Carriers of a single CFTR mutation are asymptomatic: an evolving dogma?

Eur Respir J. 2020 Sep;56(3):

Authors: Martin C, Burgel PR

PMID: 32912926 [PubMed - in process]

A simple preservation method for the storage of Aspergillus fumigatus and Scedosporium apiospermum filamentous fungi isolated from the sputum of patients with cystic fibrosis (CF).

J Microbiol Methods. 2020 Sep 07;:106052

Authors: Moore JE, Millar BC

Abstract
A novel method is described for the laboratory storage of the filamentous fungi, Aspergillus fumigatus and Scedosporium apiospermum. These fungi were isolated directly from the sputum of patients with cystic fibrosis (CF) on previously described Medium B+ fungal selective agar. Medium B+ plates containing heavy growths of filamentous fungi were air dried to completeness and the resulting dehydrated agar containing fungi were hermetically sealed within A4 plastic lamination sheets using a domestic paper laminator. Fungi were successfully recovered and recultured post lamination. This method is simple, inexpensive, versatile and widely adaptable and requires minimum preparation/handling/processing, thereby encouraging the routine archiving of fungal isolates. Laminated fungal sheets may be catalogued and stored safely and securely in fireproof lockable filing cabinets in laboratories, thereby saving valuable bench- or freezer space.

PMID: 32911036 [PubMed - as supplied by publisher]

Management of drug toxicity in M. avium complex pulmonary disease - an expert panel survey.

Clin Infect Dis. 2020 Sep 10;:

Authors: van Ingen J, Aliberti S, Andrejak C, Chalmers JD, Codecasa LR, Daley CL, Hasegawa N, Griffith DE, Hoefsloot W, Huitt G, Jarand J, Jhun BW, Loebinger MR, Marras TK, Morimoto K, Polverino E, Ringshausen FC, Santin M, Thomson R, Wagner D, Wallace RJ, Winthrop KL, Yim JJ, NTM-NET

Abstract
Adverse events are frequent in NTM pulmonary disease treatment, but evidence to support their management is scarce. An expert panel survey on management of adverse events shows consistent opinions on management of hepatoxicity, ocular toxicity, ototoxicity, tinnitus and GI upset. These opinions can provide assistance in individual patient management decisions.

PMID: 32910814 [PubMed - as supplied by publisher]

Coumaronochromone as antibacterial and carbonic anhydrase inhibitors from Aerva persica (Burm.f.) Merr.: experimental and first-principles approaches.

Z Naturforsch C J Biosci. 2020 Sep 09;:

Authors: Imran M, Irfan A, Assiri MA, Sumrra SH, Saleem M, Hussain R, Al-Sehemi AG

Abstract
The Aerva plants are exceptionally rich in phytochemicals and possess therapeutics potential. Phytochemical screening shows that Aerva persica (Burm.f.) Merr. contains highest contents i.e., total phenolics, flavonoids, flavonols, tannins, alkaloids, carbohydrates, anthraquinones and glycosides. In-vitro antibacterial and enzymatic (carbonic anhydrase) inhibition studies on methanol extracts of A. persica indicated the presence of biological active constituents within chloroform soluble portions. Investigation in the pure constituents on the chloroform portions of A. persica accomplished by column chromatography, NMR and MS analysis. The bioguided isolation yields four chemical constituents of coumaronochromone family, namely aervin (1-4). These pure chemical entities (1-4) showed significant antibacterial activity in the range of 60.05-79.21 µg/ml against various bacterial strains using ampicillin and ciprofloxacin as standard drugs. The compounds 1-4 showed promising carbonic anhydrase inhibition with IC50 values of 19.01, 18.24, 18.65 and 12.92 µM, respectively, using standard inhibitor acetazolamide. First-principles calculations revealed comprehensive intramolecular charge transfer in the studied compounds 1-4. The spatial distribution of highest occupied and lowest unoccupied molecular orbitals, ionization potential, molecular electrostatic potential and Hirshfeld analysis revealed that these coumaronochromone compounds would be proficient biological active compounds. These pure constituents may be used as a new pharmacophore to treat leaukomia, epilepsy, glaucoma and cystic fibrosis.

PMID: 32910785 [PubMed - as supplied by publisher]

Persistent Recovery of Pancreatic Function in Patients with Cystic Fibrosis after Ivacaftor.

Pediatr Pulmonol. 2020 Sep 10;:

Authors: Munce D, Lim M, Akong K

Abstract
Exocrine pancreatic insufficiency (EPI), which leads to malabsorption and poor weight gain, is seen in 85% of patients with Cystic Fibrosis (CF). EPI is treated with pancreatic enzyme replacement therapy (PERT) taken with each meal. The highly effective CFTR modulator Ivacaftor restores CFTR function in patients with responsive mutations. It is a widely held view that EPI in CF is irreversible due to complete destruction of pancreatic ducts and acinar cells. We describe three pediatric CF patients with EPI who were started on Ivacaftor, and subsequently showed evidence of restored exocrine pancreatic function with clinical and biochemical parameters. This article is protected by copyright. All rights reserved.

PMID: 32910556 [PubMed - as supplied by publisher]

Incidence of nephrotoxicity with Prolonged aminoglycoside exposure in patients with cystic fibrosis.

Pediatr Pulmonol. 2020 Sep 10;:

Authors: Saad A, Young MR, Studtmann AE, Autry EB, Schadler A, Beckman EJ, Gardner BM, Wurth MA, Kuhn RJ

Abstract
Cystic fibrosis (CF) patients, with Pseudomonas aeruginosa infection, often require repeated aminoglycoside courses for management of acute pulmonary exacerbations (APE). Acute kidney injury (AKI) due to aminoglycosides has been reported; little data exist regarding long-term nephrotoxicity with repeated exposure. The objective of this study was to describe the incidence of acute and chronic nephrotoxicity due to cumulative intravenous (IV) aminoglycoside exposure. This is a retrospective, observational study of pediatric and adult CF patients admitted to an academic medical center between January 1, 2006 and October 1, 2018 for APE management. Patients were eligible for inclusion if they received at least five courses of an IV aminoglycoside for at least seven days each. Cumulative weight based aminoglycoside dose was reported in milligrams per kilogram (mg/kg). For each admission, baseline and highest serum creatinine (SCr) were collected to assess incidence of AKI. Baseline and final estimated glomerular filtration rate (eGFR) were calculated to assess for long-term effects on renal function. Sixty-six patients, representing greater than 700 courses, were included in the final analysis. The median cumulative weight based aminoglycoside dose was 1,183 mg/kg of tobramycin or tobramycin equivalent. Twenty percent of courses resulted in AKI; 86% were Stage 1. A repeated measures multivariate model showed colistin, piperacillin/tazobactam, vancomycin and age were significant AKI risk factors. There was no correlation between cumulative aminoglycoside dose and change in eGFR. AKI from IV aminoglycoside exposure occurred in 20% of courses. Cumulative exposure to IV aminoglycosides in APE management was not correlated with long-term renal dysfunction. This article is protected by copyright. All rights reserved.

PMID: 32910553 [PubMed - as supplied by publisher]

MexXY RND pump of Pseudomonas aeruginosa PA7 effluxes bi-anionic β-lactams carbenicillin and sulbenicillin when it partners with the outer membrane factor OprA but not with OprM.

Microbiology (Reading). 2020 Sep 10;:

Authors: Singh M, Sykes EME, Li Y, Kumar A

Abstract
Antibiotic resistance in Pseudomonas aeruginosa is a serious concern in healthcare systems. Among the determinants of antibiotic resistance in P. aeruginosa, efflux pumps belonging to the resistance-nodulation-division (RND) family confer resistance to a broad range of antibacterial compounds. The MexXY efflux system is widely overexpressed in P. aeruginosa isolates from cystic fibrosis (CF) patients. MexXY can form functional complexes with two different outer membrane factors (OMFs), OprA and OprM. In this study, using state-of-the-art genetic tools, the substrate specificities of MexXY-OprA and MexXY-OprM complexes were determined. Our results show, for the first time, that the substrate profile of the MexXY system from P. aeruginosa PA7 can vary depending on which OM factor (OprM or OprA) it complexes with. While both MexXY-OprA and MexXY-OprM complexes are capable of effluxing aminoglycosides, the bi-anionic β-lactam molecules carbenicillin and sulbenicillin were found to only be the substrate of MexXY-OprA. Our study therefore shows that by partnering with different OMF proteins MexY can expand its substrate profile.

PMID: 32909933 [PubMed - as supplied by publisher]

Immune transcriptomes of highly exposed SARS-CoV-2 asymptomatic seropositive versus seronegative individuals from the Ischgl community.

medRxiv. 2020 Sep 02;:

Authors: Lee HK, Knabl L, Pipperger L, Volland A, Furth PA, Kang K, Smith HE, Knabl L, Bellmann R, Bernhard C, Kaiser N, Ganzer H, Strohle M, Walser A, von Laer D, Hennighausen L

Abstract
To investigate prevalence of ongoing activation of inflammation following asymptomatic SARS-CoV-2 infection we characterized immune cell transcriptomes from 43 asymptomatic seropositive and 52 highly exposed seronegative individuals with few underlying health issues following a community superspreading event. Four mildly symptomatic seropositive individuals examined three weeks after infection as positive controls demonstrated immunological activation. Approximately four to six weeks following the event, the two asymptomatic groups showed no significant differences. Two seropositive patients with underlying genetic disease impacting immunological activation were included (Cystic Fibrosis (CF), Nuclear factor-kappa B Essential Modulator (NEMO) deficiency). CF, but not NEMO, associated with significant immune transcriptome differences including some associated with severe SARS-CoV-2 infection (IL1B, IL17A, respective receptors). All subjects remained in their usual state of health from event through five-month follow-up. Here, asymptomatic infection resolved without evidence of prolonged immunological activation. Inclusion of subjects with underlying genetic disease illustrated the pathophysiological importance of context on impact of immunological response.

PMID: 32908998 [PubMed]

Posaconazole-Induced Hypertension Masquerading as Congenital Adrenal Hyperplasia in a Child with Cystic Fibrosis.

Case Rep Med. 2020;2020:8153012

Authors: Agarwal N, Apperley L, Taylor NF, Taylor DR, Ghataore L, Rumsby E, Treslove C, Holt R, Thursfield R, Senniappan S

Abstract
Background: Deficiency of 11β-hydroxylase is the second most common cause of congenital adrenal hyperplasia (CAH), presenting with hypertension, hypokalaemia, precocious puberty, and adrenal insufficiency. We report the case of a 6-year-old boy with cystic fibrosis (CF) found to have hypertension and cortisol insufficiency, which were initially suspected to be due to CAH, but were subsequently identified as being secondary to posaconazole therapy. Case Presentation. A 6-year-old boy with CF was noted to have developed hypertension after administration of two doses of Orkambi™ (ivacaftor/lumacaftor), which was subsequently discontinued, but the hypertension persisted. Further investigations, including echocardiogram, abdominal Doppler, thyroid function, and urinary catecholamine levels, were normal. A urine steroid profile analysis raised the possibility of CAH due to 11β-hydroxylase deficiency, and a standard short synacthen test (SST) revealed suboptimal cortisol response. Clinically, there were no features of androgen excess. Detailed evaluation of the medical history revealed exposure to posaconazole for more than 2 months, and the hypertension had been noted to develop two weeks after the initiation of posaconazole. Hence, posaconazole was discontinued, following which the blood pressure, cortisol response to the SST, and urine steroid profile were normalized.
Conclusion: Posaconazole can induce a clinical and biochemical picture similar to CAH due to 11β-hydroxylase deficiency, which is reversible. It is prudent to monitor patients on posaconazole for cortisol insufficiency, hypertension, and electrolyte abnormalities.

PMID: 32908540 [PubMed]

COVID-19 in pregnant women: A systematic review and meta-analysis.

Eur J Obstet Gynecol Reprod Biol. 2020 Sep;252:543-558

Authors: Capobianco G, Saderi L, Aliberti S, Mondoni M, Piana A, Dessole F, Dessole M, Cherchi PL, Dessole S, Sotgiu G

Abstract
OBJECTIVE: Coronavirus disease 2019 (COVID-19) is a novel infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Several reports highlighted the risk of infection and disease in pregnant women and neonates. To assess the risk of clinical complications in pregnant women and neonates infected with SARS-CoV-2 carrying out a systematic review and meta-analysis of observational studies.
DATA SOURCES: Search of the scientific evidence was performed using the engines PubMed and Scopus, including articles published from December 2019 to 15 April 2020.
STUDY ELIGIBILITY CRITERIA: Only observational studies focused on the assessment of clinical outcomes associated with pregnancy in COVID-19 women were selected.
STUDY APPRAISAL AND SYNTHESIS METHODS: The first screening was based on the assessment of titles and abstracts, followed by the evaluation of full-texts. Qualitative variables were summarized with frequencies, whereas quantitative variables with central and variability indicators depending on their parametric distribution. Forest plots were used to describe point estimates and in-between studies variability. Study quality assessment was performed.
RESULTS: Thirteen studies were selected. All of them were carried out in China. The mean (SD) age and gestational age of pregnant women were 30.3 (1.5) years and 35.9 (2.9) weeks, respectively. The mean (SD) duration from the first symptoms to the hospital admission and to labour were 5.5 (2.0) and 9.5 (8.7) days, respectively. Patients mainly complained of fever and cough (pooled (95 % CI) proportions were 76.0 % (57.0 %-90.0 %) and 38.0 (28.0 %-47.0 %), respectively). Several antibiotics, antivirals, and corticosteroids were prescribed in different combinations. The pooled prevalence of maternal complications and of caesarean section were 45.0 % (95 % CI: 24.0 %-67.0 %) and 88.0 % (95 %CI: 82.0 %-94.0 %). A proportion of pregnant women less than 20 % were admitted to ICU. The pooled proportion of preterm infants was 23.0 % (95 %CI: 11.0 %-39.0 %). The most frequent neonatal complications were pneumonia and respiratory distress syndrome. The pooled percentage of infected neonates was 6.0 % (95 %CI: 2.0 %-12.0 %).
CONCLUSIONS: The present study suggests a high rate of maternal and neonatal complications in infected individuals. However, the current scientific evidence highlights a low risk of neonatal infection. Multicentre, cohort studies are needed to better elucidate the role of SARS-CoV-2 during pregnancy.

PMID: 32713730 [PubMed - indexed for MEDLINE]

Immeasurable Time Bias In Exposure to Ivacaftor.

Health Aff (Millwood). 2019 02;38(2):328

Authors: Sarayani A, Winterstein AG

PMID: 30715971 [PubMed - indexed for MEDLINE]

Role of inhaled corticosteroids in reducing exacerbations in bronchiectasis patients with blood eosinophilia pooled post-hoc analysis of 2 randomized clinical trials.

Respir Med. 2020 Aug 25;172:106127

Authors: Martinez-Garcia MA, Posadas T, Sotgiu G, Blasi F, Saderi L, Aliberti S

PMID: 32905889 [PubMed - as supplied by publisher]

Mechanism-Based Personalized Medicine for Cystic Fibrosis by Suppressing Pseudo Exon Inclusion.

Cell Chem Biol. 2020 Sep 07;:

Authors: Shibata S, Ajiro M, Hagiwara M

Abstract
Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that compromise its chloride channel activity. Here, we present a therapeutic strategy to ameliorate RNA splicing deficiency of CFTR with a small molecule. The 3,849 + 10 kb C>T is the most common splicing mutation in CF, creating a pseudo exon with premature stop codon. We reveal that the 3,849 + 10 kb C>T-induced CFTR pseudo exon is regulated by phosphorylation of serine/arginine-rich splicing factors, and their functional inhibition by a CDC-like kinase inhibitor restores normal splicing of CFTR. Subsequent screening of our focused chemical library identified CaNDY as a rectifier of the aberrant splicing. CaNDY treatment restored normal splicing of CFTR with the 3,849 + 10 kb C>T in CF patient cells and functional CFTR protein expression in the CF model cells. Our findings open the door for mechanism-based personalized medicine for pseudo-exon-type genetic diseases.

PMID: 32905759 [PubMed - as supplied by publisher]

Azole-Resistant Aspergillus fumigatus Among Danish Cystic Fibrosis Patients: Increasing Prevalence and Dominance of TR34/L98H.

Front Microbiol. 2020;11:1850

Authors: Risum M, Hare RK, Gertsen JB, Kristensen L, Johansen HK, Helweg-Larsen J, Abou-Chakra N, Pressler T, Skov M, Jensen-Fangel S, Arendrup MC

Abstract
Azole-resistant (azole-R) Aspergillus is an increasing challenge worldwide. Patients with cystic fibrosis (CF) are at risk of Aspergillus colonization and disease due to a favorable lung environment for microorganisms. We performed a nationwide study in 2018 of azole-non-susceptible Aspergillus in CF patients and compared with data from two prior studies. All airway samples with mold isolates from patients monitored at the two CF centers in Denmark (RH, Jan-Sept and AUH, Jan-Jun) were included. Classical species identification (morphology and thermo-tolerance) was performed and MALDI-TOF/β-tubulin sequencing was performed if needed. Susceptibility was determined using EUCAST E.Def 10.1, and E.Def 9.3.2. cyp51A sequencing and STRAf genotyping were performed for azole-non-susceptible isolates and relevant sequential isolates. In total, 340 mold isolates from 159 CF patients were obtained. The most frequent species were Aspergillus fumigatus (266/340, 78.2%) and Aspergillus terreus (26/340, 7.6%). Azole-R A. fumigatus was cultured from 7.3% (10/137) of patients, including 9.5% (9/95) of patients at RH and 2.4% at AUH (1/42), respectively. In a 10-year perspective, azole-non-susceptibility increased numerically among patients at RH (10.5% in 2018 vs 4.5% in 2007-2009). Cyp51A resistance mechanisms were found in nine azole-R A. fumigatus from eight CF patients. Five were of environmental origin (TR34/L98H), three were human medicine-driven (two M220K and one M220R), and one was novel (TR34 3/L98H) and found in a patient who also harbored a TR34/L98H isolate. STRAf genotyping identified 27 unique genotypes among 45 isolates and ≥2 genotypes in 8 of 12 patients. This included one patient carrying two unique TR34/L98H isolates, a rare phenomenon. Genotyping of sequential TR34 3/L98H and TR34/L98H isolates from the same patient showed only minor differences in 1/9 markers. Finally, azole-R A. terreus was found in three patients including two with Cyp51A alterations (M217I and G51A, respectively). Azole-R A. fumigatus is increasing among CF patients in Denmark with the environmentally associated resistance TR34/L98H mechanism being dominant. Mixed infections (wildtype/non-wildtype and several non-wildtypes) and a case of potential additional tandem repeat acquisition in vivo were found. However, similar genotypes were identified from another patient (and outside this study), potentially suggesting a predominant TR34/L98H clone in DK. These findings suggest an increasing prevalence and complexity of azole resistance in A. fumigatus.

PMID: 32903400 [PubMed - as supplied by publisher]

Effects of a long-term exercise program on motor performance in children and adolescents with CF.

Pediatr Pulmonol. 2020 Sep 09;:

Authors: Gruber W, Stehling F, Olivier M, Benzrath S, Koerner-Rettberg C, Sutharsan S, Taube C, Mellies U, Welsner M

Abstract
OBJECTIVES: The aim of this study was to examine motor performance and trainability in youths with CF.
METHODS: 22 children and adolescents (11f/11m),age range 6-17 years (11.3±3.3 yrs.), mean FEV1 91.0±21.7% pred.finished the partially monitored 12-months exercise program. Patients performed the Deutsche Motorik Test (DMT) to assess flexibility, balance, strength, power and totalmotor performance. An incremental ergometer cycle test was used to assess maximal exercise capacity (Wpeak). All tests were performed before (T1), after 6months of monitored exercise training (T3) and another 6 months without monitoring (T4).
RESULTS: Motor Competence in total and test-items of the DMT (except foreward bend) improved to T3 (p<0.05).No further improvement could be observed after the end of the monitoring (T3). However, the values remained stable at the improved level(T4) Girls scored lower in test items depending on strength/power but scored higher in balancing compared to boys (p > 0.05). Wpeak and FEV1 were not influenced by the training program. From T3 to T4 a slight decrease was observed (p≤0.05).
CONCLUSIONS: The findings demonstrated benefits of an individualizedmonitored long-term exercise intervention on motor performance in CF with improvements of test-tasks to predicted normal. Monitoringseems to be a facilitator in maintaining motivation towards physical activity as no further increase in motor performance was observed after stopping supervision. The results suggest that an individually tailored monitoredregular exercise program should include all aspects of physical fitness with a variety of movement experiences. This article is protected by copyright. All rights reserved.

PMID: 32902926 [PubMed - as supplied by publisher]

Bronchiectasis Associated with Electronic Cigarette Use: A Case Series.

Pediatr Pulmonol. 2020 Sep 09;:

Authors: Mull ES, Shell R, Adler B, Holtzlander M

Abstract
Bronchiectasis (BE) is defined as a permanent, irreversible dilation of the bronchial tree. In the pediatric population, this disease process is most commonly associated with patients with cystic fibrosis (CF). However, bronchiectasis unrelated to cystic fibrosis is increasingly noted as a cause of chronic respiratory related morbidity worldwide. Chronic inflammation and recurrent infection result in cellular cascades that lead to irreversible structural changes of the airways. When these architectural changes occur, they confer extensive risks to morbidity usually due to continued infections. In the adult population, bronchiectasis has been associated with chronic obstructive pulmonary disease, which is mainly caused by cigarette smoking. In this report, the authors reviewed various cases of bronchiectasis in the pediatric population at our institution. After a comprehensive case by case review, we compiled details of 3 cases of newly diagnosed bronchiectasis where the most likely inciting factor was the electronic cigarette use. Common features of the three cases included at least a year of e-cigarette use with conjunction of Tetrahydrocannabinol (THC) and radiologic findings of bronchiectasis, ground glass opacities, and nodule formation. This article is protected by copyright. All rights reserved.

PMID: 32902877 [PubMed - as supplied by publisher]

Clinical and microbiological monitoring of Cystic Fibrosis patients, three years of follow-up via Tele-Medicine: an empirical research.

Clin Ter. 2020 Sep-Oct;171(5):e381-e384

Authors: De Biase RV, Cristiani L, Paglia C, Alghisi F, Giordani B, Lucidi V, Bella S

Abstract
OBJECTIVES: Evaluation of the effectiveness of home care through a telemonitoring system in reducing the incidence of new colonization by Pseudomonas Aeruginosa in a population of patients with Cystic Fibrosis (CF) followed by the CF clinic of the Bambino Gesù Hospital in Rome over a period of 36 months.
MATERIALS AND METHODS: Two groups of patients were recruited, homogeneous for age, sex, BMI, FEV1, prevalence of CF-related Diabetes and CF-related Hepatopathy, access to new therapies with modulators: a) an IN group (N = 44 ) followed through a home telemonitoring system, b) an OUT control group (N = 110) followed according to the standards of care. The following parameters were detected for all patients: pulmonary colonization of the lungs, number and type of hospital admissions, respiratory function, BMI.
RESULT: The OUT group had a statistically significant increase in the prevalence of Pseudomonas Aeruginosa infections during the observation period. Furthermore, a significant decrease in lung function assessed through FEV1 was also observed in the OUT group.
CONCLUSION: Adolescent and adult patients belonging to the CF center who are not followed through the dedicated home telemonitoring service show, in the three-year period 2017-19, an increase in Pseudomonas Aeruginosa infections and a greater decrease in respiratory function. The use of telemedicine in CF is therefore an effective system not only in monitoring the disease but also as a treatment strategy, in the context of an evolving multidisciplinary model. As advantages, telemedicine can reduce the number of Pseudomonas Aeruginosa lung infections and the greater stability of respiratory function over time.

PMID: 32901778 [PubMed - in process]

Differential effects of the cystic fibrosis lung inflammatory environment on mesenchymal stromal cells.

Am J Physiol Lung Cell Mol Physiol. 2020 Sep 09;:

Authors: Abreu SC, Hampton TH, Hoffman E, Dearborn J, Ashare A, Singh Sidhu K, Matthews DE, McKenna DH, Amiel E, Barua J, Krasnodembskaya A, English K, Mahon BP, Santos CD, Cruz FF, Chambers DC, Liu KD, Matthay MA, Cramer RA, Stanton BA, Rocco PRM, Wargo MJ, Weiss DJ, Rolandsson Enes S

Abstract
Growing evidence demonstrates that human mesenchymal stromal cells (MSCs) modify their in vivo anti-inflammatory actions depending on the specific inflammatory environment encountered. Understanding this better is crucial to refine MSC-based cell therapies for lung and other diseases. Using acute exacerbations of cystic fibrosis (CF) lung disease as a model, the effects of ex vivo MSC exposure to clinical bronchoalveolar lavage fluid (BALF) samples, as a surrogate for the in vivo clinical lung environment, on MSC viability, gene expression, secreted cytokines, and mitochondrial function was compared to effects of BALF collected from healthy volunteers. CF BALF samples which cultured positive for Aspergillus sp. (Asp) induced rapid MSC death, usually within several hours of exposure. Further analyses suggested the fungal toxin gliotoxin as a potential mediator contributing to CF BALF-induced MSC death. RNA sequencing analyses of MSCs exposed to either Asp+ or Asp- CF BALF samples identified a number of differentially expressed transcripts, including those involved in interferon-signaling, anti-microbial gene expression, and cell death. Toxicity did not correlate with bacterial lung infections. These results suggest that the potential use of MSC-based cell therapies for CF or other lung diseases may not be warranted in the presence of Aspergillus.

PMID: 32901521 [PubMed - as supplied by publisher]

Noninvasive Ventilation in Cystic Fibrosis: Clinical Indications and Outcomes in a Large UK Adult Cystic Fibrosis Center.

Respir Care. 2020 Sep 08;:

Authors: Spoletini G, Pollard K, Watson R, Darby MJ, Johnstone A, Etherington C, Whitaker P, Clifton IJ, Peckham DG

Abstract
BACKGROUND: Noninvasive ventilation (NIV) is routinely used to treat patients with cystic fibrosis and respiratory failure. However, evidence on its use is limited, with no data on its role in disease progression and outcomes. The aim of this study was to assess the indications of NIV use and to describe the outcomes associated with NIV in adults with cystic fibrosis in a large adult tertiary center.
METHODS: A retrospective analysis of data captured prospectively on the unit electronic patient records was performed. All patients with cystic fibrosis who received NIV over a 10-y period were included in the study. A priori, 2 groups were identified based on length of follow-up, with 2 subgroups identified based on duration of NIV treatment.
RESULTS: NIV was initiated on 64 occasions. The duration of follow-up was categorized as > 6 months or < 6 months in 31 (48.4%) and 33 (51.6%) occasions, respectively. The most common indications for starting NIV were chronic (48.5%) and acute (32.8%) hypercapnic respiratory failure. Among those with a follow-up > 6 months, subjects who stopped using NIV early showed a steady median (interquartile range) decline in FEV1 (pre-NIV: -0.04 [-0.35 to 0.03] L/y vs post-NIV: -0.07 [-0.35 to 0.01] L/y, P = .51), while among those who continued using it had an improvement in the rate of decline (pre-NIV: -0.25 [-0.52 to -0.02] L/y vs post-NIV: -0.07 [-0.13 to 0.16] L/y, P = .006). No differences in intravenous antibiotic requirement or pulmonary exacerbations were noted with the use of NIV. Pneumothorax and massive hemoptysis occurred independently in 4 cases.
CONCLUSIONS: NIV is being used in cystic fibrosis as adjunct therapy for the management of advanced lung disease in a similar fashion to other chronic respiratory conditions. Adherence to NIV treatment can stabilize lung function but does not reduce pulmonary exacerbations or intravenous antibiotic requirement.

PMID: 32900912 [PubMed - as supplied by publisher]

How can we relieve gastrointestinal symptoms in people with cystic fibrosis? An international qualitative survey.

BMJ Open Respir Res. 2020 Sep;7(1):

Authors: Smith S, Rowbotham N, Davies G, Gathercole K, Collins SJ, Elliott Z, Herbert S, Allen L, Ng C, Smyth A

Abstract
INTRODUCTION: Relieving gastrointestinal (GI) symptoms was identified as a 'top ten' priority by our James Lind Alliance Priority Setting Partnership in cystic fibrosis (CF). We conducted an online survey to find out more about the effect of GI symptoms in CF.
METHODS: We co-produced an online survey distributed to the CF community via web-based platforms. The survey consisted of open and closed questions designed to help us learn more about the effects of GI symptoms for people with CF (pwCF). We analysed the data using descriptive statistics and thematic analysis. We promoted the survey via social media and web-based platforms which allowed respondents from any country to take part. Our participants came from the CF community, including: adults and children with CF, parents and close family of pwCF and healthcare professionals (HCPs) working with pwCF.
RESULTS: There were 276 respondents: 90 (33%) pwCF, 79 (29%) family, 107 (39%) HCPs. The most commonly reported symptoms by lay respondents were stomach cramps/pain, bloating and a 'combination of symptoms'. The top three symptoms that HCPs said were reported to them were reduced appetite, bloating and constipation. Almost all (94% (85/90)) HCPs thought medications helped to relieve GI symptoms but only 58% (82/141) of lay respondents agreed.
CONCLUSIONS: Our survey has shown that GI symptoms among our participants are prevalent and intrude on daily lives of pwCF. There is a need for well-designed clinical studies to provide better evidence for management of GI symptoms and complications.

PMID: 32900780 [PubMed - in process]