Disease Severity in Respiratory Syncytial Virus Infection: Role of Viral and Host Factors

Respiratory syncytial virus (RSV) is not only a major cause of severe lower respiratory tract infection (LRTI) in infancy but is increasingly recognised as an important pathogen in later life. RSV infection is associated with a wide spectrum of disease ranging from asymptomatic infection to life-threatening bronchiolitis and pneumonia. Research has demonstrated that there exists a complex interplay between viral and host factors that determines the severity of disease following RSV infection. Several factors determine RSV virulence including the infective properties of individual strains and viral load (VL). Disease outcome from RSV infection is also impacted considerably by a variety of host factors with the host immune response increasingly recognised as pivotal. This chapter outlines our current understanding of these factors and provides an oversight of their relative importance

A public health emergency among young people.

While some countries have banned the use of e-cigarettes or vaping products altogether (eg, India), and others have strongly advised against their use (eg, Australia), in the UK, Public Health England (PHE) appears to be a lone voice in stating that vaping is 95% safer than smoking tobacco. Here we consider whether vaping can be considered safe; whether vaping is a means of smoking cessation or at least harm reduction; and the correct response to the spiralling epidemic of vaping in young people (<18 years)

Efficacy and Safety of Elexacaftor/Tezacaftor/Ivacaftor in Children 6 Through 11 Years of Age with Cystic Fibrosis Heterozygous for F508del and a Minimal Function Mutation: A Phase 3b, Randomized, Placebo-controlled Study

Rationale: The triple-combination regimen elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was shown to be safe and efficacious in children aged 6 through 11 years with cystic fibrosis and at least one F508del-CFTR allele in a phase 3, open-label, single-arm study. Objectives: To further evaluate the efficacy and safety of ELX/TEZ/IVA in children 6 through 11 years of age with cystic fibrosis heterozygous for F508del and a minimal function CFTR mutation (F/MF genotypes) in a randomized, double-blind, placebo-controlled phase 3b trial. Methods: Children were randomized to receive either ELX/TEZ/IVA (n = 60) or placebo (n = 61) during a 24-week treatment period. The dose of ELX/TEZ/IVA administered was based on weight at screening, with children <30 kg receiving ELX 100 mg once daily, TEZ 50 mg once daily, and IVA 75 mg every 12 hours, and children ⩾30 kg receiving ELX 200 mg once daily, TEZ 100 mg once daily, and IVA 150 mg every 12 hours (adult dose). Measurements and Main Results: The primary endpoint was absolute change in lung clearance index2.5 from baseline through Week 24. Children given ELX/TEZ/IVA had a mean decrease in lung clearance index2.5 of 2.29 units (95% confidence interval [CI], 1.97-2.60) compared with 0.02 units (95% CI, -0.29 to 0.34) in children given placebo (between-group treatment difference, -2.26 units; 95% CI, -2.71 to -1.81; P < 0.0001). ELX/TEZ/IVA treatment also led to improvements in the secondary endpoint of sweat chloride concentration (between-group treatment difference, -51.2 mmol/L; 95% CI, -55.3 to -47.1) and in the other endpoints of percent predicted FEV1 (between-group treatment difference, 11.0 percentage points; 95% CI, 6.9-15.1) and Cystic Fibrosis Questionnaire-Revised Respiratory domain score (between-group treatment difference, 5.5 points; 95% CI, 1.0-10.0) compared with placebo from baseline through Week 24. The most common adverse events in children receiving ELX/TEZ/IVA were headache and cough (30.0% and 23.3%, respectively); most adverse events were mild or moderate in severity. Conclusions: In this first randomized, controlled study of a cystic fibrosis transmembrane conductance regulator modulator conducted in children 6 through 11 years of age with F/MF genotypes, ELX/TEZ/IVA treatment led to significant improvements in lung function, as well as robust improvements in respiratory symptoms and cystic fibrosis transmembrane conductance regulator function. ELX/TEZ/IVA was generally safe and well tolerated in this pediatric population with no new safety findings. Keywords: children; cystic fibrosis; elexacaftor; ivacaftor; tezacaftor

Enter Mercury, Sleeping: Delivering Prayers on the Early Modern Stage

This is the author accepted manuscript. The final version is available from CUP via the DOI in this recor

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure &lt; 100 mmHg (n = 1127), estimated glomerular filtration rate &lt; 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation

Respiratory infections and the immune response to respiratory syncytial virus in the first year of life

Respiratory syncytial virus (RSV) bronchiolitis is a major cause of childhood morbidity and mortality.  Most infants are infected with respiratory syncytial virus in the first year of life, but a minority develop bronchiolitis for reasons unknown.  The primary aim of this thesis was to determine the importance of type 1 and type 2 immunity in determining the outcome of RSV infection during infancy.  Previous studies have established that antigen-specific priming of foetal T-cells can occur in utero from 22 weeks gestation.  An additional aim of this thesis was to study the potential occurrence of prenatal sensitisation to RSV and it’s immunological consequences.  This thesis also sought to establish the relative incidence of respiratory pathogen infection during infancy. It is concluded that: (a) immune priming to RSV can occur antenatally if the mother is exposed at the appropriate stage of gestation and that this exposure is associated with a type 1 response, and (b) RSV bronchiolitis is associated with a marked imbalance in type 1/type 2 cytokines in favour of a type 2 response.  These data combined suggest that priming of foetal T cells to RSV may result in a reduced severity of subsequent RSV disease by augmenting the infant’s own type 1 specific cellular immune response to RSV. This may explain much of the clinical diversity of RSV disease and raises the possibility that RSV infection/immunisation of mothers after 22 weeks gestation might represent a new strategy for prevention of RSV bronchiolitis.</p

Primary tracheomalacia and persistent wheezing in cystic fibrosis during infancy

Persistent wheezing, poorly responsive to bronchodilator therapy, raises concerns about the progression of cystic fibrosis-related lung disease. We describe 3 infants with such symptoms who were observed to have primary tracheomalacia. The diagnoses were made using flexible bronchoscopy during spontaneous respiration. Early recognition of this etiology can limit unnecessary investigation and the overuse of empirical treatments such as oral and inhaled corticosteroids.</p

The validity and acceptability of a text-based monitoring system for pediatric asthma studies

A meaningful analysis in research requires robust, valid data. Paper diaries allow the collection of data from individuals over time but are notorious for poor compliance and validity. SMS-technology is a novel method for data collection in medical research. Time-tagged SMS are transferred directly to an electronic file. We used SMS to collect symptoms and peak flow rate (PEFR) meter readings from 32 children with asthma. Parents responded first to five SMS daily for 7 days during an asymptomatic period and then for 14 days during a cold. Compliance with use of PEFR meter and SMS system were assessed. Digital PEFR meters enabled data download at the end of the study to confirm validity of transmitted data. Parents of 24 participants provided feedback about this data collection tool. Mean (±SD) "SMS-diary and PEFR-meter compliance" were 96% (±8) and 84% (±21) during baseline and 91% (±12) and 82% (±20) during cold respectively. Correctly reported PEFR values were found in 65.5% of all cases, in 8.3% PEFR values sent were "self-invented" and 2.4% of values were missing. All of the 22 parents completing the baseline questionnaire were happy to use SMS for this study. Of the 20 parents completing the follow up questionnaire, 95% (19/20) found the system user-friendly, 55% (11/20) would be more likely to participate in studies if they were using SMS data collection and 25% (5/20) were "sometimes unhappy" about receiving messages. This real-time capture of data is well accepted and could avoid some of the pitfalls of backfilled paper diaries

Frequency of detection of picornaviruses and seven other respiratory pathogens in infants

Background: Dual respiratory viral infections are frequently associated with lower respiratory tract illness in infants. This study aimed to determine the impact of a dual respiratory viral infection on specific aspects of the infant's immune response and the clinical course of illness.Methods: A prospective study was performed with 772 infants hospitalized from October 2000 through July 2004. Sensitive polymerase chain reaction methodology revealed the presence of a single respiratory virus in 443 (57%) of 772 cases, whereas dual infections were identified in 153 (20%) of cases. From 250 infants with confirmed respiratory viral infection, fresh heparinized blood was analyzed for interferon-[gamma] (IFN-[gamma]) responses by flow cytometry. Of these, 191 patients had a single infection with respiratory syncytial virus (RSV), rhinoviruses, adenoviruses or influenza viruses; and 59 patients had a dual infection with RSV and rhinoviruses, RSV and adenoviruses, influenza viruses and rhinoviruses or adenoviruses and rhinoviruses. The clinical features and peripheral lymphocyte IFN-[gamma] responses were compared among infants with single or dual infections.Results: It was found that dual infections with non-RSV respiratory viruses induced peripheral blood mononuclear cell IFN-[gamma] responses that mimic those of single infections, whereas coinfection with RSV was associated with reduced IFN-[gamma] responses and a more severe clinical course of lower respiratory tract disease.Conclusions: The results indicate that the clinical characteristics and the IFN-[gamma] response differ significantly in single and dual respiratory viral infection, depending on the nature of the simultaneously detected viruses. In dual infections, RSV involvement was associated with a decreased IFN-[gamma] response in peripheral blood mononuclear cell and an increase in severity of illness.<br/