Metabolomic biomarkers predictive of early structural lung disease in cystic fibrosis

Neutrophilic airway inflammation plays a role in early structural lung disease in cystic fibrosis (CF), but the mechanisms underlying this pathway are incompletely understood

Cystic fibrosis in premature infants

There are few reports of cystic fibrosis (CF) diagnosed in premature infants. We describe the clinical course of three patients, from our neonatal intensive care units, who were diagnosed with CF, and discuss the existing literature and treatment considerations

Production of extended-spectrum β -lactamases and the potential indirect pathogenic role of Prevotella isolates from the cystic fibrosis respiratory microbiota

Extended-spectrum β-lactamase (ESBL) production and the prevalence of the β-lactamase-encoding gene blaTEM were determined in Prevotella isolates (n = 50) cultured from the respiratory tract of adults and young people with cystic fibrosis (CF). Time–kill studies were used to investigate the concept of passive antibiotic resistance and to ascertain whether a β-lactamase-positive Prevotella isolate can protect a recognised CF pathogen from the action of ceftazidime in vitro. The results indicated that approximately three-quarters (38/50; 76%) of Prevotella isolates produced ESBLs. Isolates positive for ESBL production had higher minimum inhibitory concentrations (MICs) of β-lactam antibiotics compared with isolates negative for production of ESBLs (P < 0.001). The blaTEM gene was detected more frequently in CF Prevotella isolates from paediatric patients compared with isolates from adults (P = 0.002), with sequence analysis demonstrating that 21/22 (95%) partial blaTEM genes detected were identical to blaTEM-116. Furthermore, a β-lactamase-positive Prevotella isolate protected Pseudomonas aeruginosa from the antimicrobial effects of ceftazidime (P = 0.03). Prevotella isolated from the CF respiratory microbiota produce ESBLs and may influence the pathogenesis of chronic lung infection via indirect methods, including shielding recognised pathogens from the action of ceftazidime

Revisiting Host-Pathogen Interactions in Cystic Fibrosis Lungs in the Era of CFTR Modulators

Cystic fibrosis transmembrane conductance regulator (CFTR) modulators, a new series of therapeutics that correct and potentiate some classes of mutations of the CFTR, have provided a great therapeutic advantage to people with cystic fibrosis (pwCF). The main hindrances of the present CFTR modulators are related to their limitations in reducing chronic lung bacterial infection and inflammation, the main causes of pulmonary tissue damage and progressive respiratory insufficiency, particularly in adults with CF. Here, the most debated issues of the pulmonary bacterial infection and inflammatory processes in pwCF are revisited. Special attention is given to the mechanisms favoring the bacterial infection of pwCF, the progressive adaptation of Pseudomonas aeruginosa and its interplay with Staphylococcus aureus, the cross-talk among bacteria, the bronchial epithelial cells and the phagocytes of the host immune defenses. The most recent findings of the effect of CFTR modulators on bacterial infection and the inflammatory process are also presented to provide critical hints towards the identification of relevant therapeutic targets to overcome the respiratory pathology of pwCF

Microbiological efficacy of early MRSA treatment in cystic fibrosis in a randomised controlled trial

OBJECTIVE: To evaluate microbiological effectiveness, that is, culture negativity of a non-blinded eradication protocol (Rx) compared with observation (Obs) in clinically stable cystic fibrosis participants with newly positive methicillin resistant Staphylococcusaureus (MRSA) cultures. DESIGN: This non-blinded trial randomised participants ages 4-45 years with first or early (≤2 positive cultures within 3 years) MRSA-positive culture without MRSA-active antibiotics within 4 weeks 1:1 to Rx or Obs. The Rx protocol was: oral trimethoprim-sulfamethoxazole or if sulfa-allergic, minocycline plus oral rifampin; chlorhexidine mouthwash for 2 weeks; nasal mupirocin and chlorhexidine body wipes for 5 days and environmental decontamination for 21 days. The primary end point was MRSA culture status at day 28. RESULTS: Between 1 April 2011 to September 2014, 45 participants (44% female, mean age 11.5 years) were randomised (24 Rx, 21 Obs). At day 28, 82% (n=18/22) of participants in the Rx arm compared with 26% (n=5/19) in the Obs arm were MRSA-negative. Adjusted for interim monitoring, this difference was 52% (95% CI 23% to 80%, p<0.001). Limiting analyses to participants who were MRSA-positive at the screening visit, 67% (8/12) in the Rx arm and 13% (2/15) in the Obs arm were MRSA-negative at day 28, adjusted difference: 49% (95% CI 22% to 71%, p<0.001). Fifty-four per cent in the Rx arm compared with 10% participants in the Obs arm remained MRSA-negative through day 84. Mild gastrointestinal side effects were higher in the Rx arm. CONCLUSIONS: This MRSA eradication protocol for newly acquired MRSA demonstrated microbiological efficacy with a large treatment effect. TRIAL REGISTRATION NUMBER: NCT01349192

Upper and lower airway cultures in children with cystic fibrosis: Do not neglect the upper airways

AbstractBackgroundAirways of cystic fibrosis (CF) patients are colonised with bacteria early in life. We aimed to analyse differences between results of simultaneously taken upper airway (UAW) and lower airway (LAW) cultures, to describe clinical characteristics of patients with positive versus negative cultures and to follow up the patients with P. aeruginosa positive UAW cultures.MethodsBacteriological and clinical data from 157 children were collected during annual check up. The number of positive UAW and LAW cultures and correspondence between these results and clinical characteristics were analysed.ResultsPositive LAW and UAW cultures were found in 79.6% and 43.9% of patients respectively (p<0.001). Patients with positive LAW cultures were significantly older (11.9 vs. 9.8years, p<0.05) and had more LAW symptoms (73.6% vs. 46.7%, p<0.05), especially when P. aeruginosa was found. Patients with positive UAW cultures (especially S. aureus) had more nasal discharge (50.7% vs. 25.0%, p<0.001). In 65% of patients with positive UAW and negative LAW culture for P. aeruginosa the next LAW became P. aeruginosa positive.ConclusionUAW cultures and LAW cultures differ in children with CF and there are differences in clinical characteristics between patients with positive versus negative culture results. P. aeruginosa positive UAW cultures appeared to precede positive LAW cultures in a substantial part of patients, suggesting some kind of cross-infection between the UAW and LAW

A highly immunogenic and effective measles virus-based Th1-biased COVID-19 vaccine

The COVID-19 pandemic is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and has spread worldwide, with millions of cases and more than 1 million deaths to date. The gravity of the situation mandates accelerated efforts to identify safe and effective vaccines. Here, we generated measles virus (MeV)-based vaccine candidates expressing the SARS-CoV-2 spike glycoprotein (S). Insertion of the full-length S protein gene in two different MeV genomic positions resulted in modulated S protein expression. The variant with lower S protein expression levels was genetically stable and induced high levels of effective Th1- biased antibody and T cell responses in mice after two immunizations. In addition to neutralizing IgG antibody responses in a protective range, multifunctional CD8+and CD4+T cell responses with S protein-specific killing activity were detected. Upon challenge using a mouse-adapted SARS-CoV-2, virus loads in vaccinated mice were significantly lower, while vaccinated Syrian hamsters revealed protection in a harsh challenge setup using an early-passage human patient isolate. These results are highly encouraging and support further development of MeV-based COVID-19 vaccines

Wheeze in Preschool Age Is Associated with Pulmonary Bacterial Infection and Resolves after Antibiotic Therapy

BACKGROUND: Neonates with airways colonized by Haemophilus influenzae, Streptococcus pneumoniae or Moraxella catarrhalis are at increased risk for recurrent wheeze which may resemble asthma early in life. It is not clear whether chronic colonization by these pathogens is causative for severe persistent wheeze in some preschool children and whether these children might benefit from antibiotic treatment. We assessed the relevance of bacterial colonization and chronic airway infection in preschool children with severe persistent wheezing and evaluated the outcome of long-time antibiotic treatment on the clinical course in such children. METHODOLOGY/PRINCIPAL FINDINGS: Preschool children (n = 42) with severe persistent wheeze but no symptoms of acute pulmonary infection were investigated by bronchoscopy and bronchoalveolar lavage (BAL). Differential cell counts and microbiological and virological analyses were performed on BAL samples. Patients diagnosed with bacterial infection were treated with antibiotics for 2-16 weeks (n = 29). A modified ISAAC questionnaire was used for follow-up assessment of children at least 6 months after bronchoscopy. Of the 42 children with severe wheezing, 34 (81%) showed a neutrophilic inflammation and 20 (59%) of this subgroup had elevated bacterial counts (≥ 10⁴ colony forming units per milliliter) suggesting infection. Haemophilus influenzae, Streptococcus pneumoniae and Moraxella catarrhalis were the most frequently isolated species. After treatment with appropriate antibiotics 92% of patients showed a marked improvement of symptoms upon follow-up examination. CONCLUSIONS/SIGNIFICANCE: Chronic bacterial infections are relevant in a subgroup of preschool children with persistent wheezing and such children benefit significantly from antibiotic therapy

Parenteral provision of micronutrients to pediatric patients: an international expert consensus paper

© 2020 The Authors. Published by Wiley. This is an open access article available under a Creative Commons licence. The published version can be accessed at the following link on the publisher’s website: https://doi.org/10.1002/jpen.1990INTRODUCTION:Micronutrients (vitamins and trace elements) are essential to all nutrition. For children and neonates who are dependent upon nutrition support therapies for growth and development, the prescribed regimen must supply all essential components. This paper aims to facilitate interpretation of existing clinical guidelines into practical approaches for the provision of micronutrients in pediatric parenteral nutrition. METHODS:An international, interdisciplinary expert panel was convened to review recent evidence-based guidelines and published literature to develop consensus- based recommendation on practical micronutrient provision in pediatric parenteral nutrition. RESULTS:The guidelines and evidence have been interpreted as answers to 10 commonly asked questions around the practical principles for provision and monitoring of micronutrients in pediatric patients CONCLUSION: Micronutrients are an essential part of all parenteral nutrition and should be included in the pediatric nutrition therapy care plan.Published versio