Daily Respiratory Research Analysis
Analyzed 136 papers and selected 3 impactful papers.
Summary
Three impactful respiratory-related studies stand out today: a phase 3 RCT shows benmelstobart plus anlotinib prolongs PFS versus pembrolizumab in PD-L1–positive advanced NSCLC; a nationwide U.S. cohort links heat waves to substantial annual excess mortality including respiratory deaths; and a multi-cohort epigenetic study shows an infancy DNAm-IgE score predicts wheeze/asthma beyond measured IgE.
Research Themes
- Precision immuno-oncology for thoracic malignancies
- Climate change and respiratory mortality risk
- Early-life epigenetic biomarkers for asthma risk stratification
Selected Articles
1. Benmelstobart plus anlotinib versus pembrolizumab as first-line treatment for PD-L1-positive, advanced non-small-cell lung cancer (CAMPASS): a blinded, randomised, controlled, phase 3 trial.
In a multicenter phase 3 RCT of 531 patients with PD-L1–positive, driver gene–negative advanced NSCLC, benmelstobart plus anlotinib significantly prolonged progression-free survival versus pembrolizumab plus placebo (median 11.0 vs 7.1 months; HR 0.70). Grade ≥3 treatment-related adverse events were more frequent with the combination, notably hypertension, while no unexpected safety signals emerged.
Impact: This is a head-to-head, randomized phase 3 study demonstrating a clinically meaningful PFS benefit of a PD-L1 inhibitor plus anti-angiogenic therapy over pembrolizumab in first-line PD-L1–positive NSCLC, potentially informing treatment algorithms.
Clinical Implications: For PD-L1–positive, driver-negative advanced NSCLC, combining benmelstobart with anlotinib may be considered to extend PFS, with careful monitoring for hypertension and bleeding risks. Decisions should await mature OS data and consider patient comorbidities and regional drug availability.
Key Findings
- Median PFS improved to 11.0 months with benmelstobart+anlotinib vs 7.1 months with pembrolizumab+placebo (HR 0.70; p=0.0057).
- Grade ≥3 treatment-related adverse events were higher with the combination (59% vs 29%), with hypertension most frequent.
- Serious treatment-related events included haemoptysis (3% vs 0%) and immune-mediated pulmonary disease (2% vs 3%); treatment-related mortality was 1% vs 2%.
Methodological Strengths
- Blinded independent radiologic review of PFS with prespecified stratification factors.
- Large, multicenter randomized controlled design with active comparator.
Limitations
- Overall survival results are not yet mature; clinical benefit beyond PFS remains to be confirmed.
- Open-label to investigators and conducted exclusively in China, which may affect generalizability.
Future Directions: Longer-term OS analyses, biomarker-defined subgroup efficacy (e.g., PD-L1 strata), and global trials will clarify generalizability and survival benefit; mechanistic correlative studies could elucidate synergy between PD-L1 blockade and anti-angiogenic therapy.
BACKGROUND: PD-1 and PD-L1 inhibitors have been shown to synergise with anti-angiogenic agents in non-small-cell lung cancer (NSCLC). We aimed to compare benmelstobart plus anlotinib with pembrolizumab in patients with previously untreated, driver gene-negative, PD-L1-positive, advanced NSCLC. METHODS: The blinded, randomised, controlled, phase 3 CAMPASS trial was conducted in 79 centres across China. Patients aged 18-75 years with stage IIIB-IV squamous or non-squamous NSCLC, no previous systemic treatment for advanced, recurrent or metastatic diseases, a PD-L1 tumour proportion score of 1% or greater, a life expectancy of 3 months or longer, at least one measurable lesion, and an Eastern Cooperative Oncology Group performance status of 0 or 1 were randomly assigned (2:1) to receive intravenous benmelstobart (1200 mg once on day 1) plus oral anlotinib (12 mg daily on days 1-14) or intravenous pembrolizumab (200 mg once on day 1) plus placebo every 3 weeks. Randomisation was done centrally and stratified by tumour histology, PD-L1 tumour proportion score, and brain metastases. Treatment allocation was open label for investigators and masked to patients and statisticians. The primary endpoint was progression-free survival as assessed by a blinded independent review committee per Response Evalutation Criteria in Solid Tumours version 1.1 in the intention-to-treat population (all randomly assigned patients). Safety was assessed in all randomly assigned patients who received at least dose of study drug. Results reported here are from a preplanned final analysis for progression-free survival. This ongoing study is closed to recruitment and is registered with ClinicalTrials.gov, NCT04964479. FINDINGS: Between Aug 6, 2021, and Dec 14, 2022, 531 patients were randomly assigned (354 to the benmelstobart plus anlotinib group and 177 to the pembrolizumab plus placebo group). 449 (85%) patients were male, 82 (15%) were female, and 493 (93%) were of Han ethnicity. Two patients in the benmelstobart plus anlotinib group and one patients in the pembrolizumab plus placebo group were untreated and therefore excluded from the safety population. After a median follow-up of 11·4 months (95% CI 9·4-13·1) for the benmelstobart plus anlotinib group and 10·6 months (9·0-13·0) for the pembrolizumab plus placebo group, median progression-free survival was 11·0 months (9·2-12·6) and 7·1 months (5·8-9·5), respectively (hazard ratio [HR] 0·70 [95% CI 0·54-0·90]; log-rank p=0·0057). Grade 3 or worse treatment-related adverse events occurred in 206 (59%) of 352 patients in the benmelstobart plus anlotinib group and 51 (29%) of 176 patients in the pembrolizumab plus placebo group, and the most frequent one was hypertension (90 [26%] vs five [3%]). Serious treatment-related adverse events occurred in 89 (25%) patients in the benmelstobart plus anlotinib group and 37 (21%) patients in the pembrolizumab plus placebo group, the most common of which were haemoptysis (nine [3%] vs none) and immune-mediated pulmonary diseases (eight [2%] vs five [3%]). Five (1%) treatment-related deaths occurred in the benmelstobart plus anlotinib group (two due to haemoptysis and one each due to immune-mediated pulmonary disease, disease progression, and infection pneumonia) and four (2%) occurred in the pembrolizumab plus placebo group (one each due to respiratory failure, pulmonary inflammation, disease progression, and myocardial injury). INTERPRETATION: Benmelstobart plus anlotinib showed longer progression-free survival than pembrolizumab plus placebo and no unexpected safety signals were reported, suggesting benmelstobart plus anlotinib as a potential first-line option in driver gene-negative, PD-L1-positive, advanced NSCLC. Longer term follow-up is needed to establish effects on overall survival. FUNDING: Chia Tai Tianqing Pharmaceutical Group.
2. Heat waves and annual mortality among older adults (aged ≥65 years) in the USA.
In an open cohort of 73.8 million older adults followed for 668 million person-years, each additional heat wave was associated with 8.83 more deaths per 10,000 person-years, with excess cardiovascular, respiratory, and neurological mortality. Impacts were greater among Black and low-income neighborhoods and mitigated in greener areas.
Impact: This nationwide, policy-relevant analysis quantifies the chronic mortality burden of heat waves, including respiratory deaths, at population scale and identifies modifiable community-level factors (green space) and inequities by race and poverty.
Clinical Implications: Clinicians should anticipate and counsel high-risk older adults—especially in low-income and minority communities—about heat-related respiratory and cardiovascular risks, integrate heat wave alerts into chronic disease management, and advocate for green space and heat adaptation strategies.
Key Findings
- An additional heat wave was associated with +8.83 deaths per 10,000 person-years (95% CI 5.99–11.68).
- Excess mortality included cardiovascular, respiratory, and neurologic causes; 8,307 heat waves corresponded to an estimated 17,603 excess deaths (2000–2018).
- Disproportionate impacts occurred in Black individuals and high-poverty neighborhoods, while green space showed a protective effect.
Methodological Strengths
- Massive sample size with 668 million person-years and standardized heat wave definition at ZIP-code level.
- Adjusted quasi-Poisson regression incorporating individual and neighborhood covariates and secular trends.
Limitations
- Potential exposure misclassification (ZIP-level metrics) and residual confounding inherent to observational designs.
- Lack of indoor environment and personal cooling data may under- or overestimate risk in subgroups.
Future Directions: Integrate personal heat exposure metrics, medication and comorbidity data, and evaluate targeted community interventions (e.g., urban greening, cooling centers) to reduce respiratory and cardiovascular mortality during heat waves.
BACKGROUND: Heat waves are increasing in frequency and intensity due to climate change. While acute mortality effects are well documented, the impact on annual mortality and the modification of this association by race, poverty level, and amount of green space at a national level are less understood. We aimed to quantify the association of heat waves with annual all-cause and cause-specific mortality among older adults in the contiguous USA. METHODS: We conducted a cohort study using an open cohort of 73 769 163 Medicare beneficiaries (aged ≥65 years) residing in 27 926 ZIP codes across the contiguous USA from 2000-18, with 668 448 618 person-years of follow-up. Heat waves were defined at the ZIP-code level as 2 or more consecutive days with a minimum temperature exceeding 2·5 SDs above the local 30-year summer mean. We used quasi-Poisson regression models at the ZIP-code-year level to examine the association between the annual number of heat waves and mortality counts, adjusting for individual and neighbourhood-level characteristics and secular trends. FINDINGS: An additional heat wave was associated with an increase in the annual mortality rate of 8·83 deaths per 10 000 person-years (95% CI 5·99 to 11·68). Across the contiguous USA from 2000-18, the 8307 observed heat waves were associated with an estimated 17 603 (95% CI 11 942 to 23 287) excess deaths. Were an additional heat wave to occur in every ZIP code each decade, we estimated 56 815 (95% CI 38 651 to 74 979) premature deaths would result. Increased heatwaves were associated with cardiovascular, respiratory, and neurological deaths. In subgroup analyses, the mortality increase was significantly greater for Black individuals (16·50 per 10 000 person-years, 95% CI 8·11 to 25·04) than for White individuals (5·85 per 10 000 person-years, 2·79 to 8·93). The association was stronger in high-poverty neighbourhoods (11·09, 4·00 to 18·29) and was protective in neighbourhoods with abundant green space (-13·51, -24·92 to -1·79). INTERPRETATION: Heat waves are associated with a substantial increase in annual mortality among older US adults, with disproportionate impacts on Black communities and communities on low incomes. Our findings suggest that climate change poses a significant chronic risk to public health, highlighting the need for urgent mitigation and targeted adaptation measures to address these inequities. FUNDING: None.
3. Infancy IgE Methylation Score and Childhood Wheezing and Asthma; a Multi-Cohort Study.
Across three cohorts (n=560/177/80), an infancy DNAm-IgE score correlated with total IgE and, importantly, the DNAm-IgE residual (independent of IgE) predicted recurrent wheezing at age 3 and asthma at age 6. This suggests early-life epigenetic signatures contribute to respiratory morbidity beyond measured IgE.
Impact: Introduces and validates an epigenetic score that adds predictive information beyond IgE for early childhood wheeze/asthma, advancing risk stratification and mechanistic understanding.
Clinical Implications: While not yet ready for routine use, DNAm-based scores could eventually augment early risk stratification for wheeze/asthma and inform targeted prevention in high-risk infants.
Key Findings
- DNAm-IgE score trained in MARC-35 correlated with total IgE (R=0.502) and validated in MARC-43 and BBC (R=0.309; R=0.132).
- A 1-SD increase in the DNAm-IgE residual (independent of IgE) was associated with higher odds of recurrent wheezing (meta-analytic OR=1.33 [1.11–1.60]) and asthma at age 6.
- Epigenetic patterns in infancy contribute to later respiratory morbidity beyond measured IgE levels.
Methodological Strengths
- Training-validation framework across three independent cohorts with standardized methylation (EPIC array).
- Use of residualized DNAm-IgE to isolate epigenetic signal independent of measured IgE.
Limitations
- Validation cohorts were relatively small (n=177; n=80), limiting precision and generalizability.
- Observational design cannot infer causality; batch effects and cell-type heterogeneity may confound results.
Future Directions: Larger, diverse cohorts with longitudinal sampling and mechanistic studies (e.g., cell-type–specific methylation, functional assays) are needed to validate the score and explore intervention targets.
BACKGROUND: Early life epigenetic programming may mediate gene-environment interactions underlying recurrent wheezing and asthma. Multi-CpG methylation scores can summarize the epigenetic potential for high immunoglobulin E (IgE) beyond what is captured by observed IgE levels. OBJECTIVE: To establish and examine the residual effect of an epigenetic-total IgE (DNAm-IgE) score on respiratory morbidity in a pediatric population. METHODS: We used data from the 35th Multicenter Airway Research Collaboration (MARC-35; n=560), 43rd Multicenter Airway Research Collaboration (MARC-43; n=177), and the Boston Birth Cohort (BBC; n=80). DNA methylation (Illumina EPIC array) was measured in blood during infancy (MARC-35, MARC-43) and in cord blood at birth (BBC). Total IgE was assessed in blood at infancy, recurrent wheezing at age 3 years, and asthma at age 6 years for all cohorts. RESULTS: MARC-35 data were used to train and evaluate a DNAm-IgE score (R=0.502 vs. total IgE). MARC-43 and BBC data were used to validate the score (R=0.309 and R=0.132). In meta-analyses of the three cohorts, 1-SD of DNAm-IgE score residuals (DNAm-IgE score regressed on total IgE) was associated with recurrent wheezing (OR=1.33 [1.11,1.60], P CONCLUSION: Early-life epigenetic patterns related to total IgE may contribute to subsequent respiratory morbidity beyond measured IgE levels. The DNAm-IgE score and its residual component should be viewed as exploratory tools that require further validation and mechanistic study.