Sildenafil improves exercise capacity in patients with cystic fibrosis: a proof-of-concept clinical trial.

Ther Adv Chronic Dis. 2019;10:2040622319887879

Authors: Rodriguez-Miguelez P, Ishii H, Seigler N, Crandall R, Thomas J, Forseen C, McKie KT, Harris RA

Abstract
Background: Exercise intolerance is a common phenotype observed in patients with cystic fibrosis (CF). Treatment with sildenafil, a phosphodiesterase type 5 (PDE5) inhibitor, has previously been shown to improve exercise capacity (VO2 peak) in other patient populations. Thus, the present study sought to determine the acute and subacute effects of sildenafil on exercise capacity in patients with CF.
Methods: The present investigation utilized a randomized, double-blind, placebo-controlled, crossover study with an acute dose of either sildenafil (50 mg) or placebo (n = 13, age 25 ± 10), followed by a 4 week open-label extension with sildenafil (20 mg, TID; n = 15, age 23 ± 11). A comprehensive evaluation of pulmonary function and a maximal exercise test were each performed at every visit.
Results: A significant increase in VO2 peak was observed after the acute sildenafil dose with no changes following placebo (77 ± 13 versus 72 ± 13% predicted; p = 0.033). In addition, after 4 weeks of treatment, patients showed a significant increase in exercise capacity (72 ± 12 versus 75 ± 12% predicted; p = 0.028) and exercise duration (409 ± 98 versus 427 ± 101 s; p = 0.014). A robust correlation (r = 0.656; p = 0.008) between baseline FEV1 (% predicted) and the change in exercise capacity following 4 weeks of treatment was identified.
Conclusions: This proof-of-concept clinical trial demonstrates that sildenafil treatment can improve exercise capacity in patients with CF and that pulmonary function may play an important role in the effectiveness of treatment. Future investigations of sildenafil treatment in patients with CF are certainly warranted.

PMID: 31803404 [PubMed]

Hot topics and current controversies in non-cystic fibrosis bronchiectasis.

Breathe (Sheff). 2019 Dec;15(4):286-295

Authors: Severiche-Bueno D, Gamboa E, Reyes LF, Chotirmall SH

Abstract
Non-cystic fibrosis bronchiectasis (NCFB) is a neglected and orphan disease with poor advances through the 20th century. However, its prevalence is rising and with this come new challenges for physicians. Few guidelines are available to guide clinicians on how to diagnose and manage patients with NCFB. Many areas of debate persist, and there is lack of consensus about research priorities most needed to advance patient care and improve clinical outcomes. In this review, we highlight the current hot topics in NCFB and present updated evidence to inform the critical areas of controversy.
Key points: Postural drainage, active cycle of breathing techniques and pulmonary rehabilitation are non-pharmacological treatment options that should be offered to all patients with non-cystic fibrosis bronchiectasis (NCFB).Eradication of Pseudomonas aeruginosa (PA) colonisation in patients without an acute exacerbation remains debatable.Sputum cultures are the leading and most readily available tool to detect patients with chronic colonisation by PA and should be performed in all patients with NCFB.Antibacterial monoclonal antibodies and vaccine studies have shown promising results in the prevention of chronic colonisation with PA and should stimulate new studies in NCFB.NCFB patients colonised with PA are at more risk of a rapid decline in lung function, worsening quality of life and more hospital admissions.Dual therapy is a promising option for the management of patients with PA-related exacerbations.Patients with PA-related exacerbations benefit from prolonged courses of antibiotics (i.e. 14 days) but emerging and future studies, including dual therapy, may show promising results with shorter courses.Endophenotyping bronchiectasis to address its inherent heterogeneity is a promising avenue for future investment and research.

PMID: 31803263 [PubMed]

miR-636: A Newly-Identified Actor for the Regulation of Pulmonary Inflammation in Cystic Fibrosis.

Front Immunol. 2019;10:2643

Authors: Bardin P, Foussignière T, Rousselet N, Rebeyrol C, Porter JC, Corvol H, Tabary O

Abstract
Cystic fibrosis (CF) results from deficient CF transmembrane conductance regulator (CFTR) protein activity leading to defective epithelial ion transport. Pulmonary degradation due to excessive inflammation is the main cause of morbidity and mortality in CF patients. By analysing miRNAs (small RNAseq) in human primary air-liquid interface cell cultures, we measured the overexpression of miR-636 in CF patients compared to non-CF controls. We validated these results in explant biopsies and determined that the mechanism underlying miR-636 overexpression is linked to inflammation. To identify specific targets, we used bioinformatics analysis to predict whether miR-636 targets the 3'-UTR mRNA regions of IL1R1 and RANK (two pro-inflammatory cytokine receptors), IKBKB (a major protein in the NF-κB pathway), and FAM13A (a modifier gene of CF lung phenotype implicated in epithelial remodelling). Using bronchial epithelial cells from CF patients to conduct a functional analysis, we showed a direct interaction between miR-636 and IL1R1, RANK, and IKBKB, but not with FAM13A. These interactions led to a decrease in IL1R1 and IKKβ protein expression levels, while we observed an increase in RANK protein expression levels following the overexpression of miR-636. Moreover, NF-κB activity and IL-8 and IL-6 secretions decreased following the transfection of miR-636 mimics in CF cells. Similar but opposite effects were found after transfection with an antagomiR-636 in the same cells. Furthermore, we demonstrated that miR-636 was not regulated by Pseudomonas aeruginosa in our model. We went on to show that miR-636 is raised in the blood neutrophils, but not in the plasma, of CF patients and may have potential as a novel biomarker. Collectively, our findings reveal a novel actor for the regulation of inflammation in CF, miR-636, which is able to reduce constitutive NF-κB pathway activation when it is overexpressed.

PMID: 31803183 [PubMed - in process]

Nebulized Colistin And Continuous Cyclic Azithromycin In Severe COPD Patients With Chronic Bronchial Infection Due To Pseudomonas aeruginosa: A Retrospective Cohort Study.

Int J Chron Obstruct Pulmon Dis. 2019;14:2365-2373

Authors: Montón C, Prina E, Pomares X, Cugat JR, Casabella A, Oliva JC, Gallego M, Monsó E

Abstract
Introduction: Long-term use of nebulized or oral antibiotics is common in the treatment of cystic fibrosis and non-cystic fibrosis bronchiectasis. To date, however, few studies have focused on the use of nebulized antibiotics in COPD patients. The aims of this study are: to establish whether a combination of nebulized colistin plus continuous cyclic azithromycin in severe COPD patients with chronic bronchial infection due to Pseudomonas aeruginosa reduces the frequency of exacerbations, and to assess the effect of this treatment on microbiological sputum isolates.
Material and methods: A retrospective cohort was created for the analysis of patients with severe COPD and chronic bronchial infection due to P. aeruginosa treated with nebulized colistin at the Respiratory Day Care Unit between 2005 and 2015. The number and characteristics of COPD exacerbations (ECOPD) before and up to two years after the introduction of nebulized colistin treatment were recorded.
Results: We analyzed 32 severe COPD patients who received nebulized colistin for at least three months (median 17 months [IQR 7-24]). All patients but one received combination therapy with continuous cyclic azithromycin (median 24 months [IQR 11-30]). A significant reduction in the number of ECOPD from baseline of 38.3% at two years of follow-up was observed, with a clear decrease in P. aeruginosa ECOPD (from 59.5% to 24.6%) and a P. aeruginosa eradication rate of 28% over the two-year follow-up.
Conclusion: In patients with severe COPD and chronic bronchial infection due to P. aeruginosa, combination therapy with nebulized colistin and continuous cyclic azithromycin significantly reduced the number of ECOPD, with a marked decrease in P. aeruginosa sputum isolates.

PMID: 31802860 [PubMed - in process]

Trypsin treatment unlocks barrier for zoonotic bat coronaviruses infection.

J Virol. 2019 Dec 04;:

Authors: Menachery VD, Dinnon KH, Yount BL, McAnarney ET, Gralinski LE, Hale A, Graham RL, Scobey T, Anthony SJ, Wang L, Graham B, Randell SH, Lipkin WI, Baric RS

Abstract
Traditionally, the emergence of coronaviruses (CoVs) has been attributed to a gain in receptor binding in a new host. Our previous work with SARS-like viruses argued that bats already harbor CoVs with the ability to infect humans without adaptation. These results suggested that additional barriers limit the emergence of zoonotic CoV. In this work, we describe overcoming host restriction of two MERS-like bat CoVs using exogenous protease treatment. We found that the spike protein of PDF2180-CoV, a MERS-like virus found in a Ugandan bat, could mediate infection of Vero and human cells in the presence of exogenous trypsin. We subsequently show that the bat virus spike can mediate infection of human gut cells, but is unable to infect human lung cells. Using receptor-blocking antibodies, we show that infection with the PDF2180 spike does not require MERS-CoV receptor DPP4 and antibodies developed against the MERS spike receptor-binding domain and S2 portion are ineffective in neutralizing the PDF2180 chimera. Finally, we found that addition of exogenous trypsin also rescues HKU5-CoV, a second bat group 2c CoV. Together, these results indicate that proteolytic cleavage of the spike, not receptor binding, is the primary infection barrier for these two group 2c CoVs. Coupled with receptor binding, proteolytic activation offers a new parameter to evaluate emergence potential of bat CoVs and offer a means to recover previously unrecoverable zoonotic CoV strains.Importance Overall, our studies demonstrate that proteolytic cleavage is the primary barrier to infection for a subset of zoonotic coronaviruses. Moving forward, the results argue that both receptor binding and proteolytic cleavage of the spike are critical factors that must be considered for evaluating the emergence potential and risk posed by zoonotic coronaviruses. In addition, the findings also offer a novel means to recover previously uncultivable zoonotic coronavirus strains and argue that other tissues, including the digestive tract, could be a site for future coronavirus emergence events in humans.

PMID: 31801868 [PubMed - as supplied by publisher]

Call for papers on cystic fibrosis: a collaborative research session featuring the European Respiratory Journal, The Lancet Respiratory Medicine and the Journal of Cystic Fibrosis.

Eur Respir J. 2019 Dec;54(6):

Authors:

PMID: 31801820 [PubMed - in process]

Primary immunodeficiency-related bronchiectasis in adults: comparison with bronchiectasis of other etiologies in a French reference center.

Respir Res. 2019 Dec 04;20(1):275

Authors: Goussault H, Salvator H, Catherinot E, Chabi ML, Tcherakian C, Chabrol A, Didier M, Rivaud E, Fischer A, Suarez F, Hermine O, Lanternier F, Lortholary O, Mahlaoui N, Devillier P, Couderc LJ

Abstract
BACKGROUND: Bronchiectasis is a heterogeneous disease depending on etiology. It represents the most frequent non-infectious pulmonary complication of primary immunodeficiencies (PID). We investigated whether bronchiectasis associated with PID had a distinct course in comparison to bronchiectasis of other causes.
METHODS: Retrospective single-center study of adult patients diagnosed with non-cystic fibrosis bronchiectasis with more than 5 years of follow-up and at least 4 pulmonary functional tests available at one year apart. They were divided into three groups: PID- related bronchiectasis, idiopathic/post infectious-related bronchiectasis and other causes of bronchiectasis. Respiratory functional data and clinical outcomes were compared.
RESULTS: Of 329 patients with bronchiectasis diagnosed in Foch Hospital (Suresnes, France), 98 patients fulfilled the selected criteria (20 PID-related cases, 39 idiopathic or post-infectious cases, and 39 cases with other causes). Median time of follow-up was 9.5 years. Groups were similar concerning initial characteristics (female 70.4%, never smokers 59.2%, mild severity bronchiectasis according to the FACED score and median FEV1 at diagnosis 73.5% predicted values [Q1-Q3: 53.75-90.5]), except PID patients who were younger (median age of 51.5 vs 62 years, p = 0.02). Eighty-five percent of PID patients received immunoglobulin substitution (median trough level was measured at 10.5 g/dl [10;10.92]). Global median FEV1 annual decline was 25.03 ml/year [8.16;43.9] and 19.82 ml/year [16.08;48.02] in the PID patients group. Forty-five percent of patients had bacterial colonization, pneumoniae occurred in 56% of patients and median exacerbation annual rate was 0.8 [0.3-1.4]. Hemoptysis occurred in 31.6% of patients. Global mortality rate was 11.2%. We did not record any significant difference for all clinical and functional outcomes between patients with PID and other etiologies. The median decline in FEV1 was similar in the three groups.
CONCLUSIONS: The course of PID-related bronchiectasis was similar to bronchiectasis of other causes. Provided that patients receive immunoglobulin replacement, the course of PID-related bronchiectasis seems to be independent of the underlying immune disorder.

PMID: 31801528 [PubMed - in process]

Correction to: Circadian rhythm of COPD symptoms in clinically based phenotypes. Results from the STORICO Italian observational study.

BMC Pulm Med. 2019 12 04;19(1):235

Authors: Scichilone N, Antonelli Incalzi R, Blasi F, Schino P, Cuttitta G, Zullo A, Ori A, Canonica GW, STORICO study group

Abstract
Following publication of the original article [1], the authors flagged that the article had been provided with the names of the authors (not including the STORICO study group) in the wrong order: the 'Given Names' and Family Names' were erroneously swapped around.

PMID: 31801499 [PubMed]

Inhibition of ATP hydrolysis restores airway surface liquid production in cystic fibrosis airway epithelia.

Am J Physiol Lung Cell Mol Physiol. 2019 Dec 04;:

Authors: van Heusden C, Button B, Anderson WH, Ceppe A, Morton LC, O'Neal WK, Dang H, Alexis NE, Donaldson SH, Stephan H, Boucher RC, Lazarowski ER

Abstract
Airway surface dehydration is a pathological feature of cystic fibrosis (CF) lung disease. CF is caused by mutations in the CF transmembrane conductance regulator (CFTR), a cyclic AMP-regulated Cl- channel controlled in part by the adenosine A2B receptor. An alternative, CFTR-independent mechanism of fluid secretion is regulated by ATP, via the P2Y2 receptor (P2Y2R) that activates Ca2+-regulated Cl- channels (CaCC/TMEM16) and inhibits Na+ absorption. However, due to rapid ATP hydrolysis, steady-state ATP levels in CF airway surface liquid (ASL) are inadequate to maintain P2Y2R-mediated fluid secretion. Therefore, inhibiting airway epithelial ecto-ATPases to increase ASL ATP levels constitutes a strategy to restore airway surface hydration in CF. Using [γ32P]ATP as radiotracer, we assessed the effect of a series of ATPase inhibitory compounds on the stability of physiologically occurring ATP concentrations. We identified the polyoxometalate [Co4(H2O)2(PW9O34)2]10- (POM-5) as the most potent and effective ecto-ATPase inhibitor in CF airway epithelial cells. POM-5 caused long-lasting inhibition of ATP hydrolysis in airway epithelia, which was reversible upon removal of the inhibitor. Importantly, POM-5 markedly enhanced steady-state levels of released ATP, promoting increased ASL volume in CF cell surfaces. These results provide proof-of-concept for ecto-ATPase inhibitors as therapeutic agents to restore hydration of CF airway surfaces. As a test of this notion, cell-free sputum supernatants from CF subjects were studied and found to have abnormally elevated ATPase activity, which was markedly inhibited by POM-5.

PMID: 31800264 [PubMed - as supplied by publisher]

Clinical characteristics and outcomes of patients with Escherichia coli in airway samples.

Clin Respir J. 2019 Dec 04;:

Authors: Schneer S, Khoury J, Adir Y, Stein N, Shaked Mishan P, Ken-Dror S, Weber G, Meler R, Khateeb A, Shteinberg M

Abstract
PURPOSES: Escherichia coli (E. coli) is one of the most common pathogens in nosocomial and community-acquired infections, but is an uncommon respiratory pathogen. However, this pathogen may at times be seen in respiratory secretions. The study aims to determine the clinical and prognostic value of E. coli in respiratory secretions.
METHODS: Cultures of respiratory secretions from hospitalized and outpatients between 2009 and 2016 were screened for isolation of E. coli. We defined 3 groups of patients: "Sensitive (S)"- growth of E. coli sensitive to all antimicrobials tested; Intermediate (I) - resistant to 1-2 antimicrobial classes; and "Resistant (R)"- resistant to at least three antibiotic classes. We compared factors associated with resistant strains and outcomes between the groups.
RESULTS: Eighty patients with E. coli isolates from respiratory secretions were identified while screening 177,712 (4.5: 10,000 samples). Of the E. coli positive cultures,11 were from ambulatory patients, 31 patients were hospitalized, and 37 were hospitalized and intubated. Ten people had bronchiectasis, and 29 had COPD. Patients with resistant E. coli had significantly more hospitalization days prior to positive culture (S-1.2 ±1.89 days, I-1.23±1.5 days and R- 3.7±5.4 days respectively p=0.002). Mortality was higher in patients with a resistant strain (R) vs. (I) or (S) (76.7%, 31.8% and 26.7%, respectively p<0.0001) and remained significantly elevated after correction for prior hospital days.
CONCLUSIONS: Pulmonary infection due to E. coli is uncommon. Isolation of resistant E. coli is associated with length of previous hospitalization, elevated mortality and may be viewed as a nosocomial pathogen.

PMID: 31799802 [PubMed - as supplied by publisher]

Excessive wrinkling of the palms after brief water immersion.

JAAD Case Rep. 2019 Dec;5(12):1068-1070

Authors: Konstantinov NK, Obreshkova E

PMID: 31799354 [PubMed]

Cystic fibrosis transmembrane conductance regulator functional evaluations in a G542X+/- IVS8Tn:T7/9 patient with acute recurrent pancreatitis.

World J Clin Cases. 2019 Nov 26;7(22):3757-3764

Authors: Caldrer S, Bergamini G, Sandri A, Vercellone S, Rodella L, Cerofolini A, Tomba F, Catalano F, Frulloni L, Buffelli M, Tridello G, de Jonge H, Assael BM, Sorio C, Melotti P

Abstract
BACKGROUND: Acute recurrent pancreatitis (ARP) is characterized by episodes of acute pancreatitis in an otherwise normal gland. When no cause of ARP is identifiable, the diagnosis of "idiopathic" ARP is given. Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene increase the risk of ARP by 3- to 4-times compared to the general population, while cystic fibrosis (CF) patients present with a 40- to 80-times higher risk of developing pancreatitis.
CASE SUMMARY: In non-classical CF or CFTR-related disorders, CFTR functional tests can help to ensure a proper diagnosis. We applied an individualized combination of standardized and new CFTR functional bioassays for a patient referred to the Verona CF Center for evaluation after several episodes of acute pancreatitis. The CFTR genotype was G542X+/- with IVS8Tn:T7/9 polymorphism. The sweat (Cl-) values were borderline. Intestinal current measurements were performed according to the European Cystic Fibrosis Society Standardized Operating Procedure. Recent nasal surgery for deviated septum did not allow for nasal potential difference measurements. Lung function and sputum cultures were normal; azoospermia was excluded. Pancreas divisum was excluded by imaging but hypoplasia of the left hepatic lobe was detected. Innovative tests applied in this case include sweat rate measurement by image analysis, CFTR function in monocytes evaluated using a membrane potential-sensitive fluorescent probe, and the intestinal organoids forskolin-induced swelling assay.
CONCLUSION: Combination of innovative CFTR functional assays might support a controversial diagnosis when CFTR-related disorders and/or non-classical CF are suspected.

PMID: 31799301 [PubMed]

Congenital bilateral absence of the vas deferens (CBAVD): do genetic disorders modify assisted reproductive technologies outcomes?

Arch Esp Urol. 2020 Dec;72(10):1038-1042

Authors: Gallego Á, Rogel R, Pérez-Ardavín J, Lorenzo L, Lujan S, Oltra S, Molina I, Broseta E

Abstract
OBJECTIVES: To evaluate the impact of common Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene mutations, 5T polymorphism and presence of severe Cystic Fibrosis (CF) on fertility outcomes with Assisted Reproductive Techniques (ART) in patients presenting Congenital Bilateral Absence of Vas Deferens (CBAVD).
METHODS: A comparative observational cohort study was performed from 2002 to 2018 with 51 patients with diagnosis of CBAVD. Presence of CFTR mutations and 5T, CF, pregnancy and newborn rates were analyzed.
RESULTS: 80.4% percent had some mutation of CFTR gene being ΔF508 the most common (51%). The most frequently described genotype was the 7T/9T (31.4%) with the presence of 5T polymorphism in up to 25.5% of cases. Global newborn rates were 34% in the group using partner spermatozoa. When comparing 5T presence, we observed a decrease in newborn rates when carrying this mutation, without obtaining statistical significance (newborn rate: 5T/non-5T: 7.1/28%, p 0.45). No differences were found when comparing presence of severe CF, common CFTR gene mutations and ICSI-related parameters.
CONCLUSION: The analysis of the presence of 5T polymporphism in CBAVD patients may add information when predicting the outcome of assisted reproductive techniques.

PMID: 31797807 [PubMed - in process]

Pseudomonas aeruginosa uses multiple receptors for adherence to laminin during infection of the respiratory tract and skin wounds.

Sci Rep. 2019 Dec 03;9(1):18168

Authors: Paulsson M, Su YC, Ringwood T, Uddén F, Riesbeck K

Abstract
Pseudomonas aeruginosa efficiently adheres to human tissues, including the lungs and skin, causing infections that are difficult to treat. Laminin is a main component of the extracellular matrix, and in this study we defined bacterial laminin receptors on P. aeruginosa. Persistent clinical P. aeruginosa isolates from patients with cystic fibrosis, wounds or catheter-related urinary tract infections bound more laminin compared to blood isolates. Laminin receptors in the outer membrane were revealed by 2D-immunblotting, and the specificities of interactions were confirmed with ELISA and biolayer interferometry. Four new high-affinity laminin receptors were identified in the outer membrane; EstA, OprD, OprG and PA3923. Mutated bacteria devoid of these receptors adhered poorly to immobilized laminin. All bacterial receptors bound to the heparin-binding domains on LG4 and LG5 of the laminin alpha chain as assessed with truncated laminin fragments, transmission electron microscopy and inhibition by heparin. In conclusion, P. aeruginosa binds laminin via multiple surface receptors, and isolates from lungs of cystic fibrosis patients bound significantly more laminin compared to bacteria isolated from the skin and urine. Since laminin is abundant in both the lungs and skin, we suggest that laminin binding is an important mechanism in P. aeruginosa pathogenesis.

PMID: 31796854 [PubMed - in process]

Mortality risk and causes of death in patients with non-cystic fibrosis bronchiectasis.

Respir Res. 2019 Dec 03;20(1):271

Authors: Sin S, Yun SY, Kim JM, Park CM, Cho J, Choi SM, Lee J, Park YS, Lee SM, Yoo CG, Kim YW, Han SK, Lee CH

Abstract
BACKGROUND: All-cause mortality risk and causes of death in bronchiectasis patients have not been fully investigated. The aim of this study was to compare the mortality risk and causes of death between individuals with bronchiectasis and those without bronchiectasis.
METHODS: Patients with or without bronchiectasis determined based on chest computed tomography (CT) at one centre between 2005 and 2016 were enrolled. Among the patients without bronchiectasis, a control group was selected after applying additional exclusion criteria. We compared the mortality risk and causes of death between the bronchiectasis and control groups without lung disease. Subgroup analyses were also performed according to identification of Pseudomonas or non-tuberculous mycobacteria, airflow limitation, and smoking status.
RESULTS: Of the total 217,702 patients who underwent chest CT, 18,134 bronchiectasis patients and 90,313 non-bronchiectasis patients were included. The all-cause mortality rate in the bronchiectasis group was 1608.8 per 100,000 person-years (95% confidence interval (CI), 1531.5-1690.0), which was higher than that in the control group (133.5 per 100,000 person-years; 95% CI, 124.1-143.8; P < 0.001). The bronchiectasis group had higher all-cause (adjusted hazard ratio (aHR), 1.26; 95% CI, 1.09-1.47), respiratory (aHR, 3.49; 95% CI, 2.21-5.51), and lung cancer-related (aHR, 3.48; 95% CI, 2.33-5.22) mortality risks than the control group. In subgroup analysis, patients with airflow limitation and ever smokers showed higher all-cause mortality risk among bronchiectasis patients. Therefore, we observed significant interrelation between bronchiectasis and smoking, concerning the risks of all-cause mortality (P for multiplicative interaction, 0.030, RERI, 0.432; 95% CI, 0.097-0.769) and lung cancer-related mortality (RERI, 8.68; 95% CI, 1.631-15.736).
CONCLUSION: Individuals with bronchiectasis had a higher risk of all-cause, respiratory, and lung cancer-related mortality compared to control group. The risk of all-cause mortality was more prominent in those with airflow limitation and in ever smokers.

PMID: 31796019 [PubMed - in process]

Progressive Liver Disease in Patients With Ataxia Telangiectasia.

Front Pediatr. 2019;7:458

Authors: Donath H, Woelke S, Theis M, Heß U, Knop V, Herrmann E, Krauskopf D, Kieslich M, Schubert R, Zielen S

Abstract
Ataxia telangiectasia (A-T) is a devastating multi-system disorder characterized by progressive cerebellar ataxia, immunodeficiency, genetic instability, premature aging and growth retardation. Due to better care the patients get older than in the past and new disease entities like disturbed glucose tolerance and liver disease emerge. The objective of the present investigation is to determine the evolution of liver disease and its relation to age and neurological deterioration. The study included 67 patients aged 1 to 38 years with classical A-T. At least two measurements of liver enzymes were performed within a minimum interval of 6 months in 56 patients. The median follow-up period was 4 years (1-16 years). A total of 316 liver enzyme measurements were performed. For analysis, patients were divided into two age groups (Group 1: <12 years; group 2: ≥12 years). In addition, ultrasound of the liver and Klockgether Ataxia Score (KAS) were analyzed. We found significantly higher levels of alpha-fetoprotein (AFP) (226,8 ± 20.87 ng/ml vs. 565,1 ± 24.3 ng/ml, p < 0.0001), and liver enzymes like ALT (23.52 ± 0.77 IU/L vs. 87.83 ± 5.31 IU/L, p < 0.0001) in patients in group 2. In addition, we could show a significant correlation between age and AFP, GGT, and KAS. Ultrasound revealed hepatic steatosis in 11/19 (57.9%) patients in group 2. One female patient aged 37 years died due to a hepato-cellular carcinoma (HCC). Liver disease is present in the majority of older A-T patients. Structural changes, non-alcoholic fatty liver disease and fibrosis are frequent findings. Progress of liver disease is concomitant to neurological deterioration.

PMID: 31788461 [PubMed]

Unsolved severe chronic rhinosinusitis elucidated by extensive CFTR genotyping.

Clin Case Rep. 2019 Nov;7(11):2128-2134

Authors: Degrugillier F, Simon S, Aissat A, Remus N, Mekki C, Decrouy X, Hatton A, Hinzpeter A, Hoffmann B, Sermet-Gaudelus I, Callebaut I, Fanen P, Prulière-Escabasse V

Abstract
Severe chronic rhinosinusitis in children should alert clinicians and extensive CFTR genotyping should be performed. We propose that thorough clinical and functional assessment in severe chronic rhinosinusitis is valuable to discover rare mutations which could be treated by CFTR correctors to postpone pulmonary infection.

PMID: 31788264 [PubMed]

Patients With Cystic Fibrosis Have New Triple-Drug Combination.

JAMA. 2019 Dec 03;322(21):2068

Authors: Voelker R

PMID: 31794613 [PubMed - in process]

Resilience in adolescents and young adults with cystic fibrosis: A pilot feasibility study of the promoting resilience in stress management intervention.

Pediatr Pulmonol. 2019 Dec 03;:

Authors: Toprak D, Nay L, McNamara S, Rosenberg AR, Rosenfeld M, Yi-Frazier JP

Abstract
BACKGROUND: Disease burden in cystic fibrosis (CF) impacts quality of life, distress, and treatment adherence. The promoting resilience in stress management (PRISM), is a brief patient-focused intervention to promote resilience in adolescents and young adults (AYAs), which may mitigate the negative outcomes, and is proven to be feasible and acceptable in other diseases.
OBJECTIVE: Our aim was to test the feasibility and acceptability of PRISM among AYAs with CF in addition to collecting pilot data regarding patient-reported resilience, distress, and quality of life.
METHODS: Eligible English speaking, 12 to 21 year patients admitted to the hospital were enrolled. We defined feasibility as 80% completion of all sessions. Acceptability was defined qualitatively based on feedback about timing, content and delivery of intervention. As an exploratory aim, questionnaires measuring resilience (Connor-Davidson resilience scale), distress (Kessler-6 scale), and disease-specific health-related quality of life (CF questionnaire-revised [CFQ-R]) were given at baseline and postintervention.
RESULTS: 10 out of 17 (59%) patients consented to participate. Eight were Caucasian, eight female with age range 13 to 20 years (median: 18). Nine completed all PRISM sessions with universally positive feedback. Health perception and respiratory domain scores of the CFQ-R improved (47.2-65.1; 95% confidence interval [CI], 2.6-35.6; 50.9-61.9; 95% CI, 1.7-19.9, respectively), however in the setting of inpatient exacerbation treatment it would be hard to attribute these changes to PRISM.
CONCLUSION: PRISM was feasible and highly acceptable among AYAs with CF. Future research is needed to test the efficacy of PRISM among a larger group of patients with CF in a multicenter trial.

PMID: 31794160 [PubMed - as supplied by publisher]

Nontuberculous mycobacteria in lung transplant recipients: Prevalence, risk factors and impact on survival and chronic lung allograft dysfunction.

Transpl Infect Dis. 2019 Dec 03;:e13229

Authors: Friedman DZP, Cervera C, Halloran K, Tyrrell G, Doucette K

Abstract
BACKGROUND: Nontuberculous mycobacteria (NTM) are environmental organisms that colonize or infect lung transplant recipients. Due to differences in populations studied and geographical diversity of species, risk factors for infection and its impact on patient outcomes post-transplant are conflicting in the literature.
METHODS: We reviewed the charts of 375 lung transplant recipients at the University of Alberta Hospital (Edmonton, Canada) between 2005 and 2014 to assess NTM epidemiology and risk factors. NTM positivity was determined from a laboratory database. The impact of NTM on patient and graft survival was tested by multivariate Cox regression analysis.
RESULTS: NTM were cultured from 26 patients before and 17 patients after transplant. The most commonly isolated species were Mycobacterium avium complex (55%) and Mycobacterium abscessus (20%). Five-year mortality was significantly higher in those infected with NTM after transplant (p=0.016) but there was no difference in chronic lung allograft dysfunction (CLAD) at 5 years (p=0.999). Cystic fibrosis and lower body mass index were associated with pre-transplant but not post-transplant NTM.
CONCLUSIONS: Isolation of NTM occurred in 7% of patients before, and 4.5% of patients after transplant. In this cohort, NTM isolation was associated with increased risk of death but not CLAD onset at 5 years.

PMID: 31794120 [PubMed - as supplied by publisher]