Strong incidence of Pseudomonas aeruginosa on bacterial rrs and ITS genetic structures of cystic fibrosis sputa.

PLoS One. 2017;12(3):e0173022

Authors: Pages-Monteiro L, Marti R, Commun C, Alliot N, Bardel C, Meugnier H, Perouse-de-Montclos M, Reix P, Durieu I, Durupt S, Vandenesch F, Freney J, Cournoyer B, Doleans-Jordheim A

Abstract
Cystic fibrosis (CF) lungs harbor a complex community of interacting microbes, including pathogens like Pseudomonas aeruginosa. Meta-taxogenomic analysis based on V5-V6 rrs PCR products of 52 P. aeruginosa-positive (Pp) and 52 P. aeruginosa-negative (Pn) pooled DNA extracts from CF sputa suggested positive associations between P. aeruginosa and Stenotrophomonas and Prevotella, but negative ones with Haemophilus, Neisseria and Burkholderia. Internal Transcribed Spacer analyses (RISA) from individual DNA extracts identified three significant genetic structures within the CF cohorts, and indicated an impact of P. aeruginosa. RISA clusters Ip and IIIp contained CF sputa with a P. aeruginosa prevalence above 93%, and of 24.2% in cluster IIp. Clusters Ip and IIIp showed lower RISA genetic diversity and richness than IIp. Highly similar cluster IIp RISA profiles were obtained from two patients harboring isolates of a same P. aeruginosa clone, suggesting convergent evolution in the structure of their microbiota. CF patients of cluster IIp had received significantly less antibiotics than patients of clusters Ip and IIIp but harbored the most resistant P. aeruginosa strains. Patients of cluster IIIp were older than those of Ip. The effects of P. aeruginosa on the RISA structures could not be fully dissociated from the above two confounding factors but several trends in these datasets support the conclusion of a strong incidence of P. aeruginosa on the genetic structure of CF lung microbiota.

PMID: 28282386 [PubMed - in process]

Comparing Azole Plasma Trough Levels in Lung Transplant Recipients: Percentage of Therapeutic Levels and Intrapatient Variability.

Ther Drug Monit. 2017 Apr;39(2):93-101

Authors: Stelzer D, Weber A, Ihle F, Matthes S, Ceelen F, Zimmermann G, Kneidinger N, Schramm R, Winter H, Zoller M, Vogeser M, Behr J, Neurohr C

Abstract
BACKGROUND: This study compared therapeutic azole plasma trough levels (APL) of the azole antimycotics itraconazole (ITR), voriconazole (VOR), and posaconazole (POS) in lung transplant recipients and analyzed the influencing factors. In addition, intrapatient variability for each azole was determined.
METHODS: From July 2012 to July 2015, 806 APL of ITR, VOR, posaconazole liquid (POS-Liq), and posaconazole tablets (POS-Tab) were measured in 173 patients of the Munich Lung Transplantation Program. Therapeutic APL were defined as follows: ITR, ≥700 ng/mL; VOR, 1000-5500 ng/mL; and POS, ≥700 ng/mL (prophylaxis) and ≥1000 ng/mL (therapy).
RESULTS: VOR and POS-Tab reached the highest number of therapeutic APL, whereas POS-Liq showed the lowest percentage (therapy: ITR 50%, VOR 70%, POS-Liq 38%, and POS-Tab 82%; prophylaxis: ITR 62%, VOR 85%, POS-Liq 49%, and POS-Tab 76%). Risk factors for subtherapeutic APL of all azoles were the azole dose (ITR, P < 0.001; VOR, P = 0.002; POS-Liq, P = 0.006) and age over 60 years (ITR, P = 0.003; VOR, P = 0.002; POS-Liq, P = 0.039; POS-Tab, P < 0.001). Cystic fibrosis was a significant risk factor for subtherapeutic APL for VOR and POS-Tab (VOR, P = 0.002; POS-Tab, P = 0.005). Double lung transplantation (LTx) was significantly associated with less therapeutic APL for VOR and POS-Liq (VOR, P = 0.030; POS-Liq, P < 0.001). Concomitant therapy with 80 mg pantoprazole led to significantly fewer therapeutic POS APL as compared to 40 mg (POS-Liq, P = 0.015; POS-Tab, P < 0.001). VOR displayed the greatest intrapatient variability (46%), whereas POS-Tab showed the lowest (32%).
CONCLUSIONS: Our study showed that VOR and POS-Tab achieve the highest percentage of therapeutic APL in patients with LTx; POS-Tab showed the lowest intrapatient variability. APL are significantly influenced by azole dose, age, cystic fibrosis, type of LTx, and comedication with proton-pump inhibitors. Considering the high number of subtherapeutic APL, therapeutic drug monitoring should be integrated in the post-LTx management.

PMID: 28282366 [PubMed - in process]

Early detection of lung function decrements in children and adolescents with cystic fibrosis using new reference values.

Wien Klin Wochenschr. 2017 Mar 09;:

Authors: Zacharasiewicz A, Renner S, Haderer F, Weber M, Dehlink E, Szepfalusi Z, Frischer T

Abstract
Interpretation of lung function values in children with cystic fibrosis (CF) depends on the applied reference values. We hypothesize that differences between the new global lung function initiative (GLI) values and the formerly used Zapletal et al. values produce significantly different clinical results. We analyzed 3719 lung function measurements of 108 children and adolescents (n = 54 male; aged 6-18 years) with CF treated between September 1991 and July 2009. Data were analyzed in milliliters (ml) and % predicted (pred.) and interpreted using Zapletal and GLI reference values. Applying GLI compared to Zapletal resulted in significantly lower mean forced expiratory volume in 1s (FEV1)% pred.
VALUES: Zapletal 86.6% (SD 20.6), GLI 79.9% (SD 20.3) and 32% (n = 497/1543) were misclassified as normal when using Zapletal. Despite showing no overall differences in FEV1 and forced vital capacity (FVC) between concomitant Pseudomonas detection (PA+) in n = 938 and Pseudomonas negative (PA-) (n = 2781) using either reference PA+ resulted in lower FEV1 and FVC values with increasing age; however, measurement of small airway obstruction with forced expiratory flow at 75% of FVC (FEF75) values - available for Zapletal -showed significant differences. Reassurance regarding lung function when using old reference values may occur with potential clinical significance. Discrepancies in lung function interpretation underline the importance of using uniform and best available reference values.

PMID: 28281010 [PubMed - as supplied by publisher]

The lower airway microbiota in early cystic fibrosis lung disease: a longitudinal analysis.

Thorax. 2017 Mar 09;:

Authors: Frayman KB, Armstrong DS, Carzino R, Ferkol TW, Grimwood K, Storch GA, Teo SM, Wylie KM, Ranganathan SC

Abstract
RATIONALE: In infants and young children with cystic fibrosis, lower airway infection and inflammation are associated with adverse respiratory outcomes. However, the role of lower airway microbiota in the pathogenesis of early cystic fibrosis lung disease remains uncertain.
OBJECTIVES: To assess the development of the lower airway microbiota over time in infants and young children with cystic fibrosis, and to explore its association with airway inflammation and pulmonary function at age 6 years.
METHODS: Serial, semi-annual bronchoscopies and bronchoalveolar lavage (BAL) procedures were performed in infants newly diagnosed with cystic fibrosis following newborn screening. Quantitative microbiological cultures and inflammatory marker (interleukin 8 and neutrophil elastase) measurements were undertaken contemporaneously. 16S ribosomal RNA gene sequencing was conducted on stored BAL samples. Spirometry results recorded at 6 years of age were extracted from medical records.
MEASUREMENTS AND MAIN RESULTS: Ninety-five BAL samples provided 16S ribosomal RNA gene data. These were collected from 48 subjects aged 1.2-78.3 months, including longitudinal samples from 27 subjects and 13 before age 6 months. The lower airway microbiota varied, but diversity decreased with advancing age. Detection of recognised cystic fibrosis bacterial pathogens was associated with reduced microbial diversity and greater lower airway inflammation. There was no association between the lower airway microbiota and pulmonary function at age 6 years.
CONCLUSIONS: In infants with cystic fibrosis, the lower airway microbiota is dynamic. Dominance of the microbiota by recognised cystic fibrosis bacterial pathogens is associated with increased lower airway inflammation, however early microbial diversity is not associated with pulmonary function at 6 years of age.

PMID: 28280235 [PubMed - as supplied by publisher]

Psychosocial Response to Uncertain Newborn Screening Results for Cystic Fibrosis.

J Pediatr. 2017 Mar 06;:

Authors: Hayeems RZ, Miller FA, Barg CJ, Bombard Y, Carroll JC, Tam K, Kerr E, Chakraborty P, Potter BK, Patton S, Bytautas JP, Taylor L, Davies C, Milburn J, Price A, Gonska T, Keenan K, Ratjen F, Guttmann A

Abstract
OBJECTIVE: To explore the psychosocial implications of diagnostic uncertainty that result from inconclusive results generated by newborn bloodspot screening (NBS) for cystic fibrosis (CF).
STUDY DESIGN: Using a mixed methods prospective cohort study of children who received NBS for CF, we compared psychosocial outcomes of parents whose children who received persistently inconclusive results with those whose children received true positive or screen-negative results.
RESULTS: Mothers of infants who received inconclusive results (n = 17), diagnoses of CF (n = 15), and screen-negative results (n = 411) were surveyed; 23 parent interviews were completed. Compared with mothers of infants with true positive/screen-negative results, mothers of infants with inconclusive results reported greater perceived uncertainty (P < .006) but no differences in anxiety or vulnerability (P > .05). Qualitatively, parents valued being connected to experts but struggled with the meaning of an uncertain diagnosis, worried about their infant's health-related vulnerability, and had mixed views about surveillance.
CONCLUSION: Inconclusive CF NBS results were not associated with anxiety or vulnerability but led to health-related uncertainty and qualitative concerns. Findings should be considered alongside efforts to optimize protocols for CF screening and surveillance. Educational and psychosocial supports are warranted for these families.

PMID: 28279431 [PubMed - as supplied by publisher]

The altered gut microbiota in adults with cystic fibrosis.

BMC Microbiol. 2017 Mar 09;17(1):58

Authors: Burke DG, Fouhy F, Harrison MJ, Rea MC, Cotter PD, O'Sullivan O, Stanton C, Hill C, Shanahan F, Plant BJ, Ross RP

Abstract
BACKGROUND: Cystic Fibrosis (CF) is an autosomal recessive disease that affects the function of a number of organs, principally the lungs, but also the gastrointestinal tract. The manifestations of cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction in the gastrointestinal tract, as well as frequent antibiotic exposure, undoubtedly disrupts the gut microbiota. To analyse the effects of CF and its management on the microbiome, we compared the gut microbiota of 43 individuals with CF during a period of stability, to that of 69 non-CF controls using 454-pyrosequencing of the 16S rRNA gene. The impact of clinical parameters, including antibiotic therapy, on the results was also assessed.
RESULTS: The CF-associated microbiome had reduced microbial diversity, an increase in Firmicutes and a reduction in Bacteroidetes compared to the non-CF controls. While the greatest number of differences in taxonomic abundances of the intestinal microbiota was observed between individuals with CF and the healthy controls, gut microbiota differences were also reported between people with CF when grouped by clinical parameters including % predicted FEV1 (measure of lung dysfunction) and the number of intravenous (IV) antibiotic courses in the previous 12 months. Notably, CF individuals presenting with severe lung dysfunction (% predicted FEV1 ≤ 40%) had significantly (p < 0.05) reduced gut microbiota diversity relative to those presenting with mild or moderate dysfunction. A significant negative correlation (-0.383, Simpson's Diversity Index) was also observed between the number of IV antibiotic courses and gut microbiota diversity.
CONCLUSIONS: This is one of the largest single-centre studies on gut microbiota in stable adults with CF and demonstrates the significantly altered gut microbiota, including reduced microbial diversity seen in CF patients compared to healthy controls. The data show the impact that CF and it's management have on gut microbiota, presenting the opportunity to develop CF specific probiotics to minimise microbiota alterations.

PMID: 28279152 [PubMed - in process]

Complement effectors, C5a and C3a, in cystic fibrosis lung fluid correlate with disease severity.

PLoS One. 2017;12(3):e0173257

Authors: Hair PS, Sass LA, Vazifedan T, Shah TA, Krishna NK, Cunnion KM

Abstract
In cystic fibrosis (CF), lung damage is mediated by a cycle of obstruction, infection, inflammation and tissue destruction. The complement system is a major mediator of inflammation for many diseases with the effectors C5a and C3a often playing important roles. We have previously shown in a small pilot study that CF sputum soluble fraction concentrations of C5a and C3a were associated with clinical measures of CF disease. Here we report a much larger study of 34 CF subjects providing 169 testable sputum samples allowing longitudinal evaluation comparing C5a and C3a with clinical markers. Levels of the strongly pro-inflammatory C5a correlated negatively with FEV1% predicted (P < 0.001), whereas the often anti-inflammatory C3a correlated positively with FEV1% predicted (P = 0.01). C5a concentrations correlated negatively with BMI percentile (P = 0.017), positively with worsening of an acute pulmonary exacerbation score (P = 0.007) and positively with P. aeruginosa growth in sputum (P = 0.002). C5a levels also correlated positively with concentrations of other sputum markers associated with worse CF lung disease including neutrophil elastase (P < 0.001), myeloperoxidase activity (P = 0.006) and DNA concentration (P < 0.001). In contrast to C5a, C3a levels correlated negatively with worse acute pulmonary exacerbation score and correlated negatively with sputum concentrations of neutrophil elastase, myeloperoxidase activity and DNA concentration. In summary, these data suggest that in CF sputum, increased C5a is associated with increased inflammation and poorer clinical measures, whereas increased C3a appears to be associated with less inflammation and improved clinical measures.

PMID: 28278205 [PubMed - in process]

Nasal polyposis in cystic fibrosis: follow-up of children and adolescents for a 3-year period.

Braz J Otorhinolaryngol. 2016 Oct 17;:

Authors: Weber SA, Iyomasa RM, Corrêa CC, Florentino WN, Ferrari GF

Abstract
INTRODUCTION: Nasal polyposis is often found in patients with cystic fibrosis.
OBJECTIVE: To assess the incidence of nasal polyposis, the response to medical treatment, recurrence and the need for surgical intervention in children and adolescents with cystic fibrosis during a three-year follow-up.
METHODS: Clinical symptoms (pulmonary, pancreatic insufficiency, malnutrition, nasal obstruction), two positive sweat chloride tests, and genotype findings in 23 patients with cystic fibrosis were analyzed. All patients underwent nasal endoscopy every 12 months from January 2005 to December 2007, to assess the presence and grade of Nasal Polyps. Nasal polyposis, when present, were treated with topical corticosteroids for 6-12 months, with progress being evaluated within the 3 years of follow-up.
RESULTS: In the first evaluation, nasal polyposis was diagnosed in 30.43% of patients (3 bilateral and 4 unilateral), recurrent pneumonia in 82.6%, pancreatic insufficiency in 87%, and malnutrition in 74%. The presence of nasal polyposis was not associated with chloride values in the sweat, genotype, clinical signs of severity of cystic fibrosis, or nasal symptoms. In the three-year period of follow up, 13 patients (56.52%) had at least one event of polyposis, with the youngest being diagnosed at 32 months of age. Only one patient underwent surgery (polypectomy), and there was one diagnosis of nasopharyngeal carcinoma.
CONCLUSION: The study showed a high incidence of nasal polyposis. Monitoring through routine endoscopy in patients with cystic fibrosis, even in the absence of nasal symptoms, is highly recommended. The therapy with topical corticosteroids achieved good results. Thus, an interaction between pediatricians and otolaryngologists is necessary.

PMID: 28277226 [PubMed - as supplied by publisher]

Red blood cell distribution width is not a reliable biomarker for low iron stores in children with cystic fibrosis.

Pediatr Hematol Oncol. 2017 Feb 10;:1-7

Authors: Akkermans MD, Uijterschout L, Nuijsink M, Hendriks DM, van Goudoever JB, Brus F

Abstract
Low iron stores in children, absolute iron deficiency (AID), can lead to impaired neurodevelopment and requires iron therapy. In the presence of infection/inflammation, like in cystic fibrosis (CF), serum ferritin (SF) is not a reliable biomarker for AID. Red blood cell distribution width (RDW) is a promising alternative reported not to be influenced by infection in healthy children. Currently, there are no data on the diagnostic capacity of RDW to detect AID in pediatric CF patients. This was a prospective observational study that investigated iron status biomarkers in 53 Dutch pediatric CF patients. AID was defined using World Health Organization criteria for SF in stable patients (no recent pulmonary exacerbation) and C-reactive protein (CRP) ≤10 mg/l. Patients with AID had higher RDW levels than patients without AID (p = 0.019). An RDW ≥13.2% showed the following test statistics: sensitivity 100%; specificity 39.4%; positive predictive value 20%; and negative predictive value 100%. Furthermore, we found a correlation between RDW and CRP in the total group that originated from the stable patients (r = 0.308; p = 0.042). In conclusion, the diagnostic capacity of RDW for detecting AID in pediatric CF patients seems limited because RDW levels might also be influenced by chronic infection/inflammation in these patients.

PMID: 28276750 [PubMed - as supplied by publisher]

Immunity status of invasive pulmonary aspergillosis patients with structural lung diseases in Chinese adults.

J Thorac Dis. 2017 Feb;9(2):247-253

Authors: Liang S, Jiang R, Lu HW, Mao B, Li MH, Li CW, Gu SY, Bai JW, Xu JF

Abstract
BACKGROUND: Invasive pulmonary aspergillosis (IPA) is a fungal infection frequently observed in patients with immune dysfunction, such as those suffering from structural lung diseases. Nevertheless, studies assessing IPA combined with other common respiratory diseases remain scarce, particularly those regarding the immune status of its patients. Different structural lung diseases are known to differently affect patient immune status; however, the mechanisms by which this is conferred have yet to be determined. Thus, our study aims to compare the immune status of IPA patients with the structural lung diseases chronic obstructive pulmonary diseases (COPD), interstitial lung disease (ILD) and non-cystic fibrosis bronchiectasis (NCFB).
METHODS: This study was performed retrospectively with data collected over the years 2004 to 2013 at Shanghai Pulmonary Hospital, Tongji University, and included 77 patients whose lower respiratory tract (LRT) samples tested positive for. Our analysis considered blood examinations of CD3+, CD4+, CD8+, CD4+/CD8+, IgG, IgA and IgM levels.
RESULTS: CD4+/CD8+ double positive cells, representing cell-mediated immunity, were less abundant in IPA patients with COPD than those with ILD and NCFB (0.81±0.09 vs. 1.39±0.25 and 0.81±0.09 vs. 1.57±0.06, respectively, P<0.001). In agreement with this result, corticosteroid and broad-spectrum antibiotic use were most common in individuals with COPD (57%). IgA levels, which indicate humoral immunity, were lower in IPA patients with NCFB than those with COPD or ILD (0.95±0.28 vs. 1.64±0.40 g/L and 0.95±0.28 vs. 3.16±0.83 g/L, respectively, P<0.001).
CONCLUSIONS: Immunity status differs between IPA patients with different structural lung diseases. Among IPA patients with COPD, ILD and NCFB, those with COPD have the lowest cell-mediated immunity, while those with NCFB have the lowest humoral immunity.

PMID: 28275471 [PubMed - in process]

Low flow veno-venous extracorporeal CO2 removal for acute hypercapnic respiratory failure.

Minerva Anestesiol. 2017 Mar 08;:

Authors: Hilty MP, Riva T, Cottini SR, Kleinert EM, Maggiorini A, Maggiorini M

Abstract
BACKGROUND: Ventilation with low tidal volume and airway pressure results in a survival benefit in ARDS patients. Previous research suggests that avoiding mechanical ventilation altogether may be beneficial in some cases of respiratory failure. Our hypothesis was that low flow veno-venous extracorporeal CO2 removal (ECCO2R) enables maintenance of a lung protective ventilation strategy or awake spontaneous ventilation despite severe hypercapnic respiratory failure (HRF).
METHODS: Twenty patients with HRF were investigated while mechanically ventilated (n=14) or breathing spontaneously close to respiratory exhaustion (n=6). Low flow ECCO2R was performed using a hemoperfusion device with a polypropylene gas-exchanger.
RESULTS: Causes of HRF were severe ARDS (n=11), COPD (n=4), chronic lung transplant rejection (n=3) and cystic fibrosis (n=2). During the first 8h of ECCO2R, PaCO2 decreased from 10.6(9.3-12.9) to 7.9(7.3-9.3)kPa (p<0.001) and pH increased from 7.23(7.09-7.40) to 7.36(7.27-7.41) (p<0.05). Thereafter, steady state was achieved while maintaining lung protective tidal volume (4.7(3.8- 6.5)ml/kg) and peak ventilator pressure (28(27-30)mbar at 24h). During the first 48h, thrombocyte count decreased by 52%(p<0.01), Fibrinogen by 38%(p<0.05). Intubation could be avoided in all spontaneously breathing patients. In 4/6 high blood flow extracorporeal circulation was required due to increased oxygen demand. 6/14 mechanically ventilated patients recovered from respiratory support.
CONCLUSIONS: Our results suggest that in mechanically ventilated patients with HRF, low flow ECCO2R supports the maintenance of lung protective tidal volume and peak ventilator pressure. In selected awake patients with acute HRF, it may be a novel treatment approach to avoid mechanical ventilation, hence preventing ventilator- and sedation-associated morbidity and mortality.

PMID: 28275225 [PubMed - as supplied by publisher]

Variation in lung function as a marker of adherence to oral and inhaled medication in cystic fibrosis.

Eur Respir J. 2017 Mar;49(3):

Authors: White H, Shaw N, Denman S, Pollard K, Wynne S, Peckham DG

Abstract
The aim of this study was to characterise adherence in an adult population with cystic fibrosis (CF) and to investigate if variation in lung function was a predictor of adherence to treatment.The adherence of patients aged ≥16 years from an adult CF centre was measured by medication possession ratio (MPR) and self-report. Patients were assigned to one of three adherence categories (<50%, 50 to <80%, ≥80%) by their composite score (MPR). Ordinal regression was used to identify predictors of adherence, including coefficient variation measures for forced expiratory volume in 1 s (FEV1), weight and C-reactive protein concentration, measured from 6 months and 12 months before baseline.MPR data for 106 of 249 patients (mean age 29.8±9.2 years) was retrieved, indicating a mean adherence of 63%. The coefficient of variation for FEV1 was inversely related to adherence and was a univariate predictor of adherence (6 months: OR 0.92, 95% CI 0.87-0.98, p=0.005; 12 months: OR 0.94, 95% CI 0.93-0.99, p=0.03) and remained significant in the final models. The coefficient of variation of weight and C-reactive protein were not predictive of adherence.The coefficient of variation of FEV1 was identified as an objective predictor of adherence. Further evaluation of this potential marker of adherence is now required.

PMID: 28275171 [PubMed - in process]

CFTR is involved in the regulation of glucagon secretion in human and rodent alpha cells.

Sci Rep. 2017 Dec;7(1):90

Authors: Edlund A, Pedersen MG, Lindqvist A, Wierup N, Flodström-Tullberg M, Eliasson L

Abstract
Glucagon is the main counterregulatory hormone in the body. Still, the mechanism involved in the regulation of glucagon secretion from pancreatic alpha cells remains elusive. Dysregulated glucagon secretion is common in patients with Cystic Fibrosis (CF) that develop CF related diabetes (CFRD). CF is caused by a mutation in the Cl(-) channel Cystic fibrosis transmembrane conductance regulator (CFTR), but whether CFTR is present in human alpha cells and regulate glucagon secretion has not been investigated in detail. Here, both human and mouse alpha cells showed CFTR protein expression, whereas CFTR was absent in somatostatin secreting delta cells. CFTR-current activity induced by cAMP was measured in single alpha cells. Glucagon secretion at different glucose levels and in the presence of forskolin was increased by CFTR-inhibition in human islets, whereas depolarization-induced glucagon secretion was unaffected. CFTR is suggested to mainly regulate the membrane potential through an intrinsic alpha cell effect, as supported by a mathematical model of alpha cell electrophysiology. In conclusion, CFTR channels are present in alpha cells and act as important negative regulators of cAMP-enhanced glucagon secretion through effects on alpha cell membrane potential. Our data support that loss-of-function mutations in CFTR contributes to dysregulated glucagon secretion in CFRD.

PMID: 28273890 [PubMed - in process]

When is too little care, too much harm in cystic fibrosis? Psychological and ethical approaches to the problem.

J Cyst Fibros. 2017 Mar;16(2):299-303

Authors: Massie J, Morgan A, Gillam L

Abstract
Some parents of children with cystic fibrosis (CF) do not adhere to treatments recommended by the CF team. This can be a challenging issue for CF clinicians and can create conflict between the parents and treating team. Both parents and treating team believe they are acting in the best interests of the child, but do not share a common opinion as to what that entails. In this paper we present an understanding of the psychological framework of parents' illness representation that may foster a better understanding by CF clinicians of how to approach parents who hold a conflicting opinion regarding optimal care. Continuing to work with families towards optimal care is a moral obligation, but the key ethical decision is when to intervene to protect the child. In this paper we introduce the concept of the zone of parental discretion as an ethical tool to help decide the best way forward when parents do not accept medical advice on the optimal care of their child with CF.

PMID: 28267483 [PubMed - in process]

Hyponatremia in children with acute respiratory infections: A reappraisal.

Pediatr Pulmonol. 2017 Mar 07;:

Authors: Lavagno C, Milani GP, Uestuener P, Simonetti GD, Casaulta C, Bianchetti MG, Fare PB, Lava SA

Abstract
Hyponatremia (<135 mmol/L), typically associated with an elevated anti-diuretic hormone level, is common among children admitted with bronchiolitis, pneumonia, or pulmonary exacerbation of cystic fibrosis. The main consequences of acute hyponatremia include cerebral edema and Ayus-Arieff pulmonary edema. A widespread belief is that, in children with pneumonia or bronchiolitis, hyponatremia results from inappropriate anti-diuresis. By contrast, the pathogenic role of extracellular fluid volume depletion or decreased effective circulating blood volume is underscored. Considering the prevalence of hyponatremia, sodium determination is advised on admission in children diagnosed with bronchiolitis, pneumonia, or pulmonary exacerbation of cystic fibrosis. There is no necessity to do anything beyond reassessing the appropriateness of fluid therapy in cases with mild (130-134 mmol/L) hyponatremia. In children with sodium <130 mmol/L, the underlying etiology is sometimes evident from history and physical findings. Given that clinical assessment of fluid volume status is difficult in hyponatremia, further laboratory evaluation is often required in these patients. An increase in sodium level ≤6 mmol/L per day is currently considered the therapeutic goal in all cases. Emergency correction with a 2 mL/kg body weight bolus of 3.0% saline over 10-15 min intravenously is advised in cases with severe symptoms due to hyponatremia and in cases with symptoms, even if mild, due to a rapid-onset (<48 h) of hyponatremia (two additional doses are administered if the patient's condition does not improve).

PMID: 28267276 [PubMed - as supplied by publisher]

Propranolol treatment for infantile hemangioma does not increase risk of childhood wheezing.

Pediatr Pulmonol. 2017 Mar 07;:

Authors: Mei-Zahav M, Blau H, Hoshen M, Zvulunov A, Mussaffi H, Prais D, Stafler P, Steuer G, Lapidoth M, Amitai DB

Abstract
OBJECTIVE: Propranolol is the treatment of choice for infantile hemangiomas requiring medical intervention. Although contraindicated in asthma, its bronchoconstrictive effect in infants and children has not been extensively studied. We aimed to assess the incidence of wheezing episodes in infants and children treated with propranolol for infantile hemangiomas.
STUDY DESIGN: A retrospective case-control study.
SETTING: a tertiary pediatric hospital.
PATIENTS: All Children followed for infantile hemangioma between 2009 and 2014. Children followed conservatively served as control group and were matched 1:1 for gender and month of birth by random matching to children treated with propranolol.
INTERVENTIONS: All respiratory episodes (asthma, wheezing, stridor, and pneumonia) and respiratory associated hospitalizations were recorded from hospital records, from the primary care physician visits records and pharmacy prescriptions. The main outcome measure was the incidence of respiratory episodes in the treatment and the control groups.
RESULTS: A total of 1828 clinic visits were reviewed for 683 children. In addition, primary care physician visits records were available in 80% of them. Two hundred and sixteen children were treated with propranolol. Incidence of respiratory episodes and recurrent respiratory episodes was similar in the propranolol and control groups (8.3% vs 12%, P = 0.265; 3.7% vs 6.5%, P = 0.274, respectively). Time to first episode was similar in the treatment and control groups (5.03 ± 3.32 vs 4.45 ± 3.21 months, respectively, P = 0.09). Respiratory hospital admission rate was similar in both groups.
CONCLUSIONS: Propranolol treatment does not exacerbate wheezing episodes in infants and children.

PMID: 28267266 [PubMed - as supplied by publisher]

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Review of Metronidazole Dosing in Preterm Neonates.

Am J Perinatol. 2017 Mar 08;:

Authors: Dannelley JF, Martin EM, Chaaban H, Miller JL

Abstract
Metronidazole dosing recommendations vary significantly for premature infants in pediatric dosing references and can result in confusion for prescribers. We performed a literature search identifying articles evaluating the pharmacokinetics and dosing of metronidazole in premature infants. The search was limited to English-language articles in MEDLINE (January 1946 to December 2016), EMBASE (January 1974 to December 2016), and International Pharmaceutical Abstracts (January 1970 to December 2016). Reference citations from relevant articles were also reviewed. Six pharmacokinetic studies, representing 152 neonates, were included; however, only three of the well-defined studies were reviewed in depth, and the other three studies were considered foundational. The pharmacokinetic studies included in this review indicate that some published dosing recommendations in pediatric dosing references may result in subtherapeutic metronidazole concentrations. Therefore, postmenstrual age based dosing recommendations were provided by the authors of these pharmacokinetic studies based on a pharmacodynamic target of 6 to 8 mg/L; yet, these dosing recommendations differ from one another. The pharmacokinetic studies included in this review provide some guidance to dosing; however, a major limitation is that outcomes of clinical efficacy and safety were not evaluated. Future studies targeting the optimal dosing and serum concentrations required for clinical efficacy are needed.

PMID: 28273675 [PubMed - as supplied by publisher]

Effect of aerosolized antipseudomonals on Pseudomonas positivity and bronchiolitis obliterans syndrome after lung transplantation.

Transpl Infect Dis. 2017 Mar 08;:

Authors: Moore CA, Pilewski JM, Venkataraman R, Robinson KM, Morrell MR, Wisniewski SR, Zeevi A, McDyer JF, Ensor CR

Abstract
PURPOSE: To describe the effects of aerosolized antipseudomonals (AAP) on Pseudomonas (PS) culture positivity, bronchiolitis obliterans syndrome (BOS), and acute cellular rejection (ACR) in lung transplant recipients (LTRs).
METHODS: Single-center, retrospective cohort study of adult LTRs treated with either AAP for ≥28 days vs no AAP therapy or AAP therapy <28 days, indexed to a matched median date post lung transplantation (LT). Primary outcome was freedom from PS positivity by positive bronchoalveolar lavage (BAL) or bronchial wash at 1 year. Secondary outcomes were freedom from BOS or BOS progression and ACR burden (defined by the novel composite rejection standardized score [CRSS]). Normality was assessed and univariate and multivariate parametric and nonparametric statistical tests were used to assess baseline characteristics and outcomes, where appropriate. Freedom from events were compared using the Kaplan-Meier method with log-rank conversion and risk was assigned using multivariable Cox proportional hazards (PH) modeling.
RESULTS: In total 293 LTRs (105 with AAP, 188 with no AAP) were included. Median age in AAP and control cohorts were 51 (30-63) and 62 (54-67) years (P<0.01). Median AAP duration was 198 (interquartile range 94-395) days. Time to median positive PS culture was similar between AAP (median 1.02 [95% confidence interval {CI} 0.74-1.22] years) and control (median 0.96 [95% CI 0.72-1.21] years). Log-rank test for time-to-PS positivity was similar for both groups (log-rank P=.26). Incidence of PS culture positivity at 1 year was similar in APP vs controls (59.0% vs 54.8%, P=.48). In the non-cystic fibrosis (CF) subgroup, AAP use was protective against PS recurrence on univariate Cox PH model (hazard ratio [HR] 0.55, 95% CI 0.38-0.83) and on multivariate Cox PH adjusting for age and induction (HR 0.56, 95% CI 0.38-0.83). Incidence of new-onset BOS or BOS progression in APP vs control at 1 (17.1% vs 14.9%, P=.61) and 3 (38.1% vs 37.8%, P=.96) years was similar. CRSS was similar in APP vs control group at 1 year (0.42 vs 0.33, P=.41).
CONCLUSION: AAP use was not associated with less PS positivity, BOS, or ACR in all LTRs. In the non-CF subgroup analysis, treatment with AAP was associated with protection against recurrent PS. Limitations include retrospective design, heterogeneous AAP therapy among LTRs, and potential convenience sampling of LTRs receiving AAPs for >28 days at our center. Larger assessments and better controlled analyses are required to further define efficacy of AAPs after LT. This article is protected by copyright. All rights reserved.

PMID: 28273385 [PubMed - as supplied by publisher]

Within-host whole genome analysis of an antibiotic resistant Pseudomonas aeruginosa strain sub-type in cystic fibrosis.

PLoS One. 2017;12(3):e0172179

Authors: Sherrard LJ, Tai AS, Wee BA, Ramsay KA, Kidd TJ, Ben Zakour NL, Whiley DM, Beatson SA, Bell SC

Abstract
A Pseudomonas aeruginosa AUST-02 strain sub-type (M3L7) has been identified in Australia, infects the lungs of some people with cystic fibrosis and is associated with antibiotic resistance. Multiple clonal lineages may emerge during treatment with mutations in chromosomally encoded antibiotic resistance genes commonly observed. Here we describe the within-host diversity and antibiotic resistance of M3L7 during and after antibiotic treatment of an acute pulmonary exacerbation using whole genome sequencing and show both variation and shared mutations in important genes. Eleven isolates from an M3L7 population (n = 134) isolated over 3 months from an individual with cystic fibrosis underwent whole genome sequencing. A phylogeny based on core genome SNPs identified three distinct phylogenetic groups comprising two groups with higher rates of mutation (hypermutators) and one non-hypermutator group. Genomes were screened for acquired antibiotic resistance genes with the result suggesting that M3L7 resistance is principally driven by chromosomal mutations as no acquired mechanisms were detected. Small genetic variations, shared by all 11 isolates, were found in 49 genes associated with antibiotic resistance including frame-shift mutations (mexA, mexT), premature stop codons (oprD, mexB) and mutations in quinolone-resistance determining regions (gyrA, parE). However, whole genome sequencing also revealed mutations in 21 genes that were acquired following divergence of groups, which may also impact the activity of antibiotics and multi-drug efflux pumps. Comparison of mutations with minimum inhibitory concentrations of anti-pseudomonal antibiotics could not easily explain all resistance profiles observed. These data further demonstrate the complexity of chronic and antibiotic resistant P. aeruginosa infection where a multitude of co-existing genotypically diverse sub-lineages might co-exist during and after intravenous antibiotic treatment.

PMID: 28273168 [PubMed - in process]