Daily Respiratory Research Analysis

Respiratory syncytial virus (RSV) is a significant cause of morbidity and mortality in high-risk populations. Although prophylactic options are available, there are no effective oral therapeutics for RSV infection. Obeldesivir (ODV) is an orally bioavailable prodrug of the nucleoside analog GS-441524, which is converted intracellularly to its active nucleoside triphosphate and inhibits the RSV RNA polymerase. Here we report the potent antiviral activity of ODV against geographically and temporally diverse RSV A and B clinical isolates (EC

BACKGROUND: Multimorbidity (ie, co-existence of two or more health conditions) is highly prevalent in patients with difficult-to-treat asthma. However, it remains unclear how multimorbidity correlates with disease severity and adverse health outcomes in these patients and which comorbidities are most important. We aimed to address this knowledge gap by developing a patient-centred, clinically descriptive multimorbidity score for difficult-to-treat asthma. METHODS: We used data from the UK-based Wessex Asthma Cohort of Difficult Asthma (WATCH; n=500, data collected between April 22, 2015, and April 1, 2020) to develop the Multimorbidity in Difficult Asthma Score (MiDAS). Initially, we created a modified Asthma Severity Scoring System (m-ASSESS) in WATCH. We then conducted univariate association analysis to test the association between the 13 commonest comorbidities and m-ASSESS in WATCH and used a branch-and-bound approach to select the most relevant comorbidities for inclusion in MiDAS. We calculated MiDAS values for all patients with complete information in WATCH (n=319) and assessed them for correlation with components of m-ASSESS, proinflammatory biomarkers, and St George's Respiratory Questionnaire (SGRQ) score, a quality-of-life measure. We also assessed the association of MiDAS with multiple clinical outcomes in four international cohorts: two from Australia (n=236, data collected between June 14, 2014, and April 1, 2022; and n=140, Aug 6, 2012, to Oct 18, 2016), one from southeast Asia (n=151, March 21, 2017, to Jan 16, 2024), and one from the USA (n=100, July 9, 2021, to Dec 14, 2023). FINDINGS: We selected seven common comorbidities (ie, rhinitis, gastro-oesophageal reflux disease, breathing pattern disorder, obesity, bronchiectasis, non-steroidal anti-inflammatory drug-exacerbated respiratory disease, and obstructive sleep apnoea) for inclusion in MiDAS on the basis of the branch-and-bound analysis and combined them using multivariate linear regression to derive a MiDAS model associated with m-ASSESS in WATCH. The range of MiDAS scores was 9·6-16·2. In WATCH members, mean MiDAS value was 11·97 (SD 1·21) and MiDAS was nominally correlated with m-ASSESS components of poor asthma control (τ=0·31 [95% CI 0·24-0·38]) and exacerbations (τ=0·16 [0·08-0·24]). MiDAS was also correlated with worse total SGRQ score (r=0·39 [95% 0·28-0·49], p<0·0001) and with the proinflammatory plasma cytokines interleukin (IL)-4 (r=0·19 [95% CI 0·06-0·31], p=0·0036), IL-5 (r=0·35 [0·24-0·46], p<0·0001), and leptin (r=0·29 [0·17-0·40], p<0·0001) in WATCH. MiDAS values across the four international cohorts were similar to those of WATCH (UK cohort), with mean values of 12·33 (SD 1·47) and 12·31 (1·37) in the Australian cohorts, 11·80 (1·20) in the USA cohort, and 11·55 (1·23) in the Singapore cohort. In these cohorts, MiDAS correlated with worse asthma control, worse quality of life, anxiety, depression, and increased inflammation. INTERPRETATION: MiDAS highlights the co-occurrence of multimorbidity with the worst outcomes in difficult-to-treat asthma. These findings strongly indicate that an airway-centric approach is inadequate and that holistic and multidisciplinary care is imperative. This clinical score could help clinicians to identify patients most at risk from their multimorbidity. FUNDING: UK National Institute for Health and Care Research, Australian National Health and Medical Research Council, Hunter Medical Research Institute, University of Newcastle (Australia), and John Hunter Hospital Charitable Trust.

BACKGROUND: Cystic fibrosis is caused by mutations of the cystic fibrosis transmembrane conductance regulator, CFTR, an epithelial anion transport protein, responsible for, inter alia, sputum viscoelasticity in the lung. We previously identified the TNF receptor superfamily 1A TNFRSF1A (TNFR1) as a genetic modifier of CFTR function and disease severity in the CF twin and sibling study population. We aimed to replicate our findings in independent cohorts, assess the role of TNFR1 for patient survival and identify functional changes associated with TNFR1 polymorphisms. METHODS: We incorporated data from three independent long-term mono- and multicentric cohorts of people with cystic fibrosis (pwCF) to confirm the previously described association of TNFR1 with CFTR function and to extend our study to include survival data for our local cohort and a pan-European cohort of pwCF. We studied TNFR1 transcripts obtained from primary airway epithelia grown as air-liquid interface cultures to address possible mechanisms involved in up-stream and down-stream effects of TNFR1. FINDINGS: Survival differed by more than a decade when comparing carriers of contrasting TNFR1 genotypes among unrelated pwCF as well as among CF siblings pairs. The presence of the TNFR1 transcript variant TNFR1delEx2 in primary airway epithelia was associated with TNFR1 genotype. INTERPRETATION: The association of the TNFR1 transcript variant TNFR1delEx2 associates with the TNFR1 genotype, possibly mediating the genotype-survival association we found regarding TNFR1 genotype and patient survival in cystic fibrosis. FUNDING: Supported by the German Ministry for Education and Research (BMBF) (82DZL009B1 to MAM and 82DZL002A1, to GH, BT, AMD, FS) and the Mukoviszidose Institut gGmbH (MI-2002, to LN, AMD, FS).