Lung Ultrasound is Comparable with Chest Roentgenogram for Diagnosis of Community-Acquired Pneumonia in Hospitalised Children.

Indian J Pediatr. 2017 Mar 24;:

Authors: Yadav KK, Awasthi S, Parihar A

Abstract
OBJECTIVE: To evaluate the accuracy of lung ultrasound (LUS) in comparison to chest roentgenogram (CXR) in hospitalised children with community-acquired pneumonia (CAP).
METHODS: This study was a hospital based prospective observational study, conducted between January 2014 and December 2014. Hospitalised children aged 2 to 59 mo with community-acquired pneumonia were included in the study. The informed written consent was taken from parents (or legal guardian) before recruitment. Children with suspected or proven asthma, cystic fibrosis, congenital heart disease, immunodeficiency, malignancy and hemodynamic unstability were excluded. CXR, posterio-anterior view, and LUS were done within 24 h of the hospitalisation.
RESULTS: Of 176 consecutively hospitalised cases of CAP, 118 were recruited after screening (65, 55.1% boys; mean age in months ± SD, 26.22 ± 19.60). Abnormal CXR were found in 101 (85.6%) and abnormal LUS in 105 (89%) children. In radiologically proven CAP, LUS was positive in 99/101(98.01%) while among radiologically normal, LUS was abnormal in 6/17 (35.3%). LUS has high sensitivity (98.02%) and reasonable specificity (64.71%) for diagnosing radiologically proven CAP. In diagnosing the specific radiological type of CAP, there was very good concordance (Quadratic Weighted Cohen's Kappa =0.7) between CXR and LUS. Similarly, the authors also found excellent concordance between CXR and LUS (Linear Weighted Cohen's Kappa =0.9) for diagnosis of pleural effusion.
CONCLUSIONS: LUS can be considered to be used first before radiography in children with suspected CAP. This will reduce the exposure of radiation.

PMID: 28337699 [PubMed - as supplied by publisher]

The concentration of calprotectin in the stools of children with diagnosed cystic fibrosis.

Prz Gastroenterol. 2017;12(1):38-43

Authors: Więcek S, Woś H, Kordys-Darmolińska B, Sankiewicz-Szkółka M, Grzybowska-Chlebowczyk U

Abstract
INTRODUCTION: Calprotectin is a protein that plays a regulatory role in inflammatory reactions as an antibacterial and antiproliferative factor.
AIM: To assess the concentration of calprotectin in the stools of patients with diagnosed cystic fibrosis.
MATERIAL AND METHODS: Forty-one patients were included in the study, 24 boys and 17 girls, aged from 7 weeks to 18 years. The concentration of calprotectin in stools was assessed with the ELISA method. The analysis included clinical symptoms and the results of laboratory tests and the type of mutation.
RESULTS: An elevated level of calprotectin in the stool was observed in 4/41 (9.7%) patients, mainly in older children, and mainly delta F508/deltaF508 mutation. The correlation between the concentration of calprotectin and clinical symptoms, age, increased indicators of an inflammatory process, levels of protein and aminotransferases in blood serum and the values of acid steatocrit of the stool was not proven.
CONCLUSIONS: High concentrations of calprotectin in the stools of children with diagnosed cystic fibrosis do not correlate with the level of advancement of lesions within the gastrointestinal tract. Elevated concentrations of calprotectin in the stools of patients with cystic fibrosis may indicate inflammation of intestine and should be further scrutinised.

PMID: 28337235 [PubMed - in process]

Therapeutic Drug Monitoring of Continuous Infusion Doripenem in a Pediatric Patient on Continuous Renal Replacement Therapy.

J Pediatr Pharmacol Ther. 2017 Jan-Feb;22(1):69-73

Authors: Cies JJ, Moore WS, Conley SB, Shea P, Enache A, Chopra A

Abstract
An 11-year-old African American male with severe combined immunodeficiency variant, non-cystic fibrosis bronchiectasis, pancreatic insufficiency, chronic mycobacterium avium-intracellulare infection, chronic sinusitis, and malnutrition presented with a 1-week history of fevers. He subsequently developed respiratory decompensation and cefepime was discontinued and doripenem was initiated. Doripenem was the carbapenem used due to a national shortage of meropenem. By day 7 the patient (24.7 kg) had a positive fluid balance of 6925 mL (28% FO), and on days 7 into 8 developed acute kidney injury evidenced by an elevated serum creatinine of 0.68 mg/dL, an increase from the baseline of 0.28 mg/dL. On day 9, the patient was initiated on continuous renal replacement therapy (CRRT) and the doripenem dosing was changed to a continuous infusion of 2.5 mg/kg/hr (60 mg/kg/day). Approximately 12.5 hours after the start of the doripenem a serum concentration was obtained, which was 4.01 mg/L corresponding to a clearance of 10.5 mL/min/kg. The pediatric dosing and pharmacokinetic data available for doripenem suggest a clearance estimate of 4.4 to 4.8 mL/min/kg, and the adult clearance estimate is 2.4 to 3.78 mL/min/kg. The calculated clearance in our patient of 10.5 mL/min/kg is over double the highest clearance estimate in the pediatric literature. This case demonstrates that doripenem clearance is significantly increased with CRRT in comparison with the published pediatric and adult data. An appropriate pharmacodynamic outcome (time that free drug concentration > minimum inhibitory concentration) can be achieved by continuous infusion doripenem with concurrent therapeutic drug monitoring.

PMID: 28337084 [PubMed - in process]

Nebulized Gentamicin as an Alternative to Nebulized Tobramycin for Tracheitis in Pediatric Patients.

J Pediatr Pharmacol Ther. 2017 Jan-Feb;22(1):9-14

Authors: Chen JK, Martin-McNew BL, Lubsch LM

Abstract
OBJECTIVES: Tracheitis is an infection of the lower respiratory tract and is defined by the US Centers for Disease Control and Prevention (CDC) based on signs and symptoms with no radiographic evidence of pneumonia. One method of treatment involves the use of tobramycin given by nebulizer. The purpose of this study was to compare the safety and efficacy of nebulized gentamicin with nebulized tobramycin.
METHODS: This study was conducted in patients under 21 years of age who received greater than or equal to 1 day of gentamicin, 80 mg, or tobramycin, 300 mg, given twice a day by nebulization within the 14-month study period. The primary endpoint was amount of time until the patient no longer met the CDC definition of tracheitis.
RESULTS: There were 19 patients who presented with 60 separate encounters. The average age of the patients within the gentamicin group was 7.2 and 5 years old within the tobramycin group. The average duration of time for the gentamicin treatment encounters to be free of the CDC definition of tracheitis was 3.36 days compared to 3.17 days with tobramycin. No adverse effects were observed that were attributable to aminoglycoside nebulization.
CONCLUSIONS: No differences were detected between the safety and efficacy of intravenous gentamicin administered twice a day by nebulizer and that of tobramycin inhalation solution given twice daily in children without cystic fibrosis.

PMID: 28337076 [PubMed - in process]

Complete genome sequence of sequential Pandoraea apista isolates from the same cystic fibrosis patient supports a model of chronic colonization with in vivo strain evolution over time.

Diagn Microbiol Infect Dis. 2017 Jan;87(1):1-6

Authors: Greninger AL, Streithorst J, Golden JA, Chiu CY, Miller S

Abstract
Pandoraea apista in the family Burkholderiaceae is an emerging opportunistic pathogen in cystic fibrosis patients. Here, we describe a case from which 3 separate isolates of P. apista were recovered over a 1-year period. Using a combination of first-, second-, and third-generation sequencing technologies, we sequenced and de novo assembled the complete genomes of these 3 P. apista isolates. The genome of P. apista TF81F4 sequenced in this study was 5.58 Mb with a GC% of 62.3%, differed in sequence from other Pandoraea species by >20%, and included a number of previously undescribed loci. Three P. apista isolates cultured over a 12-month period were >99.999% identical by nucleotide, consistent with a model of chronic colonization by a single strain. Over time, the isolates accumulated point mutations, deletions, and insertions in a stepwise fashion, indicating in vivo strain evolution within the cystic fibrosis lung niche.

PMID: 28336132 [PubMed - in process]

Epidemiology of cystic fibrosis-related diabetes in Madrid (Spain) and frequency of hospitalization.

Eur J Intern Med. 2017 Mar 20;:

Authors: Zoni AC, Domínguez-Berjón MF, Esteban-Vasallo MD, Sendra JM, Astray-Mochales J

PMID: 28336126 [PubMed - as supplied by publisher]

Activity of AMP2041 against human and animal multidrug resistant Pseudomonas aeruginosa clinical isolates.

Ann Clin Microbiol Antimicrob. 2017 Mar 23;16(1):17

Authors: Cabassi CS, Sala A, Santospirito D, Alborali GL, Carretto E, Ghibaudo G, Taddei S

Abstract
BACKGROUND: Antimicrobial resistance is a growing threat to public health. Pseudomonas aeruginosa is a relevant pathogen causing human and animal infections, frequently displaying high levels of resistance to commonly used antimicrobials. The increasing difficulty to develop new effective antibiotics have discouraged investment in this area and only a few new antibiotics are currently under development. An approach to overcome antibiotic resistance could be based on antimicrobial peptides since they offer advantages over currently used microbicides.
METHODS: The antimicrobial activity of the synthetic peptide AMP2041 was evaluated against 49 P. aeruginosa clinical strains with high levels of antimicrobial resistance, isolated from humans (n = 19) and animals (n = 30). In vitro activity was evaluated by a microdilution assay for lethal dose 90% (LD90), while the activity over time was performed by time-kill assay with 12.5 µg/ml of AMP2014. Evidences for a direct membrane damage were investigated on P. aeruginosa ATCC 27853 reference strain, on animal isolate PA-VET 38 and on human isolate PA-H 24 by propidium iodide and on P. aeruginosa ATCC 27853 by scanning electron microscopy.
RESULTS: AMP2041 showed a dose-dependent activity, with a mean (SEM) LD90 of 1.69 and 3.3 µg/ml for animal and human strains, respectively. AMP2041 showed microbicidal activity on P. aeruginosa isolates from a patient with cystic fibrosis (CF) and resistance increased from first infection isolate (LD90 = 0.3 μg/ml) to the mucoid phenotype (LD90 = 10.4 μg/ml). The time-kill assay showed a time-dependent bactericidal effect of AMP2041 and LD90 was reached within 20 min for all the strains. The stain-dead assay showed an increasing of membrane permeabilization and SEM analysis revealed holes, dents and bursts throughout bacterial cell wall after 30 min of incubation with AMP2041.
CONCLUSIONS: The obtained results assessed for the first time the good antimicrobial activity of AMP2041 on P. aeruginosa strains of human origin, including those deriving from a CF patient. We confirmed the excellent antimicrobial activity of AMP2041 on P. aeruginosa strains derived from dog otitis. We also assessed that AMP2041 antimicrobial activity is linked to changes of the P. aeruginosa cell wall morphology and to the increasing of membrane permeability.

PMID: 28335779 [PubMed - in process]

Infantile Tremor Syndrome and Subdural Hemorrhage in an Infant with Cystic Fibrosis.

J Trop Pediatr. 2017 Feb 23;:

Authors: Mandal A, Priyadarshi M, Jat K, Kabra SK

Abstract
Cystic fibrosis (CF), an autosomal recessive disease with multi-system involvement, may present with bleeding in infancy owing to vitamin K malabsorption. Infantile tremor syndrome (ITS) is an obscure condition associated with vitamin B12 and other micronutrient deficiencies, described predominantly in Indian subcontinent. We describe an infant presenting with ITS and chronic subdural hemorrhage. He was subsequently diagnosed to have CF. The ITS and subdural hemorrhage is rarely reported in children with CF. In the background of increasing recognition of CF in Indian children, this case demonstrates a new association of this disease.

PMID: 28334845 [PubMed - as supplied by publisher]

Complex Relation Between Diet and Phospholipid Fatty Acids in Children With Cystic Fibrosis.

J Pediatr Gastroenterol Nutr. 2017 Apr;64(4):598-604

Authors: Moukarzel S, Dyer RA, Innis SM

Abstract
OBJECTIVES: Altered total plasma n-6 and n-3 fatty acids are common in cystic fibrosis (CF). Whether alterations extend to plasma phosphatidylcholine (PC) and phosphatidylethanolamine (PE) and are explained by diet is unclear. The present study was to describe the dietary intake of a large group of children with CF and to determine whether dietary fat composition explains differences in plasma PC and PE fatty acids between children with and without CF.
METHODS: Dietary intake was assessed using a food frequency questionnaire. Venous blood was collected. Plasma PC and PE were separately analyzed for fatty acids.
RESULTS: Children with CF, n = 74, consumed more calories and fat (g/day and % energy), with significantly more saturates mainly from dairy foods and less polyunsaturates including linoleic acid (LA), arachidonic acid (ARA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) (% fat) than reference children, n = 71. A subset of children with CF, not differing in dietary intake from the larger group, had significantly lower LA and DHA, but higher EPA in plasma PC and had higher LA and lower ARA and DHA in plasma PE, compared to a subset of reference children. In both groups, LA intake and LA in plasma PC and PE were not associated. EPA and DHA intakes were positively associated with EPA and DHA, respectively, in plasma PC, but not PE, in reference children only.
CONCLUSIONS: The fatty acid composition of plasma PC and PE is altered in CF. Fatty acid differences between children with and without CF are inconsistent between PC and PE and are not explained by dietary fat.

PMID: 28333826 [PubMed - in process]

Qualitative Assessment of the Symptoms and Impact of Pancreatic Exocrine Insufficiency (PEI) to Inform the Development of a Patient-Reported Outcome (PRO) Instrument.

Patient. 2017 Mar 22;:

Authors: Johnson CD, Arbuckle R, Bonner N, Connett G, Dominguez-Munoz E, Levy P, Staab D, Williamson N, Lerch MM

Abstract
BACKGROUND: Pancreatic exocrine insufficiency (PEI) affects patients with chronic pancreatitis (CP) and cystic fibrosis (CF) who produce insufficient digestive pancreatic enzymes. Common symptoms include steatorrhoea, diarrhea, and abdominal pain.
OBJECTIVE: The objective of the study was to develop and test the content validity of a patient-reported outcome (PRO) instrument assessing PEI symptoms and their impact on health-related quality of life.
METHODS: Instrument development was supported by a literature review, expert physician interviews (n = 10: Germany 4, UK 3, France 3), and exploratory, qualitative, concept-elicitation interviews with patients with CF and CP with PEI (n = 61: UK 29, Germany 18, France 14) and expert physicians (n = 10). Cognitive debriefing of the draft instrument was then performed with patients with PEI (n = 37: UK 24, Germany 8, France 5), and feasibility was assessed with physicians (n = 3). For all interviews, verbatim transcripts were qualitatively analysed using thematic analysis methods and Atlas.ti computerized qualitative software. All themes were data driven rather than a priori.
RESULTS: Patient interviews elicited symptoms and impacts not reported in the literature. Six symptom concepts emerged: pain, bloating, bowel symptoms, nausea/vomiting, eating problems, and tiredness/fatigue. Six impact domains were also identified. A 45-item instrument was developed in English, French, and German for testing in cognitive debriefing patient interviews. Following cognitive debriefing, 18 items were deleted.
CONCLUSION: Rigorous qualitative patient research and expert clinical input supported development of a PEI-specific PRO with the potential to aid management and monitoring of unmet needs among patients with PEI. The next step is to perform psychometric evaluation of the resulting instrument.

PMID: 28332032 [PubMed - as supplied by publisher]

A 3-year prognostic score for adults with cystic fibrosis.

J Cyst Fibros. 2017 Mar 18;:

Authors: Nkam L, Lambert J, Latouche A, Bellis G, Burgel PR, Hocine MN

Abstract
BACKGROUND: Therapeutic progress in patients with cystic fibrosis (CF) has resulted in improved prognosis over the past decades. We aim to reevaluate prognostic factors of CF and provide a prognostic score to predict the risk of death or lung transplantation (LT) within a 3-year period in adult patients.
METHODS: We developed a logistic model using data from the French CF Registry and combined the coefficients into a prognostic score. The discriminative abilities of the model and the prognostic score were assessed by c-statistic. The prognostic score was validated using a 10-fold cross-validation.
RESULTS: The risk of death or LT within 3years was related to eight characteristics. The development and the validation provided excellent results for the prognostic score; the c-statistic was 0.91 and 0.90 respectively.
CONCLUSION: The score developed to predict 3-year death or LT in adults with CF might be useful for clinicians to identify patients requiring specialized evaluation for LT.

PMID: 28330773 [PubMed - as supplied by publisher]

Cystic fibrosis pulmonary exacerbations attributable to respiratory syncytial virus and influenza: a population-based study.

Clin Infect Dis. 2017 Mar 09;:

Authors: Somayaji R, Goss CH, Khan U, Neradilek M, Neuzil KM, Ortiz JR

Abstract
Background: Characterization of the role of respiratory viral pathogens on cystic fibrosis (CF) pulmonary disease is needed. We aimed to determine the association of influenza and respiratory syncytial virus (RSV) activity with risk of pulmonary exacerbation (PEx) in persons with CF in the United States.
Methods: We conducted a cohort study from January 2003 - March 2009 using the CF Foundation Patient Registry merged with CDC respiratory virus surveillance data. The primary goal was to determine the association between regional influenza or RSV detections with risk of PEx requiring intravenous antibiotics or hospitalization. We analyzed outcomes by geographic region and week of event using multivariable regression models adjusted for demographic and clinical predictors of PEx stratified for children (<18 years) and adults (18 years) to calculate relative risks (RR) of PEx.
Results: There were 21,022 individuals (52% male) in the CF patient cohort in 2003 comprised of 12,702 children and 8,320 adults. The overall incidence rate of PEx was 521.9 per 10,000 person-months. In children, a 10% increase in the proportion of surveillance tests positive for influenza or RSV were significantly associated with increased PEx risk (RR 1.02 [95% CI 1.01-1.03] ) and (RR 1.05 [95% CI 1.02-1.07],) respectively. In adults, surveillance tests positive for influenza (RR 1.02 [95% CI 1.01-1.02]) but not RSV (RR 0.99 [0.98-1.01]), had a significant association with PEx risk.
Conclusions: Our large CF population based cohort demonstrated a significant association between PEx risk and influenza activity in children and adults and with RSV activity in children.

PMID: 28329304 [PubMed - as supplied by publisher]

Lack of small colony variants of Staphylococcus aureus from lower respiratory tract specimens.

Pediatr Pulmonol. 2017 Mar 22;:

Authors: Carzino R, Hart E, Sutton P, King L, Ranganathan S, AREST CF

Abstract
BACKGROUND: Small-colony variants (SCVs) of Staphylococcus aureus are associated with worse lung disease in children with Cystic Fibrosis (CF), exhibit a higher resistance to antibiotics and co-colonize more commonly with Pseudomonas aeruginosa compared to the normal phenotype. The prevalence of SCVs in lower airway specimens from children with CF is largely unknown.
METHODS: Each visible morphotype of S. aureus was subcultured onto horse blood agar (HBA) to enable identification of SCVs.
RESULTS: Sixty-one samples from 41 children (mean age 11.7 (SD 5.3) years) were identified with a positive S. aureus culture from lower respiratory tract specimens collected in 2014-2015. None of the differing morphotypes isolated were identified as S. aureus SCVs.
CONCLUSION: In a center where anti staphylococcal prophylaxis is adopted, S. aureus SCVs were not isolated from the lower airways specimens in young children with CF indicating that acquisition of small colony variant S. aureus may not be a significant clinical problem in young children with CF.

PMID: 28328157 [PubMed - as supplied by publisher]

The Smac Mimetic BV6 Improves NK Cell-Mediated Killing of Rhabdomyosarcoma Cells by Simultaneously Targeting Tumor and Effector Cells.

Front Immunol. 2017;8:202

Authors: Fischer K, Tognarelli S, Roesler S, Boedicker C, Schubert R, Steinle A, Klingebiel T, Bader P, Fulda S, Ullrich E

Abstract
Rhabdomyosarcoma (RMS), the most common cancer of connective tissues in pediatrics, is often resistant to conventional therapies. One underlying mechanism of this resistance is the overexpression of Inhibitor of Apoptosis (IAP) proteins, leading to a dysfunctional cell death program within tumor cells. Smac mimetics (SM) are small molecules that can reactivate the cell death program by antagonizing IAP proteins and thereby compensating their overexpression. Here, we report that SM sensitize two RMS cell lines (RD and RH30) toward natural killer (NK) cell-mediated killing on the one hand, and increase the cytotoxic potential of NK cells on the other. The SM-induced sensitization of RH30 cells toward NK cell-mediated killing is significantly reduced through blocking tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) on NK cells prior to coculture. In addition, the presence of zVAD.fmk, a pancaspase inhibitor, rescues tumor cells from the increase in killing, indicating an apoptosis-dependent cell death. On the NK cell side, the presence of SM in addition to IL-2 during the ex vivo expansion leads to an increase in their cytotoxic activity against RH30 cells. This effect is mainly TNFα-dependent and partially mediated by NK cell activation, which is associated with transcriptional upregulation of NF-κB target genes such as IκBα and RelB. Taken together, our findings implicate that SM represent a novel double-hit strategy, sensitizing tumor and activating NK cells with one single drug.

PMID: 28326081 [PubMed - in process]

Phenotypic diversity and genotypic flexibility of Burkholderia cenocepacia during long-term chronic infection of cystic fibrosis lungs.

Genome Res. 2017 Mar 21;:

Authors: Lee AH, Flibotte S, Sinha S, Paiero A, Ehrlich RL, Balashov S, Ehrlich GD, Zlosnik JE, Mell JC, Nislow C

Abstract
Chronic bacterial infections of the lung are the leading cause of morbidity and mortality in cystic fibrosis patients. Tracking bacterial evolution during chronic infections can provide insights into how host selection pressures-including immune responses and therapeutic interventions-shape bacterial genomes. We carried out genomic and phenotypic analyses of 215 serially collected Burkholderia cenocepacia isolates from 16 cystic fibrosis patients, spanning a period of 2-20 yr and a broad range of epidemic lineages. Systematic phenotypic tests identified longitudinal bacterial series that manifested progressive changes in liquid media growth, motility, biofilm formation, and acute insect virulence, but not in mucoidy. The results suggest that distinct lineages follow distinct evolutionary trajectories during lung infection. Pan-genome analysis identified 10,110 homologous gene clusters present only in a subset of strains, including genes restricted to different molecular types. Our phylogenetic analysis based on 2148 orthologous gene clusters from all isolates is consistent with patient-specific clades. This suggests that initial colonization of patients was likely by individual strains, followed by subsequent diversification. Evidence of clonal lineages shared by some patients was observed, suggesting inter-patient transmission. We observed recurrent gene losses in multiple independent longitudinal series, including complete loss of Chromosome III and deletions on other chromosomes. Recurrently observed loss-of-function mutations were associated with decreases in motility and biofilm formation. Together, our study provides the first comprehensive genome-phenome analyses of B. cenocepacia infection in cystic fibrosis lungs and serves as a valuable resource for understanding the genomic and phenotypic underpinnings of bacterial evolution.

PMID: 28325850 [PubMed - as supplied by publisher]

Impaired defenses of neonatal mouse alveolar macrophage with cftr deletion are modulated by glutathione and TGFβ1.

Physiol Rep. 2017 Mar;5(6):

Authors: Gauthier TW, Grunwell JR, Ping XD, Harris FL, Brown LA

Abstract
Our understanding of the intrinsic effects of cystic fibrosis (CF) transmembrane conductance regulator (cftr) deletion on resident neonatal alveolar macrophage (AM) remains limited. We previously demonstrated that diminished glutathione (GSH) or excessive AM transforming growth factor beta one (TGFβ1) contributes to AM dysfunction in a variety of disease states. In this study, using a gut-corrected cftr neonatal knockout (KO) mouse model and a siRNA-manipulated macrophage-like cell line (THP-1 cell), we hypothesized (1) that cftr mutation alone increases neonatal AM oxidant stress and cellular TGFβ1 signaling via altered GSH, thereby impairing cellular function, and (2) that exogenous GSH attenuates AM alterations and dysfunction in the KO AM In neonatal KO mice, the baseline bronchoalveolar lavage fluid demonstrated a near doubling in mixed disulfides (P ≤ 0.05) and oxidized GSSG (P ≤ 0.05) without concurrent inflammation compared to WT littermates. KO AM demonstrated diminished AM thiols (P ≤ 0.05), increased AM mitochondrial ROS (P ≤ 0.05), increased AM TGFβ1 (P ≤ 0.05) with increased TGFβ1 signaling (P ≤ 0.05), and impaired phagocytosis (P ≤ 0.05). KO AM mitochondrial ROS was modulated by exogenous GSH (P ≤ 0.05). Conversely, TGFβ1 was reduced (P ≤ 0.05) and impaired phagocytosis was rescued (P ≤ 0.05) by exogenous GSH in the KO AM These results suggest that an altered neonatal AM phenotype may contribute to the initiation of lung inflammation/infection in the CF lung. Modulation of the AM in the neonatal CF lung may potentially alter progression of disease.

PMID: 28325787 [PubMed - in process]

Pseudomonas aeruginosa Alginate Overproduction Promotes Coexistence with Staphylococcus aureus in a Model of Cystic Fibrosis Respiratory Infection.

MBio. 2017 Mar 21;8(2):

Authors: Limoli DH, Whitfield GB, Kitao T, Ivey ML, Davis MR, Grahl N, Hogan DA, Rahme LG, Howell PL, O'Toole GA, Goldberg JB

Abstract
While complex intra- and interspecies microbial community dynamics are apparent during chronic infections and likely alter patient health outcomes, our understanding of these interactions is currently limited. For example, Pseudomonas aeruginosa and Staphylococcus aureus are often found to coinfect the lungs of patients with cystic fibrosis (CF), yet these organisms compete under laboratory conditions. Recent observations that coinfection correlates with decreased health outcomes necessitate we develop a greater understanding of these interbacterial interactions. In this study, we tested the hypothesis that P. aeruginosa and/or S. aureus adopts phenotypes that allow coexistence during infection. We compared competitive interactions of P. aeruginosa and S. aureus isolates from mono- or coinfected CF patients employing in vitro coculture models. P. aeruginosa isolates from monoinfected patients were more competitive toward S. aureus than P. aeruginosa isolates from coinfected patients. We also observed that the least competitive P. aeruginosa isolates possessed a mucoid phenotype. Mucoidy occurs upon constitutive activation of the sigma factor AlgT/U, which regulates synthesis of the polysaccharide alginate and dozens of other secreted factors, including some previously described to kill S. aureus Here, we show that production of alginate in mucoid strains is sufficient to inhibit anti-S. aureus activity independent of activation of the AlgT regulon. Alginate reduces production of siderophores, 2-heptyl-4-hydroxyquinolone-N-oxide (HQNO), and rhamnolipids-each required for efficient killing of S. aureus These studies demonstrate alginate overproduction may be an important factor driving P. aeruginosa coinfection with S. aureusIMPORTANCE Numerous deep-sequencing studies have revealed the microbial communities present during respiratory infections in cystic fibrosis (CF) patients are diverse, complex, and dynamic. We now face the challenge of determining the influence of these community dynamics on patient health outcomes and identifying candidate targets to modulate these interactions. We make progress toward this goal by determining that the polysaccharide alginate produced by mucoid strains of P. aeruginosa is sufficient to inhibit multiple secreted antimicrobial agents produced by this organism. Importantly, these secreted factors are required to outcompete S. aureus, when the microbes are grown in coculture; thus we propose a mechanism whereby mucoid P. aeruginosa can coexist with S. aureus Finally, the approach used here can serve as a platform to investigate the interactions among other CF pathogens.

PMID: 28325763 [PubMed - in process]

Effect of allergic bronchopulmonary aspergillosis on FEV1 in children and adolescents with cystic fibrosis: a European Cystic Fibrosis Society Patient Registry analysis.

Arch Dis Child. 2017 Mar 21;:

Authors: Kaditis AG, Miligkos M, Bossi A, Colombo C, Hatziagorou E, Kashirskaya N, de Monestrol I, Thomas M, Mei-Zahav M, Chrousos G, Zolin A

Abstract
OBJECTIVE: To evaluate the effect of allergic bronchopulmonary aspergillosis (ABPA) on FEV1 percent predicted in children and adolescents with cystic fibrosis.
DESIGN: Longitudinal data analysis (2008-2010).
SETTING: Patients participating in the European Cystic Fibrosis Society Patient Registry.
PARTICIPANTS: 3350 patients aged 6-17 years.
MAIN OUTCOME MEASURE: FEV1percent predicted was the main outcome measure (one measurement per year per child). To describe the effect of ABPA (main explanatory variable) on FEV1 while controlling for other prognostic factors, a linear mixed effects regression model was applied.
RESULTS: In 2008, the mean (±SD) FEV1 percent predicted was 78.6 (±20.6) in patients with ABPA (n=346) and 88 (±19.8) in those without ABPA (n=2806). After considering other variables, FEV1 in subjects with ABPA on entry to the study was 1.47 percentage points lower than FEV1 in patients of similar age without ABPA (p=0.003). There was no FEV1 decline associated with ABPA over the subsequent study years as the interaction of ABPA with age was not significant (p>0.05). For patients aged 11.82 years (population mean age), poor body mass index had the greatest impact on FEV1 in 2008, followed by high-risk genotype (two severe mutations), female gender, diabetes mellitus, chronic Pseudomonas aeruginosa infection and ABPA in descending order of effect size.
CONCLUSIONS: In contrast to the common clinical belief of ABPA having a serious impact on lung function, the difference in FEV1 between young patients with and without the complication was found to be modest when the effect of other prognostic factors was considered.

PMID: 28325727 [PubMed - as supplied by publisher]

Real-life initiation of lumacaftor/ivacaftor combination in adults with cystic fibrosis homozygous for the Phe508del CFTR mutation and severe lung disease.

J Cyst Fibros. 2017 Mar 15;:

Authors: Hubert D, Chiron R, Camara B, Grenet D, Prévotat A, Bassinet L, Dominique S, Rault G, Macey J, Honoré I, Kanaan R, Leroy S, Desmazes Dufeu N, Burgel PR

Abstract
OBJECTIVE: To investigate the short-term adverse events and effectiveness of lumacaftor/ivacaftor combination treatment in adults with cystic fibrosis (CF) and severe lung disease in a real life setting.
METHODS: A multicentre observational study investigated adverse events, treatment discontinuation, FEV1 and body mass index (BMI) one month and three months after lumacaftor/ivacaftor initiation in adults with CF and FEV1 below 40% predicted.
RESULTS: Respiratory adverse events (AEs) were reported by 27 of 53 subjects (51%) and 16 (30%) discontinued treatment. The mean absolute change in FEV1 was +2.06% after one month of treatment (P=0.086) and +3.19% after 3 months (P=0.009). BMI was unchanged.
CONCLUSIONS: Treatment with lumacaftor/ivacaftor in patients with CF and severe lung disease was discontinued more frequently than reported in clinical trials, due to respiratory AEs. Nevertheless, the patients who continued treatment had an increase in lung function comparable to what was observed in pivotal trials.

PMID: 28325531 [PubMed - as supplied by publisher]

Relationship of Antibiotic Treatment to Recovery after Acute FEV1 Decline in Children with Cystic Fibrosis.

Ann Am Thorac Soc. 2017 Mar 21;:

Authors: Morgan WJ, Wagener JS, Pasta DJ, Millar SJ, VanDevanter DR, Konstan MW, Scientific Advisory Group, Investigators, and Coordinators of the Epidemiologic Study of Cystic Fibrosis

Abstract
RATIONALE: Children with cystic fibrosis often suffer acute declines in lung function. We previously showed that such declines are not always treated with antibiotics, but did not assess whether treatment improves the likelihood of recovery.
OBJECTIVES: To determine whether new antibiotic treatment was associated with recovery from acute FEV1 decline.
METHODS: We studied episodes of FEV1 decline (≥10% from baseline) from the Epidemiologic Study of Cystic Fibrosis. Treatments were hospitalization, home IV antibiotic, or new inhaled, oral quinolone, or other oral antibiotic. We used logistic regression to evaluate whether treatment was associated with recovery to baseline, or near baseline.
RESULTS: Logistic regression of 9,875 patients showed that new antibiotic treatment was associated with an increased likelihood of recovery to 90% of baseline (P<0.001), especially for hospitalization compared to no new antibiotic (OR 2.79, 95%CI 2.41-3.23). All four outpatient treatments were associated with greater likelihood of recovery compared to no treatment (OR 1.27 to 1.64). Inpatient treatment was better than outpatient treatments (OR 1.94, 95%CI 1.68-2.23). Treatment type odds ratios were similar across recovery criteria and levels of baseline lung function.
CONCLUSIONS: New antibiotic therapy and especially inpatient treatment is associated with greater likelihood of recovery after acute decline in FEV1. Benefits extend across all disease stages and are especially important in patients with high lung function, who are at greatest risk for FEV1 decline.

PMID: 28324670 [PubMed - as supplied by publisher]