Defining the Incidence and Associated Morbidity and Mortality of Severe Respiratory Syncytial Virus Infection Among Children with Chronic Diseases.

Infect Dis Ther. 2017 Jun 26;:

Authors: Manzoni P, Figueras-Aloy J, Simões EAF, Checchia PA, Fauroux B, Bont L, Paes B, Carbonell-Estrany X

Abstract
INTRODUCTION: REGAL (RSV Evidence-a Geographical Archive of the Literature) has provided a comprehensive review of the published evidence in the field of respiratory syncytial virus (RSV) in Western countries over the last 20 years. This review covers the risk and burden of RSV infection in children with underlying medical conditions or chronic diseases (excluding prematurity and congenital heart disease).
METHODS: A systematic review of publications between January 1, 1995 and December 31, 2015 across PubMed, Embase, The Cochrane Library, and Clinicaltrials.gov was supplemented by papers identified by the authors through March 2017. Studies reporting data for hospital visits/admissions for RSV infection as well as studies reporting RSV-associated morbidity and mortality were included. Study quality and strength of evidence (SOE) were graded.
RESULTS: A total of 2703 studies were identified and 58 were included. Down syndrome, irrespective of prematurity and congenital heart disease (moderate SOE), immunocompromised children (low SOE), cystic fibrosis (low SOE), and neurologic conditions (low SOE) were associated with a significantly increased risk of RSV hospitalization. A number of other congenital malformations and chronic conditions were also associated with severe RSV disease (low SOE). In general, pre-existing disease was also a predisposing factor for RSV-related mortality (low SOE).
CONCLUSION: Severe RSV infection in infants and young children with underlying medical conditions or chronic diseases poses a significant health burden. Further studies are needed to fully quantify the epidemiology, burden and outcomes in these populations, in particular RSV-attributable mortality.

PMID: 28653300 [PubMed - as supplied by publisher]

Azole Resistance in Aspergillus fumigatus in Patients with Cystic Fibrosis: A Matter of Concern?

Mycopathologia. 2017 Jun 26;:

Authors: Hamprecht A, Morio F, Bader O, Le Pape P, Steinmann J, Dannaoui E

Abstract
Aspergillus fumigatus is the most frequent filamentous fungus isolated from respiratory specimens from patients with cystic fibrosis (CF). Triazoles are the most widely used antifungals in the treatment of allergic bronchopulmonary aspergillosis (ABPA) and invasive aspergillosis (IA) in CF patients. Treatment success could be severely compromised by the occurrence of azole-resistant A. fumigatus (ARAf), which is increasingly reported worldwide from both clinical samples and the environment. In previous studies, ARAf has been detected in up to 8% of CF patients. Isolates from CF patients requiring antifungal treatment should therefore be routinely subjected to antifungal susceptibility testing. The optimal treatment of ABPA or IA in CF patients with azole-resistant isolates has not been established; treatment options include liposomal amphotericin B i.v. and/or echinocandins i.v.

PMID: 28653258 [PubMed - as supplied by publisher]

Determination of the spatiotemporal dependence of Pseudomonas aeruginosa biofilm viability after treatment with NLC-colistin.

Int J Nanomedicine. 2017;12:4409-4413

Authors: Sans-Serramitjana E, Jorba M, Pedraz JL, Vinuesa T, Viñas M

Abstract
The emergence of colistin-resistant Pseudomonas aeruginosa in cystic fibrosis (CF) patients, particularly after long-term inhalation treatments, has been recently reported. Nanoen-capsulation may enable preparations to overcome the limitations of conventional pharmaceutical forms. We have determined the time-dependent viability of P. aeruginosa biofilms treated with both free and nanoencapsulated colistin. We also examined the relationship between the optimal anti-biofilm activity of nanostructured lipid carrier (NLC)-colistin and the structural organization of the biofilm itself. The results showed the more rapid killing of P. aeruginosa bacterial biofilms by NLC-colistin than by free colistin. However, the two formulations did not differ in terms of the final percentages of living and dead cells, which were higher in the inner than in the outer layers of the treated biofilms. The effective anti-biofilm activity of NLC-colistin and its faster killing effect recommend further studies of its use over free colistin in the treatment of P. aeruginosa infections in CF patients.

PMID: 28652741 [PubMed - in process]

THE NON-ANTIBIOTIC MACROLIDE EM703 IMPROVES SURVIVAL IN A MODEL OF QUINOLONE-TREATED PSEUDOMONAS AERUGINOSA AIRWAY INFECTION.

Antimicrob Agents Chemother. 2017 Jun 26;:

Authors: Kasetty G, Bhongir RKV, Papareddy P, Herwald H, Egesten A

Abstract
Macrolide antibiotics are used as anti-inflammatory agents, e.g. for prevention of exacerbations in COPD and cystic fibrosis. Several studies have shown improved outcomes after addition of macrolides to beta-lactam antibiotics when treating severe community-acquired pneumonia. However, a beneficial effect of macrolides when treating Gram-negative bacterial airway infections, e.g. those caused by Pseudomonas aeruginosa, remains to be shown. Macrolide antibiotics have significant side effects, in particular motility-stimulating activity of the gastrointestinal tract and promotion of bacterial resistance. In this study, EM703, a modified macrolide lacking antibiotic and motility-stimulating activities, but with retained anti-inflammatory properties, was used as an adjunct treatment of experimental P. aeruginosa lung infection in combination with a conventional antibiotic. Airway infection in BALB/cJRj mice was induced by nasal instillation of P. aeruginosa. This was followed by treatment with the quinolone levofloxacin in the absence or presence of EM703. Survival, inflammatory responses, and cellular influx to the airways were monitored. Both pretreatment and simultaneous administration of EM703 dramatically improved survival in levofloxacin-treated mice with P. aeruginosa airway infection. In addition, EM703 reduced the levels of proinflammatory cytokines, increased the number of leukocytes in bronchoalveolar fluid, and reduced the number of neutrophils present in the lung tissue. In summary, the findings of this study show that the immunomodulatory properties of the modified macrolide EM703 can be important when treating Gram-negative pneumonia, as exemplified by P. aeruginosa infection in this study.

PMID: 28652240 [PubMed - as supplied by publisher]

A single bout of maximal exercise improves lung function in patients with cystic fibrosis.

J Cyst Fibros. 2017 Jun 23;:

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

Abstract
BACKGROUND: Responses to a single bout of exercise may provide critical information for maximizing improvements in pulmonary function following exercise training in cystic fibrosis (CF). We sought to determine if acute maximal exercise improves pulmonary function in patients with CF.
METHODS: Thirty-three patients with CF completed a comprehensive assessment of pulmonary function to determine forced vital capacity (FVC), forced expiratory volume in one second (FEV1), and lung clearance index (LCI) prior to and immediately following maximal aerobic exercise on a cycle ergometer.
RESULTS: Following exercise, FVC (∆0.08±0.14L) and FEV1 (∆0.06±0.15L/min) increased, while LCI decreased (∆-0.71±0.93) (all p<0.05). Changes in FEV1 (%predicted) were associated with peak work (r=0.40, p=0.02) and peak pulmonary ventilation (r=0.45, p=0.01).
CONCLUSIONS: A single bout of maximal exercise acutely improves pulmonary function in patients with CF and improvements may be related to peak work and peak pulmonary ventilation.

PMID: 28651845 [PubMed - as supplied by publisher]

Recovery of lung function following a pulmonary exacerbation in patients with cystic fibrosis and the G551D-CFTR mutation treated with ivacaftor.

J Cyst Fibros. 2017 Jun 24;:

Authors: Flume PA, Wainwright CE, Elizabeth Tullis D, Rodriguez S, Niknian M, Higgins M, Davies JC, Wagener JS

Abstract
BACKGROUND: Pulmonary exacerbations (PEx) are associated with acute loss of lung function that is often not recovered after treatment. We investigated lung function recovery following PEx for ivacaftor- and placebo-treated subjects.
METHODS: Short- and long-term pulmonary function recovery data after PEx were summarized from a placebo-controlled trial in 161 cystic fibrosis patients≥12years old with the G551D-CFTR mutation (NCT00909532). Short-term recovery was measured 2 to 8weeks after treatment, and long-term recovery was determined at the end-of-study, both compared with baseline measured just prior to the PEx.
RESULTS: Fewer patients receiving ivacaftor experienced a PEx than patients receiving placebo (33.7% vs. 56.4%; P=0.004) and had a lower adjusted incidence rate of PEx (0.589 vs. 1.382; P<0.001). The proportion of PEx followed by full short-term recovery of percent predicted forced expiratory volume in 1s was similar (ivacaftor vs. placebo, 57.1% vs. 53.7), as was the proportion of patients having long-term recovery (46.4% vs. 47.7%).
CONCLUSIONS: Ivacaftor treatment reduces the frequency of PEx but does not improve on the rate of complete lung function recovery after PEx when compared with placebo.

PMID: 28651844 [PubMed - as supplied by publisher]

Macrophages, but not neutrophils, are critical for proliferation of Burkholderia cenocepacia and ensuing host-damaging inflammation.

PLoS Pathog. 2017 Jun 26;13(6):e1006437

Authors: Mesureur J, Feliciano JR, Wagner N, Gomes MC, Zhang L, Blanco-Gonzalez M, van der Vaart M, O'Callaghan D, Meijer AH, Vergunst AC

Abstract
Bacteria of the Burkholderia cepacia complex (Bcc) can cause devastating pulmonary infections in cystic fibrosis (CF) patients, yet the precise mechanisms underlying inflammation, recurrent exacerbations and transition from chronic stages to acute infection and septicemia are not known. Bcc bacteria are generally believed to have a predominant extracellular biofilm life style in infected CF lungs, similar to Pseudomonas aeruginosa, but this has been challenged by clinical observations which show Bcc bacteria predominantly in alveolar macrophages. More recently, Bcc bacteria have emerged in nosocomial infections of patients hospitalized for reasons unrelated to CF. Research has abundantly shown that Bcc bacteria can survive and replicate in mammalian cells in vitro, yet the importance of an intracellular life style during infection in humans is unknown. Here we studied the contribution of innate immune cell types to fatal pro-inflammatory infection caused by B. cenocepacia using zebrafish larvae. In strong contrast to the usual protective role for macrophages against microbes, our results show that these phagocytes significantly worsen disease outcome. We provide new insight that macrophages are critical for multiplication of B. cenocepacia in the host and for development of a fatal, pro-inflammatory response that partially depends on Il1-signalling. In contrast, neutrophils did not significantly contribute to disease outcome. In subcutaneous infections that are dominated by neutrophil-driven phagocytosis, the absence of a functional NADPH oxidase complex resulted in a small but measurably higher increase in bacterial growth suggesting the oxidative burst helps limit bacterial multiplication; however, neutrophils were unable to clear the bacteria. We suggest that paradigm-changing approaches are needed for development of novel antimicrobials to efficiently disarm intracellular bacteria of this group of highly persistent, opportunistic pathogens.

PMID: 28651010 [PubMed - as supplied by publisher]

Production and purification of human Hsp90β in Escherichia coli.

PLoS One. 2017;12(6):e0180047

Authors: Radli M, Veprintsev DB, Rüdiger SGD

Abstract
The molecular chaperone Hsp90 is an essential member of the cellular proteostasis system. It plays an important role in the stabilisation and activation of a large number of client proteins and is involved in fatal disease processes, e.g. Alzheimer disease, cancer and cystic fibrosis. This makes Hsp90 a crucial protein to study. Mechanistic studies require large amounts of protein but the production and purification of recombinant human Hsp90 in Escherichia coli is challenging and laborious. Here we identified conditions that influence Hsp90 production, and optimised a fast and efficient purification protocol. We found that the nutrient value of the culturing medium and the length of induction had significant effect on Hsp90 production in Escherichia coli. Our fast, single-day purification protocol resulted in a stable, well-folded and pure sample that was resistant to degradation in a reproducible manner. We anticipate that our results provide a useful tool to produce higher amount of pure, well-folded and stable recombinant human Hsp90β in Escherichia coli in an efficient way.

PMID: 28651008 [PubMed - in process]

Primary Ciliary Dyskinesia: An Update on Clinical Aspects, Genetics, Diagnosis, and Future Treatment Strategies.

Front Pediatr. 2017;5:135

Authors: Mirra V, Werner C, Santamaria F

Abstract
Primary ciliary dyskinesia (PCD) is an orphan disease (MIM 244400), autosomal recessive inherited, characterized by motile ciliary dysfunction. The estimated prevalence of PCD is 1:10,000 to 1:20,000 live-born children, but true prevalence could be even higher. PCD is characterized by chronic upper and lower respiratory tract disease, infertility/ectopic pregnancy, and situs anomalies, that occur in ≈50% of PCD patients (Kartagener syndrome), and these may be associated with congenital heart abnormalities. Most patients report a daily year-round wet cough or nose congestion starting in the first year of life. Daily wet cough, associated with recurrent infections exacerbations, results in the development of chronic suppurative lung disease, with localized-to-diffuse bronchiectasis. No diagnostic test is perfect for confirming PCD. Diagnosis can be challenging and relies on a combination of clinical data, nasal nitric oxide levels plus cilia ultrastructure and function analysis. Adjunctive tests include genetic analysis and repeated tests in ciliary culture specimens. There are currently 33 known genes associated with PCD and correlations between genotype and ultrastructural defects have been increasingly demonstrated. Comprehensive genetic testing may hopefully screen young infants before symptoms occur, thus improving survival. Recent surprising advances in PCD genetic designed a novel approach called "gene editing" to restore gene function and normalize ciliary motility, opening up new avenues for treating PCD. Currently, there are no data from randomized clinical trials to support any specific treatment, thus, management strategies are usually extrapolated from cystic fibrosis. The goal of treatment is to prevent exacerbations, slowing the progression of lung disease. The therapeutic mainstay includes airway clearance maneuvers mainly with nebulized hypertonic saline and chest physiotherapy, and prompt and aggressive administration of antibiotics. Standardized care at specialized centers using a multidisciplinary approach that imposes surveillance of lung function and of airway biofilm composition likely improves patients' outcome. Pediatricians, neonatologists, pulmonologists, and ENT surgeons should maintain high awareness of PCD and refer patients to the specialized center before sustained irreversible lung damage develops. The recent creation of a network of PCD clinical centers, focusing on improving diagnosis and treatment, will hopefully help to improve care and knowledge of PCD patients.

PMID: 28649564 [PubMed - in process]

Phenotypic profiling of CFTR modulators in patient-derived respiratory epithelia.

NPJ Genom Med. 2017 Apr 14;2:12

Authors: Ahmadi S, Bozoky Z, Di Paola M, Xia S, Li C, Wong AP, Wellhauser L, Molinski SV, Ip W, Ouyang H, Avolio J, Forman-Kay JD, Ratjen F, Hirota JA, Rommens J, Rossant J, Gonska T, Moraes TJ, Bear CE

Abstract
Pulmonary disease is the major cause of morbidity and mortality in patients with cystic fibrosis, a disease caused by mutations in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene. Heterogeneity in CFTR genotype-phenotype relationships in affected individuals plus the escalation of drug discovery targeting specific mutations highlights the need to develop robust in vitro platforms with which to stratify therapeutic options using relevant tissue. Toward this goal, we adapted a fluorescence plate reader assay of apical CFTR-mediated chloride conductance to enable profiling of a panel of modulators on primary nasal epithelial cultures derived from patients bearing different CFTR mutations. This platform faithfully recapitulated patient-specific responses previously observed in the "gold-standard" but relatively low-throughput Ussing chamber. Moreover, using this approach, we identified a novel strategy with which to augment the response to an approved drug in specific patients. In proof of concept studies, we also validated the use of this platform in measuring drug responses in lung cultures differentiated from cystic fibrosis iPS cells. Taken together, we show that this medium throughput assay of CFTR activity has the potential to stratify cystic fibrosis patient-specific responses to approved drugs and investigational compounds in vitro in primary and iPS cell-derived airway cultures.

PMID: 28649446 [PubMed - in process]

Evolutionary adaptations of biofilms infecting cystic fibrosis lungs promote mechanical toughness by adjusting polysaccharide production.

NPJ Biofilms Microbiomes. 2017;3:1

Authors: Kovach K, Davis-Fields M, Irie Y, Jain K, Doorwar S, Vuong K, Dhamani N, Mohanty K, Touhami A, Gordon VD

Abstract
Biofilms are communities of microbes embedded in a matrix of extracellular polymeric substances, largely polysaccharides. Multiple types of extracellular polymeric substances can be produced by a single bacterial strain. The distinct polymer components of biofilms are known to provide chemical protection, but little is known about how distinct extracellular polysaccharides may also protect biofilms against mechanical stresses such as shear or phagocytic engulfment. Decades-long infections of Pseudomonas. aeruginosa biofilms in the lungs of cystic fibrosis patients are natural models for studies of biofilm fitness under pressure from antibiotics and the immune system. In cystic fibrosis infections, production of the extracellular polysaccharide alginate has long been known to increase with time and to chemically protect biofilms. More recently, it is being recognized that chronic cystic fibrosis infections also evolve to increase production of another extracellular polysaccharide, Psl; much less is known about Psl's protective benefits to biofilms. We use oscillatory bulk rheology, on biofilms grown from longitudinal clinical isolates and from genetically-manipulated lab strains, to show that increased Psl stiffens biofilms and increases biofilm toughness, which is the energy cost to cause the biofilm to yield mechanically. Further, atomic force microscopy measurements reveal greater intercellular cohesion for higher Psl expression. Of the three types of extracellular polysaccharides produced by P. aeruginosa, only Psl increases the stiffness. Stiffening by Psl requires CdrA, a protein that binds to mannose groups on Psl and is a likely cross-linker for the Psl components of the biofilm matrix. We compare the elastic moduli of biofilms to the estimated stresses exerted by neutrophils during phagocytosis, and infer that increased Psl could confer a mechanical protection against phagocytic clearance.

PMID: 28649402 [PubMed - in process]

Ecological networking of cystic fibrosis lung infections.

NPJ Biofilms Microbiomes. 2016;2:4

Authors: Quinn RA, Whiteson K, Lim YW, Zhao J, Conrad D, LiPuma JJ, Rohwer F, Widder S

Abstract
In the context of a polymicrobial infection, treating a specific pathogen poses challenges because of unknown consequences on other members of the community. The presence of ecological interactions between microbes can change their physiology and response to treatment. For example, in the cystic fibrosis lung polymicrobial infection, antimicrobial susceptibility testing on clinical isolates is often not predictive of antibiotic efficacy. Novel approaches are needed to identify the interrelationships within the microbial community to better predict treatment outcomes. Here we used an ecological networking approach on the cystic fibrosis lung microbiome characterized using 16S rRNA gene sequencing and metagenomics. This analysis showed that the community is separated into three interaction groups: Gram-positive anaerobes, Pseudomonas aeruginosa, and Staphylococcus aureus. The P. aeruginosa and S. aureus groups both anti-correlate with the anaerobic group, indicating a functional antagonism. When patients are clinically stable, these major groupings were also stable, however, during exacerbation, these communities fragment. Co-occurrence networking of functional modules annotated from metagenomics data supports that the underlying taxonomic structure is driven by differences in the core metabolism of the groups. Topological analysis of the functional network identified the non-mevalonate pathway of isoprenoid biosynthesis as a keystone for the microbial community, which can be targeted with the antibiotic fosmidomycin. This study uses ecological theory to identify novel treatment approaches against a polymicrobial disease with more predictable outcomes.

PMID: 28649398 [PubMed - in process]

Association between spirometry controlled chest CT scores using computer-animated biofeedback and clinical markers of lung disease in children with cystic fibrosis.

Eur Clin Respir J. 2017;4(1):1318027

Authors: Kongstad T, Green K, Buchvald F, Skov M, Pressler T, Nielsen KG

Abstract
Background: Computed tomography (CT) of the lungs is the gold standard for assessing the extent of structural changes in the lungs. Spirometry-controlled chest CT (SCCCT) has improved the usefulness of CT by standardising inspiratory and expiratory lung volumes during imaging. This was a single-centre cross-sectional study in children with cystic fibrosis (CF). Using SCCCT we wished to investigate the association between the quantity and extent of structural lung changes and pulmonary function outcomes, and prevalence of known CF lung pathogens. Methods: CT images were analysed by CF-CT scoring (expressed as % of maximum score) to quantify different aspects of structural lung changes including bronchiectasis, airway wall thickening, mucus plugging, opacities, cysts, bullae and gas trapping. Clinical markers consisted of outcomes from pulmonary function tests, microbiological cultures from sputum and serological samples reflecting anti-bacterial and anti-fungal antibodies. Results: Sixty-four children with CF, median age (range) of 12.7 (6.4-18.1) years, participated in the study. The median (range) CF-CT total score in all children was 9.3% (0.4-46.8) with gas trapping of 40.7% (3.7-100) as the most abundant finding. Significantly higher median CF-CT total scores (21.9%) were found in patients with chronic infections (N = 12) including Gram-negative infection and allergic bronchopulmonary aspergillosis (ABPA) exhibiting CF-CT total scores of 14.2% (ns) and 24.0% (p < 0.01), respectively, compared to 8.0% in patients with no chronic lung infection. Lung clearance index (LCI) derived from multiple breath washout exhibited closest association with total CF-CT scores, compared to other pulmonary function outcomes. Conclusions: The most prominent structural lung change was gas trapping, while CF-CT total scores were generally low, both showing close association with LCI. Chronic lung infections, specifically in the form of ABPA, were associated with increased scores in lung changes. Further investigation of impact of infections with different microorganisms on extent and progression of structural CF lung disease is needed.

PMID: 28649308 [PubMed - in process]

The use of fructosamine in cystic fibrosis-related diabetes (CFRD) screening.

J Cyst Fibros. 2017 Jun 22;:

Authors: Lam GY, Doll-Shankaruk M, Dayton J, Rodriguez-Capote K, Higgins TN, Thomas D, Mulchey K, Smith MP, Brown NE, Leung WM, Estey MP

Abstract
OBJECTIVE: To determine whether serum fructosamine correlates with glycemic control and clinical outcomes in patients being screened for cystic fibrosis-related diabetes (CFRD).
METHODS: Fructosamine and percent predicted forced expiratory volume in 1s (FEV1) were measured in patients undergoing a 2h oral glucose tolerance test (OGTT) for CFRD screening. Fractional serum fructosamine (FSF) was calculated as fructosamine/total protein.
RESULTS: FSF exhibited a positive correlation with 2h OGTT results (r(2)=0.3201, p=0.009), and ROC curve analysis suggested that FSF can identify patients with an abnormal OGTT (AUC=0.840, p=0.0002). FSF also exhibited a negative correlation with FEV1 (r(2)=0.3732, p=0.035). Patients with FSF≥3.70μmol/g had significantly lower FEV1 (median 47%) compared to those with FSF<3.70μmol/g (median 90%; p=0.015).
CONCLUSIONS: FSF correlated with both OGTT results and FEV1, and reliably identified patients with abnormal OGTT results. This simple blood test shows potential as an effective tool in CFRD screening.

PMID: 28648493 [PubMed - as supplied by publisher]

Suspicion of respiratory tract infection with multidrug-resistant Enterobacteriaceae: epidemiology and risk factors from a Paediatric Intensive Care Unit.

BMC Infect Dis. 2017 Feb 21;17(1):163

Authors: Renk H, Stoll L, Neunhoeffer F, Hölzl F, Kumpf M, Hofbeck M, Hartl D

Abstract
BACKGROUND: Multidrug-resistant (MDR) infections are a serious concern for children admitted to the Paediatric Intensive Care Unit (PICU). Tracheal colonization with MDR Enterobacteriaceae predisposes to respiratory infection, but underlying risk factors are poorly understood. This study aims to determine the incidence of children with suspected infection during mechanical ventilation and analyses risk factors for the finding of MDR Enterobacteriaceae in tracheal aspirates.
METHODS: A retrospective single-centre analysis of Enterobacteriaceae isolates from the lower respiratory tract of ventilated PICU patients from 2005 to 2014 was performed. Resistance status was determined and clinical records were reviewed for potential risk factors. A classification and regression tree (CRT) to predict risk factors for infection with MDR Enterobacteriaceae was employed. The model was validated by simple and multivariable logistic regression.
RESULTS: One hundred sixty-seven Enterobacteriaceae isolates in 123 children were identified. The most frequent isolates were Enterobacter spp., Klebsiella spp. and E.coli. Among these, 116 (69%) isolates were susceptible and 51 (31%) were MDR. In the CRT analysis, antibiotic exposure for ≥ 7 days and presence of gastrointestinal comorbidity were the most relevant predictors for an MDR isolate. Antibiotic exposure for ≥ 7 days was confirmed as a significant risk factor for infection with MDR Enterobacteriaceae by a multivariable logistic regression model.
CONCLUSIONS: This study shows that critically-ill children with tracheal Enterobacteriaceae infection are at risk of carrying MDR isolates. Prior use of antibiotics for ≥ 7 days significantly increased the risk of finding MDR organisms in ventilated PICU patients with suspected infection. Our results imply that early identification of patients at risk, rapid microbiological diagnostics and tailored antibiotic therapy are essential to improve management of critically ill children infected with Enterobacteriaceae.

PMID: 28222699 [PubMed - indexed for MEDLINE]

Risk Factors Associated With Pediatric Acute Recurrent and Chronic Pancreatitis: Lessons From INSPPIRE.

JAMA Pediatr. 2016 Jun 01;170(6):562-9

Authors: Kumar S, Ooi CY, Werlin S, Abu-El-Haija M, Barth B, Bellin MD, Durie PR, Fishman DS, Freedman SD, Gariepy C, Giefer MJ, Gonska T, Heyman MB, Himes R, Husain SZ, Lin TK, Lowe ME, Morinville V, Palermo JJ, Pohl JF, Schwarzenberg SJ, Troendle D, Wilschanski M, Zimmerman MB, Uc A

Abstract
IMPORTANCE: Pediatric acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP) are poorly understood.
OBJECTIVE: To characterize and identify risk factors associated with ARP and CP in childhood.
DESIGN, SETTING, AND PARTICIPANTS: A multinational cross-sectional study of children with ARP or CP at the time of enrollment to the INSPPIRE (International Study Group of Pediatric Pancreatitis: In Search for a Cure) study at participant institutions of the INSPPIRE Consortium. From August 22, 2012, to February 8, 2015, 155 children with ARP and 146 with CP (aged ≤19 years) were enrolled. Their demographic and clinical information was entered into the REDCap (Research Electronic Data Capture) database at the 15 centers. Differences were analyzed using 2-sample t test or Wilcoxon rank sum test for continuous variables and Pearson χ2 test or Fisher exact test for categorical variables. Disease burden variables (pain variables, hospital/emergency department visits, missed school days) were compared using Wilcoxon rank sum test.
MAIN OUTCOMES AND MEASURES: Demographic characteristics, risk factors, abdominal pain, and disease burden.
RESULTS: A total of 301 children were enrolled (mean [SD] age, 11.9 [4.5] years; 172 [57%] female); 155 had ARP and 146 had CP. The majority of children with CP (123 of 146 [84%]) reported prior recurrent episodes of acute pancreatitis. Sex distribution was similar between the groups (57% female in both). Hispanic children were less likely to have CP than ARP (17% vs 28%, respectively; odds ratio [OR] = 0.51; 95% CI, 0.29-0.92; P = .02). At least 1 gene mutation in pancreatitis-related genes was found in 48% of patients with ARP vs 73% of patients with CP (P < .001). Children with PRSS1 or SPINK1 mutations were more likely to present with CP compared with ARP (PRSS1: OR = 4.20; 95% CI, 2.14-8.22; P < .001; and SPINK1: OR = 2.30; 95% CI, 1.03-5.13; P = .04). Obstructive risk factors did not differ between children with ARP or CP (33% in both the ARP and CP groups), but toxic/metabolic risk factors were more common in children with ARP (21% overall; 26% in the ARP group and 15% in the CP group; OR = 0.55; 95% CI, 0.31-0.99; P = .046). Pancreatitis-related abdominal pain was a major symptom in 81% of children with ARP or CP within the last year. The disease burden was greater in the CP group compared with the ARP group (more emergency department visits, hospitalizations, and medical, endoscopic, and surgical interventions).
CONCLUSIONS AND RELEVANCE: Genetic mutations are common in both ARP and CP. Ethnicity and mutations in PRSS1 or SPINK1 may influence the development of CP. The high disease burden in pediatric CP underscores the importance of identifying predisposing factors for progression of ARP to CP in children.

PMID: 27064572 [PubMed - indexed for MEDLINE]

Hyperpolarized helium-3 magnetic resonance lung imaging of non-sedated infants and young children: a proof-of-concept study.

Clin Imaging. 2017 May 10;45:105-110

Authors: Altes TA, Meyer CH, Mata JF, Froh DK, Paget-Brown A, Gerald Teague W, Fain SB, de Lange EE, Ruppert K, Botfield MC, Johnson MA, Mugler JP

Abstract
PURPOSE: To develop and evaluate a protocol for hyperpolarized helium-3 (HHe) ventilation magnetic resonance imaging (MRI) of the lungs of non-sedated infants and children.
MATERIALS AND METHODS: HHe ventilation MRI was performed on seven children ≤4years old. Contiguous 2D-spiral helium-3 images were acquired sequentially with a scan time of ≤0.2s/slice.
RESULTS: Motion-artifact-free, high signal-to-noise ratio (SNR) images of lung ventilation were obtained. Gas was homogeneously distributed in healthy individuals; focal ventilation defects were found in patients with respiratory diseases.
CONCLUSION: HHe ventilation MRI can aid assessment of pediatric lung disease even at a young age.

PMID: 28646735 [PubMed - as supplied by publisher]

Pregnancy outcome in women with cystic fibrosis related diabetes.

Acta Obstet Gynecol Scand. 2017 Jun 24;:

Authors: Reynaud Q, Poupon-Bourdy S, Rabilloud M, Al Mufti L, Jablonski CR, Lemonnier L, Nove-Josserand R, Touzet S, Durieu I, French Cystic Fibrosis Registry

Abstract
INTRODUCTION: With increasing life expectancy more women with cystic fibrosis and diabetes mellitus become pregnant. We investigated how pre-gestational diabetes (cystic fibrosis related diabetes) influenced pregnancy outcome and the clinical status of these women MATERIAL AND METHODS: We analyzed all pregnancies reported to the French cystic fibrosis registry between 2001 and 2012, and compared forced expiratory volume (FEV1 ) and body mass index before and after pregnancy in women with and without pre-gestational diabetes having a first delivery RESULTS: A total 249 women delivered 314 infants. Among these, 189 women had a first delivery and 29 of these had pre-gestational diabetes. There was a trend towards a higher rate of assisted conception among diabetic women (53.8%) as compared to non-diabetic women (34.5%, p=0.06), and the rate of cesarean section was significantly higher in diabetic women (48% versus 21.4%, p=0.005). The rate of preterm birth and mean infant birth weight did not differ significantly between diabetic and non-diabetic women. Before pregnancy forced expiratory volume was significantly lower in the diabetic group. The decline in forced expiratory volume and body mass index following pregnancy did not differ between the women with and without pre-gestational diabetes CONCLUSION: Pre-gestational diabetes in cystic fibrosis women is associated with a higher rate of cesarean section, but does not seem to have a clinically significant impact on fetal growth or preterm delivery. The changes in maternal pulmonary and nutritional status following pregnancy in cystic fibrosis women were not influenced by pre-gestational diabetes. This article is protected by copyright. All rights reserved.

PMID: 28646623 [PubMed - as supplied by publisher]

Increased Soluble VCAM-1 and Normal P-Selectin in Cystic Fibrosis: a Cross-Sectional Study.

Lung. 2017 Jun 23;:

Authors: Nowak JK, Wojsyk-Banaszak I, Mądry E, Wykrętowicz A, Krzyżanowska P, Drzymała-Czyż S, Nowicka A, Pogorzelski A, Sapiejka E, Skorupa W, Szczepanik M, Lisowska A, Walkowiak J

Abstract
PURPOSE: As life expectancy in cystic fibrosis (CF) increases, questions regarding its potential impact on cardiovascular health arise. Soluble vascular cell adhesion molecule 1 (sVCAM-1), P-selectin (sP-selectin) are proposed as biomarkers of cardiovascular disease. We aimed to: compare their concentrations in clinically stable CF patients and healthy subjects (HS) and verify whether they independently correlate with CF characteristics.
METHODS: Serum sVCAM-1 and sP-selectin levels were measured using ELISA. CF was characterized using: forced expiratory volume in 1 s, exocrine pancreatic and CF-related liver disease status, Pseudomonas aeruginosa colonization, serum high-sensitivity C-reactive protein, and body mass index (BMI). CFTR genotypes were classified as severe (classes I and II) or other.
RESULTS: 108 CF patients and 51 healthy subjects volunteered for the study. In the CF group BMI was lower (median [IQR]: 20.5 kg/m(2) [18.4-22.2] vs. 21.6 kg/m(2) [19.9-23.4], p = 0.02) and hsCRP levels were higher (3.6 mg/L [1.1-7.1] vs. 0.5 mg/dL [0.3-1.0], p < 10(-10)). While sVCAM-1 concentrations were greater in CF patients (1018 ng/mL [851-1279] vs. 861 ng/mL [806-979], p < 10(-4)), sP-selectin levels did not differ (155 ng/mL [129-188] vs. 156 ng/mL [144-177], p = 0.48). None of the multivariable regression models was valid for the prediction of sVCAM-1 and sP-selectin in CF.
CONCLUSIONS: We found higher sVCAM-1 concentrations in CF patients than in healthy subjects, which were not explained by CF characteristics. Further research is required to check whether sVCAM-1 is a marker of microangiopathy in CF.

PMID: 28646244 [PubMed - as supplied by publisher]

Secretory IgA response against Pseudomonas aeruginosa in the upper airways and the link with chronic lung infection in cystic fibrosis.

Pathog Dis. 2017 Jun 22;:

Authors: Mauch R, Rossi C, Aiello T, Ribeiro J, Ribeiro A, Høiby N, Levy C

Abstract
We assessed the diagnostic ability of an ELISA test for measurement of specific secretory IgA (sIgA) in saliva to identify Cystic Fibrosis (CF) patients with P. aeruginosa chronic lung infection and intermittent lung colonization. A total of 102 Brazilian CF patients and 53 healthy controls were included. Specific serum IgG response was used as a surrogate to distinguish CF patients according to their P. aeruginosa colonization/infection status. The rate of sIgA positivity was 87.1% in CF chronically infected patients (Median value = 181.5 U/mL), 48.7% in intermittently colonized patients (Median value = 45.8 U/mL) and 21.8% in free of infection patients (Median value = 22.1 U/mL). SIgA levels in saliva were significantly associated with serum P. aeruginosa IgG and microbiological culture results. The sensitivity, specificity, PPV and NPV for differentiation between presence and absence of chronic lung infection were 87%, 63%, 51% and 92%. Measurement of sIgA in saliva may be used for screening patients in risk of developing P. aeruginosa chronic lung infection in CF and possibly also for paranasal sinusitis, and, most importantly, to efficiently rule out chronic P. aeruginosa lung infection.

PMID: 28645157 [PubMed - as supplied by publisher]