Outcomes of pulmonary Mycobacterium abscessus infection.

Int J Mycobacteriol. 2020 Jan-Mar;9(1):48-52

Authors: Flight WG, Hough NE, Chapman SJ

Abstract
Background: Treatment of Mycobacterium abscessus pulmonary disease (PD) is challenging with frequent side effects and uncertain rates of success.
Methods: We performed a retrospective review of all patients at our center with at least one respiratory sample positive for M. abscessus between 2014 and 2019. Electronic health records were reviewed to determine factors associated with M. abscessus infection and clinical outcomes.
Results: Thirty-seven patients were identified including 24 with cystic fibrosis (CF), 10 with bronchiectasis, two with chronic obstructive PD (COPD), and one with asthma. American Thoracic Society/Infectious Diseases Society of America criteria for nontuberculous mycobacteria PD were met in 21/37 (56.8%) of cases. Evidence of Aspergillus lung disease was noted in 18 (75.0%) CF patients compared with 3 (23.1%) non-CF patients (P = 0.005). Induction therapy for M. abscessus was given to 22/37 (59.5%) patients (18/24 [75%] with CF and 4/13 [30.8%] without CF). Median duration of induction therapy was 6 weeks (range 3-12). Maintenance antibiotic therapy was prescribed to 17/22 (77.3%) of treated patients. Culture conversion was seen in 15/24 (62.5%) of CF patients compared with 3/13 (23.1%) in the non-CF group (P = 0.034). Culture conversion occurred in 10/22 (45.5%) of treated patients compared with 8/15 (53.3%) untreated patients. Three patients (8.1%) died during follow-up: one with CF and two with COPD.
Conclusions: Culture conversion following isolation of M. abscessus from respiratory samples not only is more common in CF than in patients without CF but also frequently occurs spontaneously in both groups. Targeted treatment for M. abscessus did not clearly impact rates of culture conversion.

PMID: 32474488 [PubMed - as supplied by publisher]

Oral prevalence and antifungal susceptibility of Candida species in cystic fibrosis patients.

Arch Oral Biol. 2020 May 22;116:104772

Authors: Lepesqueur LSS, Tanaka MH, Lima GMG, Chiba SM, Mota AJ, Santos SF, Koga-Ito CY

Abstract
OBJECTIVE: This study aimed at assessing the oral prevalence ofCandida species in cystic fibrosis patients and the antifungal susceptibility of the isolates.
DESIGN: One hundred patients aged 3-20 years old were included in the study and were divided into three groups: G1 (low severity disease): 25 cystic fibrosis patients with Shwachman-Kulczycki score (SK) between 100 and 71; G2 (high severity disease): 25 cystic fibrosis patients with SK score under 40; and G3 (control): 50 healthy patients age- and gender-matched to cystic fibrosis patients. Stimulated saliva samples were collected and the oral fungal concentrations were assessed. Isolates were identified by phenotypic and genotypic tests. Antifungal susceptibilities to amphotericin B, flucytosine and fluconazole were determined by CLSI methodology. Fungal counts were compared by Kruskal Wallis and Dunn's test (5%).
RESULTS: A total of 68 % of Group 1, 80 % of Group 2, and 44 % of controls yielded positive Candida cultures. Oral concentrations of fungi were significantly higher in cystic fibrosis patients in relation to the control group (p < 0.0005). No significant difference was observed between low and high severity cystic fibrosis groups (p > 0.05). C. albicans was most frequently isolated species in all groups. Higher variability of Candida species was observed in the control group. C. dubliniensis and C. tropicalis were only detected among cystic fibrosis groups. All the isolates were susceptible to flucytosine and fluconazole.
CONCLUSIONS: Patients with cystic fibrosis were more frequently colonized by Candida species and showed higher oral fungal burden. No antifungal resistant isolates were detected.

PMID: 32474212 [PubMed - as supplied by publisher]

Single Lung Transplant vs Double Lung Transplant: A Single-Center Experience With Particular Consideration for Idiopathic Pulmonary Arterial Hypertension.

Transplant Proc. 2020 May 27;:

Authors: Antończyk R, Stącel T, Urlik M, Latos M, Kręt M, Borowik D, Wajda-Pokrontka M, Zawadzki F, Tatoj Z, Przybyłowski P, Zembala M, Ochman M, Nęcki M

Abstract
BACKGROUND: Lung transplant remains the only viable treatment for certain patients with end-stage lung diseases. Such patients can become either single or double lung recipients. The 2 procedures are associated with specific risks and benefits. The aim of the study was to assess the survival of patients after lung transplant in a single center.
METHODS: The retrospective study consists of 128 lung transplant recipients. Patients underwent transplant between 2004 and 2017 because of following diseases: chronic obstructive pulmonary disease (28.2%), cystic fibrosis (26.5%), and primary pulmonary hypertension (12.3%), including idiopathic pulmonary arterial hypertension and interstitial lung diseases (33%). Patients with idiopathic pulmonary arterial hypertension were not treated with postoperative extracorporeal membrane oxygenation as left heart conditioning.
RESULTS: Regardless of underlying disease, 75% of DLT recipients and 51% of SLT recipients reached 5-year survival (P = .0066). A total of 87% of lung transplant recipients with cystic fibrosis reached 1-year survival. Among lung recipients with primary pulmonary hypertension who underwent DLT and SLT, 5-year survival was reached by 84% and 51%, respectively (P = .025). Among patients with chronic obstructive pulmonary disease, 82% of DLT recipients and 62% of SLT recipients reached 1-year survival (P = .22). Patients who received transplants because of primary pulmonary hypertension presented the worst short-term survival among all SLT recipients.
CONCLUSIONS: Patients with CF have the best overall survival among all lung transplant recipients. Double lung transplant provides statistically significantly better outcomes than single lung transplant. This observation is also present among recipients who underwent transplant because of primary pulmonary hypertension, as single lung transplant is not recommended among such patients in particular.

PMID: 32474000 [PubMed - as supplied by publisher]

Testicular pain following initiation of elexacaftor/tezacaftor/ivacaftor in males with cystic fibrosis.

J Cyst Fibros. 2020 May 26;:

Authors: Rotolo SM, Duehlmeyer S, Slack SM, Jacobs HR, Heckman B

Abstract
Elexacaftor/tezacaftor/ivacaftor (Trikafta) was approved by the Food and Drug Administration in October 2019 for treatment of cystic fibrosis (CF) in patients 12 years and older with at least one F508del mutation in the CFTR protein. There were no documented reports of testicular pain during clinical trials. In this case series, we discuss 7 males between 17 and 39 years of age who reported testicular pain or discomfort within the first two weeks of starting therapy. The precise mechanism of this side effect is unknown, but it may be related to restoration of CFTR function in the male reproductive tract. All patients experienced resolution of this side effect within a week after onset, regardless of the management, except for one. Further research is needed to determine short- and long-term impact of this drug on male fertility. Until more data is available, the authors recommend counseling patients on contraceptive options.

PMID: 32471772 [PubMed - as supplied by publisher]

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Segniliparus rugosus from the sputum of a child with cystic fibrosis in Ecuador: challenges in bacterial identification.

New Microbes New Infect. 2020 May;35:100668

Authors: Zurita J, Sevillano G, González C, Lascano Y

Abstract
Using sequencing analyses of the 16S rRNA gene, we identified Segniliparus rugosus in an 8-year-old child with cystic fibrosis. We describe the difficulties we encountered in identifying this bacterium. To the best of our knowledge, this is the first reported case of S. rugosus in Ecuador.

PMID: 32461807 [PubMed]

CFTR promotes malignant glioma development via up-regulation of Akt/Bcl2-mediated anti-apoptosis pathway.

J Cell Mol Med. 2020 May 28;:

Authors: Zhao M, Zhang J, Huang W, Dong J, Guo J, U KP, Weng Z, Liu S, Chan HC, Feng H, Jiang X

Abstract
Cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-activated Cl- channel, is extensively expressed in the epithelial cells of various tissues and organs. Accumulating evidence indicates that aberrant expression or mutation of CFTR is related to carcinoma development. Malignant gliomas are the most common and aggressive intracranial tumours; however, the role of CFTR in the development of malignant gliomas is unclear. Here, we report that CFTR is expressed in malignant glioma cell lines. Suppression of CFTR channel function or knockdown of CFTR suppresses glioma cell viability whereas overexpression of CFTR promotes it. Additionally, overexpression of CFTR suppresses apoptosis and promotes glioma progression in both subcutaneous and orthotopic xenograft models. Cystic fibrosis transmembrane conductance regulator activates Akt/Bcl2 pathway, and suppression of PI3K/Akt pathway abolishes CFTR overexpression-induced up-regulation of Bcl2 (MK-2206 and LY294002) and cell viability (MK-2206). More importantly, the protein expression level of CFTR is significantly increased in glioblastoma patient samples. Altogether, our study has revealed a mechanism by which CFTR promotes glioma progression via up-regulation of Akt/Bcl2-mediated anti-apoptotic pathway, which warrants future studies into the potential of using CFTR as a therapeutic target for glioma treatment.

PMID: 32463592 [PubMed - as supplied by publisher]

Nontypeable Haemophilus influenzae Responds to Virus-Infected Cells with a Significant Increase in Type IV Pilus Expression.

mSphere. 2020 May 27;5(3):

Authors: Mokrzan EM, Dairo KA, Novotny LA, Bakaletz LO

Abstract
Nontypeable Haemophilus influenzae (NTHI) colonizes the human nasopharynx, but when the host immune response is dysregulated by upper respiratory tract (URT) virus infection, NTHI can gain access to more distal airway sites and cause disease. The NTHI type IV pilus (T4P) facilitates adherence, benign colonization, and infection, and its majority subunit PilA is in clinical trials as a vaccinogen. To further validate the strategy of immunization with PilA against multiple NTHI-induced diseases, it is important to demonstrate T4P expression under microenvironmental conditions that predispose to NTHI infection of the airway. Because URT infection commonly facilitates NTHI-induced diseases, we examined the influence of ongoing virus infection of respiratory tract epithelial cells on NTHI T4P expression in vitro Polarized primary human airway epithelial cells (HAEs) were sequentially inoculated with one of three common URT viruses, followed by NTHI. Use of a reporter construct revealed that NTHI upregulated pilA promoter activity when cultured with HAEs infected with adenovirus (AV), respiratory syncytial virus (RSV), or rhinovirus (RV) versus that in mock-infected HAEs. Consistent with these results, pilA expression and relative PilA/pilin abundance, as assessed by quantitative reverse transcription-PCR (qRT-PCR) and immunoblot, respectively, were also significantly increased when NTHI was cultured with virus-infected HAEs. Collectively, our data strongly suggest that under conditions of URT virus infection, PilA vaccinogen induction of T4P-directed antibodies is likely to be highly effective against multiple NTHI-induced diseases by interfering with T4P-mediated adherence. We hypothesize that this outcome could thereby limit or prevent the increased load of NTHI in the nasopharynx that characteristically precedes these coinfections.IMPORTANCE Nontypeable Haemophilus influenzae (NTHI) is the predominant bacterial causative agent of many chronic and recurrent diseases of the upper and lower respiratory tracts. NTHI-induced chronic rhinosinusitis, otitis media, and exacerbations of cystic fibrosis and chronic obstructive pulmonary disease often develop during or just after an upper respiratory tract viral infection. We have developed a vaccine candidate immunogen for NTHI-induced diseases that targets the majority subunit (PilA) of the type IV twitching pilus (T4P), which NTHI uses to adhere to respiratory tract epithelial cells and that also plays a role in disease. Here, we showed that NTHI cocultured with virus-infected respiratory tract epithelial cells express significantly more of the vaccine-targeted T4P than NTHI that encounters mock-infected (healthy) cells. These results strongly suggest that a vaccine strategy that targets the NTHI T4P will be effective under the most common predisposing condition: when the human host has a respiratory tract virus infection.

PMID: 32461275 [PubMed - in process]

Sleep disturbance and sleep insufficiency in primary caregivers and their children with cystic fibrosis.

J Cyst Fibros. 2020 May 25;:

Authors: Byars KC, Chini B, Hente E, Amin R, Boat T

Abstract
BACKGROUND: Chronically ill children and their parents are at risk for sleep disorders and associated morbidity. Sleep disturbance prevalence and the relationships between parent and child sleep among children with CF are not well defined. Clarifying the presence and impact of sleep disturbances among pediatric CF patients and their parents could lead to improved health in this population.
METHODS: Cross-sectional study assessing parent-reported sleep in ninety-one CF patients (mean age 8.8 years; 53.8% female) and their primary caregivers. Sleep sufficiency determined using American Academy of Sleep Medicine guidelines; correlation coefficients computed for sleep problem domains; stepwise multiple linear regression determined predictive models for sleep duration.
RESULTS: Parents reported concerns about their own sleep and that of their children. Night waking and daytime sleepiness were most common in parents; prolonged sleep latency was most common for children. Most parents and children had inadequate sleep duration. School-age children had the highest frequencies of overall sleep concerns and inadequate sleep. Most parent and child sleep problem domains were significantly associated, with large effects for similar parent and child problems. Stepwise multiple linear regression demonstrated that CF caregiver/patient sleep duration was significantly predicted by insomnia symptoms.
CONCLUSIONS: Many CF children and their parents experience sleep difficulties including inadequate sleep duration, with presence of sleep problems in many families whose children with CF had normal lung function. These data suggest that sleep health should be a CF Care Model component and should be a health care focus for families of children with other chronic illness.

PMID: 32461045 [PubMed - as supplied by publisher]

Pathophysiology of Hyperechogenic Bowel in Congenitally Human Cytomegalovirus Infected Fetuses.

Microorganisms. 2020 May 22;8(5):

Authors: Gabrielli L, Bonasoni MP, Chiereghin A, Piccirilli G, Borgatti EC, Simonazzi G, Salfi NCM, Tamagnini I, Lazzarotto T

Abstract
Hyperechogenic bowel (HB) is a nonspecific ultrasound finding that can be associated with human cytomegalovirus (CMV) congenital infection. In this study, we investigated HB pathophysiology in CMV-infected fetuses. We examined small and large intestine as well as pancreas in 8 fetuses at 22 weeks of gestation with congenital CMV infection. Ultrasound findings showed 4 fetuses with HB and 4 without. As negative group, 4 fetuses without CMV infection and without HB were studied. Immunohistochemistry for CMV, lymphocytic infiltrate, B-cell leukemia/lymphoma-2 (bcl-2), CD-117, cystic fibrosis transmembrane regulator (CFTR) were performed. HB fetuses showed multiple and sequential CMV-positive ganglion cells of Auerbach's myenteric plexus. In the ganglia, bcl-2 was weakly expressed representing a reduced neuronal functionality. CD-117 revealed a regular distribution of Cajal cells, the pacemakers of intestinal contractility. Pancreas showed normal CFTR staining, indicating a preserved exocrine secretion, thus unlikely a contributory factor in HB. In CMV-infected fetuses without HB, CMV-positive cells were scatteredly found in ganglion cells and bcl-2 was strongly expressed. Intestinal CD-117 and pancreatic CFTR expression were similar to fetuses with HB. In conclusion, fetal CMV infection of the bowel may lead to peristalsis impairment (paralytic ileus) due to intestinal plexus involvement, which at ultrasound appeared as HB.

PMID: 32455864 [PubMed]

[Dynamics of indicators of vitamin D status in children with cystic fibrosis of the Moscow region for 2016-2018].

Vopr Pitan. 2020;89(2):90-99

Authors: Kondratyeva EI, Zhekaite EK, Odinaeva ND, Voronkova AY, Sherman VD, Loshkova EV, Mel'yanovskaya YL, Zod'binova AE, Shubina YF, Budzinsky RM

Abstract
Vitamin D deficiency is widespread in patients with cystic fibrosis (CF). From 2016 to 2018, prophylactic doses of vitamin D were prescribed for the patients of the Russian cystic fibrosis Center in accordance with the National cystic fibrosis consensus and they were informed about the role of vitamin D deficiency. The aim of the study was to conduct a comparative analysis of the frequency of deficiency and insufficiency of vitamin D in children with CF of different ages in Moscow region in 2016 and 2018. Material and methods. The study involved 115 patients with CF at the age of 0-18 in 2016 and 211 children of the same age in 2018. All children underwent determination of 25(OH)D in blood serum by ELISA. Results and discussion. The frequency of vitamin D deficiency and insufficiency [25(OH)D level <30 ng/ml] in CF patients in 2016 was 64.3%, and in 2018 - 48.7%. Among children of 0-3 years normal serum 25(OH)D levels (>30 ng/ml) were registered in 62.5% in 2016 and in 62.2% in 2018, in children of 4-11 years - 28.8% in 2016 and 58.1% in 2018, among adolescents (11-18 years) - 11.8 and 30.2%, respectively. Conclusion. Comparative analysis showed a positive dynamics in reducing the proportion of CF patients with vitamin D deficiency and insufficiency against the background of continuous use of prophylactic doses of cholecalciferol and educational work for the period from 2016 to 2018. However, in a significant proportion of patients (48.7%), vitamin D level did not reach the norm in 2018 that requires the correction of preventive doses and increase in patient compliance.

PMID: 32459908 [PubMed - as supplied by publisher]

Population pharmacokinetics of ceftazidime in critically ill children: impact of cystic fibrosis.

J Antimicrob Chemother. 2020 May 26;:

Authors: Bui S, Facchin A, Ha P, Bouchet S, Leroux S, Nacka F, Fayon M, Jacqz-Aigrain E, network of Paediatric Clinical Investigation Centres

Abstract
BACKGROUND: Pharmacokinetics data on ceftazidime are sparse for the paediatric population, particularly for children with cystic fibrosis (CF) or severe infections.
OBJECTIVES: To characterize the population pharmacokinetics of ceftazidime in critically ill children, identify covariates that affect drug disposition and evaluate the current dosing regimens.
METHODS: The study was registered with Clinicaltrials.gov (NCT01344512). Children receiving ceftazidime were selected in 13 French hospitals. Plasma concentrations were determined by UPLC-MS/MS. Population pharmacokinetic analyses were performed using NONMEN software.
RESULTS: One hundred and eight patients, aged 28 days to 12 years, with CF (n = 32), haematology and/or oncology disorders (n = 47) or severe infection (n = 29) were included. Ceftazidime was administered by continuous or intermittent infusions; 271 samples were available for analysis. A two-compartment model with first-order elimination and allometric scaling was developed and covariate analysis showed that ceftazidime pharmacokinetics were also significantly affected by CLCR and CF. Ceftazidime clearance was 82% higher in CF than in non-CF patients. Monte Carlo simulations showed that the percentage of target attainment (PTA) for the target of T>MIC = 65% was (i) lower in CF than in non-CF children with intermittent infusions and (ii) higher with continuous than intermittent infusion in all children.
CONCLUSIONS: The population pharmacokinetics model for ceftazidime in children was influenced by body weight, CLCR and CF. A higher PTA was obtained with continuous versus intermittent infusions. Further studies should explore the benefits of continuous versus intermittent infusion of ceftazidime, including current versus increased doses in CF children.

PMID: 32457995 [PubMed - as supplied by publisher]

The Antimicrobial Peptide Human Beta-Defensin 2 Inhibits Biofilm Production of Pseudomonas aeruginosa Without Compromising Metabolic Activity.

Front Immunol. 2020;11:805

Authors: Parducho KR, Beadell B, Ybarra TK, Bush M, Escalera E, Trejos AT, Chieng A, Mendez M, Anderson C, Park H, Wang Y, Lu W, Porter E

Abstract
Biofilm production is a key virulence factor that facilitates bacterial colonization on host surfaces and is regulated by complex pathways, including quorum sensing, that also control pigment production, among others. To limit colonization, epithelial cells, as part of the first line of defense, utilize a variety of antimicrobial peptides (AMPs) including defensins. Pore formation is the best investigated mechanism for the bactericidal activity of AMPs. Considering the induction of human beta-defensin 2 (HBD2) secretion to the epithelial surface in response to bacteria and the importance of biofilm in microbial infection, we hypothesized that HBD2 has biofilm inhibitory activity. We assessed the viability and biofilm formation of a pyorubin-producing Pseudomonas aeruginosa strain in the presence and absence of HBD2 in comparison to the highly bactericidal HBD3. At nanomolar concentrations, HBD2 - independent of its chiral state - significantly reduced biofilm formation but not metabolic activity, unlike HBD3, which reduced biofilm and metabolic activity to the same degree. A similar discrepancy between biofilm inhibition and maintenance of metabolic activity was also observed in HBD2 treated Acinetobacter baumannii, another Gram-negative bacterium. There was no evidence for HBD2 interference with the regulation of biofilm production. The expression of biofilm-related genes and the extracellular accumulation of pyorubin pigment, another quorum sensing controlled product, did not differ significantly between HBD2 treated and control bacteria, and in silico modeling did not support direct binding of HBD2 to quorum sensing molecules. However, alterations in the outer membrane protein profile accompanied by surface topology changes, documented by atomic force microscopy, was observed after HBD2 treatment. This suggests that HBD2 induces structural changes that interfere with the transport of biofilm precursors into the extracellular space. Taken together, these data support a novel mechanism of biofilm inhibition by nanomolar concentrations of HBD2 that is independent of biofilm regulatory pathways.

PMID: 32457749 [PubMed - in process]

ILC2 Lung-Homing in Cystic Fibrosis Patients: Functional Involvement of CCR6 and Impact on Respiratory Failure.

Front Immunol. 2020;11:691

Authors: Schulz-Kuhnt A, Greif V, Hildner K, Knipfer L, Döbrönti M, Zirlik S, Fuchs F, Atreya R, Zundler S, López-Posadas R, Neufert C, Ramming A, Kiefer A, Grüneboom A, Strasser E, Wirtz S, Neurath MF, Atreya I

Abstract
Cystic fibrosis patients suffer from a progressive, often fatal lung disease, which is based on a complex interplay between chronic infections, locally accumulating immune cells and pulmonary tissue remodeling. Although group-2 innate lymphoid cells (ILC2s) act as crucial initiators of lung inflammation, our understanding of their involvement in the pathogenesis of cystic fibrosis remains incomplete. Here we report a marked decrease of circulating CCR6+ ILC2s in the blood of cystic fibrosis patients, which significantly correlated with high disease severity and advanced pulmonary failure, strongly implicating increased ILC2 homing from the peripheral blood to the chronically inflamed lung tissue in cystic fibrosis patients. On a functional level, the CCR6 ligand CCL20 was identified as potent promoter of lung-directed ILC2 migration upon inflammatory conditions in vitro and in vivo using a new humanized mouse model with light-sheet fluorescence microscopic visualization of lung-accumulated human ILC2s. In the lung, blood-derived human ILC2s were able to augment local eosinophil and neutrophil accumulation and induced a marked upregulation of pulmonary type-VI collagen expression. Studies in primary human lung fibroblasts additionally revealed ILC2-derived IL-4 and IL-13 as important mediators of this type-VI collagen-inducing effect. Taken together, the here acquired results suggest that pathologically increased CCL20 levels in cystic fibrosis airways induce CCR6-mediated lung homing of circulating human ILC2s. Subsequent ILC2 activation then triggers local production of type-VI collagen and might thereby drive extracellular matrix remodeling potentially influencing pulmonary tissue destruction in cystic fibrosis patients. Thus, modulating the lung homing capacity of circulating ILC2s and their local effector functions opens new therapeutic avenues for cystic fibrosis treatment.

PMID: 32457736 [PubMed - in process]

A helper-dependent adenoviral vector rescues CFTR to wild type functional levels in CF epithelial cells harbouring class I mutations.

Eur Respir J. 2020 May 26;:

Authors: Cao H, Ouyang H, Laselva O, Bartlett C, Zhou ZP, Duan C, Gunawardena T, Avolio J, Bear CE, Gonska T, Hu J, Moraes TJ

Abstract
Cystic Fibrosis (CF) is a genetic disorder affecting multiple organs, including the pancreas, hepatobiliary system and reproductive organs however lung disease is responsible for the majority of morbidity and mortality. Management of CF involves CFTR modulator agents including corrector drugs to augment cellular trafficking of mutant CFTR as well as potentiators that open defective CFTR channels. These therapies are poised to help most individuals with CF, with the notable exception of individuals with class I mutations where full length CFTR protein is not produced. For these mutations, gene replacement has been suggested as a potential solution.In this work, we used a helper dependent adenoviral vector (HD-CFTR) to express CFTR in nasal epithelial cell cultures derived from CF subjects with class I CFTR mutations. CFTR function was significantly restored in CF cells by HD-CFTR and reached healthy control functional levels as detected by Ussing chamber and membrane potential (FLIPR) assay. A dose response relationship was observed between the amount of vector used and subsequent functional outcomes; small amounts of HD-CFTR were sufficient to correct CFTR function. At higher doses, HD-CFTR did not increase CFTR function in healthy control cells above baseline values. This latter observation allowed us to use this vector to benchmark in vitro efficacy testing of CFTR-modulator drugs. In summary, we demonstrate the potential for HD-CFTR to inform in vitro testing and to restore CFTR function to healthy control levels in airway cells with class I or CFTR nonsense mutations.

PMID: 32457197 [PubMed - as supplied by publisher]

Identification of a Mutation in the Novel Compound Heterozygous CFTR in a Chinese Family with Cystic Fibrosis.

Can Respir J. 2020;2020:6507583

Authors: Shao H, Hua J, Wu Q, Li X, Zhang M, Wang H, Wu J, Xu L, Xie Y, Li L, Chen H

Abstract
Cystic fibrosis (CF) is one of the most common autosomal recessive disorders among Caucasians of Northern European descent but is uncommon in the Chinese population. Objectives. To elucidate the mutation in the novel compound heterozygous CFTR causing CF in Chinese family. Materials and Methods. Clinical samples were obtained from a Chinese family, the brother and sister with recurrent airway infections, hypoxemia and obstructive ventilatory impairment, sinusitis, clubbed fingers, salty sweat, and nasal polyposis. We performed whole-exome sequencing on the family and validated all potential variants by Sanger sequencing. Results. Next-generation sequencing showed a novel compound heterozygous CFTR mutation (c.400 A > G p.Arg134Gly and c.3484 C > T p.Arg1162 ∗ ) which resulted in CF in the family. Conclusions. As this mutation is consistent with the observed clinical manifestations of CF and no other mutations were detected after scanning the gene sequence, we suggest that their CF phenotypes are caused by the compound heterozygous mutation, c.400 A > G p.Arg134Gly and c.3484 C > T p.Arg1162 ∗ . As c.400 A > G is not currently listed in the Cystic Fibrosis Mutation Database, this information, regarding the CF-causing mutations in two Chinese patients, is of interest.

PMID: 32454915 [PubMed - as supplied by publisher]

Patients eligible for modulator drugs: Data from cystic fibrosis registry of Turkey.

Pediatr Pulmonol. 2020 May 26;:

Authors: Çobanoğlu N, Özçelik U, Çakır E, Şişmanlar Eyüboğlu T, Pekcan S, Cinel G, Yalçın E, Kiper N, Emiralioğlu N, Şen V, Şen HS, Ercan Ö, Çokuğraş H, Kılınç AA, Al Shadfan LM, Yazan H, Altıntaş DU, Karagöz D, Demir E, Kartal Öztürk G, Bingöl A, Başaran AE, Sapan N, Çekiç Ş, Çelebioğlu E, Aslan AT, Gürsoy TR, Tuğcu G, Özdemir A, Harmancı K, Yıldırım GK, Köse M, Hangül M, Tamay Z, Süleyman A, Yüksel H, Yılmaz Ö, Özcan G, Topal E, Can D, Korkmaz Ekren P, Çaltepe G, Kılıç M, Özdoğan Ş, Doğru D

Abstract
BACKGROUND: A better understanding of cystic fibrosis transmembrane conductance regulator biology has led to the development of modulator drugs such as ivacaftor, lumacaftor-ivacaftor, tezacaftor-ivacaftor, and elexacaftor-tezacaftor-ivacaftor. This cross-sectional study evaluated cystic fibrosis (CF) patients eligible for modulator drugs.
METHODS: Data for age and genetic mutations from the Cystic Fibrosis Registry of Turkey collected in 2018 were used to find out the number of patients who are eligible for modulator therapy.
RESULTS: Of registered 1488 CF patients, genetic analysis was done for 1351. The numbers and percentages of patients and names of the drugs, that the patients are eligible for, are as follows: 122 (9.03%) for ivacaftor, 156 (11.54%) for lumacaftor-ivacaftor, 163 (11.23%) for tezacaftor-ivacaftor, and 57 (4.21%) for elexacaftor-tezacaftor-ivacaftor. Among 1351 genotyped patients total of 313 (23.16%) patients are eligible for currently licensed modulator therapies (55 patients were shared by ivacaftor and tezacaftor-ivacaftor, 108 patients were shared by lumacaftor-ivacaftor and tezacaftor-ivacaftor, and 22 patients were shared by tezacaftor-ivacaftor and elexacaftor-tezacaftor-ivacaftor groups).
CONCLUSIONS: The present study shows that approximately one-fourth of the registered CF patients in Turkey are eligible for modulator drugs. As, frequent mutations that CF patients have in Turkey are different from North American and European CF patients, developing modulator drugs effective for those mutations is necessary. Furthermore, as modulator drugs are very expensive currently, financial support of the government in developing countries like Turkey is noteworthy.

PMID: 32453906 [PubMed - as supplied by publisher]

Exercise testing for children with cystic fibrosis: A systematic review.

Pediatr Pulmonol. 2020 May 26;:

Authors: Lang RL, Stockton K, Wilson C, Russell TG, Johnston LM

Abstract
BACKGROUND: Exercise testing is routinely used to measure exercise capacity in children with cystic fibrosis (CF). Various tests are available, however the psychometric properties of these measures have not been systematically reviewed for this population.
METHOD: A systematic search of electronic databases (PubMed, Web of Science, Medline, CINHAL, Cochrane, and PEDro) was performed to identify papers that: (a) reported original psychometric data, (b) examined a measure of exercise capacity, (c) examined children with CF aged eight to 18 years; and (d) were published in English after 1950. The level of psychometric evidence was evaluated using the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) checklist.
RESULTS: Searches identified 1025 papers. Forty-six papers were included, covering 15 tests: incremental cardiopulmonary exercise test using a cycle ergometer (CPET(cycle)) or treadmill (CPET(treadmill)), 6 minute walk test (6MWT), modified shuttle test (MST), 3-minute step test (3MST), 2 minute walk test (2MWT), Bratteby walk test, intermittent sprint test, speed ramp test, incremental step test, forward-backwards jump test (FBJT), astride jump test (AJT), motor quotient test, Munich fitness test, and Glittre ADL test.
CONCLUSION: There is a plethora of exercise tests available with varying psychometric robustness. The CPET, 6MWT, and MST have fair to good psychometric properties, but each with their clinical advantages and limitations. Thus, a Selection Guide was developed to assist clinicians and researchers in selecting the most appropriate exercise test for various situations.

PMID: 32453897 [PubMed - as supplied by publisher]

Three-dimensional Ultrashort Echotime Magnetic Resonance Imaging for Combined Morphologic and Ventilation Imaging in Pediatric Patients With Pulmonary Disease.

J Thorac Imaging. 2020 May 22;:

Authors: Veldhoen S, Heidenreich JF, Metz C, Petritsch B, Benkert T, Hebestreit HU, Bley TA, Köstler H, Weng AM

Abstract
PURPOSE: Ultrashort echotime (UTE) sequences aim to improve the signal yield in pulmonary magnetic resonance imaging (MRI). We demonstrate the initial results of spiral 3-dimensional (3D) UTE-MRI for combined morphologic and functional imaging in pediatric patients.
METHODS: Seven pediatric patients with pulmonary abnormalities were included in this observational, prospective, single-center study, with the patients having the following conditions: cystic fibrosis (CF) with middle lobe atelectasis, CF with allergic bronchopulmonary aspergillosis, primary ciliary dyskinesia, air trapping, congenital lobar overinflation, congenital pulmonary airway malformation, and pulmonary hamartoma.Patients were scanned during breath-hold in 5 breathing states on a 3-Tesla system using a prototypical 3D stack-of-spirals UTE sequence. Ventilation maps and signal intensity maps were calculated. Morphologic images, ventilation-weighted maps, and signal intensity maps of the lungs of each patient were assessed intraindividually and compared with reference examinations.
RESULTS: With a scan time of ∼15 seconds per breathing state, 3D UTE-MRI allowed for sufficient imaging of both "plus" pathologies (atelectasis, inflammatory consolidation, and pulmonary hamartoma) and "minus" pathologies (congenital lobar overinflation, congenital pulmonary airway malformation, and air trapping). Color-coded maps of normalized signal intensity and ventilation increased diagnostic confidence, particularly with regard to "minus" pathologies. UTE-MRI detected new atelectasis in an asymptomatic CF patient, allowing for rapid and successful therapy initiation, and it was able to reproduce atelectasis and hamartoma known from multidetector computed tomography and to monitor a patient with allergic bronchopulmonary aspergillosis.
CONCLUSION: 3D UTE-MRI using a stack-of-spirals trajectory enables combined morphologic and functional imaging of the lungs within ~115 second acquisition time and might be suitable for monitoring a wide spectrum of pulmonary diseases.

PMID: 32453280 [PubMed - as supplied by publisher]

Pseudomonas aeruginosa Isolates From a Cohort of Mexican Children With Cystic Fibrosis Show Adaptation to a Chronic Phenotype.

Pediatr Infect Dis J. 2020 May 20;:

Authors: Rosales-Reyes R, Rodríguez-Alvarado M, Lezana-Fernández JL, Sánchez-Lozano JY, Gayosso-Vázquez C, Jarillo-Quijada MD, Toledano-Tableros JE, Arredondo-Mercado MJ, Alcántar-Curiel MD, Lincopan N, Vidal JE, Lascurain R, Valvano MA, Santos-Preciado JI

Abstract
BACKGROUND: Long-term persistence of Pseudomonas aeruginosa in the lung of individuals with cystic fibrosis (CF) is associated with progressive selection of diverse genotypes and phenotypes. This bacterial adaptation leads to chronic infection and increased morbidity and mortality. The aim of this study was to establish the prevalence, clonal relatedness, antimicrobial susceptibility and virulence-associated phenotypes of P. aeruginosa isolates in a cohort of 50 Mexican children with CF-associated chronic lung infection.
METHODS: Clonal relatedness of P. aeruginosa isolates was verified by pulsed-field gel electrophoresis. The antimicrobial susceptibility was determined by an automated system that performs bacterial identificación and antibiotic susceptibility testing (VITEK 2) and/or broth microdilution method. Biofilm formation was quantified with the crystal violet method; swarming motility was measured on soft agar, and susceptibility to normal human serum determined by reduction of colony formed units (CFUs).
RESULTS: High prevalence of P. aeruginosa colonization among Mexican children with CF was confirmed; 20% (10/49) of clones identified showed a multidrug-resistant phenotype and 8.2% (4/49) an extensive drug resistance phenotype; 26.5% (13/49) of the isolates were resistant to colistin, 42.9% (21/49) presented a phenotype of adaptation associated with chronic infection and 79.6% (39/49) showed increased ability to survive in normal human serum.
CONCLUSIONS: This cohort of children with CF reveals that colonizing P. aeruginosa strains predominantly display resistance to several first-line antibiotics, although most isolates were susceptible to meropenem and tobramycin; 42.9% of isolates showed a phenotype consistent with adaptation to chronic lung infection.

PMID: 32453200 [PubMed - as supplied by publisher]