The utility of moment ratios and abbreviated endpoints of the multiple breath washout test in preschool children with cystic fibrosis.

Pediatr Pulmonol. 2020 Jan 03;:

Authors: Shaw M, Oppelaar MC, Jensen R, Stanojevic S, Davis SD, Retsch-Bogart G, Ratjen FA

Abstract
BACKGROUND: The multiple breath washout (MBW) test may be most useful in tracking disease progression over time to inform treatment decisions. In the clinical setting, alternative outcomes, which can be obtained quickly and easily, may facilitate interpretation of clinically relevant changes in lung function.
METHODS: In this secondary analysis of data from 78 cystic fibrosis (CF) and 72 healthy control (HC) subjects between the ages of 2.6 and 5.9 years, MBW was performed at enrollment, 1, 3, 6, 9, and 12 months, as well as during symptomatic visits using the Exhalyzer D (EcoMedics AG, Duernten, Switzerland). The lung clearance index, LCI2.5, was compared to moment ratios (M1 /M0 and M2 /M0 ) at the standard cutoff (1/40th of starting tracer gas concentration) as well as LCI5 and moment ratios at 1/20th of the starting concentration (M1 /M0 at LCI5 , and M2 /M0 at LCI5 ).
RESULTS: All outcomes were able to distinguish between health and disease. LCI5 reduced testing time by 40% and increased feasibility by more than 10%. The limits of biological reproducibility in healthy children were similar between LCI2.5 (15%), LCI5 (12%), M1 /M0 at LCI2.5 (14%), and M1 /M0 at LCI5 (12%), but markedly larger for M2 /M0 at LCI2.5 (30%) and M2 /M0 at LCI5 (25%). Each outcome deteriorated significantly with worsening pulmonary symptoms, the magnitude of deterioration was greatest for M2 /M0 .
CONCLUSIONS: In preschool children with CF, LCI5 was more feasible to obtain and track disease progression. The second moment ratio was most sensitive to pulmonary symptoms, but had the greatest variability both within and between subjects.

PMID: 31899855 [PubMed - as supplied by publisher]

Bronchial Artery Embolization for Hemoptysis in Cystic Fibrosis Patients: A 17-Year Review.

J Vasc Interv Radiol. 2019 Dec 30;:

Authors: Martin LN, Higgins L, Mohabir P, Sze DY, Hofmann LV

Abstract
PURPOSE: To review safety and efficacy of bronchial artery embolization (BAE) for treatment of hemoptysis in adult patients with cystic fibrosis (CF) and to report 30-day, 1-year, and 3-year outcomes.
MATERIALS AND METHODS: Between January 2001 and April 2018, 242 patients with CF were evaluated for hemoptysis. Thirty-eight BAEs were performed in 28 patients with hemoptysis. Technical success was defined as freedom from repeat embolization and hemoptysis-related mortality. Clinical success was defined as freedom from repeat embolization and mortality from any cause. Technical and clinical success were examined at 30 days, 1 year, and 3 years after initial BAE. Mean patient age was 32 years, and median follow-up was 4.8 years (range, 10 mo to 16.7 y).
RESULTS: Technical and clinical success rates at 30 days were 89% (25/28) and 82% (23/28), respectively. Success rates at 1 year were 86% (24/28) and 79% (22/28), respectively, and at 3 years were 82% (23/28) and 75% (21/28), respectively. The 30-day overall complication rate was 7.9% (3/38) with 2.6% (1/38) major complication rate and 5.2% (2/38) minor complication rate. Overall 3-year mortality rate was 25% (7/28).
CONCLUSIONS: BAE is safe and effective in patients with CF presenting with life-threatening hemoptysis. BAE results in high rates of long-term technical and clinical success in this patient population despite progressive chronic disease. Repeat embolization is necessary only in a minority of patients.

PMID: 31899109 [PubMed - as supplied by publisher]

TMEM16A Potentiation: A Novel Therapeutic Approach for the Treatment of Cystic Fibrosis.

Am J Respir Crit Care Med. 2020 Jan 03;:

Authors: Danahay HL, Lilley S, Fox R, Charlton H, Sabater J, Button B, McCarthy C, Collingwood SP, Gosling M

Abstract
Rationale: Enhancing non-CFTR mediated anion secretion is an attractive therapeutic approach for the treatment of cystic fibrosis and other muco-obstructive diseases. Objectives: To determine the effects of TMEM16A potentiation upon epithelial fluid secretion and mucociliary clearance. Methods: The effects of a novel low molecular weight TMEM16A potentiator (ETX001) were evaluated in human cell and animal models of airway epithelial function and mucus transport. Measurements & Main Results: Potentiating the activity of TMEM16A with ETX001 increased the Ca2+-activated Cl- channel activity and anion secretion in human bronchial epithelial cells from cystic fibrosis patients without impacting on calcium signalling. ETX001 rapidly increased fluid secretion and airway surface liquid height in cystic fibrosis human bronchial epithelial cells under both static and conditions designed to mimic the shear stress associated with tidal breathing. In ovine models of mucus clearance (tracheal mucus velocity and mucociliary clearance), inhaled ETX001 was able to accelerate clearance both when CFTR function was reduced by administration of a pharmacological blocker and when CFTR was fully functional. Conclusions: Enhancing the activity of TMEM16A increases epithelial fluid secretion and enhances mucus clearance independent of CFTR function. TMEM16A potentiation is a novel approach for the treatment of patients with cystic fibrosis and non-CF muco-obstructive diseases. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

PMID: 31898911 [PubMed - as supplied by publisher]

Osmoregulation in children with cystic fibrosis.

Eur J Pediatr. 2020 Jan 02;:

Authors: Natochin YV, Kuznetsova AA, Prokopenko AV, Milani GP, Lava SAG, Marina AS

Abstract
Hyponatremia is not rare in cystic fibrosis and might be due to several mechanisms. An endocrine and renal imbalance in water and salt homeostasis was suggested. To address this hypothesis, we assessed the urinary concentrating and diluting ability in 12 cystic fibrosis patients (6 females, 6 males) and in two control groups: 14 children with pneumonia (9 females, 5 males) and in 13 healthy children (9 females, 4 males). Renal concentrating ability was evaluated following overnight water deprivation. Urine osmolality was not significantly different between groups. Renal diluting ability was assessed by means of a water-load test. This provoked a decrease in urine osmolality, as well as an increase in diuresis and solute-free water excretion. These changes were comparable among groups.Conclusion: Children with cystic fibrosis show a preserved renal concentrating and diluting capacity. A generalized endocrine and renal imbalance in water and salt homeostasis therefore appears unlikely.What is Known:•Hyponatremia sometimes occurs in cystic fibrosis.What is New:•Osmoregulation is normal in cystic fibrosis.

PMID: 31897839 [PubMed - as supplied by publisher]

Relevance between clinical status and exhaled molecules related to neutrophilic inflammation in pediatric cystic fibrosis.

J Breath Res. 2020 Jan 02;:

Authors: Kanik ET, Yilmaz O, Ozdogru E, Alper H, Ulman C, Kanık A, Simsek Y, Yuksel H

Abstract
INTRODUCTION: Cystic fibrosis (CF) is characterized with chronic inflammation with neutrophil and related cytokines in airway secretions. We aimed to measure the levels of neutrophil related inflammatory markers as nitric oxide, IL-8, IL-17, leukotriene B4 and neutrophil elastase as well as e-cadherin in exhaled breath condensate (EBC) and to determine their relation with clinical findings.
METHODS: We consecutively enrolled cystic fibrosis patients in our clinics aged above five years who could cooperate for exhaled breath condensate to this case-control study (n=30). The age and sex matched control group (n=26) was enrolled. Spirometry was performed during the stable period and EBC samples were obtained for measurement of the markers.
RESULTS: Mean age of the subjects enrolled was 12.1(4.2) years and 40% were positive for pseudomonas aeruginosa in sputum. Subjects who had pseudomonas aeruginosa in sputum cultures had significantly lower FEV1, FVC and FEF 25/75 values compared to the ones without pseudomonas aeruginosa (p=0.002, p=0.002 and p=0.005 respectively). EBC neutrophil elastase levels were significantly higher in the CF patients compared to non-CF controls (3.11 ±4.71 vs 0.90 ±2.68, p=0.04). Nitric oxide, IL-17, IL-8, e-cadherin, neutrophil elastase or leukotriene B4 levels in EBC of CF patients were not related to pseudomonas infection, FEV1 levels or hospital admission in the last year.
CONCLUSION: In our study, neutrophil elastase levels in EBC are higher in CF patients compared to non-CF controls. This is independent of acute infection and is evidence to persistence of neutrophilic lung injury. However, EBC NO, IL-8, IL-17, e-cadherin, neutrophil elastase and leukotriene B4 levels as inflammatory markers, are not correlated with disease progression or clinical findings.

PMID: 31896101 [PubMed - as supplied by publisher]

Antibiofilm effect of mesoporous titania coatings on Pseudomonas aeruginosa biofilms.

J Photochem Photobiol B. 2019 Dec 24;203:111762

Authors: Pezzoni M, Catalano PN, Delgado DC, Pizarro RA, Bellino MG, Costa CS

Abstract
Activation of photocatalytic titania by ultraviolet-A (UVA) radiation has been proposed as a good approach for combating bacteria. Titania powder, in solution or immobilized on a surface, has excellent UVA-assisted killing properties on several microorganisms. However, these properties could not be demonstrated in biofilms of Pseudomonas aeruginosa, a resistant opportunistic human pathogen that can cause severe complications in patients who are immunocompromised or have burn wounds or cystic fibrosis. P. aeruginosa biofilms have detrimental effects on health and industry, causing serious economic damage. In this study, the effect of titania photocatalysis for controlling P. aeruginosa biofilms was investigated by employing different coatings obtained through sol-gel and evaporation-induced self-assembly. Biofilms were grown on non-mesoporous and mesoporous titania surfaces with different pore sizes, which were achieved based on the use of surfactants Brij-58 and Pluronics-F127. In addition, two structural forms of titania were assayed: amorphous and anatase. As well as inhibiting biofilm formation, these coatings significantly enhanced the bactericidal effect of UVA on P. aeruginosa biofilms. The most efficient surface with regard to total antibacterial effect was the mesoporous Brij-58-templated anatase film, which, compared to control biofilms, decreased the number of viable bacteria by about 5 orders, demonstrating the efficacy of this methodology as a disinfection system.

PMID: 31896049 [PubMed - as supplied by publisher]

Importance of superoxide dismutase A and M for protection of Staphylococcus aureus in the oxidative stressful environment of cystic fibrosis airways.

Cell Microbiol. 2020 Jan 02;:e13158

Authors: Treffon J, Chaves-Moreno D, Niemann S, Pieper DH, Vogl T, Roth J, Kahl BC

Abstract
Staphylococcus aureus is one of the earliest pathogens that persists the airways of cystic fibrosis (CF) patients and contributes to increased inflammation and decreased lung function. In contrast to other staphylococci, S. aureus possesses two superoxide dismutases (SODs), SodA and SodM, with SodM being unique to S. aureus. Both SODs arm S. aureus for its fight against oxidative stress, a byproduct of inflammatory reactions. Despite complex investigations it is still unclear, if both enzymes are crucial for the special pathogenicity of S. aureus. To investigate the role of both SODs during staphylococcal persistence in CF airways, we analyzed survival and gene expression of S. aureus CF isolates and laboratory strains in different CF-related in vitro and ex vivo settings. Bacteria located in inflammatory and oxidized CF sputum transcribed high levels of sodA and sodM. Especially expression values of sodM were remarkably higher in CF sputum than in bacterial in vitro cultures. Interestingly, also S. aureus located in airway epithelial cells expressed elevated transcript numbers of both SODs, indicating that S. aureus is exposed to oxidative stress at various sites within CF airways. Both enzymes promoted survival of S. aureus during PMN killing and seem to act compensatory, thereby giving evidence that the interwoven interaction of SodA and SodM contributes to S. aureus virulence and facilitates S. aureus persistence within CF airways. This article is protected by copyright. All rights reserved.

PMID: 31895486 [PubMed - as supplied by publisher]

Effect of lentivirus-mediated CFTR overexpression on oxidative stress injury and inflammatory response in the lung tissue of COPD mouse model.

Biosci Rep. 2020 Jan 02;:

Authors: Xu X, Huang H, Yin X, Fang H, Shen X

Abstract
We aimed to investigate the regulatory mechanism of lentivirus-mediated overexpression of cystic fibrosis transmembrane conductance regulator (CFTR) in oxidative stress injury and inflammatory response in the lung tissue of mouse model of chronic obstructive pulmonary disease (COPD). COPD mouse model induced by cigarette smoke was established and normal mice were used as control. The mice were assigned into a normal group (control), a model group (untreated), an oe-CFTR group (injection of lentivirus overexpressing CFTR), and an oe-NC group (negative control, injection of lentivirus expressing irrelevant sequences). Compared with the oe-NC group, the oe-CFTR group had higher CFTR expression and a better recovery of pulmonary function. CFTR overexpression could inhibit the pulmonary endothelial cell apoptosis, reduce the levels of glutathione, reactive oxygen species, and malondialdehyde, and increase the values of superoxide dismutase, glutathione peroxidase, and total antioxidant capacity. The overexpression also led to reductions in the white blood cell count in alveolus pulmonis, the concentrations of C-reactive protein, interleukin -6, and tumor necrosis factor -α, and the proteins expressions of NF-κB p65, ERK, JNK, p-EPK, and p-JNK related to MAPK/NF-κB p65 signaling pathway. In conclusion, CFTR overexpression can protect lung tissues from injuries caused by oxidative stress and inflammatory response in COPD mouse model. The mechanism behind this may be related to the suppression of MAPK/NF-κB p65 signaling pathway.

PMID: 31894837 [PubMed - as supplied by publisher]

Electrostatic Tuning of Anion Attraction from the Cytoplasm to the Pore of the CFTR Chloride Channel.

Cell Biochem Biophys. 2019 Dec 31;:

Authors: Linsdell P, Negoda A, Cowley EA, El Hiani Y

Abstract
Anions enter from the cytoplasm into the channel pore of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel not via a central pathway but via a single lateral portal or fenestration. High Cl- conductance is dependent on electrostatic attraction of cytoplasmic Cl- ions by four positively charged amino acid side-chains located within this portal. Here we use a mutagenic approach to investigate the functional effects of transplanting or supplementing these positive charges at nearby portal-lining sites. Using patch clamp recording, we find that the functionally important positive charges at K190 and R303 can be transplanted to four nearby sites (N186, L197, W356, and A367) with little loss of Cl- conductance. Introduction of additional positive charge at these sites had almost no effect on Cl- conductance, but did increase the sensitivity to channel block by intracellular suramin and Pt(NO2)42- anions. We suggest that it is the number of positive charges within the portal, rather than their exact location, that is the most important factor influencing Cl- conductance. The portal appears well optimized in terms of charge distribution to maximize Cl- conductance.

PMID: 31893350 [PubMed - as supplied by publisher]

Disorders of FZ-CRD; insights towards FZ-CRD folding and therapeutic landscape.

Mol Med. 2019 Dec 31;26(1):4

Authors: Milhem RM, Ali BR

Abstract
The ER is hub for protein folding. Proteins that harbor a Frizzled cysteine-rich domain (FZ-CRD) possess 10 conserved cysteine motifs held by a unique disulfide bridge pattern which attains a correct fold in the ER. Little is known about implications of disease-causing missense mutations within FZ-CRD families. Mutations in FZ-CRD of Frizzled class receptor 4 (FZD4) and Muscle, skeletal, receptor tyrosine kinase (MuSK) and Receptor tyrosine kinase-like orphan receptor 2 (ROR2) cause Familial Exudative Vitreoretinopathy (FEVR), Congenital Myasthenic Syndrome (CMS), and Robinow Syndrome (RS) respectively. We highlight reported pathogenic inherited missense mutations in FZ-CRD of FZD4, MuSK and ROR2 which misfold, and traffic abnormally in the ER, with ER-associated degradation (ERAD) as a common pathogenic mechanism for disease. Our review shows that all studied FZ-CRD mutants of RS, FEVR and CMS result in misfolded proteins and/or partially misfolded proteins with an ERAD fate, thus we coin them as "disorders of FZ-CRD". Abnormal trafficking was demonstrated in 17 of 29 mutants studied; 16 mutants were within and/or surrounding the FZ-CRD with two mutants distant from FZ-CRD. These ER-retained mutants were improperly N-glycosylated confirming ER-localization. FZD4 and MuSK mutants were tagged with polyubiquitin chains confirming targeting for proteasomal degradation. Investigating the cellular and molecular mechanisms of these mutations is important since misfolded protein and ER-targeted therapies are in development. The P344R-MuSK kinase mutant showed around 50% of its in-vitro autophosphorylation activity and P344R-MuSK increased two-fold on proteasome inhibition. M105T-FZD4, C204Y-FZD4, and P344R-MuSK mutants are thermosensitive and therefore, might benefit from extending the investigation to a larger number of chemical chaperones and/or proteasome inhibitors. Nonetheless, FZ-CRD ER-lipidation it less characterized in the literature and recent structural data sheds light on the importance of lipidation in protein glycosylation, proper folding, and ER trafficking. Current treatment strategies in-place for the conformational disease landscape is highlighted. From this review, we envision that disorders of FZ-CRD might be receptive to therapies that target FZ-CRD misfolding, regulation of fatty acids, and/or ER therapies; thus paving the way for a newly explored paradigm to treat different diseases with common defects.

PMID: 31892318 [PubMed - in process]

Perinatal Reduced Blood Concentrations of Free Carnitine and Acylcarnitines in Infants with Cystic Fibrosis.

Am J Perinatol. 2019 Dec 31;:

Authors: Schulpis KH, Molou E, Manta-Vogli P, Dotsikas Y, Thodi G, Chatzidaki M, Loukas YL

Abstract
OBJECTIVE:  Cystic fibrosis (CF) is a multisystemic inherited disease. The aim of this study was to determine free carnitine (FC) and acylcarnitine concentrations in CF newborns with various mutations of the CFTR gene perinatally.
STUDY DESIGN:  FC/acylcarnitines were determined in dried blood spots via liquid chromatography-tandem mass spectrometry (LC-MS/MS) on the third day of life of full-term normal (n = 50) and CF (n = 28) newborns. For infants with elevated immunoreactive trypsinogen values, FC/acylcarnitines were quantified again 48 hours later, followed by mutational analysis of CFTR gene via Sanger sequencing.
RESULTS:  Initial FC and sums of acylcarnitine concentrations were statistically significantly lower in CF patients than in controls and even lower 48 hours later. The mutations F508del and 621 + 1G > T were predominantly identified among CF patients.
CONCLUSION:  Low FC and acylcarnitine concentrations were measured perinatally in CF patients, for all CFTR mutations detected. Carnitine supplementation of breastfeeding mothers could be beneficial.

PMID: 31891954 [PubMed - as supplied by publisher]

Antibiotic treatment adequacy and death among patients with Pseudomonas aeruginosa airway infection.

PLoS One. 2019;14(12):e0226935

Authors: Eklöf J, Gliese KM, Ingebrigtsen TS, Bodtger U, Jensen JS

Abstract
OBJECTIVE: The effect of antibiotics on survival in patients with pulmonary Pseudomonas aeruginosa is controversial. The aim of this study is to i) determine the prevalence of adequate antibiotic treatment of P. aeruginosa in an unselected group of adult non-cystic fibrosis patients and ii) to assess the overall mortality in study patients treated with adequate vs. non-adequate antibiotics.
METHODS: Prospective, observational study of all adult patients with culture verified P. aeruginosa from 1 January 2010-31 December 2012 in Region Zealand, Denmark. Patients with cystic fibrosis were excluded. Adequate therapy was defined as any antibiotic treatment including at least one antipseudomonal beta-lactam for a duration of at least 10 days. Furthermore, P. aeruginosa had to be tested susceptible to the given antipseudomonal drug and treatment had to be approved by senior clinician to fulfil the adequate-criteria.
RESULTS: A total of 250 patients were identified with pulmonary P. aeruginosa. The vast majority (80%) were treated with non-adequate antibiotic therapy. All-cause mortality rate after 12 months was 49% in adequate treatment group vs. 52% in non-adequate treatment group. Cox regression analysis adjusted for age, gender, bacteraemia, comorbidities and bronchiectasis showed no significant difference in mortality between treatment groups (adequate vs. non-adequate: hazard ratio 0.95, 95% CI 0.59-1.52, P = 0.82).
CONCLUSION: Adequate antipseudomonal therapy was only provided in a minority of patients with pulmonary P. aeruginosa. Adequate therapy did not independently predict a favourable outcome. New research initiatives are needed to improve the prognosis of this vulnerable group of patients.

PMID: 31891624 [PubMed - in process]

Biomarkers Predictive of Exacerbations in the SPIROMICS and COPDGene Cohorts.

Am J Respir Crit Care Med. 2020 Jan 01;201(1):473-481

Authors: Keene JD, Jacobson S, Kechris K, Kinney GL, Foreman MG, Doerschuk CM, Make BJ, Curtis JL, Rennard SI, Barr RG, Bleecker ER, Kanner RE, Kleerup EC, Hansel NN, Woodruff PG, Han MK, Paine R, Martinez FJ, Bowler RP, O'Neal WK, COPDGene and SPIROMICS Investigators

Abstract
Rationale: Chronic obstructive pulmonary disease exacerbations are associated with disease progression, higher healthcare cost, and increased mortality. Published predictors of future exacerbations include previous exacerbation, airflow obstruction, poor overall health, home oxygen use, and gastroesophageal reflux.Objectives: To determine the value of adding blood biomarkers to clinical variables to predict exacerbations.Methods: Subjects from the SPIROMICS (Subpopulations and Intermediate Outcomes Measures in COPD Study) (n = 1,544) and COPDGene (Genetic Epidemiology of COPD) (n = 602) cohorts had 90 plasma or serum candidate proteins measured on study entry using Myriad-RBM multiplex panels. We defined total exacerbations as subject-reported worsening in respiratory health requiring therapy with corticosteroids and/or antibiotics, and severe exacerbations as those leading to hospitalizations or emergency room visits. We assessed retrospective exacerbations during the 12 months before enrollment and then documented prospective exacerbations in each cohort. Exacerbations were modeled for biomarker associations with negative binomial regression including clinical covariates (age, sex, percent predicted FEV1, self-reported gastroesophageal reflux, St. George's Respiratory Questionnaire score, smoking status). We used the Stouffer-Liptak test to combine P values for metaanalysis.Measurements and Main Results: Between the two cohorts, 3,471 total exacerbations (1,044 severe) were reported. We identified biomarkers within each cohort that were significantly associated with a history of exacerbation and with a future exacerbation, but there was minimal replication between the cohorts. Although established clinical features were predictive of exacerbations, of the blood biomarkers only decorin and α2-macroglobulin increased predictive value for future severe exacerbations.Conclusions: Blood biomarkers were significantly associated with the occurrence of exacerbations but were not robust between cohorts and added little to the predictive value of clinical covariates for exacerbations.

PMID: 31891318 [PubMed - in process]

Ciliary Localization of the Intraflagellar Transport Protein IFT88 Is Disrupted in Cystic Fibrosis.

Am J Respir Cell Mol Biol. 2020 Jan;62(1):120-123

Authors: Stevens EM, Vladar EK, Alanin MC, Christensen ST, von Buchwald C, Milla C

PMID: 31891309 [PubMed - in process]

Bi-allelic Homology-Directed Repair with Helper-Dependent Adenoviruses.

Mol Ther Methods Clin Dev. 2019 Dec 13;15:285-293

Authors: Palmer DJ, Turner DL, Ng P

Abstract
We describe a strategy to achieve footprintless bi-allelic homology-directed repair (HDR) using helper-dependent adenoviruses (HDAds). This approach utilizes two HDAds to deliver the donor DNA. These two HDAds are identical except for their selectable marker. One expresses the puromycin N-acetyltransferase-herpes simplex virus I thymidine kinase fusion gene (PACTk), while the other expresses the hygromycin phosphotransferase-herpes simplex virus I thymidine kinase fusion gene (HyTk). Therefore, puromycin and hygromycin double resistance can be used to select for targeted HDAd integration into both alleles. Subsequently, piggyBac-mediated excision of both PACTk and HyTk will confer resistance to gancyclovir, resulting in footprintless HDR at both alleles. However, gene-targeting frequency was not high enough to achieve simultaneous targeting at both alleles. Instead, sequential targeting, whereby the two alleles were targeted one at a time, was required in order to achieve bi-allelic HDR with HDAd.

PMID: 31890728 [PubMed]

Ivacaftor for the Treatment of Cystic Fibrosis Coexisting with Trisomy 21: A Case Report.

Cureus. 2019 Nov 18;11(11):e6179

Authors: Charbek E, Kamel G, Nayak RP

Abstract
The association between cystic fibrosis (CF) and trisomy 21, or Down Syndrome (DS) is rare, and it pertains a poor prognosis with the majority of patients dying in infancy. We report a case of a 28-year-old male with DS and moderate CF (ΔF508/G551D, FEV1 1.92 L, 60% predicted at the age of 18 years) diagnosed in childhood. The patient's lung function continued to deteriorate over time (FEV1 nadir of 1.29 L), and he was started on ivacaftor in the year 2012 following ivacaftor release and approval. FEV1 and FVC improved significantly along with an increase in the patient's body mass index. Ivacaftor potentiates the open-channel probability of the G551D-CFTR. It has been shown to improve lung function, symptoms, weight, and sweat chloride concentration and decrease the risk of pulmonary exacerbations in patients with severe pulmonary CF (G551D). Our case argues against the reported literature of poor prognosis when the two chronic diseases coexist as only one case report in the literature described a DS patient with CF surviving into adulthood. In our patient, treatment with ivacaftor resulted in an increase in FEV1 and weight that exceeded the response observed in the ivacaftor landmark trial. Genetic studies are underway to understand the genetic basis of the large variation in DS phenotypes, which is probably caused by allelic heterogeneity on multiple chromosomes. The latter may explain the enhanced response observed in our patient and suggests that although patients with concomitant DS and CF may have worse lung disease, their response to novel therapies may be intensified. Further studies are needed in this subset of patient population to better characterize CF with trisomy and other genetic disorders.

PMID: 31890385 [PubMed]

Sleep-disordered breathing in cystic fibrosis pediatric subjects.

Sleep Sci. 2019 Jul-Sep;12(3):165-170

Authors: Lumertz MS, Pinto LA

Abstract
Objectives: To describe the frequency of sleep-disordered breathing (SDB) in pediatric cystic fibrosis (CF) and to study associations between polysomnographic respiratory parameters and available clinical information.
Methods: This was a retrospective, cross-sectional study. The sample data were obtained from information recorded on patient charts in 2015 and 2016. The study included all individuals with CF aged from 2 to 20 years for whom records were available for polysomnography performed within the previous two years.
Results: Sixteen individuals with CF (mean age 11 ± 5.6 years old) were included. Polysomnographic respiratory parameter abnormalities were defined as an apnea-hypopnea index (AHI) exceeding one event per hour of sleep or an oxyhemoglobin saturation (SpO2) nadir below 90%; observed in 10 subjects (62.5%). Forced expiratory volume in first second (FEV1) was correlated (r=0.602, p=0.023) with mean sleep SpO2. FEV1 was also negatively correlated with sleep peak end-tidal carbon dioxide (EtpCO2) (r=-0.645, p=0.024). Additionally, chronic airway colonization by Pseudomonas aeruginosa was associated with mean EtpCO2 in non-REM sleep (p=0.024).
Discussion: SDB was frequently observed in this sample of children with CF. There was an association between CF respiratory disease progression markers and sleep breathing parameters in children. Sleep studies appear to be an important tool for assessment of the respiratory status of these individuals with CF, although further studies are needed, especially with carbon dioxide sleep analysis.

PMID: 31890091 [PubMed]

ANALYSIS OF LOCAL IMMUNITY INDICATORS OF THE ORAL CAVITY AND DEGREE OF GINGIVITIS DEPENDING ON MUTATION OF CFTR GENE IN CHILDREN WITH CYSTIC FIBROSIS.

Georgian Med News. 2019 Nov;(296):27-31

Authors: Nazaryan R, Tkachenko M, Kovalenko N, Babai O, Karnaukh O, Gargin V

Abstract
The aim of the work was to establish the relationship between the genotype of the cystic fibrosis transmembrane conductance regulator (CFTR), the level of local immune reactivity and the degree of chronic gingivitis in children with cystic fibrosis. The study has shown significant differences in the local immunity indices of the oral mucosa and the condition of periodontal tissues in children with cystic fibrosis in comparison with the control group. The features of the course of dental pathology among sick children, depending on the type of CFTR gene mutation are determined. Disturbance of mucosal immunity of the oral cavity in children with cystic fibrosis is manifested by a decrease in lysozyme activity in mixed saliva by 1.5 times and level of secretory immunoglobulins IgA by 1.4 times. A consequence of this is an increase of the degree of dysbiosis of the oral cavity by 3.7 times. At the same time, a lesser imbalance in the microflora and lysozyme activity observed in the homozygote group of the F508del mutation, and heterozygotes of the F508del mutation have the most severe manifestations of chronic gingivitis.

PMID: 31889700 [PubMed - in process]

Inhalation delivery of host defence peptides (HDP) using nano-formulation strategies: A pragmatic approach for therapy of pulmonary ailments.

Curr Protein Pept Sci. 2019 Dec 30;:

Authors: Adlakha S, Sharma A, Vaghasiya K, Ray E, Verma RK

Abstract
Host defense peptides (HDP) are small cationic molecules released by the immune systems of the body, having multidimensional properties including anti-inflammatory, anticancer, antimicrobial and immune-modulatory activity. These molecules gained importance due to their broad-spectrum pharmacological activities, and hence being actively investigated. Presently, respiratory infections represent a major global health problem, and HDP has an enormous potential to be used as an alternative therapeutics against respiratory infections and related inflammatory ailments. Because of their short half-life, protease sensitivity, poor pharmacokinetics, and first-pass metabolism, it is challenging to deliver HDP as such inside the physiological system in a controlled way by conventional delivery systems. Many HDPs are efficacious only at practically high molar-concentrations, which is not convincing for the development of drug regimen due to their intrinsic detrimental effects. To avail the efficacy of HDP in pulmonary diseases, it is essential to deliver an appropriate payload into the targeted site of lungs. Inhalable HDP can be a potentially suitable alternative for various lung disorders including tuberculosis, Cystic fibrosis, Pneumonia, Lung cancer, and others as they are active against resistant microbes and cells and exhibit improved targeting with reduced adverse effects. In this review, we give an overview of the pharmacological efficacy of HDP and deliberate strategies for designing inhalable formulations for enhanced activity and issues related to their clinical implications.

PMID: 31889487 [PubMed - as supplied by publisher]

Size-adjusted muscle power and muscle metabolism in patients with cystic fibrosis are equal to healthy controls - a case control study.

BMC Pulm Med. 2019 Dec 30;19(1):269

Authors: Ruf K, Beer M, Köstler H, Weng AM, Neubauer H, Klein A, Platek K, Roth K, Beneke R, Hebestreit H

Abstract
BACKGROUND: Skeletal muscle function dysfunction has been reported in patients with cystic fibrosis (CF). Studies so far showed inconclusive data whether reduced exercise capacity is related to intrinsic muscle dysfunction in CF.
METHODS: Twenty patients with CF and 23 age-matched controls completed an incremental cardiopulmonary cycling test. Further, a Wingate anaerobic test to assess muscle power was performed. In addition, all participants completed an incremental knee-extension test with 31P magnetic resonance spectroscopy to assess muscle metabolism (inorganic phosphate (Pi) and phosphocreatinine (PCr) as well as intracellular pH). In the MRI, muscle cross-sectional area of the M. quadriceps (qCSA) was also measured. A subgroup of 15 participants (5 CF, 10 control) additionally completed a continuous high-intensity, high-frequency knee-extension exercise task during 31P magnetic resonance spectroscopy to assess muscle metabolism.
RESULTS: Patients with CF showed a reduced exercise capacity in the incremental cardiopulmonary cycling test (VO2peak: CF 77.8 ± 16.2%predicted (36.5 ± 7.4 ml/qCSA/min), control 100.6 ± 18.8%predicted (49.1 ± 11.4 ml/qCSA/min); p < 0.001), and deficits in anaerobic capacity reflected by the Wingate test (peak power: CF 537 ± 180 W, control 727 ± 186 W; mean power: CF 378 ± 127 W, control 486 ± 126 W; power drop CF 12 ± 5 W, control 8 ± 4 W. all: p < 0.001). In the knee-extension task, patients with CF achieved a significantly lower workload (p < 0.05). However, in a linear model analysing maximal work load of the incremental knee-extension task and results of the Wingate test, respectively, only muscle size and height, but not disease status (CF or not) contributed to explaining variance. In line with this finding, no differences were found in muscle metabolism reflected by intracellular pH and the ratio of Pi/PCr at submaximal stages and peak exercise measured through MRI spectroscopy.
CONCLUSIONS: The lower absolute muscle power in patients with CF compared to controls is exclusively explained by the reduced muscle size in this study. No evidence was found for an intrinsic skeletal muscle dysfunction due to primary alterations of muscle metabolism.

PMID: 31888580 [PubMed - in process]