Daily Respiratory Research Analysis

BACKGROUND: Pleural infection is associated with marked local and systemic inflammation leading to significant morbidity. It may be possible to therapeutically augment this response and interleukin-6 is a key signalling cascade in inflammatory pathologies. METHODS: We performed a prospective observational study recruiting patients with pleural effusions secondary to infection and measured interleukin-6 in matched pleural fluid and serum (n = 76). We subsequently performed a large-scale, two sample Mendelian Randomisation study (1601 cases and 830,709 controls), using genetic variation at IL6R to proxy the effect of interleukin-6 inhibition on pleural infection and overcome confounding inherent in observational analyses. FINDINGS: Pleural interleukin-6 levels in infection were 5000-fold higher than matched serum levels (median 72,752 pg/ml vs. 15 pg/ml). Pleural interleukin-6 predicted systemic inflammation (neutrophil count, C- reactive protein), correlated with clinical markers of disease severity (effusion size, pH, glucose), and was strongly associated with length of hospital stay. In Mendelian randomisation analyses, interleukin-6 inhibition was predicted to have a large protective effect on the incidence of infection (OR 0.23; 95% CI 0.14-0.39 per standard deviation decrease in C- reactive protein). The effect size was larger than that seen in COVID-19 and coronary artery disease, where interleukin-6 inhibition has been successful in trials. INTERPRETATION: Multiple lines of evidence suggest pleural interleukin-6 drives pathology in pleural infection. Targeting interleukin-6 may hold promise and should be considered in randomised trials.

BACKGROUND: Respiratory syncytial virus (RSV) is a major cause of acute lower respiratory infections globally in children under five years. With the development of RSV prevention strategies, understanding risk factors and relation to age and population is useful for deciding the type of program implemented. METHODS: We used a probabilistically-linked population cohort of children born in Western Australia from 2010 to 2020 and hospitalised before age five years from 2010 to 2021. The primary outcome was the first laboratory-confirmed RSV-hospitalisation. Risk factor exposures included perinatal, socio-demographic, household, environmental, congenital, and comorbid conditions antecedent to RSV-hospitalisation. Adjusted hazard ratios (aHR) and population attributable fractions (PAF) were calculated using survival analysis techniques and Cox regression. FINDINGS: Risk factors for RSV-hospitalisation in 365,582 children included demographic (male sex, Aboriginal ethnicity), perinatal (younger maternal age, maternal asthma, prematurity, maternal prenatal smoking) household/environmental (household size, season of birth), and comorbid and congenital conditions (cardiovascular defects, Trisomy 21 and cerebral palsy). Aboriginal and preterm children had an excess risk of hospitalisation at every age group. Larger households and being born moderate-late preterm had the highest PAFs (36.90% [95% CI: 35.01%, 38.74%] and 7.40% [95% CI: 6.75%, 8.04%]). While the risk of hospitalisation for children with some comorbid and congenital conditions was high (immunological conditions, aHR: 3.94 [95% CI: 2.98, 5.23], respiratory system defects, aHR: 3.13 [95% CI: 1.87, 5.25]), the PAFs were relatively small (1.70% [95% CI: 1.53%, 1.86%] and 0.40% [95% CI: 0.30%, 0.49%]). INTERPRETATION: While children with comorbid conditions were at higher risk of RSV-hospitalisation, the importance of socio-demographic risk factors, particularly modifiable factors such as maternal prenatal smoking and household transmission, should not be undervalued. Our analysis provides information for funders, vaccine policy makers, parents/carers, and immunisation providers.

BACKGROUND: In last decades, biologic therapies have been approved for severe allergic and/or eosinophilic asthma. Limited studies have investigated the effect of biologics on (acute) cardiovascular events, which have reported conflicting results. We aimed to investigate the potential cardiovascular risk of anti-immunoglobulin(Ig)-E (omalizumab) and anti-interleukin(IL)-5/IL5 receptor (IL5R) therapies (mepolizumab and benralizumab) in patients with severe asthma compared with non-biologic users. METHODS: Adult asthma patients eligible for biologics were identified in Belgian nationwide data between 2017 and 2022. Inverse probability of treatment weighted Cox regression was used to investigate cardiovascular outcomes and all-cause mortality, while controlling for age, sex, obesity, smoking, comorbidities, comedication, exacerbations, and frailty. FINDINGS: This cohort study consisted of 171,865 patients (mean age 64 years; 55% females) including 1826 (1.1%) anti-IgE users and 2398 (1.4%) anti-IL5/IL5R users. Anti-IgE exposure was associated with a significantly lower risk of mortality (aHR 0.48, 95% CI 0.40-0.58), congestive heart failure (aHR 0.79, 95% CI 0.65-0.95), peripheral artery disease (aHR 0.66, 95% CI 0.51-0.86), and stroke (aHR 0.54, 95% CI 0.36-0.81). Anti-IL5/IL5R use was associated with a significantly lower risk of mortality (aHR 0.35, 95% CI 0.29-0.42), congestive heart failure (aHR 0.63, 95% CI 0.52-0.76), arrythmia (aHR 0.78, 95% CI 0.68-0.90), and peripheral artery disease (aHR 0.69, 95% CI 0.54-0.87) compared with non-biologic users. No significant differences in the risk of myocardial infarction and pulmonary embolism were observed. INTERPRETATION: In this nationwide observational study, biologic therapies for patients with severe asthma were associated with a significantly lower risk of all-cause mortality and specific cardiovascular diseases compared with non-biologic users. FUNDING: None.