Omics in CF - Where are we now?

J Cyst Fibros. 2019 07;18(4):443-444

Authors: Farinha CM

PMID: 31155455 [PubMed - indexed for MEDLINE]

Assessing the impact of cystic fibrosis on the antipyretic response of ibuprofen in children: physiologically-based modeling as a candle in the dark.

Br J Clin Pharmacol. 2020 Apr 25;:

Authors: Cicali B, Long T, Kim S, Cristofoletti R

Abstract
AIM: The goal of this study is to present the utility of quantitative modeling for extrapolation of drug safety and efficacy to underrepresented populations in controlled clinical trials. To illustrate this, the stepwise development of an integrated disease/pharmacokinetics/pharmacodynamics model of antipyretic efficacy of ibuprofen in children with cystic fibrosis (CF) is presented along with therapy optimization suggestions.
METHOD: Published clinical trials, in vitro data and drug physiochemical properties were used to develop an ibuprofen-mediated antipyresis model for febrile children also having CF. Workflow included first developing a mechanistic absorption model using in vitro-in vivo extrapolation followed by physiologically-based pharmacokinetic (PBPK) modeling. The verified PBPK model was then scaled to pediatric patients with CF. Once verified, the PBPK model was linked to an indirect response model of antipyresis for simulation of the overall antipyretic efficacy of ibuprofen in CF children.
RESULTS: Model simulations showed therapeutic inequivalence between healthy children and pediatric patients with CF; Cmax and AUC decreased by 39% (32-46%) and 44% (36-52%), respectively, in patients. Further and in agreement with literature reports, predicted pharmacodynamics time courses suggest a slower onset and faster offset of action in patients compared to healthy children, 30 and 60 minutes, respectively. Exploratory simulations suggest an increase in dosing frequency for CF children as a better therapeutic strategy.
CONCLUSION: Model-informed approaches to leveraging knowledge obtained throughout the life cycle of drug development may play a key role in extrapolating drug efficacy and safety to underrepresented populations.

PMID: 32335930 [PubMed - as supplied by publisher]

The specialist as primary care provider in CF.

J Cyst Fibros. 2020 Apr 22;:

Authors: Haywood KB, Goralski JL

PMID: 32335024 [PubMed - as supplied by publisher]

Use of a mobile application for self-management of pancreatic enzyme replacement therapy is associated with improved gastro-intestinal related quality of life in children with Cystic Fibrosis.

J Cyst Fibros. 2020 Apr 22;:

Authors: Boon M, Calvo-Lerma J, Claes I, Havermans T, Asseiceira I, Bulfamante A, Garriga M, Masip E, van Schijndel BAM, Fornes V, Barreto C, Colombo C, Crespo P, Vicente S, Janssens H, Hulst J, Witters P, Nobili R, Pereira L, Ruperto M, Van der Wiel E, Mainz JG, De Boeck K, Ribes-Koninckx C

Abstract
BACKGROUND: Most patients with cystic fibrosis (CF) suffer from pancreatic insufficiency (PI), leading to fat malabsorption, malnutrition, abdominal discomfort and impaired growth. Pancreatic enzyme replacement therapy (PERT) is effective, but evidence based guidelines for dose adjustment are lacking. A mobile app for self-management of PERT was developed in the context of the HORIZON 2020 project MyCyFAPP. It contains an algorithm to calculate individual PERT-doses for optimal fat digestion, based on in vitro and in vivo studies carried out in the same project. In addition, the app includes a symptoms diary, educational material, and it is linked to a web tool allowing health care professionals to evaluate patient's data and provide feedback.
METHODS: A 6-month open label prospective multicenter interventional clinical trial was performed to assess effects of using the app on gastro-intestinal related quality of life (GI QOL), measured by the CF-PedsQL-GI (shortened, CF specific version of the Pediatric Quality of Life Inventory, Gastrointestinal Symptoms Module).
RESULTS: One hundred and seventy-one patients with CF and PI between 2 and 18 years were recruited at 6 European CF centers. Self-reported CF-PedsQL-GI improved significantly from month 0 (M0) (84.3, 76.4-90.3) to month 6 (M6) (89.4, 80.35-93.5) (p< 0.0001). Similar improvements were reported by parents. Lower baseline CF-PedsQL-GI was associated with a greater improvement at M6 (p < 0.001).
CONCLUSIONS: The results suggest that the MyCyFAPP may improve GI QOL for children with CF. This tool may help patients to improve self-management of PERT, especially those with considerable GI symptoms.

PMID: 32335023 [PubMed - as supplied by publisher]

[Computed tomography in children with cystic fibrosis: The role of an expiratory protocol].

Rev Mal Respir. 2020 Apr 22;:

Authors: Simon S, Baunin C, Vial J, Mas E, Roditis L, Michelet M, Mittaine M

Abstract
INTRODUCTION: Chest computed tomography (CT) is essential to monitor lung disease in children with cystic fibrosis, but it involves recurrent exposure to ionizing radiation. The aim of this study was to compare the current complete CT protocol (volumetric end-inspiratory plus sequential expiratory acquisition) to a sequential expiratory acquisition protocol alone in terms of image analysis and ionizing radiation dose.
METHODS: Seventy-eight CT scans from 57 children aged 5 to 18 years old were scored on the complete protocol images and on the expiratory sequential images only. Each CT protocol was scored independently, using the Brody scoring system, by two paediatric radiologists.
RESULTS: Correlations between the Brody global scores of the two different CT protocols were very good (r=0.90 for both observers), for the bronchiectasis score (r=0.72 and 0.86), mucus plugging score (r=0.87 and 0.83), and expiratory trapped air (r=0.96 and 0.92). Total ionizing radiation dose was reduced, with the measured dose length product (DLP) reduced from 103.31mGy.cm (complete protocol) to 3.06mGy.cm (expiratory protocol) (P<0.001).
CONCLUSION: An expiratory chest CT protocol was accurate in diagnosing early signs of CF disease and permitted significant reduction of radiation dose. This protocol would allow spacing out of complete CT scanning with its higher radiation dose and should be considered for the monitoring of lung disease severity in children with CF.

PMID: 32334966 [PubMed - as supplied by publisher]

Comparison of MycoPrep and the new MYCO-TB kit: rapid and efficient digestion and decontamination of respiratory specimens for the detection of Mycobacteria.

New Microbiol. 2020 Jan;43(1):13-16

Authors: Bisognin F, Lombardi G, Lombardo D, Re MC, Dal Monte P

Abstract
The long incubation time required for Mycobacteria detection may allow cultures to become overgrown by contaminating organisms. Therefore, samples need to be decontaminated before solid and liquid culture. MYCO-TB is a ready-to-use digestion and decontamination kit with single-sample formulation developed by Copan. Sample processing time (3 minutes) is shorter than that of other commercial kits. The aim of this study was to compare the performance of MYCO-TB with MycoPrep, both based on N-acetyl-Lcysteine and sodium hydroxide solution, in terms of culture contamination and Mycobacterial detection by culture. We tested 162 respiratory samples: the overall proportions of contamination of both liquid and solid media were 1.8% for MYCO-TB and 1.8% for MycoPrep. Mycobacterial growth was detected without significant differences in times to positivity (TTP) in liquid culture: 10.5 days for MYCO-TB and 11.1 days for MycoPrep. Samples decontaminated with MYCO-TB were suitable for molecular assays such as Xpert MTB/RIF Ultra and GenoType CMdirect. Extending decontamination times (up to 10 minutes) with MYCO-TB of 20 Mycobacteria-positive specimens did not produce any difference in TTP in liquid culture or in Ultra IS1081/IS6110 probe Ct values. In conclusion, the MYCO-TB kit proved to be effective for the rapid digestion and decontamination of respiratory materials for the detection of Mycobacteria, making it possible to reduce the manual skills required and lower the risk of contamination. Longer decontamination time could be used for samples with a high level of contamination, such as those from cystic fibrosis patients.

PMID: 32334488 [PubMed - as supplied by publisher]

A new future for patients with cystic fibrosis.

Am J Transplant. 2020 May;20(5):1213-1214

Authors: Pullen LC

PMID: 32333514 [PubMed - as supplied by publisher]

Expression of Cl- channels/transporters in nasal polyps.

Eur Arch Otorhinolaryngol. 2020 Apr 24;:

Authors: Nguyen TN, Do BH, Kitamura T, Ohkubo JI, Wakasugi T, Ohbuchi T, Suzuki H

Abstract
PURPOSE: Nasal polyp formation is a common sequela of prolonged chronic rhinosinusitis, but the mechanism underlying this disease state is still controversial. We compared the expressions of Cl- channels/transporters in nasal polyps with those in inferior turbinates to explore whether a deficiency in Cl- transport may participate in the pathophysiology of nasal polyp formation as in patients with cystic fibrosis.
METHODS: Nasal polyps and inferior turbinates were collected from 12 chronic rhinosinusitis patients with hypertrophic rhinitis and/or nasal polyps. Expressions of cystic fibrosis transmembrane conductance regulator (CFTR), pendrin, Na+-K+-2Cl- cotransporter 1 (NKCC1), SLC26A3, TMEM16A and anion exchanger 2 (AE2) were examined by fluorescence immunohistochemistry using Alexa Fluor 488.
RESULTS: CFTR was weakly expressed on the epithelial surface of the turbinate mucosa whereas the nasal polyps showed almost no fluorescence. Pendrin was mainly expressed on the epithelial surface in both tissues. The fluorescence was moderate in the nasal polyps and strong in the turbinate mucosa. For NKCC1, moderate fluorescence was observed throughout the entire epithelial layer of the nasal polyps, but the turbinate mucosa exhibited almost no fluorescence. On the other hand, no fluorescence for SLC26A3, TMEM16A or AE2 was seen in either tissue.
CONCLUSION: These results suggest that CFTR, pendrin and NKCC1 may participate in the pathogenesis of nasal mucosal edema and play roles in the mechanism of nasal polyp formation.

PMID: 32333139 [PubMed - as supplied by publisher]

Chemical modifications of adenine base editor mRNA and guide RNA expand its application scope.

Nat Commun. 2020 Apr 24;11(1):1979

Authors: Jiang T, Henderson JM, Coote K, Cheng Y, Valley HC, Zhang XO, Wang Q, Rhym LH, Cao Y, Newby GA, Bihler H, Mense M, Weng Z, Anderson DG, McCaffrey AP, Liu DR, Xue W

Abstract
CRISPR-Cas9-associated base editing is a promising tool to correct pathogenic single nucleotide mutations in research or therapeutic settings. Efficient base editing requires cellular exposure to levels of base editors that can be difficult to attain in hard-to-transfect cells or in vivo. Here we engineer a chemically modified mRNA-encoded adenine base editor that mediates robust editing at various cellular genomic sites together with moderately modified guide RNA, and show its therapeutic potential in correcting pathogenic single nucleotide mutations in cell and animal models of diseases. The optimized chemical modifications of adenine base editor mRNA and guide RNA expand the applicability of CRISPR-associated gene editing tools in vitro and in vivo.

PMID: 32332735 [PubMed - as supplied by publisher]

Redesign of the Australian Cystic Fibrosis Data Registry: A multidisciplinary collaboration.

Paediatr Respir Rev. 2020 Mar 26;:

Authors: Ahern S, Dean J, Liman J, Ruseckaite R, Burke N, Gollan M, Keatley L, King S, Kotsimbos T, Middleton PG, Schultz A, Wainwright C, Wark P, Bell S

Abstract
Clinical registries that monitor and review outcomes for patients with cystic fibrosis have existed internationally for many decades. However, their purpose continues to evolve and now includes the capability to support clinical effectiveness research, clinical trials and Phase IV studies, and international data comparisons and projects. To achieve this, registries must regularly update the information that they collect and ensure design that is adaptable and flexible to changing needs. The Australian Cystic Fibrosis Data Registry commenced in 1998, and in 2018-19 undertook a transformation to enable it to meet the needs of multiple stakeholders into the future. This included a comprehensive, multidisciplinary review of the registry's data elements, and a redesign and rebuild of the registry's database. The data element review comprised the processes of alignment, comparison, selection, consolidation, revision and definition of finalised data elements. The database redesign included attention to each of the registry functions of data collection, storage and management, and reporting. The revision of a national data collection system is a time-intensive process, and requires significant clinical and other expert engagement. The resulting database, while being continually refined, is now fit for purpose to support Australian clinicians and patients with CF to receive best practice care.

PMID: 32331762 [PubMed - as supplied by publisher]

Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Ubiquitylation as a Novel Pharmaceutical Target for Cystic Fibrosis.

Pharmaceuticals (Basel). 2020 Apr 22;13(4):

Authors: Fukuda R, Okiyoneda T

Abstract
Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene decrease the structural stability and function of the CFTR protein, resulting in cystic fibrosis. Recently, the effect of CFTR-targeting combination therapy has dramatically increased, and it is expected that add-on drugs that modulate the CFTR surrounding environment will further enhance their effectiveness. Various interacting proteins have been implicated in the structural stability of CFTR and, among them, molecules involved in CFTR ubiquitylation are promising therapeutic targets as regulators of CFTR degradation. This review focuses on the ubiquitylation mechanism that contributes to the stability of mutant CFTR at the endoplasmic reticulum (ER) and post-ER compartments and discusses the possibility as a pharmacological target for cystic fibrosis (CF).

PMID: 32331485 [PubMed - as supplied by publisher]

Discovery of Cephalosporin-3´-Diazeniumdiolates that show Dual Antibacterial and Antibiofilm Effects against Pseudomonas aeruginosa Clinical Cystic Fibrosis Isolates and Efficacy in a Murine Respiratory Infection Model.

ACS Infect Dis. 2020 Apr 24;:

Authors: Rineh A, Soren O, McEwan T, Ravikumar V, Poh WH, Azamifar F, Naimi-Jamal MR, Cheung CY, Elliott AG, Zuegg J, Blaskovich MAT, Cooper MA, Dolange V, Christodoulides M, Cook GM, Rice SA, Faust SN, Webb JS, Kelso MJ

Abstract
The formation of biofilms provides a formidable defense for many bacteria against antibiotics and host immune responses. As a consequence, biofilms are thought to be the root cause of most chronic infections, including those occurring on medical indwelling devices, endocarditis, urinary tract infections, diabetic and burn wounds and bone and joint infections. In cystic fibrosis (CF), chronic Pseudomonas aeruginosa respiratory infections are the leading cause of morbidity and mortality in adults. Previous studies have shown that many bacteria can undergo a coordinated dispersal event in the presence of low concentrations of nitric oxide (NO), suggesting that NO could be used to trigger biofilm dispersal in chronic infections and enable clearance of the more vulnerable planktonic cells. In this proof-of-principle study, we describe efforts to create 'all-in-one' cephalosporin-based NO donor prodrugs (cephalosporin-3´-diazeniumdiolates, C3Ds) that show both direct beta-lactam mediated antibacterial activity and NO-induced antibiofilm effects. Twelve novel C3Ds were synthesized and screened against a panel of P. aeruginosa CF clinical isolates and other human pathogens. The most active compound, AMINOPIP2-ceftazidime 12, showed higher antibacterial potency than its parent cephalosporin and front-line antipseudomonal antibiotic ceftazidime, good stability against beta-lactamases, activity against ceftazidime-resistant P. aeruginosa in vitro biofilms and efficacy equivalent to ceftazidime in a murine P. aeruginosa respiratory infection model. The results support further evaluation of AMINOPIP2-ceftazidime 12 for P. aeruginosa lung infections in CF and broader study of 'all-in-one' C3Ds for other chronic infections.

PMID: 32329596 [PubMed - as supplied by publisher]

Bilateral Pneumonia in a Patient with Chronic Bronchiectasis Caused by Achromobacter xylosoxidans Subspecies denitrificans.

Cureus. 2020 Mar 23;12(3):e7381

Authors: Stepman G, Dabb K, Khan IA, Young JT, Frunzi J

Abstract
Achromobacter xylosoxidans is a gram-negative bacillus that has a multitude of inherent and acquired antimicrobial resistance. It is a rare, isolated pathogen in patients without cystic fibrosis (CF). We report the case of a 76-year-old Caucasian male with a history of chronic obstructive pulmonary disease (COPD), previous Mycobacterium-avium intracellulare (MAI) infection, and chronic bronchiectasis who did not respond to three courses of outpatient antibiotics for a chronic cough. He also had a 21-lb weight loss. The diagnosis of Achromobacter xylosoxidans subspecies denitrificans was made through bronchoscopy with bronchoalveolar lavage (BAL). There are few case reports describing Achromobacter xylosoxidans subspecies denitrificans in non-CF patients. Achromobacter xylosoxidans colonization might be linked to predisposing lung damage such as in CF and bronchiectasis. The bacterium is frequently multidrug-resistant. More studies are needed to develop recommendations for clinical guidelines to address the increasing antibiotic resistance to Achromobacter xylosoxidans.

PMID: 32328391 [PubMed]

Rhinovirus Infection Is Associated With Airway Epithelial Cell Necrosis and Inflammation via Interleukin-1 in Young Children With Cystic Fibrosis.

Front Immunol. 2020;11:596

Authors: Montgomery ST, Frey DL, Mall MA, Stick SM, Kicic A, AREST CF

Abstract
Introduction: The responses of cystic fibrosis (CF) airway epithelial cells (AEC) to rhinovirus (RV) infection are likely to contribute to early pathobiology of lung disease with increased neutrophilic inflammation and lower apoptosis reported. Necrosis of AEC resulting in airway inflammation driven by IL-1 signaling is a characteristic finding in CF detectable in airways of young children. Being the most common early-life infection, RV-induced epithelial necrosis may contribute to early neutrophilic inflammation in CF via IL-1 signaling. As little is known about IL-1 and biology of CF lung disease, this study assessed cellular and pro-inflammatory responses of CF and non-CF AEC following RV infection, with the hypothesis that RV infection drives epithelial necrosis and IL-1 driven inflammation. Methods:Primary AEC obtained from children with (n = 6) and without CF (n = 6) were infected with RV (MOI 3) for 24 h and viable, necrotic and apoptotic events quantified via flow cytometry using a seven-step gating strategy (% total events). IL-1α, IL-1β, IL-1Ra, IL-8, CXCL10, CCL5, IFN-β, IL-28A, IL-28B, and IL-29 were also measured in cell culture supernatants (pg/mL). Results:RV infection reduced viable events in non-CF AEC (p < 0.05), increased necrotic events in non-CF and CF AEC (p < 0.05) and increased apoptotic events in non-CF AEC (p < 0.05). Infection induced IL-1α and IL-1β production in both phenotypes (p < 0.05) but only correlated with necrosis (IL-1α: r = 0.80; IL-1β: r = 0.77; p < 0.0001) in CF AEC. RV infection also increased IL-1Ra in non-CF and CF AEC (p < 0.05), although significantly more in non-CF AEC (p < 0.05). Finally, infection stimulated IL-8 production in non-CF and CF AEC (p < 0.05) and correlated with IL-1α (r = 0.63 & r = 0.74 respectively; p < 0.0001). Conclusions:This study found RV infection drives necrotic cell death in CF AEC. Furthermore, RV induced IL-1 strongly correlated with necrotic cell death in these cells. As IL-1R signaling drives airway neutrophilia and mucin production, these observations suggest RV infection early in life may exacerbate inflammation and mucin accumulation driving early CF lung disease. Since IL-1R can be targeted therapeutically with IL-1Ra, these data suggest a new anti-inflammatory therapeutic approach targeting downstream effects of IL-1R signaling to mitigate viral-induced, muco-inflammatory triggers of early lung disease.

PMID: 32328066 [PubMed - in process]

The Contribution of Membrane Vesicles to Bacterial Pathogenicity in Cystic Fibrosis Infections and Healthcare Associated Pneumonia.

Front Microbiol. 2020;11:630

Authors: Vitse J, Devreese B

Abstract
Almost all bacteria secrete spherical membranous nanoparticles, also referred to as membrane vesicles (MVs). A variety of MV types exist, ranging from 20 to 400 nm in diameter, each with their own formation routes. The most well-known vesicles are the outer membrane vesicles (OMVs) which are formed by budding from the outer membrane in Gram-negative bacteria. Recently, other types of MVs have been discovered and described, including outer-inner membrane vesicles (OIMVs) and cytoplasmic membrane vesicles (CMVs). The former are mainly formed by a process termed endolysin-triggered cell lysis in Gram-negative bacteria, the latter are formed by Gram-positive bacteria. MVs carry a wide range of cargo, such as nucleic acids, virulence factors and antibiotic resistance components. Moreover, they are involved in a multitude of biological processes that increase bacterial pathogenicity. In this review, we discuss the functional aspects of MVs secreted by bacteria associated with cystic fibrosis and nosocomial pneumonia. We mainly focus on how MVs are involved in virulence, antibiotic resistance, biofilm development and inflammation that consequently aid these bacterial infections.

PMID: 32328052 [PubMed]

Cell free DNA from respiratory pathogens is detectable in the blood plasma of Cystic Fibrosis patients.

Sci Rep. 2020 Apr 23;10(1):6903

Authors: Barrett SLR, Holmes EA, Long DR, Shean RC, Bautista GE, Ravishankar S, Peddu V, Cookson BT, Singh PK, Greninger AL, Salipante SJ

Abstract
Diagnostically informative microbial cell-free DNA (cfDNA) can be detected from blood plasma during fulminant infections such as sepsis. However, the potential for DNA from airway pathogens to enter the circulation of cystic fibrosis (CF) patients during chronic infective states has not yet been evaluated. We assessed whether patient blood contained measurable quantities of cfDNA from CF respiratory microorganisms by sequencing plasma from 21 individuals with CF recruited from outpatient clinics and 12 healthy controls. To account for possible contamination with exogenous microbial nucleic acids, statistical significance of microbe-derived read counts from CF patients was determined relative to the healthy control population. In aggregate, relative abundance of microbial cfDNA was nearly an order of magnitude higher in CF patients than in healthy subjects (p = 8.0×10-3). 15 of 21 (71%) CF patients demonstrated cfDNA from one or more relevant organisms. In contrast, none of the healthy subjects evidenced significant microbial cfDNA for any of the organisms examined. Concordance of cfDNA with standard microbiological culture of contemporaneously collected patient sputum was variable. Our findings provide evidence that cfDNA from respiratory pathogens are present in the bloodstream of most CF patients, which could potentially be exploited for the purposes of noninvasive clinical diagnosis.

PMID: 32327704 [PubMed - in process]

Dyslipidemia is not associated with the development of glucose intolerance or diabetes in cystic fibrosis.

J Cyst Fibros. 2020 Apr 20;:

Authors: Colomba J, Rabasa-Lhoret R, Bonhoure A, Bergeron C, Boudreau V, Tremblay F, Senior P, Potter K

Abstract
BACKGROUND: A high-fat, high-calorie diet is recommended in patients with cystic fibrosis (CF) as it improves nutritional status, respiratory health and longevity. In the general population, this diet is associated with the risk of diabetes. It is unknown whether dyslipidemic changes might contribute to the development of CF-related diabetes (CFRD).
OBJECTIVE: This study aimed to (i) characterize dyslipidemia and (ii) examine the association between dyslipidemia and development of glucose intolerance.
METHODS: Prospective observational study with serial assessments of pulmonary function, glucose tolerance, and lipid profile. Due to intrinsically low total, HDL and LDL cholesterol in patients with CF, subjects were characterized as having dyslipidemia if they had i) HDL in the lowest quartile and/or ii) hypertriglyceridemia (≥1.7 mmol/L).
RESULTS: A total of 256 patients with CF were included (age: 25.5 ± 7.7 years; BMI: 21.7 ± 3.0 kg/m2; FEV1%: 73.2 ± 22.1%; pancreatic insufficiency: 87%). Amongst these patients, 22.7% had low HDL, 9.0% had hypertriglyceridemia and 3.9% had mixed dyslipidemia. There were no differences in HbA1c (p = 0.583) or estimated insulin resistance [HOMA-IR (p = 0.206) or Stumvoll index (p = 0.397)]. Patients with hypertriglyceridemia had higher fat mass (p = 0.038) and fewer had pancreatic insufficiency. Lipid profiles were similar between subjects with CF and subjects with de novo CFRD. There was no effect of low HDL or hypertriglyceridemia on the development of CFRD over 10 years (p = 0.683).
CONCLUSION: In adult patients with CF, dyslipidemia is not associated with the risk of developing hyperglycemia or CFRD.

PMID: 32327389 [PubMed - as supplied by publisher]

Penetrance is a critical parameter for assessing the disease liability of CFTR variants.

J Cyst Fibros. 2020 Apr 20;:

Authors: Boussaroque A, Audrézet MP, Raynal C, Sermet-Gaudelus I, Bienvenu T, Férec C, Bergougnoux A, Lopez M, Scotet V, Munck A, Girodon E

Abstract
BACKGROUND: Major issues of newborn screening (NBS) for CF are the assessment of disease liability of variants and of the penetrance of clinical CF, notably in inconclusive diagnosis. The penetrance of CF is defined as the risk of a particular genotype to lead to a CF phenotype.
METHODS: We aimed to get insight into the penetrance of CF for fifteen CFTR variants: 5 frequent CF-causing and 10 classified as of varying clinical consequence (VCC) or associated with a CFTR-related disorder (CFTR-RD) in CFTR2 or CFTR-France databases. The penetrance was approached by: (1) comparison of variant allelic frequencies in CF patients (CFTR2) and in the general population; (2) estimation of the likelihood of a positive NBS test for the 14 compound heterozygous with F508del and the F508del homozygous genotypes, defined as the ratio of detected/expected number of neonates with a given genotype in the 2002-2017 period.
RESULTS: A full penetrance was observed for severe CF-causing variants. Five variants were more frequently found in the general population than in CF patients: TG11T5, TG12T5, TG13T5, L997F and R117H;T7. The likelihood of a positive NBS test was 0.03% for TG11T5, 0.3% for TG12T5, 1.9% for TG13T5, 0.6% for L997F, 11.7% for D1152H, and 17.8% for R117H;T7. Penetrance varied greatly for variants with discrepant classification between CFTR2 and CFTR-France: 5.1% for R117C, 12.3% for T338I, 43.5% for D110H and 52.6% for L206W.
CONCLUSION: These results illustrate the contribution of genetics population data to assess the disease liability of variants for diagnosis and genetic counselling purposes.

PMID: 32327388 [PubMed - as supplied by publisher]

Whole genome sequencing of Nontuberculous Mycobacterium (NTM) isolates from sputum specimens of co-habiting patients with NTM pulmonary disease and NTM isolates from their environment.

BMC Genomics. 2020 Apr 23;21(1):322

Authors: Yoon JK, Kim TS, Kim JI, Yim JJ

Abstract
BACKGROUND: Nontuberculous mycobacterium (NTM) species are ubiquitous microorganisms. NTM pulmonary disease (NTM-PD) is thought to be caused not by human-to-human transmission but by independent environmental acquisition. However, recent studies using next-generation sequencing (NGS) have reported trans-continental spread of Mycobacterium abscessus among patients with cystic fibrosis.
RESULTS: We investigated NTM genomes through NGS to examine transmission patterns in three pairs of co-habiting patients with NTM-PD who were suspected of patient-to-patient transmission. Three pairs of patients with NTM-PD co-habiting for at least 15 years were enrolled: a mother and a daughter with M. avium-PD, a couple with M. intracellulare-PD, and a second couple, one of whom was infected with M. intracellulare and the other of whom was infected with M. abscessus. Whole genome sequencing was performed using patients' NTM isolates as well as environmental specimens. Genetic distances were estimated based on single nucleotide polymorphisms (SNPs). By comparison with the genetic distances among 78 publicly available NTM genomes, NTM isolates derived from the two pairs of patients infected with the same NTM species were not closely related to each other. In phylogenetic analysis, the NTM isolates from patients with M. avium-PD clustered with isolates from different environmental sources.
CONCLUSIONS: In conclusion, considering the genetic distances between NTM strains, the likelihood of patient-to-patient transmission in pairs of co-habiting NTM-PD patients without overt immune deficiency is minimal.

PMID: 32326890 [PubMed - in process]

Salivary Cytokines and Airways Disease Severity in Patients with Cystic Fibrosis.

Diagnostics (Basel). 2020 Apr 15;10(4):

Authors: Castaldo A, Iacotucci P, Carnovale V, Cimino R, Liguori R, Comegna M, Raia V, Corso G, Castaldo G, Gelzo M

Abstract
About 50% of patients with cystic fibrosis (CF) have sinonasal complications, which include inferior turbinate hypertrophy (NTH) and/or nasal polyposis (NP), and different degrees of lung disease, which represents the main cause of mortality. Monitoring of sinonasal disease requires complex instrumental procedures, while monitoring of lung inflammation requires invasive collection of bronchoalveolar lavage fluid. The aim of this study was to investigate the associations between salivary cytokines levels and CF-related airway diseases. Salivary biochemical parameters and cytokines, i.e., interleukin-6 (IL-6), IL-8, and tumor necrosis factor alpha (TNF-α), were analyzed in resting saliva from healthy subjects and patients with CF. Patients with CF showed significantly higher levels of salivary chloride, IL-6, IL-8, and TNF-α and lower calcium levels than healthy subjects. Among patients with CF, IL-6 and IL-8 were significantly higher in patients with NTH, while TNF-α was significantly lower in patients with NP. A decreasing trend of TNF-α in patients with severe lung disease was also observed. On the other hand, we did not find significant correlation between cytokine levels and Pseudomonas aeruginosa or Stenotrophomonas maltophilia colonization. These preliminary results suggest that salivary IL-6 and IL-8 levels increase during the acute phase of sinonasal disease (i.e., NTH), while the end stages of pulmonary disease and sinonasal disease (i.e., NP) show decreased TNF-α levels.

PMID: 32326546 [PubMed]