番茄社区

An oral abstract session at CHEST 2021 on Wednesday devoted to chronic obstructive pulmonary disease (COPD) offered a prime example of how a question-and-answer segment can be far more interesting than the actual presentations.

One of the abstracts was a run-of-the-mill secondary analysis of years-old clinical trial data, while another examined claims data related to COPD inhalers. But both prompted an extensive discussion among the lead authors, the session moderator, and presenters of some of the session's other studies: what's the real benefit of inhaled steroids in COPD, are patients even diagnosed correctly, and should biomarkers be part of COPD management?

Another abstract, in which the authors identified a relationship between e-cigarette use and COPD in federal health survey data, was followed by questioning of all research into vaping, given the wide variability in the available products and how people use them.

CHEST 2021, the American College of Chest Physicians' annual meeting, was held entirely online this year. Perhaps more than anything, this session demonstrated a major advantage of virtual meetings over the traditional in-person variety: all of the studies' lead authors and the two moderators stayed on for the nearly 40 minutes of Q&A (more than 10 minutes longer than were taken by the five formal presentations), responding to attendees' typed-in questions and then discussing among themselves. One rarely sees such impromptu roundtables during normal abstract sessions, where presenters, when they're done speaking, return to their seats or often leave the room entirely.

Triple vs Dual Therapy for COPD

Reynold Panettieri Jr., MD, of Rutgers University in New Brunswick, New Jersey, presented a of data from the FULFIL trial, a pivotal study testing a triple therapy for COPD now sold as Trelegy Ellipta -- the inhaled corticosteroid (ICS) fluticasone; vilanterol, a long-acting beta agonist (LABA); and umeclidinium, a long-acting muscarinic antagonist (LAMA) -- against a standard ICS/LABA, budesonide plus formoterol. Panettieri reported on how trial participants fared with severe exacerbations. Overall, the triple therapy was more effective for this outcome than the ICS/LABA.

The analysis came more than 4 years after the were published and the three-drug combination won FDA approval. One might question the importance of these data after such a long delay. But that wasn't what interested the moderators or other presenters.

William Feldman, MD, DPhil, of Brigham and Women's Hospital in Boston, had kicked off the session with a (specifically, claims from the Optum commercial database) starting on maintenance inhalers, and the resulting effects on severe exacerbations and pneumonia risk. In that study, it appeared that LAMA/LABA products were more effective than ICS/LABA agents at preventing the adverse outcomes.

Co-moderator Andrew Berman, MD, of the Rutgers Newark campus, asked him to comment on the general issue of ICS versus LABA/LAMAs alone in COPD patients. In particular, Berman wondered, "is it the addition of having two bronchodilators, or conceivably could it be the removing of the ICS?"

"Our interpretation is that it [ICS] is not beneficial in this population," Feldman responded. He went on to argue that combination inhalers including ICS are overprescribed in COPD, noting that more than half of patients in his dataset had not had spirometry testing, nor were they using any inhalers before being started on multiple-drug products.

Another aspect of Feldman's study was that some patients had high eosinophil counts -- an immune cell species more commonly considered in asthma than in COPD. Their outcomes differed from those with lower eosinophil levels, to the point where Feldman questioned whether these patients necessarily had COPD versus some other condition.

Berman suggested that it may make sense going forward to pay at least as much attention to biomarkers such as eosinophils and not focus exclusively on exacerbation history in making treatment decisions.

At this point, Panettieri jumped in. "I agree entirely with that approach," he said. "What we've learned most recently in COPD is that there's clearly some patients that have T2 inflammation defined by high eosinophils, and maybe ultimately revisiting FeNO [fractional exhaled nitric oxide] in these people to predict whether an ICS would be valuable. Because not all patients are the same."

He drew the contrast with asthma, in which high eosinophil counts (>300) predict response to certain biologic agents. "It's different in COPD." He also noted, later in the discussion, that obtaining eosinophil counts is a simple matter in most patients. It's one of the components of a complete blood count, which the vast majority of patients, especially in the demographic for which COPD is most common, get done regularly. Thus, the doctor doesn't even have to order a special test to check this biomarker, which could be important in diagnosis and prognosis.

One of the other presenters, Jill Ohar, MD, of Wake Forest Baptist Health in Winston-Salem, North Carolina, also joined in, taking up Feldman's point about improper diagnoses. "There's a ton of people out there who have restricted ventilatory defects either due to interstitial lung disease, obesity, etc. ... Using an inhaled glucocorticoid in a population that does not have an established track record of exacerbations, we know that that is associated with more harm than good."

It's clear, she added, that the published research and guidelines are not being adhered to in COPD management -- to which Feldman responded that, in his data, more than 80% of inhaler prescriptions were written by non-pulmonologists.

E-Cigarettes and COPD

Emmanuella Onaku, MBBS, of Comprehensive Research Solutions, an NIH/NCI contractor in Bethesda, Maryland, based on data from 3 years of the federal Behavioral Risk Factor Surveillance System (BRFSS) survey. The upshot was that, across all age groups, respondents who said they used e-cigarettes had substantially greater odds of also reporting a COPD diagnosis after adjusting for age and cigarette smoking status (OR 1.43, 95% CI 1.34-1.54) relative to non-users, which was significantly stronger than the corresponding link between vaping and asthma.

Secondary findings in the study included that the connection with COPD was strongest for women, Hispanics, and individuals ages 65 and older. (In this last group, the odds of having COPD in e-cigarette users was more than double that in non-users.)

Of course, being based on cross-sectional data from a wide-ranging survey, the study came with substantial limitations, such that a causal connection was far from proved. (Ohar, for example, speculated that older people with COPD might have switched from regular cigarettes to vaping because it feels better or seems safer -- and one could imagine any number of other reverse-causality or epiphenomenal explanations.)

But the online Q&A and discussion among the speakers focused on one particular limitation -- the BRFSS's yes-no question about e-cigarette use. Onaku acknowledged that a "yes" response fails to capture the type, frequency, or intensity of use, noting that vape products during the study years (2016-2018) came in a variety of flavors and nicotine content. One commenter online said it would be necessary to know the vape liquid volume consumed per day, as well as the nicotine concentration.

It's a problem for any study of e-cigarettes "for any outcome at all," Onaku said.

Then Berman raised a different issue. While it's clear that cigarette smoking, for example, leads to COPD, "we don't actually know what causes COPD." Tobacco has thousands of components, he noted. "It could be almost anything."

If it's true that e-cigarettes can also lead to COPD, it's "some kind of opportunity to understand at the molecular level [what] leads to airway obstruction," he said, with which Onaku agreed.

Comment