John Oppenheimer, MD, clinical professor of medicine at Rutgers New Jersey Medical School and allergist at Pulmonary and Allergy Associates of New Jersey

Explanatory phase 3 trials of single-inhaler triple therapy (SITT) in

have enrolled patients with moderate to severe disease, impaired lung function, and a history of exacerbations, leaving infrequently exacerbating patients outside the evidence base.¹ Even among patients adherent to medium- and high-dose ICS/LABA, 63.8% and 70.0%, respectively, remain uncontrolled, underscoring the unmet need in this population.¹ PERFORM was designed to close this gap using a pragmatic, open-label design reflecting routine clinical practice, without restricting patients by treatment history, smoking status, comorbidities, or exacerbation frequency.

PERFORM randomized 1236 adults with uncontrolled asthma 1:1 to once-daily FF/UMEC/VI via the ELLIPTA inhaler or non-ELLIPTA usual care ICS/LABA More than 80% of enrolled patients reported no severe exacerbation in the prior year.¹

At week 24, FF/UMEC/VI produced a significantly greater improvement in trough FEV

 versus usual care ICS/LABA (least squares mean difference, 68 mL [95% CI, 36-99]; 

<.001).¹ Overall, 79.0% of patients achieved a clinically meaningful ACQ-7 response with FF/UMEC/VI versus 71.8% with usual care (odds ratio, 1.47 [95% CI, 1.13-1.92]; 

 =.004).¹ These results mark the first pragmatic randomized controlled trial evidence for FF/UMEC/VI in patients with uncontrolled, infrequently exacerbating asthma, a population historically excluded from SITT trials.¹

European Respiratory Society (ERS) Congress 2026

 in Barcelona, Spain, John Oppenheimer, MD, clinical professor of medicine at Rutgers New Jersey Medical School and allergist at Pulmonary and Allergy Associates of New Jersey, presented a late-breaking abstract on PERFORM.

ahead of the meeting about how the secondary endpoint data reshape thinking on triple therapy escalation.

Q&A: PERFORM Data Support Earlier Triple Therapy in Milder Uncontrolled Asthma

 Why has this uncontrolled, infrequently exacerbating population been overlooked in prior SITT trials, and why does pragmatic RCT data here matter clinically?

We’ve generally examined new medicines by [conducting] a very rigid phase 3 trial, so we exclude people that may smoke or may have other comorbidities. We also exclude people that are not adherent [to treatments] because, obviously, this diminishes the efficacy of the study when you're trying to get FDA or EMA approval.

The analogy I draw is when I have somebody that tells me how many miles per gallon and how good a car is, it's done under ideal conditions. We drive it with somebody that's got their foot in the pedal, not escalating up and down. That's just consistent. I look at pragmatic trials as kicking the tire and letting it be in the real world, and it really shows if the signal can translate from a well-controlled trial to the real world, and that's exactly what this pragmatic study did.

How did the secondary endpoint findings presented at ERS change your interpretation of the PERFORM data?

It reinforces a lot of PERFORM data. What we've done in this particular study is we've looked at things like asthma control. If you think about many of the studies with regard to more severe asthmatics, the outcome we look at is exacerbation because that's an easy signal. It really is very palpable, and it's very expensive.

Only about 10% of patients with moderate disease with ongoing symptoms have [an] exacerbation once a year, and only 22% of those people having 1 exacerbation will go on to another exacerbation. Meaning that when we look at the exacerbation population, it is a real small minority of those patients with uncontrolled asthma.

What's really neat about PERFORM is we're looking at the average patient that really has moderate to severe asthma that needs to have their therapy escalated to gain control, and what PERFORM does is show that moving from dual therapy ICS/LABA to triple therapy ICS/LABA/LAMA translates to better outcomes [and] translates to better control.

 Is PERFORM data sufficient to shift guideline conversations for milder uncontrolled disease?

Yes. What the study shows us is that many patients that are uncontrolled can do better if we step up therapy.

We need to be more aggressive early on in treating patients with triple therapy versus dual therapy, and if they do fail, then we would move to biologics if they're appropriate candidates.

 How does heterogeneity in the usual care arm affect interpretation of the findings?

That's part of the problem. When you have a pragmatic study, it may not be as controlled as, say, a phase 3 trial, so heterogeneity will exist. But it just shows that a very diverse population still shows a signal of efficacy [with] triple versus dual.

Why might that be? You're already on dual therapy. What does adding the LAMA do? I don't know that we have a good answer, but there's interesting data that's translated from studies looking at small airways’ disease. What they do is they look at the ability for the inhaled therapy to result in less heterogeneity of the lung.

A study done by Tetsch-Kirschner in Advanced Therapeutics 2025 looks at visualized improvements of airway dysfunction comparing dual to triple therapy. People on dual therapy had areas of their lungs that weren't ventilating, and adding the LAMA resulted in a greater improvement in their ability to ventilate the peripheral airway compared to dual therapy.

Maybe we're getting the medicine to where the problem is, and we're opening up the lungs. It's exciting new data showing that adding this third arm on our controller therapy really translates to improve ventilation of the lung, improve symptoms, [and] improve lung function.

Do patients with this infrequently exacerbating phenotype notice lung function improvements day to day, or does symptom benefit stem from another mechanism?

 It’s all over the page. There's real heterogeneity in lung function changes in patients’ perception of their shortness of breath. There were several studies done, one by Magdle in Chest almost 20 years ago, showing that a subgroup of people will perceive change in their lung function profoundly, while others may not.

The nice thing about PERFORM, by looking at the asthma control patient perception, [it] really speaks to the fact that they felt better on this therapy. You could see a difference in their feeling of control.

 Did regional differences in asthma management affect generalizability of PERFORM findings for US allergists and pulmonologists?

The main thrust of controller therapy, whether we look at GINA or NHLBI, so ex-US versus US, is really very similar. It's controller therapy and escalation of the controller arm. I don't think it varies enough to make a big difference in the outcome.

 Is there anything else about PERFORM you would like to highlight?

One of the things that I think is very exciting right now is the concept of remission in asthma. Remission is the nirvana of asthma. It is our goal. It's aspirational from the standpoint of doctors having to work harder than ever before, and it's inspirational because patients realize that they have the ability to have a level of control that nobody ever perceived before. What's exciting is PERFORM demonstrated that remission was more likely to occur with triple versus dual therapy.

Penz E, Noorduyn SG, Moore AC, et al. Effectiveness of FF/UMEC/VI versus ICS/LABA in patients with uncontrolled asthma treated in routine clinical practice (PERFORM): a pragmatic randomized controlled trial. 

Oppenheimer J. The PERFORM Pragmatic RCT Comparing FF/UMEC/VI Versus ICS/LABA in Asthma. Late-breaker presented at the European Respiratory Society (ERS) Congress 2026 in Barcelona, Spain from September 5 – 9.

Articles

Pragmatic evidence is emerging for single-inhaler triple therapy in uncontrolled asthma that seldom exacerbates. PERFORM randomized 1,236 adults to once-daily FF/UMEC/VI or non-ELLIPTA usual-care ICS/LABA without typical phase 3 exclusions; >80% had no prior-year severe exacerbation. At 24 weeks, triple therapy improved trough FEV1 by 68 mL versus dual therapy and increased clinically meaningful ACQ-7 responses (79.0% vs 71.8%). Secondary analyses support earlier escalation, potential remission gains, and benefits plausibly linked to improved peripheral-airway ventilation despite broad heterogeneity in background regimens across routine-practice settings.

At ERS 2026, John Oppenheimer, MD, discusses how PERFORM supports earlier escalation in patients with uncontrolled, infrequently exacerbating asthma.

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Q&A: PERFORM Data Support Triple Therapy in Milder Uncontrolled Asthma

Victoria Johnson joined MJH Life Sciences in 2020 and has written for NeurologyLive, CGTLive, and is now an assistant managing editor for HCPLive and RheumatologyLive. She doesn’t have enough time for her numerous hobbies. You can reach her at vjohnson@mjhlifesciences.com.

New data from the ADVANCE Outcomes trial, presented at the 

 in Barcelona, Spain, held September 5 to 9, detail the baseline characteristics and clinical improvement outcomes behind ralinepag, an investigational oral prostacyclin (IP) receptor agonist whose new drug application (NDA) for 

PAH is a progressive disease leading to right ventricular failure and death, and mortality remains high despite treatment advances, according to the study investigators.

 ADVANCE Outcomes (NCT03626688) is a global, randomized, double-blind, placebo-controlled, event-driven trial evaluating ralinepag added to background PAH-specific therapy in participants with WHO Group 1 PAH.

 Ralinepag is a potent, once-daily oral IP receptor agonist with high selectivity and 6-fold higher binding affinity for the IP receptor than the prostacyclin analog MRE-269.

“In our clinical trial, ralinepag delayed disease progression, achieved clinical improvement, and provided durability of effect over many years,” said Martine Rothblatt, PhD, chairperson and chief executive officer of United Therapeutics.

ADVANCE Outcomes baseline characteristics and trial design

ADVANCE Outcomes randomized 687 participants with PAH in a 1:1 ratio to ralinepag (n = 350) or placebo (n = 337) added to background PAH-specific therapy, with dosing individualized and titrated without a prespecified ceiling.

 The trial population reflected a contemporary, pretreated PAH cohort: 79.8% of participants were receiving dual background therapy, 70.5% were WHO Functional Class II, and mean baseline 6-minute walk distance (6MWD) was 439 m (SD, 105).

The primary endpoint was time to first adjudicated clinical worsening event, and key secondary endpoints included change in NT-proBNP, 6MWD, and a composite clinical improvement outcome requiring at least 2 of 3 criteria: an increase in 6MWD of 10% or more (or 30 m or more), improvement to or maintenance of WHO Functional Class I or II, or a decrease in NT-proBNP of 30% or more.

 These findings build on the phase 3 ADVANCE Outcomes data supporting the ralinepag NDA, which the FDA accepted for review in August 2026 with a Prescription Drug User Fee Act target action date of June 24, 2027.

Ralinepag clinical improvement and safety outcomes

What did the ADVANCE Outcomes trial show for ralinepag in PAH?

Ralinepag reduced the risk of a clinical worsening event by 55% compared with placebo and increased the odds of achieving a composite clinical improvement outcome by 47% at week 28.

How was clinical improvement defined in ADVANCE Outcomes?

Clinical improvement required an absence of clinical worsening plus at least 2 of 3 criteria: a 6MWD increase of 10% or more (or 30 m or more), improvement to or maintenance of WHO Functional Class I or II, or an NT-proBNP decrease of 30% or more.

Yes. Ralinepag was generally well tolerated, with no new safety signals observed and adverse events consistent with the known prostacyclin drug class.

Ralinepag reduced the risk of a clinical worsening event by 55% compared with placebo (hazard ratio, 0.45; 95% CI, 0.33-0.62; 

 At week 28, participants receiving ralinepag had 47% greater odds of achieving the composite clinical improvement outcome than those receiving placebo (

 Ralinepag also produced significant improvements in NT-proBNP (24.3% reduction over placebo; 95% CI, -36.1% to -10.3%; 

 = .001) and 6MWD (20.4 m placebo-corrected increase; 95% CI, 6.81 to 34.02; 

Ralinepag was generally well tolerated, and no new safety signals were observed relative to the known prostacyclin-related adverse event profile.

 Common adverse events were consistent with the prostacyclin drug class, including headache, diarrhea, nausea, and myalgia.

 Results were also consistent across prespecified subgroups, including disease etiology, 6MWD, WHO Functional Class, NT-proBNP levels, and background therapy use.

If approved, ralinepag would become the first once-daily oral prostacyclin agent available to patients with PAH, according to United Therapeutics.

 Patients completing ADVANCE Outcomes had the option to enroll in an ongoing open-label extension, ADVANCE Extension, and the trial results have also been published in 

contemporary pulmonary arterial hypertension population: insights from the ADVANCE Outcomes study. Abstract 131722. Presented at: European Respiratory Society (ERS) Congress 2026; September 5-9, 2026; Barcelona, Spain.

Livingston R. FDA accepts NDA for ralinepag in pulmonary arterial hypertension. HCPLive. Published August 24, 2026. Accessed September 6, 2026. 

https://www.hcplive.com/view/fda-accepts-nda-for-ralinepag-in-pulmonary-arterial-hypertension

ADVANCE Outcomes evaluated once-daily oral IP receptor agonist ralinepag added to contemporary background PAH therapy in WHO Group 1 disease. In 687 largely pretreated participants (predominantly FC II; mean 6MWD 439 m; ~80% on dual therapy), ralinepag significantly delayed adjudicated clinical worsening and increased odds of composite clinical improvement at week 28. Biomarker and functional measures improved, including NT-proBNP and 6MWD. Tolerability aligned with the prostacyclin class without new safety signals. An FDA review is underway with a June 2027 PDUFA date.

ADVANCE Outcomes at ERS 2026 demonstrated improved odds of improvement and reduced odds of worsening.

Cardiology

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Ralinepag Improves Clinical Outcomes in Contemporary PAH Population

Charalambos Antoniades, MD, PhD, is the director of the Acute Multidisciplinary Imaging & Interventional Centre and BHF chair of cardiovascular medicine at the University of Oxford and founder and chief scientific officer at Caristo Diagnostics.

The ORFAN-MAESTRIA trial has demonstrated that AI can detect and predict 

 from routine cardiac computed tomography (CT) scans of patients.

ORFAN-MAESTRIA: AI Predicts Cardioembolic Stroke, Atrial Fibrillation from CT Scans

European Society of Cardiology (ESC) Congress 2026

 in Munich, Germany, by Charalambos Antoniades, MD, PhD, director of the Acute Multidisciplinary Imaging & Interventional Centre and BHF chair of cardiovascular medicine at the University of Oxford and founder and chief scientific officer at Caristo Diagnostics.

“The main key message of the study is that we have atrial myopathy that can be detected on routine CT angiography,” Antoniades told 

 in an exclusive interview. “These atrial myopathy signals predict stroke independently from atrial fibrillation.”

Coronary computed tomography angiography (CCTA) is the first investigative step for patients with chest pain. However, its widespread application has revealed a population without CAD with unclear prognosis and management. To this end, the ORFAN and MAESTRIA programs were enacted to determine whether the use of the perivascular fat attenuation index (FAI) Score could enable risk prediction and guide management in this population.

ORFAN-MAESTRIA was a multicenter cohort study of 81,127 adult patients undergoing coronary CT angiography (CCTA) across 10 European centers. Antoniades and colleagues trained a fully automated pipeline for left atrium (LA) and peri-atrial adipose tissue (PAAL) segmentation via a deep learning model. The team extracted volumetric, morphologic, and higher-order radiomic features from the LA, PAAT, epicardial adipose tissue (EAT), and the whole heart – AI-based ensemble models generated the Atriomic Stroke Algorithm (ASA) and the AF prediction algorithm (AFA), trained in 40,513 patients from 7 UK centers and externally validated in 40,614 patients from an additional 3.

Over 10 years of follow-up, Antoniades and colleagues found that 648 patients developed cardioembolic stroke, and 3463 developed AF. ASA successfully stratified stroke risk, identifying intermediate- and high-risk groups with 4.4-fold and 17.1-fold higher risks of cardioembolic stroke, respectively, versus low-risk (

 <.001). Of the top 10 radiomic features included in the model, 7 were derived from the peri-atrial space, and only 3 from the LA itself.

AFA also identified individuals at significantly elevated AF risk, with 3.1-fold and 11.5-fold higher AF incidence in intermediate- and high-risk groups versus low risk (

 <.001). All 10 radiomic features contributing to the AFA model were derived from the LA. Additionally, AFA use improved prediction over the age- and sex-based model.

Ultimately, Antoniades and colleagues determined that fully automated phenotyping of the peri-LA space enables detection of LA myopathy and predicts cardioembolic stroke from routine CCTA. However, AF prediction is achieved via radiomic phenotyping of the LA itself, dissociating the 2 conditions early on in their development.

“At the moment, we predict stroke very accurately. The area under the curve, which is one of the metrics that they use to evaluate the quality of these models, is very high for this type of prediction,” Antoniades said. “Now, the predictions for stroke seem to be driven by inflammation in the atrium, at least based on the findings that we have. The treatments for stroke may not be only anticoagulants or antiplatelets in the future; it could be a combination, but this remains to be seen.”

Editors’ Note: Antoniades reports disclosures with AstraZeneca, Caristo Diagnostics, Lexicon, Novo Nordisk, Sanofi, Silence Therapeutics, and others.

Antoniades C. Using AI to detect atrial myopathy and predict cardioembolic stroke from routine cardiac CT: the ORFAN-MAESTRIA study. Presented at the European Society of Cardiology (ESC) Congress 2026, Munich, Germany. August 28-31, 2026.

Chan K, Wahome E, Tsiachristas A, et al. Inflammatory risk and cardiovascular events in patients without obstructive coronary artery disease: The ORFAN multicentre, Longitudinal Cohort Study. The Lancet. 2024;403(10444):2606-2618. 

Videos

Charalambos Antoniades, MD, PhD, discusses the recent trial investigating an AI-powered stroke and atrial fibrillation predictor.

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On the HCPLive stroke page, resources on the topics of medical news and expert insight into CVA can be found. Content includes articles, interviews, videos, podcasts, and breaking news on stroke medicine, and more.

Arrhythmia

GRI-0621, an oral retinoic acid receptor beta/gamma (RARβ/γ)-selective agonist, produced a placebo-adjusted increase in forced vital capacity (FVC) and reduced markers of fibrotic remodeling in patients with 

, according to phase 2a data presented at the 

 in Barcelona, Spain, held September 5 to 9.

IPF is driven by epithelial injury, immune dysregulation, and excess extracellular matrix, and approved antifibrotics slow disease decline but do not restore lung architecture, according to the study investigators.

 GRI-0621-IPF-02 (NCT06331624) is a phase 2a, randomized, double-blind, placebo-controlled trial evaluating GRI-0621, a molecule from GRI Bio also known generically as tazarotene.

“The breadth of data being presented at ERS marks an important step forward for GRI-0621 and our understanding of its potential in IPF,” said Marc Hertz, PhD, chief executive officer of GRI Bio.

 “We believe these findings provide a compelling foundation for the continued advancement of GRI-0621 and reinforce our conviction in its potential to meaningfully impact the treatment landscape for patients with IPF.”

GRI-0621 improves FVC in the GRI-0621-IPF-02 trial

GRI-0621-IPF-02 randomized 35 patients with IPF in a 2:1 ratio to oral GRI-0621 4.5 mg once daily (n = 23) or placebo (n = 12) for 12 weeks, with 80% of patients receiving background pirfenidone or nintedanib.

 Endpoints included adverse events, RNA sequencing, serum collagen and injury biomarkers, flow cytometry immune phenotyping, and FVC.

 Findings from the trial were presented across a late-breaking oral presentation and 3 posters covering lung function, translational biomarkers, and safety.

Placebo-adjusted FVC change was +99 mL overall and +139 mL among patients also receiving background antifibrotic therapy.

 The proportion of patients with no FVC decline rose to 39% with GRI-0621 versus 20% with placebo, while the proportion with a decline of 10% or more fell to 8% versus 20% with placebo.

 A pre-specified per-protocol analysis showed a similar placebo-adjusted FVC benefit, surpassing the estimated 30 to 40 mL of natural-history decline expected over 12 weeks, according to the poster.

GRI-0621 reduces fibrotic biomarkers with favorable tolerability

GRI-0621, known generically as tazarotene, is an oral retinoic acid receptor beta/gamma (RARβ/γ)-selective agonist from GRI Bio being developed for idiopathic pulmonary fibrosis (IPF).

Did GRI-0621 improve lung function in the phase 2a trial?

Placebo-adjusted FVC change was +99 mL overall and +139 mL with background antifibrotic therapy, and fewer patients on GRI-0621 had a significant FVC decline compared with placebo.

Yes. The most common adverse events were mild dry lips, dry skin, and musculoskeletal symptoms, and patients on GRI-0621 reported less cough, dyspnea, and diarrhea than those on placebo.

Biomarker analyses showed GRI-0621 reduced type III and VI collagen formation while increasing collagen degradation, increased type IV collagen formation, and lowered neutrophil, macrophage, and pro-fibrotic T-helper 2 (Th2) cell activity relative to placebo.

 Whole-blood RNA sequencing identified concordant transcriptional changes across curated anchor genes linked to fibrosis, epithelial injury, and tissue repair pathways, according to the poster.

GRI-0621 was well tolerated; the most common adverse events were mild dry lips (30%), dry skin (22%), and musculoskeletal symptoms (13%).

 Patients treated with GRI-0621 reported less cough (0% versus 25% with placebo), dyspnea (4% versus 17%), and diarrhea (13% versus 33%), with no cases of weight loss compared with 17% among patients receiving placebo.

 Investigators noted these tolerability findings held despite most patients continuing background pirfenidone or nintedanib, both of which carry their own gastrointestinal and dermatologic adverse effects.

Investigators said the convergent molecular, biomarker, immune, and functional signals support larger, adequately powered trials of GRI-0621 in IPF.

 GRI-0621, known generically as tazarotene, received FDA orphan drug designation for IPF in June 2026, potentially providing a pathway to 7 years of US market exclusivity upon approval.

 The oral presentation and posters were delivered by investigators from University College London, University Hospitals Birmingham, Edinburgh, Cambridge, and other UK and international sites collaborating with GRI Bio.

Parfrey H, Porter J, Saunders P, et al. Safety, translational biomarkers and lung function with the oral RARβ/γ-selective agonist GRI-0621 in idiopathic pulmonary fibrosis: a Phase 2a randomised, double-blind, placebo-controlled trial (GRI-0621-IPF-02). Abstract OA2380/63931. Presented at: European Respiratory Society (ERS) Congress 2026; September 5-9, 2026; Barcelona, Spain.

GRI Bio, Inc. GRI Bio to present late-breaking Phase 2a GRI-0621 data highlighting lung function, anti-fibrotic biomarkers and favorable tolerability in IPF at ERS 2026. Published August 24, 2026. Accessed September 6, 2026. 

https://www.globenewswire.com/news-release/2026/08/24/3349779/0/en/gri-bio-to-present-late-breaking-phase-2a-gri-0621-data-highlighting-lung-function-anti-fibrotic-biomarkers-and-favorable-tolerability-in-ipf-at-ers-2026.html

GRI Bio, Inc. GRI Bio secures FDA orphan drug designation for GRI-0621 (tazarotene) in idiopathic pulmonary fibrosis. Published June 18, 2026. Accessed September 6, 2026. 

https://www.globenewswire.com/news-release/2026/06/18/3314182/0/en/gri-bio-secures-fda-orphan-drug-designation-for-gri-0621-tazarotene-in-idiopathic-pulmonary-fibrosis.html

An oral RARβ/γ-selective agonist (GRI-0621; tazarotene) showed efficacy signals in idiopathic pulmonary fibrosis in a 12‑week randomized phase 2a trial. Among 35 patients, 80% on pirfenidone or nintedanib, placebo-adjusted FVC improved 99 mL overall and 139 mL with background antifibrotics, with fewer ≥10% declines. Biomarkers indicated reduced type III/VI collagen formation, increased degradation, and lower neutrophil/macrophage and Th2 activity with aligned RNA changes. FDA orphan designation (June 2026) supports larger trials. Respiratory symptoms and gastrointestinal AEs occurred less frequently than with placebo. Mild mucocutaneous events predominated.

The oral RARβ/γ agonist improved FVC and reduced fibrotic biomarkers over 12 weeks in a phase 2a trial presented at the ERS Congress 2026.

Pulmonary Fibrosis

GRI-0621 Improves FVC, Reduces Fibrotic Biomarkers in IPF

A polygenic risk score for chronic obstructive pulmonary disease (

) was associated with reduced lung function growth from infancy to age 6, but only among children exposed to high levels of air pollution, according to data presented at the 

Applying adult-derived COPD polygenic risk scores (PRS) in childhood may help elucidate early-life risk factors influencing lung function growth, according to the study investigators.

 Researchers led by Carla da Silva Sena, MD, of University Children's Hospital Basel UKBB and Bern University Hospital, analyzed longitudinal lung function data from 484 children enrolled in the Basel-Bern Infant Lung Development (BILD) cohort, an ongoing Swiss birth cohort study following children born between 1999 and 2020.

“COPD develops through a combination of genetic factors and environmental exposures across the lifespan, leading to an accelerated decline in lung function,” said da Silva Sena, who presented the findings.

 “Studying these trajectories from the earliest stages of life is key to understanding how COPD develops.”

What were lung function trajectories and polygenic risk in the BILD cohort?

Investigators assessed lung function using the infant tidal breathing test (tPTEF/tE) in the first month of life and spirometry (FEV1, FVC) at age 6, converting results to comparable z-scores.

 A COPD PRS derived from adult genome-wide association studies was calculated from blood samples, and outdoor exposure to fine particulate matter (PM2.5) and nitrogen dioxide (NO2) was estimated from birth to age 6. Associations between PRS and lung function trajectories were modeled using linear mixed-effects models with a PRS-by-time interaction term, stratified by the highest versus lower tertiles of PM2.5 and NO2 exposure.

In stratified analysis, a 1-SD increase in COPD PRS was associated with a decrease in tPTEF/tE-FEV1 z-score over time among children in the highest PM2.5 tertile (β = -0.47; 95% CI, -0.80 to -0.14; n = 140) and the highest NO2 tertile (β = -0.61; 95% CI, -0.99 to -0.24; n = 148).

 No significant association was observed among children in the lower exposure tertiles (β = -0.15; 95% CI, -0.37 to 0.07; n = 344).

How does air pollution act as an effect modifier?

A similar pattern was observed for tPTEF/tE-FVC z-score, but only in the highest NO2 tertile (β = -0.66; 95% CI, -1.11 to -0.22; n = 108).

 The high-exposure PM2.5 tertile averaged 15.3 μg/m³, and the high-exposure NO2 tertile averaged 28.3 μg/m³, according to the study investigators.

 The pattern suggests a gene-environment interaction, in which genetic susceptibility to reduced lung growth becomes apparent only under sufficient pollution exposure.

Does genetic risk for COPD affect lung function in children?

A COPD polygenic risk score was associated with reduced lung function growth between infancy and age 6, but only among children exposed to high levels of air pollution.

Which pollutants were linked to the effect?

The association was seen with high exposure to fine particulate matter (PM2.5, averaging 15.3 μg/m³) and nitrogen dioxide (NO2, averaging 28.3 μg/m³) from birth to age 6.

What are the limitations of this research?

Infant and school-age lung function were measured using different tests requiring statistical harmonization, and the polygenic risk score was developed in populations of European ancestry, so findings may not generalize to other populations.

Investigators noted 2 limitations: infant and school-age lung function were assessed using different tests, requiring statistical harmonization for longitudinal comparison, and the PRS was developed using populations of European ancestry, so findings may not directly apply to children from other backgrounds.

 The prospective cohort design allowed researchers to link genetic risk, air pollution exposure, and lung function measured before children displayed respiratory symptoms.

“This shows how genes and environment in the early years can combine to set children on a path to lung disease much later in life,” said Barbara Hoffmann, MD, chair of the ERS Advocacy Council at the University of Dusseldorf, who was not involved in the research.

 “It may help explain why COPD can also occur in non-smokers.”

Hoffmann said the findings align with a 2022 Lancet Commission report describing COPD as shaped by risk pathways across the lifespan rather than by adult smoking alone.

 Researchers plan to follow the BILD cohort into adolescence and adulthood to determine whether the early lung function differences persist or widen over time.

da Silva Sena CR, Gorlanova O, Gwerder M, et al. Early-life lung function trajectories are associated with COPD polygenic risk score only in the presence of high air pollution exposure from infancy to school age. Abstract 6810. Presented at: European Respiratory Society (ERS) Congress 2026; September 5-9, 2026; Barcelona, Spain.

European Respiratory Society. Origins of COPD may lie in how some children's lungs develop, but only when they are exposed to polluted air. Published September 6, 2026. Accessed September 6, 2026. 

https://www.ersnet.org/news-and-features/news/origins-of-copd-may-lie-in-how-some-childrens-lungs-develop-but-only-when-they-are-exposed-to-polluted-air/

Adult-derived COPD polygenic risk scores were linked to impaired lung function growth from infancy to age 6 only under higher early-life air pollution exposure. In the Swiss BILD birth cohort (n=484), lung function was harmonized across infant tidal breathing metrics and age-6 spirometry into z-score trajectories. A 1-SD higher PRS predicted steeper declines in tPTEF/tE-to-FEV1 and, for NO2, tPTEF/tE-to-FVC trajectories among children in the highest PM2.5 or NO2 tertiles, supporting gene–environment interaction.

A COPD genetic risk score was linked to reduced lung function growth from birth to age 6, but only in children with high air pollution exposure.

COPD

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Childhood Pollution Exposure May Trigger COPD Polygenic Risk

Kyle Hogarth, MD, professor of medicine and medical director of the Pulmonary Rehabilitation Program and director of the Alpha-1 Antitrypsin Deficiency Clinical Resource Center at University of Chicago Medicine. 

Kyle Hogarth, MD, urges physicians to complete Alpha-1 testing during every COPD or asthma workup, warning that skipped tests delay diagnosis.

Why Doctors Need to Complete the COPD or Asthma Workup to Rule Out Alpha-1

Deepak Bhatt, MD, MPH, MBA, discusses the next steps for pacibekitug in cardiovascular disease following its success in the phase 2 trial.

Chronic Kidney Disease

Next Steps for Pacibekitug Following Positive TRANQUILITY Results

Patrick Campbell is the editorial director of HCPLive. Patrick has spent years spearheading coverage surrounding cardiometabolic health and rheumatic disease for MJH Life Sciences. Before joining MJH Life Sciences in 2019, he spent time as a beat reporter and/or multimedia specialist with the Pocono Record, Star News Group, and NJ Advance Media. He is the executive producer for multiple HCPLive podcasts, including Diabetes Dialogue, Don't Miss a Beat, Kidney Compass, Medical Ethics Unpacked, The Medical Sisterhood, and Skin of Color Savvy. 


Follow him on Twitter @RealPatCampbell or reach him via email at PCampbell@mjhlifesciences.com.

Novartis announced pelacarsen did not meet its primary endpoint in the phase 3 Lp(a)HORIZON cardiovascular outcomes trial despite Lp(a) lowering.

Dyslipidemia

Pelacarsen Misses Primary Endpoint in Lp(a)HORIZON Phase 3 Trial

Paired airway and tissue sampling from 100 patients found greater microplastic burden in those with lung cancer.

Lung Cancer

Lung Cancer Diagnosis Linked to Lung Microplastic Presence, Quantity

Ross M. Levy, MD, serves as a dermatologist at Endeavor Health in Illinois, specializing in cosmetic and surgical dermatology with expertise in Mohs surgery for skin cancer.

Ross Levy, MD, explains why the LEADderm Skin Angels panel matters and what dermatology innovation looks like in daily practice.

Dermatology

The HCPLive dermatology page is a resource for medical news and expert insights on skin disease. This page features expert-led coverage, articles, videos and research on the therapies and development of treatments for dermatologic conditions, and more.

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