Real-life acute lung function changes after lumacaftor/ivacaftor first administration in pediatric patients with cystic fibrosis.

J Cyst Fibros. 2017 May 18;:

Authors: Labaste A, Ohlmann C, Mainguy C, Jubin V, Perceval M, Coutier L, Reix P

Abstract
The combination of lumacaftor and ivacaftor (LUM/IVA) has been reported to induce a mean acute absolute drop of -4.1% predicted forced expiratory volume in 1s (FEV1) after a unique administration in healthy subjects. The aim of the present study was to assess acute FEV1 changes after the first dose of LUM/IVA in CF patients. A total of 32 pediatric patients were included. Respiratory manifestations occurred in only 3 patients (9.4%), but FEV1 consistently decreased (-10.4±4.6%, range: -1.5; -21.8%). FEV1 only partially resumed after salbutamol inhalation. Patients with previously known significant reversible airway obstruction and low FEV1 were more at risk of FEV1 decrease.

PMID: 28529073 [PubMed - as supplied by publisher]

Discovery and biosynthesis of gladiolin: a Burkholderia gladioli antibiotic with promising activity against Mycobacterium tuberculosis.

J Am Chem Soc. 2017 May 22;:

Authors: Song L, Jenner M, Masschelein J, Jones C, Bull MJ, Harris SR, Hartkoorn RC, Vocat A, Romero-Canelón I, Coupland P, Webster G, Dunn M, Weiser R, Paisey C, Cole ST, Parkhill J, Mahenthiralingam E, Challis GL

Abstract
An antimicrobial activity screen of Burkholderia gladioli BCC0238, a clinical isolate from a cystic fibrosis patient, led to the discovery of gladiolin, a novel macrolide antibiotic with potent activity against Mycobacterium tuberculosis H37Rv. Gladiolin is structurally-related to etnangien, a highly unstable antibiotic from Sorangium cellulosum that is also active against Mycobacteria. Like etnangien, gladiolin was found to inhibit RNA polymerase, a validated drug target in M. tuberculosis. However, gladiolin lacks the highly labile hexaene moiety of etnangien and was thus found to possess significantly increased chemical stability. Moreover, gladiolin displayed low mammalian cytotoxicity and good activity against several M. tuberculosis clinical isolates, including four that are resistant to isoniazid and one that is resistant to both isoniazid and rifampicin. Overall, these data suggest that gladiolin may represent a useful starting point for the development of novel drugs to tackle multidrug-resistant tuberculosis. The B. gladioli BCC0238 genome was sequenced using Single Molecule Real Time (SMRT) technology. This resulted in four contiguous sequences: two large circular chromosomes and two smaller putative plasmids. Analysis of the chromosome sequences identified 49 putative specialized metabolite biosynthetic gene clusters. One such gene cluster, located on the smaller of the two chromosomes, encodes a trans-acyltransferase (trans-AT) polyketide synthase (PKS) multienzyme that was hypothesized to assemble gladiolin. Insertional inactivation of a gene in this cluster encoding one of the PKS subunits abrogated gladiolin production, confirming that the gene cluster is responsible for biosynthesis of the antibiotic. Comparison of the PKSs responsible for the assembly of gladiolin and etnangien showed that they possess a remarkably similar architecture, obfuscating the biosynthetic mechanisms responsible for most of the structural differences between the two metabolites.

PMID: 28528545 [PubMed - as supplied by publisher]

Urging Europe to put non-adherence to inhaled respiratory medication higher on the policy agenda: a report from the First European Congress on Adherence to Therapy.

Eur Respir J. 2017 May;49(5):

Authors: van Boven JFM, Lavorini F, Dekhuijzen PNR, Blasi F, Price DB, Viegi G

PMID: 28526801 [PubMed - in process]

Swimming Motility Mediates the Formation of Neutrophil Extracellular Traps Induced by Flagellated Pseudomonas aeruginosa.

PLoS Pathog. 2016 Nov;12(11):e1005987

Authors: Floyd M, Winn M, Cullen C, Sil P, Chassaing B, Yoo DG, Gewirtz AT, Goldberg JB, McCarter LL, Rada B

Abstract
Pseudomonas aeruginosa is an opportunistic pathogen causing severe infections often characterized by robust neutrophilic infiltration. Neutrophils provide the first line of defense against P. aeruginosa. Aside from their defense conferred by phagocytic activity, neutrophils also release neutrophil extracellular traps (NETs) to immobilize bacteria. Although NET formation is an important antimicrobial process, the details of its mechanism are largely unknown. The identity of the main components of P. aeruginosa responsible for triggering NET formation is unclear. In this study, our focus was to identify the main bacterial factors mediating NET formation and to gain insight into the underlying mechanism. We found that P. aeruginosa in its exponential growth phase promoted strong NET formation in human neutrophils while its NET-inducing ability dramatically decreased at later stages of bacterial growth. We identified the flagellum as the primary component of P. aeruginosa responsible for inducing NET extrusion as flagellum-deficient bacteria remained seriously impaired in triggering NET formation. Purified P. aeruginosa flagellin, the monomeric component of the flagellum, does not stimulate NET formation in human neutrophils. P. aeruginosa-induced NET formation is independent of the flagellum-sensing receptors TLR5 and NLRC4 in both human and mouse neutrophils. Interestingly, we found that flagellar motility, not flagellum binding to neutrophils per se, mediates NET release induced by flagellated bacteria. Immotile, flagellar motor-deficient bacterial strains producing paralyzed flagella did not induce NET formation. Forced contact between immotile P. aeruginosa and neutrophils restored their NET-inducing ability. Both the motAB and motCD genetic loci encoding flagellar motor genes contribute to maximal NET release; however the motCD genes play a more important role. Phagocytosis of P. aeruginosa and superoxide production by neutrophils were also largely dependent upon a functional flagellum. Taken together, the flagellum is herein presented for the first time as the main organelle of planktonic bacteria responsible for mediating NET release. Furthermore, flagellar motility, rather than binding of the flagellum to flagellum-sensing receptors on host cells, is required for P. aeruginosa to induce NET release.

PMID: 27855208 [PubMed - indexed for MEDLINE]

The WinCF Model - An Inexpensive and Tractable Microcosm of a Mucus Plugged Bronchiole to Study the Microbiology of Lung Infections.

J Vis Exp. 2017 May 08;(123):

Authors: Comstock WJ, Huh E, Weekes R, Watson C, Xu T, Dorrestein PC, Quinn RA

Abstract
Many chronic airway diseases result in mucus plugging of the airways. Lungs of an individual with cystic fibrosis are an exemplary case where their mucus-plugged bronchioles create a favorable habitat for microbial colonization. Various pathogens thrive in this environment interacting with each other and driving many of the symptoms associated with CF disease. Like any microbial community, the chemical conditions of their habitat have a significant impact on the community structure and dynamics. For example, different microorganisms thrive in differing levels of oxygen or other solute concentrations. This is also true in the CF lung, where oxygen concentrations are believed to drive community physiology and structure. The methods described here are designed to mimic the lung environment and grow pathogens in a manner more similar to that from which they cause disease. Manipulation of the chemical surroundings of these microbes is then used to study how the chemistry of lung infections governs its microbial ecology. The method, called the WinCF system, is based on artificial sputum medium and narrow capillary tubes meant to provide an oxygen gradient similar to that which exists in mucus-plugged bronchioles. Manipulating chemical conditions, such as the media pH of the sputum or antibiotics pressure, allows for visualization of the microbiological differences in those samples using colored indicators, watching for gas or biofilm production, or extracting and sequencing the nucleic acid contents of each sample.

PMID: 28518116 [PubMed - in process]

Body Sanctification and Sleep in Adolescents with Cystic Fibrosis: A Pilot Study.

J Relig Health. 2017 May 17;:

Authors: Kopp AT, Chini BA, Dimitriou SM, Grossoehme DH

Abstract
Imbuing one's body with divine significance is associated with health-protective behaviors. The purpose of this study was to determine whether adolescents with a life-shortening, chronic disease (cystic fibrosis) who sanctified their bodies also received adequate sleep. Data from Daily Phone Diaries and questionnaire replies from 45 adolescents with cystic fibrosis (ages 11-19 years) were analyzed. A significant relationship between body sanctification and sleep was found, with between-gender differences. Body sanctification is an understudied construct which is associated with healthy behaviors.

PMID: 28516396 [PubMed - as supplied by publisher]

Aspergillus Species in Bronchiectasis: Challenges in the Cystic Fibrosis and Non-cystic Fibrosis Airways.

Mycopathologia. 2017 May 17;:

Authors: Chotirmall SH, Martin-Gomez MT

Abstract
Bronchiectasis is a chronic irreversible airway abnormality associated with infectious agents that either cause or superinfect the airways. While the role of bacteria is well studied, much remains to be determined about fungi in both cystic fibrosis- and non-cystic fibrosis-related bronchiectasis. The airway is constantly exposed to inhaled ambient moulds of which Aspergillus represent the most ubiquitous. In a normal healthy host, this situation is of little consequence. The presence of anatomical or immunological abnormalities such as those in bronchiectasis leads to a range of fungal-related pathologies from asymptomatic airway colonization to fungal sensitization, allergic bronchopulmonary aspergillosis or chronic pulmonary aspergillosis. These entities are difficult to recognize, diagnose and treat due in part to a lack of validated biomarkers. Our true understanding of the complex relationships that regulate fungal-host interactions is still in its infancy and, several questions remain. This includes if fungal epidemiology in bronchiectasis is uniform across countries, and to what extent immunopathological mechanisms-related to fungal airway infections-occurs in different disease states. Specific triggers to allergic or infectious responses to Aspergillus require further exploration. How transition occurs between allergic and invasive phenotypes and their respective biomarkers is also important. Whether anti-fungal treatment is warranted in all cases and what the optimal management strategy is, particularly when treatment should commence and its expected duration remains unclear. Further research is clearly necessary and should be prioritized to better understand the clinical effects and impact of Aspergillus in the setting of bronchiectasis.

PMID: 28516246 [PubMed - as supplied by publisher]

A neutralizing anti-G-CSFR antibody blocks G-CSF-induced neutrophilia without inducing neutropenia in nonhuman primates.

J Leukoc Biol. 2017 May 17;:

Authors: Scalzo-Inguanti K, Monaghan K, Edwards K, Herzog E, Mirosa D, Hardy M, Sorto V, Huynh H, Rakar S, Kurtov D, Braley H, Wilson N, Busfield S, Nash A, Andrews A

Abstract
Neutrophils are the most abundant WBCs and have an essential role in the clearance of pathogens. Tight regulation of neutrophil numbers and their recruitment to sites of inflammation is critical in maintaining a balanced immune response. In various inflammatory conditions, such as rheumatoid arthritis, vasculitis, cystic fibrosis, and inflammatory bowel disease, increased serum G-CSF correlates with neutrophilia and enhanced neutrophil infiltration into inflamed tissues. We describe a fully human therapeutic anti-G-CSFR antibody (CSL324) that is safe and well tolerated when administered via i.v. infusion to cynomolgus macaques. CSL324 was effective in controlling G-CSF-mediated neutrophilia when administered either before or after G-CSF. A single ascending-dose study showed CSL324 did not alter steady-state neutrophil numbers, even at doses sufficient to completely prevent G-CSF-mediated neutrophilia. Weekly infusions of CSL324 (≤10 mg/kg) for 3 wk completely neutralized G-CSF-mediated pSTAT3 phosphorylation without neutropenia. Moreover, repeat dosing up to 100 mg/kg for 12 wk did not result in neutropenia at any point, including the 12-wk follow-up after the last infusion. In addition, CSL324 had no observable effect on basic neutrophil functions, such as phagocytosis and oxidative burst. These data suggest that targeting G-CSFR may provide a safe and effective means of controlling G-CSF-mediated neutrophilia as observed in various inflammatory diseases.

PMID: 28515226 [PubMed - as supplied by publisher]

Lung function imaging methods in Cystic Fibrosis pulmonary disease.

Respir Res. 2017 May 17;18(1):96

Authors: Kołodziej M, de Veer MJ, Cholewa M, Egan GF, Thompson BR

Abstract
Monitoring of pulmonary physiology is fundamental to the clinical management of patients with Cystic Fibrosis. The current standard clinical practise uses spirometry to assess lung function which delivers a clinically relevant functional readout of total lung function, however does not supply any visible or localised information. High Resolution Computed Tomography (HRCT) is a well-established current 'gold standard' method for monitoring lung anatomical changes in Cystic Fibrosis patients. HRCT provides excellent morphological information, however, the X-ray radiation dose can become significant if multiple scans are required to monitor chronic diseases such as cystic fibrosis. X-ray phase-contrast imaging is another emerging X-ray based methodology for Cystic Fibrosis lung assessment which provides dynamic morphological and functional information, albeit with even higher X-ray doses than HRCT. Magnetic Resonance Imaging (MRI) is a non-ionising radiation imaging method that is garnering growing interest among researchers and clinicians working with Cystic Fibrosis patients. Recent advances in MRI have opened up the possibilities to observe lung function in real time to potentially allow sensitive and accurate assessment of disease progression. The use of hyperpolarized gas or non-contrast enhanced MRI can be tailored to clinical needs. While MRI offers significant promise it still suffers from poor spatial resolution and the development of an objective scoring system especially for ventilation assessment.

PMID: 28514950 [PubMed - in process]

Aspergillus fumigatus in cystic fibrosis: an update on immune interactions and molecular diagnostics in ABPA.

Allergy. 2017 May 17;:

Authors: Carsin A, Romain T, Ranque S, Reynaud-Gaubert M, Dubus JC, Mège JL, Vitte J

Abstract
A wide spectrum of pathological conditions may result from the interaction of Aspergillus fumigatus and the immune system of its human host. Allergic bronchopulmonary aspergillosis is one of the most severe Aspergillus fumigatus-related diseases due to possible evolution towards pleuropulmonary fibrosis and respiratory failure. Allergic bronchopulmonary aspergillosis occurs almost exclusively in cystic fibrosis or asthmatic patients. An estimated 8 to 10% of cystic fibrosis patients experience this condition. The diagnosis of allergic bronchopulmonary aspergillosis relies on criteria first established in 1977. Progress in the understanding of host-pathogen interactions in Aspergillus fumigatus and cystic fibrosis patients and the ongoing validation of novel laboratory tools concur to update and improve the diagnosis of allergic bronchopulmonary aspergillosis. This article is protected by copyright. All rights reserved.

PMID: 28513848 [PubMed - as supplied by publisher]

Cleaning and infection control of airway clearance devices used by CF patients.

Chron Respir Dis. 2017 Jan 01;:1479972317707652

Authors: Manor E, Gur M, Geffen Y, Bentur L

Abstract
Respiratory treatment for cystic fibrosis (CF) patients includes use of respiratory devices. Contamination of airway clearance devices has not been adequately explored. We aimed to determine whether airway clearance devices are contaminated after use and whether cleaning guidelines for nebulizers are as effective for airway clearance devices. Patients brought their airway clearance devices to the clinic. Swabs from the devices were taken before and after cleaning and were cultured for bacterial counts. Total colony-forming units (CFU) was determined, and predominant colonies were identified using Matrix-Assisted Laser Desorption Ionization Time-of-Flight Mass Spectrometry technology. Thirty devices were collected from 23 patients. Most of the devices (28/30) were contaminated when brought to the clinic. Complete bacterial eradication was achieved in 15 (50%) samples and partial eradication in 9 (30%). The cleaning was totally ineffective in four samples. Median CFU decreased significantly from 1250 (IQR 25-75% 175-10.000) to 0 (IQR 25-75% 0-700) before and after cleaning ( p < 0.0001). The predominant organisms were identified in five samples only, and there was no concordance with sputum culture results. Airway clearance devices are contaminated after use, and appropriate cleaning can reduce contamination. The effect on disease progression in CF patients is unclear. There is a need for infection prevention and control guidelines for the growing number of respiratory devices.

PMID: 28513198 [PubMed - as supplied by publisher]

Pseudomonas aeruginosa Inhibits the Growth of Scedosporium and Lomentospora In Vitro.

Mycopathologia. 2017 May 16;:

Authors: Chen SC, Patel S, Meyer W, Chapman B, Yu H, Byth K, Middleton PG, Nevalainen H, Sorrell TC

Abstract
In vitro bacterial-fungal interaction studies in cystic fibrosis (CF) have mainly focused on interactions between bacteria and Candida. Here we investigated the effect of Pseudomonas aeruginosa on the growth of Scedosporium/Lomentospora spp. Standard suspensions of P. aeruginosa (16 non-mucoid and nine mucoid isolates) were dropped onto paper disks, placed on lawns of Lomentospora prolificans (formerly Scedosporium prolificans) strain WM 14.140 or Scedosporium aurantiacum strain WM 11.78 on solid agar. The median inhibitory activity (mIz) was calculated for each fungal-bacterial combination. As a group, mIz values for non-mucoid phenotype P. aeruginosa strains were significantly lower than those for mucoid strains (P < 0.001); 14/16 (87.5%) non-mucoid strains had mIz <1.0 against both fungi versus just 3/9 mucoid strains (33.4%) (P = 0.01). One non-mucoid (PA14) and one mucoid (CIDMLS-PA-28) P. aeruginosa strain effecting inhibition were selected for further studies. Inhibition of both L. prolificans and S. aurantiacum by these strains was confirmed using the XTT (2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino)carbonyl]-2H-tetrazolium hydroxide) reduction assay. Following incubation with XTT, inhibition of fungal growth was determined as the ratio of absorbance in liquid culture with Pseudomonas to that in control fungal cultures. An absorbance ratio of <1.0 consistent with bacterial inhibition of fungal growth was observed for all four P. aeruginosa-fungal combinations (P < 0.05). Fluorescence microscopy, subsequent to co-culture of either fungal isolate with P. aeruginosa strain PA14 or CIDMLS-PA-28 revealed poorly formed hyphae, compared with control fungal cultures. P. aeruginosa inhibits growth of L. prolificans and S. aurantiacum in vitro, with non-mucoid strains more commonly having an inhibitory effect. As P. aeruginosa undergoes phenotype transitions from non-mucoid to the mucoid form with progression of CF lung disease, this balance may influence the appearance of Scedosporium fungi in the airways.

PMID: 28512704 [PubMed - as supplied by publisher]

Serum Albumin and Disease Severity of Non-Cystic Fibrosis Bronchiectasis.

Respir Care. 2017 May 16;:

Authors: Lee SJ, Kim HJ, Kim JY, Ju S, Lim S, Yoo JW, Nam SJ, Lee GD, Cho HS, Kim RB, Cho YJ, Jeong YY, Kim HC, Lee JD

Abstract
BACKGROUND: A clinical classification system has been developed to define the severity and predict the prognosis of subjects with non-cystic fibrosis bronchiectasis (non-CF bronchiectasis). We aimed to identify laboratory parameters that are correlated with the bronchiectasis severity index (BSI) and FACED score.
METHODS: The medical records of 107 subjects with non-CF bronchiectasis for whom BSI and FACED scores could be calculated were retrospectively reviewed. The correlations between the laboratory parameters and BSI or FACED score were assessed, and multiple-linear regression analysis was performed to identify variables independently associated with BSI and FACED score. An additional subgroup analysis was performed according to sex.
RESULTS: Among all of the enrolled subjects, 49 (45.8%) were male and 58 (54.2%) were female. The mean BSI and FACED scores were 9.43 ± 3.81 and 1.92 ± 1.59, respectively. The serum albumin level (r = -0.49), bilirubin level (r = -0.31), C-reactive protein level (r = 0.22), hemoglobin level (r = -0.2), and platelet/lymphocyte ratio (r = 0.31) were significantly correlated with BSI. Meanwhile, serum albumin (r = -0.37) and bilirubin level (r = -0.25) showed a significant correlation with the FACED score. Multiple-linear regression analysis showed that the serum bilirubin level was independently associated with BSI, and the serum albumin level was independently associated with both scoring systems. Subgroup analysis revealed that the level of uric acid was also a significant variable independently associated with the BSI in male bronchiectasis subjects.
CONCLUSIONS: Several laboratory variables were identified as possible prognostic factors for non-CF bronchiectasis. Among them, the serum albumin level exhibited the strongest correlation and was identified as an independent variable associated with the BSI and FACED scores.

PMID: 28512120 [PubMed - as supplied by publisher]

High-resolution mucociliary transport measurement in live excised large animal trachea using synchrotron X-ray imaging.

Respir Res. 2017 May 16;18(1):95

Authors: Donnelley M, Morgan KS, Awadalla M, Farrow NR, Hall C, Parsons DW

Abstract
BACKGROUND: The Australian Synchrotron Imaging and Medical Beamline (IMBL) was designed as the world's widest synchrotron X-ray beam, enabling both clinical imaging and therapeutic applications for humans as well as the imaging of large animal models. Our group is developing methods for imaging the airways of newly developed CF animal models that display human-like lung disease, such as the CF pig, and we expect that the IMBL can be utilised to image airways in animals of this size.
METHODS: This study utilised samples of excised tracheal tissue to assess the feasibility, logistics and protocols required for airway imaging in large animal models such as pigs and sheep at the IMBL. We designed an image processing algorithm to automatically track and quantify the tracheal mucociliary transport (MCT) behaviour of 103 μm diameter high refractive index (HRI) glass bead marker particles deposited onto the surface of freshly-excised normal sheep and pig tracheae, and assessed the effects of airway rehydrating aerosols.
RESULTS: We successfully accessed and used scavenged tracheal tissue, identified the minimum bead size that is visible using our chosen imaging setup, verified that MCT could be visualised, and that our automated tracking algorithm could quantify particle motion. The imaging sequences show particles propelled by cilia, against gravity, up the airway surface, within a well-defined range of clearance speeds and with examples of 'clumping' behaviour that is consistent with the in vivo capture and mucus-driven transport of particles.
CONCLUSION: This study demonstrated that the wide beam at the IMBL is suitable for imaging MCT in ex vivo tissue samples. We are now transitioning to in vivo imaging of MCT in live pigs, utilising higher X-ray energies and shorter exposures to minimise motion blur.

PMID: 28511651 [PubMed - in process]

Community Acquired Burkholderia cepacia Bacteraemia Presenting as MODS in an Immunocompetent Individual: An Unusual Case.

J Clin Diagn Res. 2017 Mar;11(3):DD01-DD02

Authors: Ranjan R, Chowdhary P, Kamra A

Abstract
Burkholderia cepacia has been recognized as a group of highly virulent organisms known as Burkholderia cepacia complex (Bcc). Bcc are ubiquitous in nature and most commonly found in moist environment, on plant roots and soil. Because of its high intrinsic antibiotic resistance, Bcc is a major cause of morbidity and mortality in hospitalized patients. It is reported most commonly in immunocompromised patients especially in patients with cystic fibrosis. Here, we report a rare case report of bacteraemia by Burkholderia cepacia in an immunocompetent male, who presented with fever and Multiple Organ Dysfunction Syndrome (MODS). Burkholderia cepacia was isolated from his blood culture, which he acquired from his work place. He was treated successfully and discharged after negative blood culture.

PMID: 28511384 [PubMed - in process]

Alteration of protein function by a silent polymorphism linked to tRNA abundance.

PLoS Biol. 2017 May;15(5):e2000779

Authors: Kirchner S, Cai Z, Rauscher R, Kastelic N, Anding M, Czech A, Kleizen B, Ostedgaard LS, Braakman I, Sheppard DN, Ignatova Z

Abstract
Synonymous single nucleotide polymorphisms (sSNPs) are considered neutral for protein function, as by definition they exchange only codons, not amino acids. We identified an sSNP that modifies the local translation speed of the cystic fibrosis transmembrane conductance regulator (CFTR), leading to detrimental changes to protein stability and function. This sSNP introduces a codon pairing to a low-abundance tRNA that is particularly rare in human bronchial epithelia, but not in other human tissues, suggesting tissue-specific effects of this sSNP. Up-regulation of the tRNA cognate to the mutated codon counteracts the effects of the sSNP and rescues protein conformation and function. Our results highlight the wide-ranging impact of sSNPs, which invert the programmed local speed of mRNA translation and provide direct evidence for the central role of cellular tRNA levels in mediating the actions of sSNPs in a tissue-specific manner.

PMID: 28510592 [PubMed - in process]

Inhaled Antibiotic Therapy in Chronic Respiratory Diseases.

Int J Mol Sci. 2017 May 16;18(5):

Authors: Maselli DJ, Keyt H, Restrepo MI

Abstract
The management of patients with chronic respiratory diseases affected by difficult to treat infections has become a challenge in clinical practice. Conditions such as cystic fibrosis (CF) and non-CF bronchiectasis require extensive treatment strategies to deal with multidrug resistant pathogens that include Pseudomonas aeruginosa, Methicillin-resistant Staphylococcus aureus, Burkholderia species and non-tuberculous Mycobacteria (NTM). These challenges prompted scientists to deliver antimicrobial agents through the pulmonary system by using inhaled, aerosolized or nebulized antibiotics. Subsequent research advances focused on the development of antibiotic agents able to achieve high tissue concentrations capable of reducing the bacterial load of difficult-to-treat organisms in hosts with chronic respiratory conditions. In this review, we focus on the evidence regarding the use of antibiotic therapies administered through the respiratory system via inhalation, nebulization or aerosolization, specifically in patients with chronic respiratory diseases that include CF, non-CF bronchiectasis and NTM. However, further research is required to address the potential benefits, mechanisms of action and applications of inhaled antibiotics for the management of difficult-to-treat infections in patients with chronic respiratory diseases.

PMID: 28509852 [PubMed - in process]

Palivizumab prophylaxis in infants with cystic fibrosis does not delay first isolation of Pseudomonas aeruginosa or Staphylococcus aureus.

Eur J Pediatr. 2017 May 16;:

Authors: Buchs C, Dalphin ML, Sanchez S, Perceval M, Coutier L, Mainguy C, Kassaï-Koupaï B, Reix P

Abstract
Respiratory syncytial virus (RSV) infections may worsen cystic fibrosis (CF) lung disease and favor Pseudomonas aeruginosa (Pa) or Staphylococcus aureus (Sa) acquisition, which is of particular importance in the youngest patients. We aimed to determine the effectiveness of PVZ on microbiological outcomes in young children with CF. We conducted a retrospective case-control study to compare these outcomes in children who systematically received PVZ (PVZ+; n = 40) or not (PVZ-; n = 140). One case was matched with at least three same-gender controls born the same year and month. Median (range) age at first Pa isolation was not statistically different between PVZ- (12.3 [3.8-32.6] months) and PVZ+ (10.4 [1.2-33.0] months; p = 0.953) patients. A similar trend was found for Sa (PVZ+: 6.4 [2.0-59.0] months; PVZ-: 3.8 [0.1-74.1] months; p = 0.191). The proportion of Pa isolations by 3 years of age did not differ between groups (PVZ+ 40% vs. PVZ- 41.4%), but this proportion was higher for Sa in the PVZ+ group (97%) than in the PVZ- group (85%; p = 0.001). Healthcare consumption and growth outcomes did not significantly differ between groups.
CONCLUSION: Systematic PVZ use did not delay key pathogen acquisition in young children with CF. What is known: • Palivizumab is the only available monoclonal antibody against respiratory syncytial virus infection. • Whether or not it is useful in infants with cystic fibrosis remains controversial. What is new: • Palivizumab does not delay key pathogens (Pseudomonas aeruginosa, Staphylococcus aureus) first isolation in young children with cystic fibrosis. • Palivizumab does not reduce healthcare consumption or improve growth during the first 3 years of life of young children with cystic fibrosis.

PMID: 28508992 [PubMed - as supplied by publisher]

The Vitamin D for Enhancing the Immune System in Cystic Fibrosis (DISC) trial: Rationale and design of a multi-center, double-blind, placebo-controlled trial of high dose bolus administration of vitamin D3 during acute pulmonary exacerbation of cystic fibrosis.

Contemp Clin Trials Commun. 2017 Jun;6:39-45

Authors: Tangpricha V, Smith EM, Binongo J, Judd SE, Ziegler TR, Walker S, Tirouvanziam R, Zughaier SM, Lee MJ, Chesdachai S, Hermes WA, Chmiel JF, Gaggar A, Grossmann RE, Joseph PM, Alvarez JA

Abstract
Vitamin D deficiency is highly prevalent in children and adults with cystic fibrosis (CF). Recent studies have found an association between vitamin D status and risk of pulmonary exacerbations in children and adults with CF. The ongoing Vitamin D for enhancing the Immune System in Cystic fibrosis (DISC) study is a multi-center, double-blind, randomized, placebo-controlled trial that will test the hypothesis of whether high dose vitamin D given as a single oral bolus of 250,000 IU to adults with CF during a pulmonary exacerbation followed by a maintenance dose of vitamin D will improve time to next pulmonary exacerbation and re-hospitalization, improve survival and lung function compared to placebo and reduce the rates of pulmonary exacerbation,. Subjects will be randomized 1:1 at each clinical site to vitamin D or placebo within 72 hours of hospital admission for pulmonary exacerbation. Clinical follow-up visits will occur at 1, 2, 3, and 7 days, and 1, 3, 6 and 12 months after randomization. Blood and sputum will be collected and determination of clinical outcomes will be assessed at each visit. The primary endpoint will be the time to next pulmonary exacerbation requiring antibiotics, re-hospitalization or death. The secondary endpoints will include lung function assessed by forced expiratory volume in 1 second (FEV1), blood markers of inflammatory cytokines, anti-microbial peptide expression by peripheral blood mononuclear cells and circulating concentrations in blood. Other exploratory endpoints will examine the phenotype of neutrophils and monocyte/macrophages in sputum. Nutritional status will be assessed by 3 day food records and food frequency questionnaire.

PMID: 28508087 [PubMed - in process]

Investigating the feasibility of text message reminders to improve adherence to nebulized medication in children and adolescents with cystic fibrosis.

Patient Prefer Adherence. 2017;11:861-869

Authors: Morton RW, Elphick HE, Edwards E, Daw WJ, West NS

Abstract
BACKGROUND: Children with cystic fibrosis (CF) often have suboptimal adherence rates to nebulized medication. Adherence barriers cited include forgetting to take the nebulizers, due to busy home and social lives. Text message reminders have been shown to be effective at improving adherence rates in other chronic diseases such as asthma and diabetes.
OBJECTIVE: The objective of this study was to assess the feasibility and efficacy of sending text reminders for a prolonged period of time to children with CF.
MATERIALS AND METHODS: Children with CF aged 5-16 years taking at least one medication via a nebulizer with an electronic adherence monitor were consented for the study. Text message reminders were sent to participants and/or parents via the hospital's automated text service, up to twice a day, for 6 months. The adherence rates for the 6-month text period were compared to the previous 6 months before the study. Rates were calculated for weekdays, weekends, and school holidays.
RESULTS: Seventeen participants were recruited to the study, with a mean age of 12 years and a mean forced expiratory volume in 1 second (FEV1) of 81% predicted. Fifteen children completed the 6-month text period, and I-neb data were accurately analyzed for 13 participants. The mean adherence rate in the 6 months receiving texts was 80%, compared to 81% in the prior 6 months. Overall adherence rates on weekdays, weekends, and school holidays were equivalent during the 2 time periods. A subgroup of patients with moderate baseline adherence showed increased adherence during the text period, particularly at weekends.
CONCLUSION: It is feasible to send text message reminders to children with CF, and they are amenable to this approach. Although text reminders do not increase rates in patients with existing optimal adherence, they may be of value in patients with more moderate baseline rates.

PMID: 28507430 [PubMed - in process]