Non-Cystic Fibrosis Bronchiectasis: from Programmatic Management to Personalized Medicine.

Respiration. 2017 Apr 27;:

Authors: Munteanu O, Salzer HJF

PMID: 28445890 [PubMed - as supplied by publisher]

Two common human CLDN5 alleles encode different open reading frames but produce one protein isoform.

Ann N Y Acad Sci. 2017 Apr 26;:

Authors: Cornely RM, Schlingmann B, Shepherd WS, Chandler JD, Neujahr DC, Koval M

Abstract
Claudins provide tight junction barrier selectivity. The human CLDN5 gene contains a high-frequency single-nucleotide polymorphism (rs885985), where the G allele codes for glutamine (Q) and the A allele codes for an amber stop codon. Thus, these different CLDN5 alleles define nested open reading frames (ORFs) encoding claudin-5 proteins that are 303 or 218 amino acids in length. Interestingly, human claudin-16 and claudin-23 also have long ORFs. The long form of claudin-5 contrasts with the majority of claudin-5 proteins in the National Center for Biotechnology Information protein database, which are less than 220 amino acids in length. Screening of genotyped human lung tissue by immunoblot revealed only the 218 amino acid form of claudin-5 protein; the long-form claudin-5 protein was not detected. Moreover, when forcibly expressed in transfected cells, the long form of human claudin-5 was retained in intracellular compartments and did not localize to the plasma membrane, in contrast to the 218 amino acid form, which localized to intercellular junctions. This suggests that the 303 amino acid claudin-5 protein is rarely expressed, and, if so, is predicted to adversely affect cell function. Potential roles for upstream ORFs in regulating claudin-5 expression are also discussed.

PMID: 28445614 [PubMed - as supplied by publisher]

CFTR-dependent chloride efflux in cystic fibrosis mononuclear cells is increased by ivacaftor therapy.

Pediatr Pulmonol. 2017 Apr 26;:

Authors: Guerra L, D'Oria S, Favia M, Castellani S, Santostasi T, Polizzi AM, Mariggiò MA, Gallo C, Casavola V, Montemurro P, Leonetti G, Manca A, Conese M

Abstract
AIM: The Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) potentiator ivacaftor (Kalydeco®) improves clinical outcome in G551D cystic fibrosis (CF) patients. Here, we have investigated whether ivacaftor has a clinical impact on non-G551D gating mutations and function of circulating leukocytes as well.
METHODS: Seven patients were treated with ivacaftor and evaluated at baseline, and at 1-3 and 6 months. Besides clinical and systemic inflammatory parameters, circulating mononuclear cells (MNC) were evaluated for CFTR-dependent chloride efflux by spectrofluorimetry, neutrophils for oxidative burst by cytofluorimetry and HVCN1 mRNA expression by real time PCR.
RESULTS: Ivacaftor determined a significant decrease in sweat chloride concentrations at all time points during treatment. Body mass index (BMI), FEV1 , and FVC showed an increasing trend. While C-reactive protein decreased significantly at 2 months, the opposite behavior was noticed for circulating monocytes. CFTR activity in MNC was found to increase significantly at 3 and 6 months. Neutrophil oxidative burst peaked at 2 months and then decreased to baseline. HVCN1 mRNA expression was significantly higher than baseline at 1-3 months and decreased after 6 months of treatment. The chloride efflux in MNC correlated positively with both FEV1 and FVC. On the other hand, sweat chloride correlated positively with CRP and WBC, and negatively with both respiratory function tests. A cluster analysis confirmed that sweat chloride, FEV1 , FVC, BMI, and MNC chloride efflux behaved as a single entity over time.
DISCUSSION: In patients with non-G551D mutations, ivacaftor improved both chloride transport in sweat ducts and chloride efflux in MNC, that is, functions directly imputed to CFTR.

PMID: 28445004 [PubMed - as supplied by publisher]

[Newborn Screening on Cystic Fibrosis in Germany: Comparison of the new Screening Protocol with an Alternative Protocol].

Klin Padiatr. 2017 Mar;229(2):59-66

Authors: Sommerburg O, Stahl M, Hammermann J, Okun JG, Kulozik A, Hoffmann G, Mall M

Abstract
Background For the new cystic fibrosis (CF) newborn screening program in Germany the Federal Joint Committee (G-BA) implemented a new screening protocol using immunoreactive trypsinogen (IRT) as first and pancreatitis associated protein (PAP) as second tier. Gene analysis with a panel of 31 CFTR-mutations is used as third tier to increase the positive predictive value (PPV) which is known to be low in pure biochemical IRT/PAP protocols. Methods For post hoc analysis the data pool (n=372 906) of a study evaluating a pure biochemical IRT/PAP protocol was used for assessment of the 3-step G-BA protocol in comparison with an alternative screening protocol recommended by the authors. The difference between the 2 protocols is the procedure when IRT>99.9(th) percentile. In the G BA protocol PAP and DNA analysis will be by-passed while in the alternative protocol only the PAP step will be circumvented. Results Both 3-tier IRT/PAP+SN/DNA protocols did not lose sensitivity due to addition of genetic analysis when the results were compared to those of the 2-tier biochemical IRT/PAP protocol. However, the protocols provide different results regarding PPV. The G-BA protocol showed with 351 a much higher number of false-positively detected newborns (PPV 20.2%) when compared to 31 false-positively detected newborns in the alternative protocol (PPV 69.6%). Conclusions The G-BA protocol had a worse performance when compared with the alternative protocol recommended by the authors. The higher number of false-positively detected newborns using the G-BA protocol will lead to more consultations including sweat tests, will create more anxiety in parents, and will result in higher costs after screening.

PMID: 28444650 [PubMed - in process]

[Cystic Fibrosis Screening in Germany].

Klin Padiatr. 2017 Mar;229(2):55-56

Authors: Gortner L

PMID: 28444649 [PubMed - in process]

Emerging Roles of Carbonyl Sulfide (COS) in Chemical Biology: Sulfide Transporter or Gasotransmitter?

Antioxid Redox Signal. 2017 Apr 26;:

Authors: Steiger AK, Zhao Y, Pluth MD

Abstract
SIGNIFICANCE: Carbonyl sulfide (COS) is the most prevalent sulfur-containing gas in Earth's atmosphere and plays important roles in the global sulfur cycle. COS has been implicated in origin of life peptide ligation, is the primary energy source for certain bacteria, and has been detected in mammalian systems. Despite this long and intertwined history with terrestrial biology, limited attention has focused on potential roles of COS as a biological mediator. Recent Advances. Although bacterial COS production is well documented, definitive sources of mammalian COS production have not been confirmed. Enzymatic COS consumption in mammals, however, is well documented and occurs primarily by carbonic anhydrase (CA) mediated conversion to H2S. COS has been detected in ex vivo mammalian tissue culture, as well as in exhaled breath as a potential biomarker for different disease pathologies including cystic fibrosis and organ rejection. Recently, chemical tools for COS delivery have emerged and are poised to advance future investigations into the role of COS in different biological contexts.
CRITICAL ISSUES: Possible roles of COS as an important biomolecule, gasotransmitter, or sulfide transport intermediate remain to be determined. Key advances in both biological and chemical tools for COS research are needed to further investigate these questions.
FUTURE DIRECTIONS: Further evaluation of the biological roles of COS and disentangling the chemical biology of COS from that of H2S is needed to further elucidate these interactions. Chemical tools for COS delivery and modulation may provide a first avenue of investigative tools to answer many of these questions.

PMID: 28443679 [PubMed - as supplied by publisher]

Plastic bronchitis: An unusual complication of acute chest syndrome in adult.

Respir Med Case Rep. 2017;21:93-95

Authors: Feray S, Mora P, Decavele M, Pham T, Hafiani EM, Fartoukh M

Abstract
Plastic bronchitis is used to designate endobronchial plugs of rubber-like consistency that form into bronchial trees. It has been described in several diseases like asthma, cystic fibrosis, pulmonary infection, cyanotic congenital heart disease and in few young children with homozygous sickle cell disease. We report the first sickle cell adult case of plastic bronchitis during acute chest syndrome. He developed severe acute respiratory distress syndrome. This unusual presentation related to obstruction by voluminous casts may alert physicians to focus more on the bronchi in sickle cell patients. Realization of fiberoptic bronchoscopy to diagnose endobronchial injury and preventive measures such as fluidification of sputum at the early stage of thoracic vaso-occlusive crisis are essential.

PMID: 28443234 [PubMed - in process]

Natural Killer Group 2D Ligand Depletion Reconstitutes Natural Killer Cell Immunosurveillance of Head and Neck Squamous Cell Carcinoma.

Front Immunol. 2017;8:387

Authors: Weil S, Memmer S, Lechner A, Huppert V, Giannattasio A, Becker T, Müller-Runte A, Lampe K, Beutner D, Quaas A, Schubert R, Herrmann E, Steinle A, Koehl U, Walter L, von Bergwelt-Baildon MS, Koch J

Abstract
Head and neck squamous cell carcinoma (HNSCC) is a highly heterogeneous and aggressive tumor originating from the epithelial lining of the upper aero-digestive tract accounting for 300,000 annual deaths worldwide due to failure of current therapies. The natural killer group 2D (NKG2D) receptors on natural killer (NK) cells and several T cell subsets play an important role for immunosurveillance of HNSCC and are thus targeted by tumor immune evasion strategies in particular by shedding of various NKG2D ligands (NKG2DLs). Based on plasma and tumor samples of 44 HNSCC patients, we found that despite compositional heterogeneity the total plasma level of NKG2DLs correlates with NK cell inhibition and disease progression. Strikingly, based on tumor spheroids and primary tumors of HNSCC patients, we found that NK cells failed to infiltrate HNSCC tumors in the presence of high levels of NKG2DLs, demonstrating a novel mechanism of NKG2DL-dependent tumor immune escape. Therefore, the diagnostic acquisition of the plasma level of all NKG2DLs might be instrumental for prognosis and to decipher a patient cohort, which could benefit from restoration of NKG2D-dependent tumor immunosurveillance. Along these lines, we could show that removal of shed NKG2DLs (sNKG2DLs) from HNSCC patients' plasma restored NK cell function in vitro and in individual patients following surgical removal of the primary tumor. In order to translate these findings into a therapeutic setting, we performed a proof-of-concept study to test the efficacy of adsorption apheresis of sNKG2DLs from plasma after infusion of human MICA in rhesus monkeys. Complete removal of MICA was achieved after three plasma volume exchanges. Therefore, we propose adsorption apheresis of sNKG2DLs as a future preconditioning strategy to improve the efficacy of autologous and adoptively transferred immune cells in cellular cancer immunotherapy.

PMID: 28443091 [PubMed - in process]

Peroxisome proliferator-activated receptor-γ agonists attenuate biofilm formation by Pseudomonas aeruginosa.

FASEB J. 2017 Apr 25;:

Authors: Bedi B, Maurice NM, Ciavatta VT, Lynn KS, Yuan Z, Molina SA, Joo M, Tyor WR, Goldberg JB, Koval MH, Hart CM, Sadikot RT

Abstract
Pseudomonas aeruginosa is a significant contributor to recalcitrant multidrug- resistant infections, especially in immunocompromised and hospitalized patients. The pathogenic profile of P. aeruginosa is related to its ability to secrete a variety of virulence factors and to promote biofilm formation. Quorum sensing (QS) is a mechanism wherein P. aeruginosa secretes small diffusible molecules, specifically acyl homo serine lactones, such as N-(3-oxo-dodecanoyl)-l-homoserine lactone (3O-C12-HSL), that promote biofilm formation and virulence via interbacterial communication. Strategies that strengthen the host's ability to inhibit bacterial virulence would enhance host defenses and improve the treatment of resistant infections. We have recently shown that peroxisome proliferator-activated receptor γ (PPARγ) agonists are potent immunostimulators that play a pivotal role in host response to virulent P. aeruginosa Here, we show that QS genes in P. aeruginosa (PAO1) and 3O-C12-HSL attenuate PPARγ expression in bronchial epithelial cells. PAO1 and 3O-C12-HSL induce barrier derangements in bronchial epithelial cells by lowering the expression of junctional proteins, such as zonula occludens-1, occludin, and claudin-4. Expression of these proteins was restored in cells that were treated with pioglitazone, a PPARγ agonist, before infection with PAO1 and 3O-C12-HSL. Barrier function and bacterial permeation studies that have been performed in primary human epithelial cells showed that PPARγ agonists are able to restore barrier integrity and function that are disrupted by PAO1 and 3O-C12-HSL. Mechanistically, we show that these effects are dependent on the induction of paraoxonase-2, a QS hydrolyzing enzyme, that mitigates the effects of QS molecules. Importantly, our data show that pioglitazone, a PPARγ agonist, significantly inhibits biofilm formation on epithelial cells by a mechanism that is mediated via paraoxonase-2. These findings elucidate a novel role for PPARγ in host defense against P. aeruginosa Strategies that activate PPARγ can provide a therapeutic complement for treatment of resistant P. aeruginosa infections.-Bedi, B., Maurice, N. M., Ciavatta, V. T., Lynn, K. S., Yuan, Z., Molina, S. A., Joo, M., Tyor, W. R., Goldberg, J. B., Koval, M., Hart, C. M., Sadikot, R. T. Peroxisome proliferator-activated receptor-γ agonists attenuate biofilm formation by Pseudomonas aeruginosa.

PMID: 28442545 [PubMed - as supplied by publisher]

The role of neutrophil elastase inhibitors in lung diseases.

Chest. 2017 Apr 22;:

Authors: Polverino E, Rosales-Mayor E, Dale GE, Dembowsky K, Torres A

Abstract
In many respiratory diseases characterised by an intense inflammatory response, the balance between proteolytic enzymes (proteases, including elastases) and their inhibitors (proteinases inhibitors) is not neutral. In fact, an excess activity of neutrophil elastase (NE) and similar proteases has been reported to cause tissue damage and to alter the remodelling process in many clinical conditions such as pneumonia, respiratory distress and acute lung injury [ALI]. In recent years, several experimental NE inhibitors have been tested in preclinical and clinical studies of different conditions of inflammatory lung injury such as ALI and pneumonia, with contrasting results. This study reviews the literature regarding NE inhibitors in the field of respiratory diseases and reflects on possible future developments. In particular, we highlight potential gaps in the current scientific evidence and discuss potential strategies for focusing investigation on anti-elastases in clinical practice through the selection of targeted populations and proper outcomes.

PMID: 28442313 [PubMed - as supplied by publisher]

Sleep Phase Delay in Cystic Fibrosis: A Potential New Manifestation of Cystic Fibrosis Transmembrane Regulator Dysfunction.

Chest. 2017 Apr 22;:

Authors: Jensen JL, Jones CR, Kartsonaki C, Packer KA, Adler FR, Liou TG

Abstract
BACKGROUND: Cystic fibrosis (CF) transmembrane regulator (CFTR) protein dysfunction causes CF. Improving survival allows detection of increasingly subtle disease manifestations. CFTR dysfunction in the central nervous system (CNS) may disturb circadian rhythm and thus sleep phase. We studied sleep in adults to better understand potential CNS CFTR dysfunction.
METHODS: We recruited participants from April 2012 through April 2015 and administered the Munich Chronotype Questionnaire (MCTQ). We compared free-day sleep measurements between CF and non-CF participants and investigated associations with CF survival predictors.
RESULTS: We recruited 23 female and 22 male adults with CF aged 18-46 years and 26 female and 22 male volunteers aged 18-45 years. Compared to non-CF volunteers, patients with CF had delayed sleep-onset (0.612 hrs, P = 0.015), mid-sleep (1.11 hrs, P < 0.001) and wake-up (1.15 hrs, P < 0.001) times and prolonged sleep latency (7.21 min, P = 0.05) and duration (0.489 hr, P = 0.05). Every hour delay in sleep-onset time was associated with shorter sleep duration by 0.29 hours in CF and 0.75 hours in non-CF (P = 0.007) and longer sleep latency by 0.15 hours in CF and 0.05 in non-CF (P = 0.035). Among patients with CF, FEV1%, prior acute pulmonary exacerbations and weight were independent of all free-day sleep measurements.
CONCLUSION: CF in adults is associated with marked delays in sleep phase consistent with circadian rhythm phase delays. Independence from disease characteristics predictive of survival suggests that sleep phase delay is a primary manifestation of CFTR dysfunction in the CNS.

PMID: 28442311 [PubMed - as supplied by publisher]

Feasibility and normal values of an integrated conductivity (Nanoduct™) sweat test system in healthy newborns.

J Cyst Fibros. 2017 Apr 22;:

Authors: Kuehni CE, Schindler M, Mazur A, Malzacher A, Hornung R, Barben J

Abstract
BACKGROUND: Nanoduct™ is a simple and practical sweat analysis system measuring conductivity in situ. It requires only three microlitres of sweat, making it especially applicable to newborns.
METHODS: We measured conductivity in 260 healthy term infants at the age of four days, and again at four weeks to determine the proportion of successful tests, test duration, and normal values for sweat conductivity in newborns.
RESULTS: Sufficient sweat was collected in 159/260 of four-day olds (61%), and in 225/239 of four-week olds (94%). Mean (sd) test duration was 27 (5) and 25 (5) min. Mean (sd, range) conductivity was 53mmol/l (16, 8-114) at age four days, and 36 (9, 12-64) at four weeks.
CONCLUSIONS: Determination of sweat conductivity using Nanoduct™ cannot be recommended for four-day old newborns. However, at the age of four weeks the success rate is high (94%), and conductivity values at that age are comparable to older healthy children.

PMID: 28442278 [PubMed - as supplied by publisher]

Keep them breathing: Cystic fibrosis pathophysiology, diagnosis, and treatment.

JAAPA. 2017 May;30(5):23-27

Authors: Brown SD, White R, Tobin P

Abstract
Cystic fibrosis (CF) affects more than 30,000 people in the United States and 80,000 people worldwide. This life-threatening genetic disorder causes a buildup of thick, viscous mucus secretions in various organ systems, most commonly the gastrointestinal, pulmonary, and genitourinary systems. This article reviews the clinical manifestations, diagnosis, and monitoring of patients with CF as well as guidelines for management and emerging pharmacologic treatments.

PMID: 28441669 [PubMed - in process]

Piperacillin-tazobactam versus cefepime incidence of acute kidney injury in combination with vancomycin and tobramycin in pediatric cystic fibrosis patients.

Pediatr Pulmonol. 2017 Apr 25;:

Authors: LeCleir LK, Pettit RS

Abstract
BACKGROUND: Cystic fibrosis (CF) patients often receive prolonged courses of broad spectrum antibiotics, such as piperacillin-tazobactam or cefepime in combination with vancomycin and tobramycin. The objective of this study was to determine the difference in AKI for pediatric CF patients receiving piperacillin-tazobactam or cefepime in combination with vancomycin and tobramycin.
METHODS: IRB approval from a single CF center was obtained for this retrospective cohort study. Charts were evaluated from December 1, 2008 to June 30,2015. Patients were included if they had a diagnosis of CF, age 30 days to 18 years, and received intravenous vancomycin, tobramycin, and piperacillin-tazobactam or cefepime. The primary outcome was difference of AKI incidence in patients receiving piperacillin-tazobactam or cefepime, as defined by modified pediatric risk, injury, failure, loss, end stage renal disease (pRIFLE) criteria.
RESULTS: Seventy-one patients were included with a median (interquartile range) age 11 years (7-16) and weight 36.2 kg (22.7-50). AKI was identified in 54.5% (18/33) of patients receiving piperacillin-tazobactam and 13.2% (5/38) of patients receiving cefepime (P ≤ 0.0001). One patient receiving piperacillin-tazobactam experienced acute renal failure. There was a slight difference in length of admission (13 vs 10 days, P = 0.042), but no difference in days to maximum SCr (6 vs 3, P = 0.127) nor FEV1 percent predicted on admission (69% vs 65%, P = 1.00).
CONCLUSIONS: AKI occurred in nearly 55% of patients with piperacillin-tazobactam therapy versus 13% of patients with cefepime therapy, which suggests cefepime may be preferred in combination with vancomycin and tobramycin for pediatric CF patients.

PMID: 28440913 [PubMed - as supplied by publisher]

Antibiotic strategies for eradicating Pseudomonas aeruginosa in people with cystic fibrosis.

Cochrane Database Syst Rev. 2017 Apr 25;4:CD004197

Authors: Langton Hewer SC, Smyth AR

Abstract
BACKGROUND: Respiratory tract infection with Pseudomonas aeruginosa occurs in most people with cystic fibrosis. Once chronic infection is established, Pseudomonas aeruginosa is virtually impossible to eradicate and is associated with increased mortality and morbidity. Early infection may be easier to eradicate.This is an update of a Cochrane review first published in 2003, and previously updated in 2006, 2009 and 2014.
OBJECTIVES: To determine whether antibiotic treatment of early Pseudomonas aeruginosa infection in children and adults with cystic fibrosis eradicates the organism, delays the onset of chronic infection, and results in clinical improvement. To evaluate whether there is evidence that a particular antibiotic strategy is superior to or more cost-effective than other strategies and to compare the adverse effects of different antibiotic strategies (including respiratory infection with other micro-organisms).
SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings.Most recent search: 10 October 2016.
SELECTION CRITERIA: We included randomised controlled trials of people with cystic fibrosis, in whom Pseudomonas aeruginosa had recently been isolated from respiratory secretions. We compared combinations of inhaled, oral or intravenous antibiotics with placebo, usual treatment or other combinations of inhaled, oral or intravenous antibiotics. We excluded non-randomised trials, cross-over trials, and those utilising historical controls.
DATA COLLECTION AND ANALYSIS: Both authors independently selected trials, assessed risk of bias and extracted data.
MAIN RESULTS: The search identified 60 trials; seven trials (744 participants) with a duration between 28 days and 27 months were eligible for inclusion. Three of the trials are over 10 years old and their results may be less applicable today given the changes in standard treatment. Some of the trials had low numbers of participants and most had relatively short follow-up periods; however, there was generally a low risk of bias from missing data. In most trials it was difficult to blind participants and clinicians to treatment given the interventions and comparators used. Two trials were supported by the manufacturers of the antibiotic used.Evidence from two trials (38 participants) at the two-month time-point showed treatment of early Pseudomonas aeruginosa infection with inhaled tobramycin results in microbiological eradication of the organism from respiratory secretions more often than placebo, odds ratio 0.15 (95% confidence interval (CI) 0.03 to 0.65) and data from one of these trials, with longer follow up, suggested that this effect may persist for up to 12 months.One randomised controlled trial (26 participants) compared oral ciprofloxacin and nebulised colistin versus usual treatment. Results after two years suggested treatment of early infection results in microbiological eradication of Pseudomonas aeruginosa more often than no anti-pseudomonal treatment, odds ratio 0.12 (95% CI 0.02 to 0.79).One trial comparing 28 days to 56 days treatment with nebulised tobramycin solution for inhalation in 88 participants showed that both treatments were effective and well-tolerated, with no notable additional improvement with longer over shorter duration of therapy. However, this trial was not powered to detect non-inferiority or equivalence .A trial of oral ciprofloxacin with inhaled colistin versus nebulised tobramycin solution for inhalation alone (223 participants) failed to show a difference between the two strategies, although it was underpowered to show this. A further trial of inhaled colistin with oral ciprofloxacin versus nebulised tobramycin solution for inhalation with oral ciprofloxacin also showed no superiority of the former, with increased isolation of Stenotrophomonas maltophilia in both groups.A recent, large trial in 306 children aged between one and 12 years compared cycled nebulised tobramycin solution for inhalation to culture-based therapy and also ciprofloxacin to placebo. The primary analysis showed no difference in time to pulmonary exacerbation or proportion of Pseudomonas aeruginosa positive cultures. An analysis performed in this review (not adjusted for age) showed fewer participants in the cycled therapy group with one or more isolates of Pseudomonas aeruginosa, odds ratio 0.51 (95% CI 0.31 to 0.28). Using GRADE, the quality of evidence for outcomes was downgraded to moderate to very low. Downgrading decisions for Pseudomonas aeruginosa eradication and lung function were based on applicability (participants mostly children) and limitations in study design, with imprecision an additional limitation for lung function, growth parameters and adverse effects.
AUTHORS' CONCLUSIONS: We found that nebulised antibiotics, alone or in combination with oral antibiotics, were better than no treatment for early infection with Pseudomonas aeruginosa. Eradication may be sustained for up to two years. There is insufficient evidence to determine whether antibiotic strategies for the eradication of early Pseudomonas aeruginosa decrease mortality or morbidity, improve quality of life, or are associated with adverse effects compared to placebo or standard treatment. Four trials comparing two active treatments have failed to show differences in rates of eradication of Pseudomonas aeruginosa. There have been no published randomised controlled trials that investigate the efficacy of intravenous antibiotics to eradicate Pseudomonas aeruginosa in cystic fibrosis. Overall, there is still insufficient evidence from this review to state which antibiotic strategy should be used for the eradication of early Pseudomonas aeruginosa infection in cystic fibrosis.

PMID: 28440853 [PubMed - as supplied by publisher]

Massive nasal polyposis in a patient with newly diagnosed cystic fibrosis.

Adv Respir Med. 2017;85(2):121-123

Authors: Olszowiec-Chlebna M, Trzciński K, Stelmach I

Abstract
INTRODUCTION: Cystic fibrosis (CF) - is the most common fatal autosomal recessive disease in Caucasians. A number of reports have described patients who do not meet diagnostic criteria for cystic fibrosis. Atypical or nonclassic CF is characterised by normal or borderline sweat test, pancreatic sufficiency and a monosymptomatic phenotype. For these reasons clinicians should remain alert to the possibility of the occurrence of CF.
CASE REPORT: We described a case presentation of massive nasal polyposis and recurrent sinusitis leading to the diagnosis ofcystic fibrosis in a 11-year-old male.
CONCLUSION: Our study indicates that chronic sinusitis and/or polyposis should raise the clinicians suspicion of a potential presentation of undiagnosed CF and require further investigations.

PMID: 28440538 [PubMed - in process]

Socioeconomic status and its relationship to chronic respiratory disease.

Adv Respir Med. 2017;85(2):97-108

Authors: Sahni S, Talwar A, Khanijo S, Talwar A

Abstract
Socioeconomic status (SES) is defined as an individual's social or economic standing, and is a measure of an individual's or family's social or economic position or rank in a social group. It is a composite of several measures including income, education, occupation, location of residence or housing. Studies have found a lower SES has been linked to disproportionate access to health care in many diseases. There is emerging data in pulmonary diseases such as COPD, asthma, cystic fibrosis, pulmonary hypertension and other chronic respiratory conditions that allude to a similar observation noted in other chronic diseases. In the setting of COPD, SES has an inverse relationship with COPD prevalence, mortality, health utilization costs and HRQoL. Asthma and cystic fibrosis show an increased severity and hospitalizations in relationship to a lower SES. Similar observations were seen in sarcoidosis, PHTN and obstructive sleep apnea. There remains a limited data on non-CF bronchiectasis and interstitial lung diseases. Population SES may be gauged by various measures such as education, occupation, marital status but no value is more indicative than income. Currently guidelines and management algorithms do not factor the effect of SES in the disease process. Despite the great amount of data available, a standardized method must be created to include SES in the prognostic calculations and management of chronic pulmonary diseases.

PMID: 28440535 [PubMed - in process]

Microbiology of the Upper and Lower Airways in Pediatric Cystic Fibrosis Patients.

Otolaryngol Head Neck Surg. 2017 Apr 01;:194599817702332

Authors: Sobin L, Kawai K, Irace AL, Gergin O, Cunningham M, Sawicki GS, Adil EA

Abstract
Objective To evaluate the microbiology of the upper and lower airways in pediatric cystic fibrosis (CF) patients who underwent sinus surgery. Study Design Retrospective case series with chart review. Setting Tertiary care children's hospital. Subjects and Methods A total of 201 paired sinus and pulmonary cultures from 105 CF patients were identified between 1996 and 2014. Demographics and culture results were analyzed. Results The mean age of patients was 11.2 ± 5.4 years (range, 1-27 years), and approximately one-half were female. Methicillin-sensitive Staphylococcus aureus was the most common pathogen overall. A significantly higher prevalence of Pseudomonas aeruginosa (32% for pulmonary and 37% for sinus cultures) was observed in older patients versus younger patients ( P < .001). There was low to moderate agreement between sinus and pulmonary cultures (Kappa statistic range, 0.03-0.56). The prevalence of methicillin-resistant S aureus (MRSA) increased significantly for lower respiratory tract culture (from 5% to 16%) and sinus culture (from 5% to 27%) between 1996-2004 and 2010-2014 ( P = .016 and P < .001, respectively). The prevalence of positive sinus cultures increased from 40% to 85% between 1996-2004 and 2010-2014 ( P = .018). Patients with pulmonary MRSA were more likely to be coinfected with pulmonary P aeruginosa (risk ratio, 2.4; 95% CI, 1.2-4.8; P = .015) or Aspergillus fumigatus (risk ratio, 2.2; 95% CI, 1.2-4.8; P = .035). Conclusions There is low to moderate correlation between pulmonary and sinus pathogens in CF patients. This is important to consider when treating infections. The prevalence of MRSA in sinus cultures has increased over time and warrants further investigation.

PMID: 28440108 [PubMed - as supplied by publisher]

Myriocin treatment of CF lung infection and inflammation: complex analyses for enigmatic lipids.

Naunyn Schmiedebergs Arch Pharmacol. 2017 Apr 24;:

Authors: Caretti A, Vasso M, Bonezzi FT, Gallina A, Trinchera M, Rossi A, Adami R, Casas J, Falleni M, Tosi D, Bragonzi A, Ghidoni R, Gelfi C, Signorelli P

Abstract
Our aim was to use quantitative and qualitative analyses to gain further insight into the role of ceramide in cystic fibrosis (CF). Sphingolipid ceramide is a known inflammatory mediator, and its accumulation in inflamed lung has been reported in different types of emphysema, chronic obstructive pulmonary disease and CF. CF is caused by a mutation of the chloride channel and associated with hyperinflammation of the respiratory airways and high susceptibility to ongoing infections. We have previously demonstrated that de novo ceramide synthesis is enhanced in lung inflammation and sustains Pseudomonas aeruginosa pulmonary infection in a CF murine model. We used liquid chromatography and matrix-assisted laser desorption/ionization (MALDI) imaging coupled with mass spectrometry, confocal laser scan microscopy and histology analyses to reveal otherwise undecipherable information. We demonstrated that (i) upregulated ceramide synthesis in the alveoli is strictly related to alveolar infection and inflammation, (ii) alveolar ceramide (C16) can be specifically targeted by nanocarrier delivery of the ceramide synthesis inhibitor myriocin (Myr) and (iii) Myr is able to downmodulate pro-inflammatory lyso-PC, favouring an increase in anti-inflammatory PCs. We concluded that Myr modulates alveolar lipids milieu, reducing hyperinflammation and favouring anti-microbial effective response in CF mouse model.

PMID: 28439630 [PubMed - as supplied by publisher]

Cytokine-Regulation of Na(+)-K(+)-Cl(-) Cotransporter 1 and Cystic Fibrosis Transmembrane Conductance Regulator-Potential Role in Pulmonary Inflammation and Edema Formation.

Front Immunol. 2017;8:393

Authors: Weidenfeld S, Kuebler WM

Abstract
Pulmonary edema, a major complication of lung injury and inflammation, is defined as accumulation of extravascular fluid in the lungs leading to impaired diffusion of respiratory gases. Lung fluid balance across the alveolar epithelial barrier protects the distal airspace from excess fluid accumulation and is mainly regulated by active sodium transport and Cl(-) absorption. Increased hydrostatic pressure as seen in cardiogenic edema or increased vascular permeability as present in inflammatory lung diseases such as the acute respiratory distress syndrome (ARDS) causes a reversal of transepithelial fluid transport resulting in the formation of pulmonary edema. The basolateral expressed Na(+)-K(+)-2Cl(-) cotransporter 1 (NKCC1) and the apical Cl(-) channel cystic fibrosis transmembrane conductance regulator (CFTR) are considered to be critically involved in the pathogenesis of pulmonary edema and have also been implicated in the inflammatory response in ARDS. Expression and function of both NKCC1 and CFTR can be modulated by released cytokines; however, the relevance of this modulation in the context of ARDS and pulmonary edema is so far unclear. Here, we review the existing literature on the regulation of NKCC1 and CFTR by cytokines, and-based on the known involvement of NKCC1 and CFTR in lung edema and inflammation-speculate on the role of cytokine-dependent NKCC1/CFTR regulation for the pathogenesis and potential treatment of pulmonary inflammation and edema formation.

PMID: 28439270 [PubMed - in process]