Daily Respiratory Research Analysis
Analyzed 58 papers and selected 3 impactful papers.
Summary
Analyzed 58 papers and selected 3 impactful articles.
Selected Articles
1. Polygenic risk and rare variants in endotypes of idiopathic pulmonary fibrosis: a genetic analysis of population-based and case-control cohorts.
Across discovery and validation cohorts (n≈408,000), both a telomere length PRS and an IPF PRS excluding MUC5B independently associated with IPF risk (OR ~1.6 in discovery), with the telomere PRS exerting the strongest effect among patients without rare variants and with short telomeres. Integrating rare variants, MUC5B, PRSs, and clinical variables yielded high discrimination (AUC up to 0.89), indicating cooperative and context-specific genetic architecture in IPF.
Impact: This study reframes IPF risk around integrated polygenic and rare-variant contributions, highlighting telomere-associated polygenic risk as a major driver and enabling precision endotyping with strong predictive performance.
Clinical Implications: Genetic endotyping using telomere length PRS, IPF PRS, MUC5B, and rare-variant screening could inform risk stratification, surveillance, and trial enrichment in IPF, particularly for telomere-driven endotypes.
Key Findings
- Telomere length PRS and IPF-PRS-noMUC5B independently associated with IPF (discovery ORs 1.63 and 1.60).
- Greatest telomere PRS effect in patients without rare variants and with telomere length <10th percentile (OR ~2.0).
- Combining genetic variables and clinical data achieved AUC up to 0.89; telomere PRS explained 8–13% of genetic liability.
Methodological Strengths
- Whole-genome sequencing across discovery and two large replication cohorts
- Independent validation and cross-validated AUC with endotype-specific analyses
Limitations
- Case-control design limits causal inference and is susceptible to selection bias
- Leukocyte telomere length may not fully reflect lung tissue biology; ancestry-specific generalizability needs assessment
Future Directions: Prospective validation of genetic endotyping in clinical workflows, integration with longitudinal biomarkers, and trials targeting telomere maintenance pathways in defined IPF endotypes.
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) and telomere length are both strongly linked to rare and common genetic variants. Shortened telomere length might itself be causal for IPF. We aimed to evaluate whether rare and common variants compete or cooperate to confer genetic risk of IPF uniformly. METHODS: In this genetic analysis, we used whole-genome sequencing (WGS) data from a discovery case-control cohort sequenced at Columbia University and validated findings using WGS data from Trans-Omics for Precision Medicine (TOPMed) and UK Biobank. In all cohorts, we identified rare damaging variants in disease-associated genes and computed control-normalised non-overlapping polygenic risk scores (PRS) for IPF and telomere length. We assessed the MUC5B rs35705950 single-nucleotide polymorphism (SNP), an IPF common risk variant with a large effect, independently from the polygenic scores. Telomere length in blood leukocytes was measured using a quantitative PCR assay for the discovery cohort and UK Biobank validation cohort. We conducted logistic regression (adjusting for age, sex, and principal components of ancestry) to evaluate the association between IPF risk and the MUC5B SNP, the IPF PRS excluding MUC5B (IPF-PRS-noMUC5B), and the PRS for telomere length in the overall cohort and analysed their effects in patient subgroups for IPF endotypes (carriers and non-carriers of rare variants stratified by telomere length cutoffs). To assess disease prediction, we calculated cross-validated area under the receiver operating receiver operating curve (AUC). We also compared the liability of IPF explained by genetic variables. FINDINGS: The discovery cohort was recruited between April 23, 2003 and June 19, 2019 and included 777 patients with IPF and 2905 controls. We replicated the analyses in the TOPMed (1148 patients with IPF and 5202 controls) and UK Biobank (2739 patients with IPF and 395 331 controls) cohorts. 23-43% of patients with IPF had damaging rare variants or telomeres shorter than the tenth percentile. Analysis of the association of genetic variables with IPF diagnosis yielded odds ratios of 1·63 (95% CI 1·47-1·81) for telomere length PRS and 1·60 (1·44-1·77) for IPF-PRS-noMUC5B in the discovery cohort, with similar effect sizes for the two variables in the replication cohorts (1·47, 1·36-1·59 vs 1·37, 1·25-1·50 in TOPMed; 1·24, 1·19-1·29 vs 1·25, 1·21-1·30 in UK Biobank). The telomere length PRS had the greatest effect on disease risk in patients with IPF not harbouring rare variants and with telomere length shorter than the tenth percentile in the discovery cohort (2·02, 1·76-2·33) and UK Biobank replication cohort (1·70, 1·56-1·85). Accounting for clinical variables and all genetic variables (rare variants, MUC5B SNP, IPF PRS, and telomere length PRS) led to the best disease prediction in the discovery cohort (combined AUC 0·89), TOPMed cohort (0·89), and UK Biobank cohort (0·77). Rare and common variants contributed jointly to the genetic liability of IPF. The telomere length PRS accounted for 13% of the explained genetic liability of IPF in the discovery cohort and 8% and 13% in the TOPMed and UK Biobank cohorts, respectively. INTERPRETATION: Common and rare genetic variation confer context-specific genetic risk in patients with IPF both competitively and cooperatively. In contrast to known IPF common risk variants, the telomere length PRS, which includes more than 180 genetic loci not previously associated with IPF, is associated with increased risk of disease in patients with specific IPF endotypes. Polygenic risk from telomere-associated common variants is a key feature of genetic heterogeneity in IPF. FUNDING: US National Institutes of Health, UK Medical Research Council, and UK National Institute for Health and Care Research.
2. Paracetamol versus ibuprofen as required for fever or pain in the first year of life and the risk of eczema and bronchiolitis at age 1 year in New Zealand (PIPPA Tamariki): a multicentre, open-label, parallel-group, superiority, randomised controlled trial.
In 3908 infants randomized to paracetamol or ibuprofen as needed during the first year, the risks of eczema (16.2% vs 15.4%) and bronchiolitis hospitalisation (4.9% vs 4.3%) did not differ significantly, and no serious adverse events were attributed to study medication. Findings counter prior observational concerns about paracetamol and support either agent for symptomatic relief.
Impact: A large, pragmatic RCT provides high-level evidence that early-life use of paracetamol versus ibuprofen does not alter 1-year eczema or bronchiolitis risk, informing pediatric analgesic choices.
Clinical Implications: Either paracetamol or ibuprofen can be selected for infant fever/pain based on efficacy, safety, availability, and parental preference without concern for 1-year eczema or bronchiolitis risk differences.
Key Findings
- No significant difference in eczema at 1 year between paracetamol (16.2%) and ibuprofen (15.4%) groups.
- No significant difference in bronchiolitis hospitalisation (4.9% vs 4.3%).
- Serious adverse events were rare and none were attributed to study medication.
Methodological Strengths
- Multicentre randomized, parallel-group design with intention-to-treat analysis
- Robust stratified randomization and prespecified outcomes
Limitations
- Open-label design may introduce performance/reporting bias
- Follow-up limited to 1 year; longer-term wheeze/asthma outcomes not assessed
Future Directions: Extend follow-up for wheeze/asthma trajectories, evaluate subgroups (e.g., atopy risk), and assess dose-response and co-medication effects.
BACKGROUND: In non-experimental studies, early-life exposure to paracetamol is associated with an increased risk of eczema and wheeze. We aimed to compare paracetamol with ibuprofen, as required for fever or pain in the first year of life, for the risk of eczema and bronchiolitis at age 1 year. METHODS: PIPPA Tamariki is a multicentre, open-label, two-arm, parallel-group, superiority, randomised controlled trial done at three sites in Auckland and Wellington in New Zealand. Infants younger than 8 weeks and born in New Zealand were randomly assigned (1:1) to paracetamol alone (15 mg/kg every 6 h at age <1 months and every 4 h at age ≥1 months) or ibuprofen alone (5 mg/kg every 6 h at age <3 months and 10 mg/kg every 6 h at age ≥3 months), received orally as required for fever or pain, until age 1 year. Dosing was based on the New Zealand Formulary for Children. Research staff used REDCap for randomisation, which was stratified by recruitment site, maternal asthma status, and multiple birth. Key outcomes were eczema as defined by the UK Diagnostic Criteria or eczema hospitalisation in the first year of life, and hospitalisation for bronchiolitis as defined by at least one hospitalisation for bronchiolitis, viral-induced wheeze, or asthma in the first year of life. Analysis was according to the intention-to-treat principle. This trial is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12618000303246 (active, not recruiting). FINDINGS: Between April 18, 2018, and July 28, 2023, 3923 infants were enrolled. 15 participants withdrew, leaving 3908 infants (1985 were randomly assigned to the paracetamol group, and 1923 to the ibuprofen group) in the intention-to-treat population. Of these participants, 1914 (49·0%) were female and 1994 (51·0%) were male; 609 (15·6%) were Māori, 607 (15·5%) were Pacific, 926 (23·7%) were Asian, and 1754 (44·9%) were New Zealand European or other. Eczema occurred in 322 (16·2%) of 1985 participants in the paracetamol group and 296 (15·4%) of 1923 participants in the ibuprofen group (absolute risk difference 0·8% [95% CI -1·5 to 3·1]; p=0·48; adjusted odds ratio [OR] 1·10 [95% CI 0·92 to 1·32]; p=0·29). Bronchiolitis occurred in 98 (4·9%) participants in the paracetamol group and 82 (4·3%) participants in the ibuprofen group (absolute risk difference 0·7% [95% CI -0·6 to 2·0]; p=0·32; adjusted OR 1·23 [95% CI 0·82 to 1·71]; p=0·21). 19 serious adverse events were reported in 17 participants (eight [0·4%] of 1985 in the paracetamol group and nine [0·5%] of 1923 in the ibuprofen group; adjusted OR 0·47 [95% CI 0·14-1·56; p=0·21]); none were attributed to trial medication. INTERPRETATION: There was no evidence of an important difference between paracetamol and ibuprofen in the risk of eczema or bronchiolitis at age 1 year. FUNDING: Health Research Council of New Zealand, Cure Kids New Zealand, University of Auckland.
3. Automated titration of nasal high flow oxygen in the emergency department: a randomised controlled trial.
In a single-centre, open-label RCT in hypoxaemic ED patients (n=52 randomized; n=49 analyzed for the primary endpoint), automated oxygen titration during nasal high-flow therapy significantly increased the proportion of time within the prescribed SpO2 target range compared with manual titration.
Impact: Demonstrates the clinical utility of automation to optimize oxygen therapy targets in acute care, addressing common deviations that risk hypo- or hyperoxaemia.
Clinical Implications: Emergency departments could consider automated titration for nasal high-flow to improve adherence to SpO2 targets and potentially reduce oxygen-related harm, pending larger multicentre confirmation.
Key Findings
- Automated titration significantly increased time within target SpO2 compared to manual titration in ED hypoxaemic adults.
- Feasibility demonstrated with randomized design in a real-world ED setting.
- Primary endpoint analyzed in 49 of 52 randomized participants, supporting robustness of findings despite modest sample size.
Methodological Strengths
- Randomized, parallel-group comparison in an acute care environment
- Clear, clinically meaningful primary endpoint (time in target SpO2)
Limitations
- Single-centre, open-label design with modest sample size limits generalizability
- Incomplete reporting in abstract for secondary outcomes and safety endpoints
Future Directions: Conduct multicentre RCTs powered for clinical endpoints (e.g., hypoxia/hyperoxia episodes, escalation of care, LOS) and evaluate workflow impact and cost-effectiveness.
BACKGROUND: When delivering nasal high flow (NHF) therapy in a medical ward, a high dependency unit or an intensive care unit, automated oxygen titration increases time spent within a target oxygen saturation (SpO METHOD: This open-label, parallel groups, randomised controlled trial compared automated to manual oxygen titration using NHF therapy in hypoxaemic adult patients in the Wellington Regional Hospital ED between October 2022 and December 2023. Participants with a prescribed target SpO RESULTS: 83 participants were screened, 52 were randomised and 49 had data for the primary endpoint. Median (IQR) proportion of time spent within the target SpO CONCLUSION: Automatically titrated oxygen therapy significantly increased time spent within a target SpO