a result of antibiotic treatment. The resulting dysbiosis may have significant functional consequences for the microbial ecosystem in CF patients.

PMID: 32487494 [PubMed - as supplied by publisher]

Metabolomics profiling of tobacco exposure in children with cystic fibrosis.

J Cyst Fibros. 2020 May 30;:

Authors: Wisniewski BL, Shrestha CL, Zhang S, Thompson R, Gross M, Groner JA, Uppal K, Ramilo O, Mejias A, Kopp BT

Abstract
BACKGROUND: Inflammation is integral to early disease progression in children with CF. The effect of modifiable environmental factors on infection and inflammation in persons with CF is poorly understood. Our prior studies determined that secondhand smoke exposure (SHSe) is highly prevalent in young children with CF. SHSe is associated with increased inflammation, heightened bacterial burden, and worsened clinical outcomes. However, the specific metabolite and signaling pathways that regulate responses to SHSe in CF are relatively unknown.
METHODS: High-resolution metabolomics was performed on plasma samples from infants (n = 25) and children (n = 40) with CF compared to non-CF controls (n = 15). CF groups were stratified according to infant or child age and SHSe status.
RESULTS: Global metabolomic profiles segregated by age and SHSe status. SHSe in CF was associated with changes in pathways related to steroid biosynthesis, fatty acid metabolism, cysteine metabolism, and oxidative stress. CF infants with SHSe demonstrated enrichment for altered metabolite localization to the small intestine, liver, and striatum. CF children with SHSe demonstrated metabolite enrichment for organs/tissues associated with oxidative stress including mitochondria, peroxisomes, and the endoplasmic reticulum. In a confirmatory analysis, SHSe was associated with changes in biomarkers of oxidative stress and cellular adhesion including MMP-9, MPO, and ICAM-1.
CONCLUSIONS: SHSe in young children and infants with CF is associated with altered global metabolomics profiles and specific biochemical pathways, including enhanced oxidative stress. SHSe remains an important but understudied modifiable variable in early CF disease.

PMID: 32487493 [PubMed - as supplied by publisher]

Short-term effects of Lumacaftor/Ivacaftor (Orkambi™) on exertional symptoms, exercise performance, and ventilatory responses in adults with cystic fibrosis.

Respir Res. 2020 Jun 01;21(1):135

Authors: Quon BS, Ramsook AH, Dhillon SS, Mitchell RA, Boyle KG, Wilcox PG, Guenette JA

Abstract
RATIONALE: Lumacaftor/ivacaftor (LUM/IVA) modestly improves lung function following 1 month of treatment but it is unknown if this translates into improvements in exercise endurance and exertional symptoms.
METHODS: Adult CF participants completed a symptom-limited constant load cycling test with simultaneous assessments of dyspnea and leg discomfort ratings pre- and 1 month post-initiation of LUM/IVA.
RESULTS: Endurance time, exertional dyspnea and leg discomfort ratings at submaximal exercise did not change significantly. There was a significant inverse correlation between changes in leg discomfort and endurance time (r = - 0.88; p = 0.009) following 1-month of LUM/IVA.
CONCLUSIONS: Overall, 1-month of LUM/IVA did not increase endurance time or modify exertional dyspnea or leg discomfort ratings. However, individuals who experienced a reduction in leg discomfort following LUM/IVA had an improvement in endurance time. Future studies with a larger sample size are needed to verify these findings and to assess the long-term effects of LUM/IVA on exercise outcomes.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02821130. Registered July 1, 2016.

PMID: 32487229 [PubMed - in process]