CHEST Journal Highlights Practice-Changing Therapy and Strategies

Three key papers that changed practice strategy in the field of chronic obstructive pulmonary disease (COPD) got a second look Sunday as authors whose work had appeared in CHEST journal detailed key papers from the past 18 months—ranging from twin trials that led to an FDA to a new risk stratification approach.

Sunday’s session helped kick off CHEST: the American College of Chest Physicians annual meeting, taking place in Phoenix Arizona. Moderated by Erika Penz MD, MSc, FRCPC, associate professor,Respirology and Sleep Medicine, College of Medicine at the University of Saskatchewan, the session featured the following presenters and papers:

Frank Sciurba MD, FCCP, professor of Medicine and Education, and director of Emphysema/COPD Research Center and the Pulmonary Function Exercise Physiology Laboratory at the University of Pittsburgh, discussed the paper, “Effect of Dual Phosphodiesterase 3 and 4 Inhibitor Ensifentrine on Exacerbation Rate and Risk in Patients With Moderate to Severe COPD,” which appeared in February 2025, following June 2024 approval of ensifentrine (Ohtuvayre; Verona Pharma/Merck) a first-in-class therapy for maintenance treatment of COPD adults.^1,2 Sciurba was the lead author.

Victor Pinto-Plata MD, FCCP, chief of Pulmonary-Critical Care Medicine at Baystate Medical Center, in Massachusetts, discussed the paper, “Cardiovascular Events in COPD: Complementary Role of Cardiac Risk and Coronary Artery Calcium Scores,’ for which he was a co-author.³

Nicola Hanania MD, MS, FCCP, associate professor of medicine, Baylor College of Medicine Airways Clinical Research Center, elaborated on the paper, “Effect of Dupilumab on Health-Related Quality of Life and Respiratory Symptoms in Patients With COPD and Type 2 Inflammation: BOREAS and NOTUS,” which explored the use of patient-reported outcomes (PROs). Hanania was a coauthor.⁴

Speakers each noted the journal’s growing influence. In August, leaders of CHEST announced that the organization’s flagship journal received a 2025 Journal Impact Factor™ of 10.2, measure of its continued influence within pulmonary, critical care, and sleep medicine. The Impact Facto is released annually by Clarivate in the Journal Citation Reports.⁵

Ensifentrine: A Different Kind of Drug Required a Different Kind of Trial

Sciurba first reviewed data from pooled analysis of the phase 3 ENHANCE-1 and ENHANCE-2 trials for ensifentrine,² a nebulized therapy given at 3 mg twice daily. He noted that ensifentrine is the first drug to inhibit both phosphodiesterase (PDE) 3, active mainly in airway smooth muscle, and PDE4, active in inflammatory cells. Blocking both raises cyclic AMP, which relaxes smooth muscle and dampens inflammation.

Unlike the trials that brought biologics into COPD care, Sciurba explained that ENHANCE did not enrich for frequent exacerbators; patients with recent COPD hospitalizations or steroid-treated exacerbations were excluded. Participants could take no maintenance therapy or a single long-acting bronchodilator, with or without an inhaled corticosteroid (ICS), but not dual bronchodilators.

The primary end point, FEV₁ area under the curve, is “an old outcome measure,” Sciurba said, but it is the one used to approve long-acting bronchodilators. Both trials met it. Exacerbations were only an additional end point.

Exacerbations fell across subgroups. The pooled analysis included 975 patients who received ensifentrine and 574 who received placebo; more than 80% in each group completed 24 weeks. About 38% took no background maintenance therapy, 18% took an ICS, and 55% were current smokers.

Ensifentrine reduced the rate of moderate to severe exacerbations by 41% (rate ratio, 0.59; 95% CI, 0.43-0.80; P < .001) and lowered the risk of a first exacerbation by a similar margin (hazard ratio [HR], 0.59; 95% CI, 0.44-0.81; P < .001).² Sciurba emphasized that the number needed to treat to prevent 1 exacerbation annually was 6.25.

Ensifentrine also numerically delayed the transition from Global Initiative for Chronic Obstructive Lung Disease (GOLD) group B to the higher-risk group E (HR, 0.64; 95% CI, 0.41-1.01; P = .058). Diarrhea, a known problem with oral PDE4 inhibitors, occurred in less than 1% of patients, he said.

Treatment effects favored ensifentrine in every subgroup, although the post hoc analyses were not powered to detect differences. Effects appeared smaller in patients with severe COPD and with blood eosinophil counts of 300 cells/μL or higher. “It works in patients you may not have expected it to work in as an anti-inflammatory, but it seems to work across the board,” Sciurba said.

Where ensifentrine fits. Sciurba said the exacerbation outcome in ENHANCE is “very different from what has been used by other biologics and put into the guidelines,” so further studies are needed to position the drug. The company is moving forward with a dedicated exacerbation trial, which he said will mirror biologic trials by enrolling patients with frequent exacerbations who are mostly on triple therapy.

During questions, a physician from UT Southwestern Medical Center stated he prescribes the therapy for patients who already taking guideline-directed dual or triple therapy. He then asked of Sciurba thought the modest benefit was worth it.

“Apparently you do,” Sciurba replied.

Clinical trials aside, patients in specialty COPD clinics often ask whether anything else is available. “And I think there is,” he said. “It’s a different class of drug, and anecdotally, it seems to work in some patients that are on dual or triple therapy.”

Some patients feel the benefit and others do not, he added. “We need to find that out, and that’s why this clinical trial moving forward has to happen.”

Asked about cost-effectiveness given the drug’s price, Sciurba said the original trials were not designed to answer that question, but he expects economic analyses to be part of the exacerbation study.

In October 2025, Merck acquired Verona Pharma, the original developer of the drug.⁶

Pairing Risk Scores With Coronary Calcium Sharpens Prediction of Cardiac Events in COPD

Cardiovascular disease is a leading cause of death in COPD, yet the risk calculators clinicians use to predict heart attacks and strokes perform poorly in these patients. Pinto-Plata highlighted findings that suggest adding a simple visual read of coronary calcium on chest CT closes much of this gap. The study, led by Juan P. de Torres, MD, of Clínica Universidad de Navarra in Pamplona, Spain, appeared in the March 2026 issue of CHEST.⁴

GOLD recommends evaluating patients with COPD for cardiovascular disease but offers no guidance on which screening tool to use, Pinto-Plata explained. He cited a recent cross-sectional study in which coronary artery calcium (CAC) outperformed standard risk scores in detecting severe coronary disease in patients with COPD, but it lacked follow-up.⁷

Two tools, 4 risk groups. The investigators analyzed 549 patients from 4 Spanish centers in the BODE cohort who had a low-dose chest CT scan at enrollment and were followed for a mean of 98 months. Patients were mostly male (80%), with a mean age of 63 years, and 75% had GOLD stage 1 or 2 disease.

Each patient received a 10-year cardiovascular risk score using the European SCORE2 family of calculators, with 10% or higher considered elevated. Radiologists also scored calcium visually in each of the 4 major coronary arteries, from 0 to 3 per artery, for a total of 0 to 12; a score above 3 was considered high.

Combining the 2 thresholds created 4 groups: low on both (group I), high risk score only (group II), high calcium only (group III), and high on both (group IV). The end point was a 4-point MACE, for major adverse cardiovascular event: cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina.

When both scores climbed, so did the risk. Over follow-up, 131 patients (24%) had a MACE and 28% died. Risk scores were similar across GOLD stages, while calcium scores rose with worsening airflow obstruction. Yet MACE was most common in GOLD stages 1 and 2, where both tools underestimated risk.

The probability of a MACE was 12% in group I and 49% in group IV, more than 4 times higher, Pinto-Plata said. Compared with group I, hazard ratios were 2.6 for group II, 3.1 for group III, and 7.7 (95% CI, 4.9-11.9) for group IV.¹

Groups II and III had similar overall risk, but their paths differed. Patients in group II, with an elevated risk score but little calcium, looked like low-risk patients for about 5 years before their event rate climbed to match group III. In their study, the authors suggest these patients may warrant a repeat calcium score every 2 to 3 years.

In time-dependent receiver operating characteristic analysis, the combination predicted MACE better than either tool alone, with an area under the curve of 0.72 vs 0.69 for the risk score and 0.66 for calcium. Using the 2 scores together significantly improved risk stratification over 8 years, Pinto-Plata said. “Both can be implemented clinically.”

Do the findings apply elsewhere? The authors note that lung cancer screening programs, which use the same low-dose CT, offer a ready opportunity to score coronary calcium in patients with COPD and identify those who may need further cardiac testing or more intensive prevention.⁴

Pinto-Plata acknowledged several limitations. The cohort was 80% male and drawn entirely from Spain, a country with low cardiovascular risk, so the findings need validation in women and non-European populations. The study was observational and can show only association. Investigators also did not track exacerbations or medication use, both of which could affect cardiovascular risk.

Dupilumab Improves QOL, Symptoms in COPD With Type 2 Inflammation, Pooled Analysis Shows

When patients with COPD arrive at his clinic, Hanania asks what brings them in. “They don’t tell you, ‘I want to reduce my exacerbations,’ ” he said.

He conceded that some may say this, but mostly they say, “I want to play with my grandkids.”

That gap between trial end points and patient priorities framed his presentation as he presented a pooled analysis of PROs from the phase 3 BOREAS and NOTUS trials of dupilumab (Dupixent; Sanofi/Regeneron), which appeared in July 2025.¹ The lead author was Surya P. Bhatt, MD, MSPH, of the University of Alabama at Birmingham.

Measuring what patients feel. Dupilumab, which blocks the shared receptor for interleukin-4 and interleukin-13, became the first biologic approved for COPD based on BOREAS and NOTUS. The trials enrolled 1874 patients with type 2 inflammation (blood eosinophils of 300 cells/μL or more), chronic bronchitis, and at least 2 moderate or 1 severe exacerbation in the prior year. Nearly all were on triple inhaled therapy. Both trials met their primary end point of reducing exacerbations and showed lung function gains.

The analysis covered the 1660 patients who could reach week 52 and used 2 research instruments. The St. George's Respiratory Questionnaire (SGRQ), scored 0 to 100, measures health-related quality of life across symptom, activity, and impact domains; a 4-point drop is the minimal clinically important difference (MCID). The Evaluating Respiratory Symptoms in COPD (E-RS:COPD) daily diary, scored 0 to 40, tracks breathlessness, cough and sputum, and chest symptoms, with a 2-point drop considered meaningful.

Both are research tools that take time to collect, Hanania noted; clinics typically rely on the COPD Assessment Test instead.

Rapid, sustained improvement. At week 52, dupilumab reduced SGRQ total scores by 3.4 points more than placebo (95% CI, –5.0 to –1.8; P < .0001). The effect was “pretty quick and actually was sustained over the 1 year of the study,” Hanania said, as he highlighted the separation from placebo by week 4. Dupilumab also outperformed placebo in each SGRQ domain: symptoms, activity, and impacts.

Hanania said responder analyses are a better way to judge PROs than mean change across a whole population. On that measure, 51.4% of patients on dupilumab reached the 4-point MCID vs 44.6% on placebo (odds ratio [OR], 1.3). The gap widened at higher thresholds: 34.5% vs 26.3% achieved a 12-point improvement (OR, 1.5).

For respiratory symptoms, 38.4% of dupilumab-treated patients reached the 2-point E-RS:COPD threshold vs 30.6% on placebo (OR, 1.4). Responder rates also favored dupilumab in all 3 symptom domains, including cough and sputum, which Hanania said investigators analyzed separately because of its importance to patients.

He acknowledged a placebo effect on both instruments, as in most trials, and cautioned that the 8- and 12-point SGRQ thresholds were analyzed post hoc.

The mechanism question. Why patients feel better remains unclear, Hanania said, whether from reduced inflammation, less mucus, or bronchodilation. Some therapies in COPD and asthma cut exacerbations or improve lung function without moving PROs, he noted.

Asked which domains matter most, he pointed to activity and impacts on the SGRQ, which patients relate to most. Feeling better “is very subjective,” he said, “and each patient has different thresholds.”

Structured trial data cannot fully capture that, so Hanania’s team is working with the Veterans Affairs AI group, applying natural language processing to electronic medical records to find what physicians document, such as a note that a patient feels better, across millions of patients. “AI research actually is helping us,” he said.

References

1. Sciurba FC, Christenson SA, Rheault T, Bengtsson T, Rickard K, Barjaktarevic IZ. Effect of dual phosphodiesterase 3 and 4 inhibitor ensifentrine on exacerbation rate and risk in patients with moderate to severe COPD. Chest. 2025;167(2):425-435. doi:10.1016/j.chest.2024.07.168
2. McCormick B. FDA approves ensifentrine for maintenance treatment of adult patients with COPD. AJMC. June 26, 2024. Accessed October 18, 2026. https://www.ajmc.com/view/fda-approves-ensifentrine-for-maintenance-treatment-of-adult-patients-with-copd
3. de-Torres JP, Casanova C, Zagaceta J, et al. Cardiovascular events in COPD: complementary role of cardiac risk and coronary artery calcium scores. Chest. 2026;169(3):631-640. doi:10.1016/j.chest.2025.09.133. Erratum in: Chest. 2026;170(2):632. doi:10.1016/j.chest.2026.06.027.
4. Bhatt SP, Rabe KF, Hanania NA, et al. Effect of dupilumab on health-related quality of life and respiratory symptoms in patients with COPD and type 2 inflammation: BOREAS and NOTUS. Chest. 2025;168(1):56-66. doi:10.1016/j.chest.2025.01.029.
5. CHEST Journal earns 10.2 Impact Factor, reflecting continued scholarly influence. News release. CHEST. August 19, 2026. Accessed October 17, 2026. https://www.chestnet.org/newsroom/press-releases/2026/08/chest-receives-impact-factor
6. Merck completes acquisition of Verona Pharma. News release. Merck. October 7, 2025. Accessed October 18, 2026. https://www.merck.com/news/merck-completes-acquisition-of-verona-pharma/
7. MacLeod MA, Knott KD, Allinson JP, et al. Prevalence and clinical correlates of radiologically detected coronary artery disease in COPD: a cross-sectional observational study. Am J Respir Crit Care Med. 2025;211(6):946-956.