Diagnosis, follow-up and treatment of cystic fibrosis-related liver disease.

Curr Opin Pulm Med. 2017 Aug 23;:

Authors: van de Peppel IP, Bertolini A, Jonker JW, Bodewes FAJA, Verkade HJ

Abstract
PURPOSE OF REVIEW: To provide an insight and overview of the challenges in the diagnosis, follow-up and treatment of cystic fibrosis-related liver disease (CFLD).
RECENT FINDINGS: The variable pathophysiology of CFLD complicates its diagnosis and treatment. A 'gold standard' for CFLD diagnosis is lacking. Over the past years, new techniques to diagnose features of CFLD, such as transient elastography, have been investigated. Although most of these tests confirm cystic fibrosis-related liver involvement (CFLI), they are, however, not suitable to distinguish various phenotypical presentations or predict progression to clinically relevant cirrhosis or portal hypertension. A combined initiative from the European and the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition has been started, aimed to obtain consensus on CFLD criteria and definitions. Currently, only ursodeoxycholic acid is used in CFLD treatment, although it has not been convincingly demonstrated to change the natural course of the disease. Drugs that directly target cystic fibrosis transmembrane conductance regulator protein dysfunction show promising results; however, more long-term follow-up and validation studies are needed.
SUMMARY: CFLD is an umbrella term referring to a wide variety of liver manifestations with variable clinical needs and consequences. CFLD with portal hypertension is the most severe form of CFLD due to its significant implications on morbidity and mortality. The clinical relevance of other CFLI is uncertain. Consensus on CFLD definitions is essential to validate new diagnostic tools and therapeutic outcome measures.

PMID: 28837442 [PubMed - as supplied by publisher]

Mycobacterium abscessus glycopeptidolipids inhibit macrophage apoptosis and bacterial spreading by targeting mitochondrial cyclophilin D.

Cell Death Dis. 2017 Aug 24;8(8):e3012

Authors: Whang J, Back YW, Lee KI, Fujiwara N, Paik S, Choi CH, Park JK, Kim HJ

Abstract
Mycobacterium abscessus (MAB) is a species of nontuberculous mycobacteria (NTM) and a major causative pathogen of pulmonary diseases especially in patients with cystic fibrosis. MAB infection is notoriously difficult to treat because of its intrinsic or inducible resistance to most antibiotics. The rough (R) morphotype of MAB, lacking cell surface glycopeptidolipids (GPLs), is associated with more severe and persistent infection than the smooth (S) type; however, the mechanisms underlying the R type's virulence and the relation with GPLs remain unclear. In this study, we found that R-type MAB is much more proapoptotic than the S type, as a result of GPL-mediated inhibition of macrophage apoptosis. Polar GPLs inhibited an apoptotic response (induced by proapoptotic stimuli) by suppressing ROS production and the cytochrome c release and by preserving mitochondrial transmembrane potential. Furthermore, GPLs were found to be targeted to mitochondria and interacted with cyclophilin D; their acetylation was essential for this interaction. Finally, GPLs inhibited the intracellular growth and bacterial spreading of R-type MAB among macrophages via apoptosis inhibition. These findings suggest that GPLs limit MAB virulence by inhibiting apoptosis and the spread of bacteria and therefore provide a novel insight into the mechanism underlying virulence of MAB.

PMID: 28837151 [PubMed - in process]

Effectiveness of Smartphone Devices in Promoting Physical Activity and Exercise in Patients with Chronic Obstructive Pulmonary Disease: A Systematic Review.

COPD. 2017 Aug 24;:1-9

Authors: Martínez-García MDM, Ruiz-Cárdenas JD, Rabinovich RA

Abstract
The objectives of this systematic review were to analyse existing evidence on the efficacy of smartphone devices in promoting physical activity (PA) in patients with chronic obstructive pulmonary disease (COPD) and to identify the validity and precision of their measurements. A systematic review was undertaken across nine electronic databases: WOS Core Collection, PubMed, CINAHL, AMED, Academic Search Complete, Cochrane Central Register of Controlled Trials, SciELO, LILACS and ScienceDirect. Randomized and non-randomized controlled clinical trials were identified. To obtain additional eligible articles, the reference lists of the selected studies were also checked. Eligibility criteria and risk of bias were assessed by two independent authors. A total of eight articles met eligibility criteria. The studies were focused on promoting PA (n  =  5) and the precision of device measurements (n = 3). The effectiveness of smartphones in increasing PA level (steps/day) at short and long term is very limited. Mobile-based exercise programs reported improvements in exercise capacity (i.e. incremental Shuttle-Walk-Test) at short and long term (18.3% and 21%, respectively). The precision of device measurements was good-to-excellent (r = 0.69-0.99); however, these data should be interpreted with caution due to methodological limitations of studies. The effectiveness of smartphone devices in promoting PA levels in patients with COPD is scarce. Further high-quality studies are needed to evaluate the effectiveness of smartphone devices in promoting PA levels. Registration number: CRD42016050048.

PMID: 28836871 [PubMed - as supplied by publisher]

Src kinase inhibition reduces inflammatory and cytoskeletal changes in ΔF508 human cholangiocytes and improves CFTR correctors efficacy.

Hepatology. 2017 Jul 24;:

Authors: Fiorotto R, Amenduni M, Mariotti V, Fabris L, Spirli C, Strazzabosco M

Abstract
CFTR, the channel mutated in cystic fibrosis (CF), is expressed by the biliary epithelium (i.e cholangiocytes) of the liver. Progressive clinical liver disease (CFLD) occurs in about 10% of CF patients and represents the third leading cause of death. Impaired secretion and inflammation contribute to CFLD, however the lack of human-derived experimental models has hampered the understanding of CFLD pathophysiology and the search for a cure. We have investigated the cellular mechanisms altered in human CF cholangiocytes using induced pluripotent stem cells (iPSC) derived from healthy controls and a ΔF508 CFTR patient. We have devised a novel protocol for the differentiation of human iPSC into polarized monolayers of cholangiocytes. Our results show that iPSC-cholangiocytes reproduced the polarity and the secretory function of the biliary epithelium. PKA/c-AMP mediated fluid secretion was impaired in ΔF508 cholangiocytes and negligibly improved by VX-770 and VX-809, two small molecule drugs used to correct and potentiate ΔF508 CFTR. Moreover, ΔF508 cholangiocytes showed increased phosphorylation of Src kinase and TLR4 and pro-inflammatory changes including increased NF-kB activation, secretion of pro-inflammatory chemokines (i.e MCP-1 and IL8), as well as alterations of the F-actin cytoskeleton. Treatment with Src inhibitor (PP2) decreased the inflammatory changes and improved cytoskeletal defects. Inhibition of Src along with administration of VX-770 and VX-809 successfully restored fluid secretion to normal levels.
CONCLUSIONS: Our findings have strong translational potential and indicate that targeting Src kinase and decreasing inflammation may increase the efficacy of pharmacological therapies aimed at correcting the basic ΔF508 defect in CF liver patients. These studies also demonstrate the promise of applying iPSC technology in modeling human cholangiopathies. This article is protected by copyright. All rights reserved.

PMID: 28836688 [PubMed - as supplied by publisher]

Effects of Photodynamic Therapy on the Growth and Antifungal Susceptibility of Scedosporium and Lomentospora spp.

Mycopathologia. 2017 Aug 23;:

Authors: Lu Q, Sun Y, Tian D, Xiang S, Gao L

Abstract
Scedosporium and Lomentospora species are the second most frequent colonizing, allergenic, or invasive fungal pathogens in patients with cystic fibrosis, and are responsible for infections varying from cutaneous and subcutaneous tissue infections caused by traumatic inoculation to severe systemic diseases in immunocompromised patients. The clinical relevance of fungal airway colonization for individual patients harboring Scedosporium and Lomentospora species is still an underestimated issue. The high resistance of Scedosporium and Lomentospora species to antifungal drugs has highlighted the need for alternative treatment modalities, and antimicrobial photodynamic therapy may be one such alternative. In this study, methylene blue was applied as a photosensitizing agent to 6 type strains of Scedosporium and Lomentospora species, and we irradiated the strains using a light-emitting diode (635 ± 10 nm, 12 J/cm(2)). We evaluated the effects of photodynamic therapy on strain growth and on the in vitro susceptibility of the strains to itraconazole, voriconazole, posaconazole, and amphotericin B. A colony-forming unit reduction of up to 5.2 log10 was achieved. Minimal inhibitory concentration ranges also decreased significantly with photoinactivation. Photodynamic therapy improved both the inactivation rates and the antifungal susceptibility profile of all fungal isolates tested.

PMID: 28836110 [PubMed - as supplied by publisher]

A role for the cystic fibrosis transmembrane conductance regulator in the nitric oxide-dependent release of Cl(-) from acidic organelles in amacrine cells.

J Neurophysiol. 2017 Aug 23;:jn.00511.2017

Authors: Krishnan V, Maddox JW, Rodriguez T, Gleason EL

Abstract
Gamma-amino butyric acid (GABA) and glycine typically mediate synaptic inhibition because their ligand-gated ion channels support the influx of Cl(-) However, the electrochemical gradient for Cl(-) across the postsynaptic plasma membrane determines the voltage response of the postsynaptic cell. Typically low cytosolic Cl(-) supports inhibition while higher levels of cytosolic Cl(-) can suppress inhibition or promotes depolarization. We previously reported that nitric oxide (NO) releases Cl(-) from acidic organelles and transiently elevates cytosolic Cl(-) making the response to GABA and glycine excitatory. Here, we test the hypothesis that the cystic fibrosis transmembrane conductance regulator (CFTR) is involved in the NO-dependent efflux of organellar Cl(-) We first establish the mRNA and protein expression of CFTR in our model system, cultured chick retinal amacrine cells. Using whole cell voltage clamp recordings of currents through GABA-gated Cl(-) channels, we examine the effects of pharmacological inhibition of CFTR on the NO-dependent release of internal Cl-. To interfere with the expression of CFTR, we used clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 genome editing. We find that both pharmacological inhibition and CRISPR/Cas9-mediated knockdown of CFTR blocks the ability of NO to release Cl(-) from internal stores. These results demonstrate that CFTR is required for the NO-dependent efflux of Cl(-) from acidic organelles.

PMID: 28835528 [PubMed - as supplied by publisher]

Neutrophil Membrane Cholesterol Content is a Key Factor in Cystic Fibrosis Lung Disease.

EBioMedicine. 2017 Aug 16;:

Authors: White MM, Geraghty P, Hayes E, Cox S, Leitch W, Alfawaz B, Lavelle GM, McElvaney OJ, Flannery R, Keenan J, Meleady P, Henry M, Clynes M, Gunaratnam C, McElvaney NG, Reeves EP

Abstract
BACKGROUND: Identification of mechanisms promoting neutrophil trafficking to the lungs of patients with cystic fibrosis (CF) is a challenge for next generation therapeutics. Cholesterol, a structural component of neutrophil plasma membranes influences cell adhesion, a key step in transmigration. The effect of chronic inflammation on neutrophil membrane cholesterol content in patients with CF (PWCF) remains unclear. To address this we examined neutrophils of PWCF to evaluate the cause and consequence of altered membrane cholesterol and identified the effects of lung transplantation and ion channel potentiator therapy on the cellular mechanisms responsible for perturbed membrane cholesterol and increased cell adhesion.
METHODOLOGY: PWCF homozygous for the ΔF508 mutation or heterozygous for the G551D mutation were recruited (n=48). Membrane protein expression was investigated by mass spectrometry. The effect of lung transplantation or ivacaftor therapy was assessed by ELISAs, and calcium fluorometric and μ-calpain assays.
FINDINGS: Membranes of CF neutrophils contain less cholesterol, yet increased integrin CD11b expression, and respond to inflammatory induced endoplasmic reticulum (ER) stress by activating μ-calpain. In vivo and in vitro, increased μ-calpain activity resulted in proteolysis of the membrane cholesterol trafficking protein caveolin-1. The critical role of caveolin-1 for adequate membrane cholesterol content was confirmed in caveolin-1 knock-out mice. Lung transplant therapy or treatment of PWCF with ivacaftor, reduced levels of circulating inflammatory mediators and actuated increased caveolin-1 and membrane cholesterol, with concurrent normalized neutrophil adhesion.
INTERPRETATION: Results demonstrate an auxiliary benefit of lung transplant and potentiator therapy, evident by a reduction in circulating inflammation and controlled neutrophil adhesion.

PMID: 28835336 [PubMed - as supplied by publisher]

Structures of the N-terminal domain of PqsA in complex with anthraniloyl- and 6-fluoroanthraniloyl-AMP: substrate activation in Pseudomonas Quinolone Signal (PQS) biosynthesis.

Chembiochem. 2017 Aug 18;:

Authors: Witzgall F, Ewert W, Blankenfeldt W

Abstract
Pseudomonas aeruginosa, a prevalent pathogen in nosocomial infections and a major burden in cystic fibrosis, uses three interconnected quorum-sensing systems to coordinate virulence processes. At variance with other Gram-negatives, one of these systems relies on alkylquinolones (Pseudomonas Quinolone Signal, PQS) and may hence be an attractive target for new anti-infectives. Here, we report crystal structures of the N-terminal domain of anthranilate-CoA ligase PqsA, the first enzyme of PQS biosynthesis, in complex with anthraniloyl-AMP and 6-fluoroanthraniloyl-AMP (6FABA-AMP) at 1.4 and 1.7 Å resolution. We find that PqsA belongs to an unrecognized subfamily of anthranilate-CoA ligases that recognizes the amino group of anthranilate through a water-mediated hydrogen bond. The complex with 6FABA-AMP explains why 6FABA, an inhibitor of PQS biosynthesis, is a good substrate of PqsA. Together, our data may pave a way to new pathoblockers in P. aeruginosa infections.

PMID: 28834007 [PubMed - as supplied by publisher]

A novel approach based on low-field NMR for the detection of the pathological components of sputum in cystic fibrosis patients.

Magn Reson Med. 2017 Aug 22;:

Authors: Abrami M, Ascenzioni F, Di Domenico EG, Maschio M, Ventura A, Confalonieri M, Di Gioia S, Conese M, Dapas B, Grassi G, Grassi M

Abstract
PURPOSE: Development of a reliable, simple method to monitor lung condition in cystic fibrosis (CF) patients. Lung functionality assessment in CF patients is relevant, as most of them still die of respiratory failure. In lung mucus (sputum) of CF patients, components such as proteins, biopolymers, DNA, bacteria, and mucin are pathologically increased. As lung functionality is related to the amount of the pathological components in the sputum, their determination can help clinicians in monitoring lung condition and planning therapy.
METHODS: Low-field NMR was used to evaluate the variation of the relaxation time (T2m ) of the water hydrogens present in CF sputum in relation to the amounts of the pathological components. Low-field NMR was tested in artificial samples (mucin or alginates), then in conditional sputum (saliva from healthy volunteers, added by different amounts of the pathological components), and finally in 12 patients' sputums, in which T2m was correlated to a commonly used lung monitoring test (i.e., forced expiratory volume in the first second).
RESULTS: T2m significantly (P < 0.05) differed between samples with and without pathological components and between healthy and CF patients (P < 0.05), in which T2m correlated (r = 0.87) with FEV1 .
CONCLUSIONS: The presented method can potentially become a valuable lung-monitoring tool in CF patients. Magn Reson Med, 2017. © 2017 International Society for Magnetic Resonance in Medicine.

PMID: 28833401 [PubMed - as supplied by publisher]

Methicillin-resistant Staphylococcus aureus in cystic fibrosis patients: do we need to care? A cohort study.

Sao Paulo Med J. 2017 Aug 21;:0

Authors: Cohen RWF, Folescu TW, Daltro P, Boechat MCB, Lima DF, Marques EA, Leão RS

Abstract
CONTEXT AND OBJECTIVE:: The prevalence of a variety of potentially pathogenic microorganisms in cystic fibrosis patients, such as methicillin-resistant Staphylococcus aureus (MRSA), has increased over the past decade. Given the increasing prevalence of MRSA and the few data available in the literature, better understanding of the clinical repercussions of colonization by this bacterium in cystic fibrosis patients becomes essential. This study aimed to evaluate the repercussions of chronic colonization by MRSA in cystic fibrosis patients.
DESIGN AND SETTING:: Retrospective cohort study from January 2004 to December 2013 in a cystic fibrosis reference center.
METHODS:: Each patient with cystic fibrosis was evaluated for nutritional status (body mass index, BMI, and BMI percentile), pulmonary function and tomographic abnormalities (modified Bhalla scores) at the time of chronic colonization by MRSA or methicillin-susceptible Staphylococcus aureus (MSSA) and throughout the study period.
RESULTS:: Twenty pairs of patients were included. There were no significant differences between the groups regarding nutritional characteristics. Spirometric data showed a trend towards greater obstruction of the airways in patients with MRSA. Patients with MRSA presented greater structural damage to their lungs, demonstrated not only by the total Bhalla score but also by its parameters individually.
CONCLUSIONS:: Patients colonized by MRSA presented greater functional and structural respiratory impairment at the time of chronic colonization. Disease progression was also faster in patients chronically colonized by MRSA than in those with MSSA. This was shown through comparisons that avoided possible confounding variables.

PMID: 28832807 [PubMed - as supplied by publisher]

Pseudomonas aeruginosa proteome under hypoxic stress conditions mimicking the cystic fibrosis lung.

J Proteome Res. 2017 Aug 23;:

Authors: Kamath KS, Krisp C, Chick J, Pascovici D, Gygi SP, Molloy MP

Abstract
Pseudomonas aeruginosa is a ubiquitous Gram-negative pathogen known to inhabit hypoxic mucus plugs of cystic fibrosis (CF) patient lungs. Despite the high prevalence and related patient mortality, the protein machinery enabling the bacterium to adapt to low oxygen environment remains to be fully elucidated. We investigated this by performing both SWATH mass spectrometry and data-dependent SPS-MS3 of TMT labelled peptides to profile the proteomes of two P. aeruginosa CF isolates, PASS2 and PASS3, and a laboratory reference strain, PAO1, grown under hypoxic stress (O2<1%) in media that mimic the nutrient components of the CF lung. 3,967 P. aeruginosa proteins were quantitated across all three strains, reflecting approximately 71% of predicted ORFs in PAO1 and representing the most comprehensive proteome of clinically relevant P. aeruginosa to date. Comparative analysis revealed 735, 640 and 364 proteins were altered by two-fold or more when comparing low oxygen to aerobic growth in PAO1, PASS2 and PASS3 respectively. Strikingly, under hypoxic stress, all strains showed concurrent increased abundance of proteins required for both aerobic (cbb3-1 and cbb3-2 terminal oxidases) and anaerobic denitrification and arginine fermentation, with the two clinical isolates showing higher relative expression of proteins in these pathways. Additionally, functional annotation revealed that clinical strains portray a unique expression profile of replication, membrane biogenesis and virulence proteins during hypoxia which may endow these bacteria with a survival advantage. These protein profiles illuminate the diversity of P. aeruginosa mechanisms to adapt to low oxygen and shows that CF isolates initiate a robust molecular response to persist under these conditions.

PMID: 28832155 [PubMed - as supplied by publisher]

Cystic fibrosis: the conductance regulator, ceramides, and possible treatments.

J Mol Med (Berl). 2017 Aug 22;:

Authors: Luft FC

PMID: 28831504 [PubMed - as supplied by publisher]

Spiritual Struggle in Parents of Children with Cystic Fibrosis Increases Odds of Depression.

Depress Res Treat. 2017;2017:5670651

Authors: Szczesniak RD, Zou Y, Stamper SM, Grossoehme DH

Abstract
OBJECTIVE: Spiritual struggle (SS) is associated with poorer health outcomes including depression. The study's main objectives were to characterize change in depression over time, examine longitudinal associations between SS and depression, and determine the extent to which experiencing SS at baseline was predictive of developing depression at follow-up.
METHODS: A two-site study collected questionnaire responses of parents (N = 112; 72% female) of children with cystic fibrosis followed longitudinally. Generalized linear mixed effects modeling examined the association between depression and SS over time and assessed potential mediators, moderators, and confounders.
RESULTS: Prevalence of depression increased from baseline to follow-up (OR: 3.6, P < 0.0001), regardless of degree of SS. Parents with Moderate/Severe SS were more likely to have depressive symptoms, compared to parents without SS (OR: 15.2, P = 0.0003) and parents who had Mild SS (OR: 10.2, P = 0.0001). Being female and feeling less "at peace" also significantly predicted increased depression (OR: 2.5, P = 0.0397, and OR: 1.15, P = 0.0419, resp.). Experiencing SS at baseline was not predictive of having depression subsequently at follow-up.
CONCLUSIONS: Parents experiencing SS were significantly more likely to report depressive symptoms. Interventions to reduce SS have shown efficacy and may be considered.

PMID: 28831310 [PubMed]

Physical Activity Counseling for Children With Cystic Fibrosis.

Respir Care. 2017 Aug 22;:

Authors: Moola FJ, Garcia E, Huynh E, Henry L, Penfound S, Consunji-Araneta R, Faulkner GEJ

Abstract
BACKGROUND: Physical activity is recommended as a component of the cystic fibrosis (CF) treatment regimen. However, to date, there is limited research examining the effects of behavioral counseling interventions aimed at increasing physical activity. The aim of this study was to assess the feasibility of a theoretically informed, parent-mediated counseling intervention in increasing habitual physical activity and quality of life among children and youth with CF.
METHODS: Participants were recruited from the pediatric respirology clinic at the Children's Hospital of Winnipeg. Participants ranged in age between 8 and 18 y. A randomized control feasibility trial was implemented, and participants were randomized to the intervention (n = 7) or control group (n = 6). Intervention group participants engaged in 4 counseling sessions to examine the acceptability and feasibility of physical activity counseling in the care of children with CF. The primary outcome was study feasibility, as measured by recruitment, retention, adherence, acceptability, and the frequency of adverse events. Secondary outcomes included physical activity and quality of life, as measured by accelerometry and the Pediatric Quality of Life Inventory.
RESULTS: Thirteen subjects completed the study. No adverse events were found in this trial. The intervention was found to be feasible and acceptable with good recruitment, retention, adherence, and acceptability. Positive trends were also reported in terms of increases in physical activity, reductions in time spent being sedentary, and improvements in most dimensions of quality of life pre- to post-intervention.
CONCLUSIONS: The findings suggest that counseling is feasible for the CF community. An appropriately powered randomized controlled trial is required in the future to investigate the utility of counseling as a means to enhance quality of life and physical activity behavior.

PMID: 28830927 [PubMed - as supplied by publisher]

Implementation of Depression Screening and Global Health Assessment in Pediatric Subspecialty Clinics.

J Adolesc Health. 2017 Aug 19;:

Authors: Iturralde E, Adams RN, Barley RC, Bensen R, Christofferson M, Hanes SJ, Maahs DM, Milla C, Naranjo D, Shah AC, Tanenbaum ML, Veeravalli S, Park KT, Hood KK

Abstract
PURPOSE: Adolescents with chronic illness face greater risk of psychosocial difficulties, complicating disease management. Despite increased calls to screen for patient-reported outcomes, clinical implementation has lagged. Using quality improvement methods, this study aimed to investigate the feasibility of standardized screening for depression and assessment of global health and to determine recommended behavioral health follow-up, across three pediatric subspecialty clinics.
METHODS: A total of 109 patients aged 12-22 years (median = 16.6) who were attending outpatient visits for treatment of diabetes (80% type 1), inflammatory bowel disease, or cystic fibrosis completed the 9-item Patient Health Questionnaire (PHQ-9) depression and Patient-Reported Outcomes Measurement Information System (PROMIS) Pediatric Global Health measures on electronic tablets. Patients screening positive on the PHQ-9 received same-day behavioral health assessment and regular phone check-ins to facilitate necessary follow-up care.
RESULTS: Overall, 89% of 122 identified patients completed screening during a 6-month window. Patients completed measures in a timely manner (within 3 minutes) without disruption to clinic flow, and they rated the process as easy, comfortable, and valuable. Depression scores varied across disease type. Patients rated lower global health relative to a previously assessed validation cohort. Depression and global health related significantly to certain medical outcomes. Fifteen percent of patients screened positive on the PHQ-9, of whom 50% confirmed attending behavioral health appointments within 6 months of screening.
CONCLUSIONS: A standardized depression and global health assessment protocol implemented across pediatric subspecialties was feasible and effective. Universal behavioral health screening for adolescents and young adults living with chronic disease is necessary to meet programmatic needs in pediatric subspecialty clinics.

PMID: 28830798 [PubMed - as supplied by publisher]

What can the CF registry tell us about rare CFTR-mutations? A Belgian study.

Orphanet J Rare Dis. 2017 Aug 22;12(1):142

Authors: De Wachter E, Thomas M, Wanyama SS, Seneca S, Malfroot A

Abstract
BACKGROUND: CFTR2 provides clinical and functional information of the most common CFTR-mutations. Rare mutations (RMs) occur in only a few patients with limited reported clinical data. Their role in CF-disease liability is hardly documented.
METHODS: Belgian CF-Registry 2013 data were analyzed to identify CF with at least 1 RM (CF+RM). Clinical data and sweat chloride of CF+RM were compared to CF-controls, carrying 2 class 1 to 3 mutations (CFclassic). Disease severity was compared between both groups. To avoid bias in the comparison, transplanted patients were excluded from each group.
RESULTS: Seventy-seven CF+RM were identified (77/1183 = 6.5%). Sixty-four different RM were detected, of which 21 had not been previously reported. All RMs, corresponding to HGVS (Human Genome Variation Society) nomenclature, were listed in supplementary data. Seven transplanted CF+RM were excluded for further analysis. CF+RM had higher age at diagnosis [median (IQR)] [3.7 y (0.3-18.3) vs. 0.3y (0.1-2,0) (p < 0.0001)], lower sweat chloride [96 mmol/L (64-107) vs. 104 mmol/L (97-115) (p < 0.0001)], higher FEV1%pred [77%pred (58-96) vs. 68%pred (48-86) (p = 0.017)], were less frequently pancreatic insufficient [56% vs. 98% (p < 0.0001)], Pseudomonas aeruginosa colonized [24% vs. 44% (p = 0.0093)] and needed fewer IV antibiotics [36% vs. 51% (p = 0.041)] than CFclassic. However, a wide spectrum of disease severity was seen amongst CF+RM.
CONCLUSIONS: CF-patients with a RM cover 6.5% of the Belgian CF-population. Rare mutations can be found in severely ill patients, but more often in late diagnosed, pancreatic sufficient patients.

PMID: 28830496 [PubMed - in process]

The Role of Sensitization to Allergen in Asthma Prediction and Prevention.

Front Pediatr. 2017;5:166

Authors: Moustaki M, Loukou I, Tsabouri S, Douros K

Abstract
The burden of asthma in childhood is considerable worldwide, although some populations are much more affected than others. Many attempts have been made by different investigators to identify the factors that could predict asthma development or persistence in childhood. In this review, the relation between atopic sensitization as an indicator of allergy and asthma in childhood will be discussed. Cross sectional studies, carried out in different countries, failed to show any firm correlation between asthma and atopic sensitization. Birth cohort mainly of infants at high risk for asthma and case-control studies showed that atopic sensitization was a risk factor for current asthma in children older than 6 years. In general, clear relations are observed mostly in affluent Western countries, whereas in less affluent countries, the picture is more heterogeneous. For the prediction of asthma development or persistence in school age children, other prerequisites should also be fulfilled such as family history of asthma and wheezing episodes at preschool age. Despite the conductance of different studies regarding the potential role of allergen avoidance for the primary prevention of childhood asthma, it does not seem that this approach is of benefit for primary prevention purposes. However, the identification of children at risk for asthma is of benefit as these subjects could be provided with the best management practices and with the appropriate secondary prevention measures.

PMID: 28824890 [PubMed]

Chest CT Signs in Pulmonary Disease: A Pictorial Review.

Chest. 2017 Jun;151(6):1356-1374

Authors: Raju S, Ghosh S, Mehta AC

Abstract
CT scanning of the chest is one of the most important imaging modalities available to a pulmonologist. The advent of high-resolution CT scanning of the chest has led to its increasing use. Although chest radiographs are still useful as an initial test, their utility is limited in the diagnosis of lung diseases that depend on higher resolution images such as interstitial lung diseases and pulmonary vascular diseases. Several metaphoric chest CT scan signs have been described linking abnormal imaging patterns to lung diseases. Some of these are specific to a disease, whereas others help narrow the differential diagnosis. Recognizing these imaging patterns and CT scan signs are thus vitally important. In the present article, we describe a comprehensive list of the commonly encountered metaphoric chest CT scan signs and their clinical relevance.

PMID: 28212835 [PubMed - indexed for MEDLINE]

Aspergillus Bronchitis in Patients with Cystic Fibrosis.

Mycopathologia. 2017 Aug 17;:

Authors: Brandt C, Roehmel J, Rickerts V, Melichar V, Niemann N, Schwarz C

Abstract
Aspergillus fumigatus frequently colonizes the airways of patients with cystic fibrosis (CF) and may cause various severe infections, such as bronchitis. Serological data, sputum dependent markers and longitudinal data of treated cases of Aspergillus bronchitis were evaluated for further description of this infection. This study, which comprises three substudies, aimed to analyze epidemiological data of Aspergillus in CF and the entity of Aspergillus bronchitis. In a first step, data of the German Cystic Fibrosis Registry were used to evaluate the frequency of Aspergillus colonization in patients with CF (n = 2599). Then a retrospective analysis of 10 cases of Aspergillus bronchitis was performed to evaluate longitudinal data for lung function and clinical presentation parameters: sputum production, cough and physical capacity. Finally, a prospective cohort study (n = 22) was conducted to investigate serological markers for Aspergillus bronchitis: total serum IgE, specific serum IgE, specific serum IgG, as well as sputum galactomannan, real-time PCR detection of Aspergillus DNA in sputum and fungal cultures. Analysis of the German CF registry revealed an Aspergillus colonization rate of 32.5% among the 2599 patients. A retrospective data analysis of 10 treated cases revealed the clinical course of Aspergillus bronchitis, including repeated positive sputum culture findings for A. fumigatus, no antibiotic treatment response, total serum IgE levels <200 kU/l, no observation of new pulmonary infiltrates and appropriate antifungal treatment response. Antifungal treatment durations of 4 ± 1.6 (2-6) weeks significantly reduced cough (P = 0.0067), sputum production (P < 0.0001) and lung function measures (P = 0.0358) but not physical capacity (P = 0.0794). From this retrospective study, a prevalence of 1.6% was calculated. In addition, two cases of Aspergillus bronchitis were identified in the prospective cohort study according to immunological, molecular and microbiological parameters. A prevalence of 9% was assessed. Aspergillus bronchitis appears to occur in a minority of colonized CF patients. Antifungal treatment may reduce respiratory symptoms and restore lung function.

PMID: 28819878 [PubMed - as supplied by publisher]

In vivo therapeutic efficacy of frog skin-derived peptides against Pseudomonas aeruginosa-induced pulmonary infection.

Sci Rep. 2017 Aug 17;7(1):8548

Authors: Chen C, Mangoni ML, Di YP

Abstract
Pseudomonas aeruginosa is an opportunistic and frequently drug-resistant pulmonary pathogen especially in cystic fibrosis sufferers. Recently, the frog skin-derived antimicrobial peptide (AMP) Esc(1-21) and its diastereomer Esc(1-21)-1c were found to possess potent in vitro antipseudomonal activity. Here, they were first shown to preserve the barrier integrity of airway epithelial cells better than the human AMP LL-37. Furthermore, Esc(1-21)-1c was more efficacious than Esc(1-21) and LL-37 in protecting host from pulmonary bacterial infection after a single intra-tracheal instillation at a very low dosage of 0.1 mg/kg. The protection was evidenced by 2-log reduction of lung bacterial burden and was accompanied by less leukocytes recruitment and attenuated inflammatory response. In addition, the diastereomer was more efficient in reducing the systemic dissemination of bacterial cells. Importantly, in contrast to what reported for other AMPs, the peptide was administered at 2 hours after bacterial challenge to better reflect the real life infectious conditions. To the best of our knowledge, this is also the first study investigating the effect of AMPs on airway-epithelia associated genes upon administration to infected lungs. Overall, our data highly support advanced preclinical studies for the development of Esc(1-21)-1c as an efficacious therapeutic alternative against pulmonary P. aeruginosa infections.

PMID: 28819175 [PubMed - in process]