Understanding Early COPD

Abstract

Whereas COPD is currently defined as the presence of spirometric obstruction, the pathologic changes in individuals at risk including chronic mucus hypersecretion and emphysema have been recognized for centuries. At the same time, we have struggled to define criteria that would help us identify patients at an early stage, prior to the development of pulmonary function abnormality. The concept of GOLD 0 was introduced in the hopes that symptoms would help to identify those at greatest risk for progression. While symptoms are a risk factor, in particular chronic bronchitis, the term was abandoned as the majority of individuals at risk who progress to COPD do not have symptoms. Since then, the related terms pre-COPD and early COPD have been introduced. They are similar in that the term pre-COPD identifies individuals based on symptoms, physiologic, or radiographic abnormality that do not meet criteria for COPD but are clearly at risk. The term early COPD extends that concept further, focusing on individuals who have early physiologic or radiographic abnormality but at the same time are young, thereby excluding those with late mild disease who may be less likely to progress. Whereas individuals with early COPD are now being recruited for observational studies, we are still challenged with determining the best way to identify patients at risk who should undergo additional testing as well as developing specific therapies for patients with early-stage disease.

Introduction

Whereas COPD is currently defined as the presence of spirometric obstruction, the pathologic changes in individuals at risk including chronic mucus hypersecretion and emphysema have been recognized for centuries. At the same time, we have struggled to define criteria that would help us identify patients at an early stage, prior to the development of pulmonary function abnormality. As we do not implement routine screening for COPD, patients are often diagnosed late in the disease course where it is more difficult to impact disease progression. This recognition has led in recent years to the introduction of 2 related concepts, pre-COPD and early COPD. Both groups may have disease burden in their own right and may advance to more severe disease. This perspective reviews both of these concepts, highlighting the disease burden present even among patients who do not meet spirometric criteria for COPD and our quest to identify patients at risk for progression to even more severe disease.

A Brief History of COPD

To understand how we conceptualize COPD today, it is helpful first to consider how the term came to be. Building on Bonet’s earliest mention of emphysema in 1679, Badham is recorded as using the word catarrh to explain cough and mucus hypersecretion, characteristics of bronchitis, in 1814.¹ In 1821, though smoking was not common then, Laennec identified both characteristic features of what we now call COPD: emphysema and chronic bronchitis in Treatise of Disease of the Chest.² Yet it wasn’t until 1965 that Dr William Briscoe at the 9th Aspen Emphysema Conference first introduced the term COPD.³ Several years later in 1976, Charles Fletcher and Richard Peto published their seminal work supporting the link between smoking and the development of COPD. They recognized that FEV₁ falls gradually in certain populations. But in the susceptible tobacco-exposed individual, continued smoking accelerates lung function loss.⁴ It was in 1987 that the American Thoracic Society and European Respiratory Society introduced the modern definition of COPD as “a preventable and treatable disease state characterized by air flow limitation that is not fully reversible. The air flow limitation is usually progressive and is associated with an abnormal inflammatory response of the lungs to noxious particles or gases, primarily caused by cigarette smoking.” It is at this point that spirometric criteria were laid out as being central to the definition of COPD.

GOLD 0: Gone, but Not Forgotten

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) group currently defines COPD as the presence of air flow limitation defined as a post-bronchodilator FEV₁/FVC < 0.7.⁵ This fixed FEV₁/FVC of < 0.70 is most commonly used. Whereas there has been some debate as to whether a varying ratio, below the fifth percentile of a healthy, non-smoking population (lower limit of normal [LLN]), should be used, ultimately GOLD recommended the fixed ratio for simplicity although this may overdiagnose older, shorter individuals. Supporting this definition is that it provides good discrimination for COPD-related hospitalization and mortality.⁶ However, significant lung damage may already be present at the point an individual meets this spirometric criteria. Hence in 2001, the first GOLD report proposes an at-risk stage (GOLD stage 0) defined by the presence of risk factors (smoking) and symptoms (chronic cough and sputum production) in the absence of spirometrically defined air flow limitation.⁷ The hope was that symptoms would help to identify a population of patients who progress to COPD. However, it has become clear that whereas there is a relationship between symptoms and the development of air flow obstruction, it does not represent the majority of individuals at risk who develop obstruction. In the Copenhagen City Heart Study, 7.2% of smokers fit into the criteria for GOLD stage 0 at enrollment.⁸ Among those, COPD developed after 5 and 15 y in 13.2% and 20.5%, respectively. However, 11.6% and 18.5% of smokers without respiratory symptoms also were GOLD stage 1 or worse at 5 and 15 y, respectively.⁹ Hence, GOLD discarded the term GOLD 0 as it did not help to identify the majority of individuals at risk of developing COPD.⁸

The Story Continues: Abnormalities in Individuals With Normal Spirometry

Nevertheless, since GOLD abandoned GOLD 0, we have come to realize that many tobacco-exposed individuals with normal spirometry still have significant pathology. Some of these individuals may not progress to COPD but still experience respiratory morbidity, and some with the pre-COPD condition may ultimately develop established COPD. Several abnormalities in individuals with normal spirometry include respiratory symptoms, exacerbation, mucus hypersecretion, and computed tomography (CT) imaging abnormalities.

In the Genetic Epidemiology of COPD (COPDGene) cohort, more than half of the current and former smokers with a normal post-bronchodilator FEV₁/FVC had one or more respiratory-related impairments. A Modified Medical Research Council dyspnea score ≥2 was noted in 23.5% of tobacco-exposed non-obstructed individuals and 22.4% of GOLD 1 group, whereas only 3.7% of never smokers. Compared to never smokers, such individuals also had worse quality of life (St. George’s Respiratory Questionnaire [SGRQ] total score, 17.0 vs 3.8 for the never smokers, P < .001) and less functional exercise tolerance (mean 6-min walk distance, 447 m vs 493 m, P < .001).¹⁰ On CT, 42.3% (127 of 300) of tobacco-exposed individuals at risk showed evidence of emphysema or airway thickening.¹⁰ COPDGene also identified a group of individuals with FEV₁ < 80% predicted but preserved FEV₁/FVC (> 0.7), termed preserved ratio impaired spirometry, who also have increased symptoms and increased bronchial wall thickening as compared to never smokers.¹¹ Others have since reported increased mortality in this patient subpopulation as well.¹²

Martinez et al¹³ further looked at individuals with non-obstructive chronic bronchitis in the COPDGene cohort. Those with non-obstructive chronic bronchitis showed worse quality of life (SGRQ 35.6 vs 15.1, P < .001), impaired exercise capacity (6-min walk distance 415 m vs 449 m, P < .001), and more frequent respiratory events requiring antibiotics or corticosteroids both before and after enrollment (0.30 annual events/subject vs 0.10 annual events/subject, P < .001, prior to enrollment; 0.34 annual events/subject vs 0.16 annual events/subject during follow-up).

The Subpopulations and Intermediate Outcome Measures in COPD Study cohort revealed similar findings. Symptomatic non-obstructive current smokers or former smokers with COPD Assessment Test (CAT) score ≥ 10 were roughly half of the tobacco-exposed subject population in this cohort with normal spirometry. Such participants had more significant airway wall thickening on high-resolution CT than asymptomatic participants.¹⁴ These individuals also experienced more exacerbations than those with lesser symptoms despite preserved pulmonary function (0.27 ± 0.67 events vs 0.08 ± 0.31 events, respectively, per year, P < .001). Physical activity was more limited in symptomatic current or former smokers with preserved pulmonary function than in asymptomatic ones or participants with GOLD stage 1 or 2 COPD with CAT < 10. The mean total mucin concentration was also higher than asymptomatic individuals. In never smokers, showing the association between mucin concentration and the severity of air flow obstruction.¹⁵ In addition, total mucin concentration in GOLD 0 with CAT score ≥ 10 was significantly higher compared to GOLD 0 with CAT < 10.¹⁵ Other studies have also demonstrated that chronic bronchitis symptoms are specifically associated with progression to COPD.¹⁶

Tan et al¹⁷ compared COPD and non-COPD using Canadian Cohort Obstructive Lung Disease (CanCOLD) cohort. Events similar to exacerbation happened in 3.9% of non-COPD participants. Though the proportion of people experiencing exacerbation-like events was smaller in the non-COPD group than in the COPD group, the impact on health care utilization was similar or greater in this group. Moreover, they also had a worse health-related quality of life and more negative social impacts such as missing more social activities and work (more likely to have missed social activities [58.5% vs 18.8%], missed work for income [41.5% vs 17.3%], missed housework [55.6% vs 16.5%]). In some of the participants in non-COPD with CT, emphysema score was higher when they experienced exacerbation-like events (mean score 0.82 vs 0.32, P = .032).

Unfortunately, at the current moment, whereas we are beginning to understand the morbidity present in this population, we still do not fully understand how to treat these patients or identify which will go on to develop spirometric obstruction. This does matter, as a recent study of dual bronchodilators among symptomatic, tobacco-exposed individuals failed to demonstrate any respiratory symptom improvement.¹⁸ Hence, at least with respect to current treatments, it remains important to distinguish symptomatic patients with and without spirometric abnormality.

Early COPD Definition and Pre-COPD Definition

As previously mentioned, a large volume of data suggests that symptomatic smokers without air flow limitation experience respiratory morbidity. However, as these individuals are not candidates for clinical trials of COPD, many vital questions, such as whether they will benefit from medication or eventually progress to air flow limitation, remain unanswered. We need to study true early disease in order to better understand disease pathogenesis. Whereas it has been argued that perhaps we could move away completely from spirometrically defined COPD, this remains challenging as recent data suggest that bronchodilator therapy does not improve symptoms among individuals at risk with normal spirometry.¹⁸ However, several groups have outlined potential approaches to this problem. The COPDGene research group has suggested a potential approach to this problem by defining COPD as possible, probable, or definite based on the presence of exposures, symptoms, CT imaging, and spirometry.¹⁹ A separate COPD commission recently reported in Lancet suggests diagnosis for COPD must also consider a combination of symptoms and a broad list of risk factors in combination with lung function testing if available but that other criteria including CT imaging, impaired diffusion capacity, or forced oscillometric evidence of increased airway resistance could support a diagnosis of COPD.²⁰

In the absence of a widely supported new definition for COPD itself, others have worked to clarify other facets of the disease. The term early COPD was introduced as referring to the first signs of disease developing in a young individual that must be distinguished from late mild disease, meaning disease that is mild in severity in an older individual but may have had it for decades. More specifically, Martinez et al proposed the definition of early COPD as follows: an individual < 50 y with 10 pack-years or more smoking history and either (1) signs of early air flow limitation (post-bronchodilator FEV₁/FVC < LLN), or (2) emphysema or airway abnormalities on CT imaging, or (3) evidence of accelerated FEV₁ decline (≥ 60 mL/y) compared with FVC.⁶ Symptoms are absent from this operational definition because of the frequent discordance between patient-reported respiratory symptoms and structural changes in the lung.²¹

Later in 2021, the term pre-COPD was proposed by members of the GOLD Science Committee to identify persons with normal spirometry but at risk of progressing to COPD with air flow limitation.¹⁶ These individuals with pre-COPD have (1) respiratory symptoms, especially cough with phlegm; (2) physiologic abnormalities such as low-normal FEV₁, diffusing capacity of the lung for carbon monoxide, and/or accelerated FEV₁ decline; and/or (3) radiologic abnormalities, including airway abnormalities and emphysema. Though aging and multimorbidity may confound these conditions, it is worth recognizing these individuals to provide risk-reduction measures and possibly early intervention and disease modification trials in the near future. The relationship between pre-COPD and early COPD is conceptualized in Figure 1.

Fig. 1.

Relationship between pre-COPD and early COPD. Adapted from Reference 16. D_LCO = diffusing capacity of the lung for carbon monoxide.

The Role of the Small Airway in COPD Development

To identify those at risk for rapid lung function decline, we need to understand the role of small-airway abnormality in the pathogenesis of COPD. Small airways are conventionally defined as airways < 2 mm in diameter. These small airways represent a silent zone in the early stages of COPD where damage and obliteration of small airways may build up before they are detectable with conventional spirometry. McDonough et al²² compared the number of airways measuring 2.0–2.5 mm in persons with various airway obstructions. The number of small airways was reduced through GOLD stages 1 to 4. In this analysis, comparing the number of terminal bronchioles and dimensions at varying levels of emphysema revealed that terminal bronchioles were narrowed and lost before emphysematous destruction in COPD.

Though spirometry is crucial and most widely used to diagnose COPD, it is relatively insensitive to the early obstructive small airway. Thus, its role in screening early disease is limited.²³ However, the concave pattern on the flow-volume curve confined in the terminal portion is associated with small-airway dysfunction. Concavity units can be an option to identify small-airway abnormalities.²⁴ Global concavity and peripheral concavity can be calculated using measured FEF₅₀, measured FEF_75, and their reference values from the ideal straight line to assess concavity objectively. Noninvasive physiological studies like impedance oscillometry and nitrogen washout techniques can detect small-airway abnormalities.²⁵

CT imaging can be another helpful approach to finding small-airway disease. Parametric response mapping (PRM) combines data from inspiratory and expiratory phases and quantifies regional lung density changes. Thus, PRM can distinguish emphysema from non-emphysematous gas trapping, representing functional small-airway disease.²⁶ Using PRM in the COPDGene study, a wide range of functional small-airway disease (PRM^fSAD) was seen among current and former smokers at risk and associated with subsequent excess FEV₁ decline.²⁷ Individuals within the highest quartile of PRM^fSAD (> 16%) demonstrated an FEV₁ decline of 49.2 mL/y compared with those in the lowest quartile, who showed a 35.4 mL/y decline. The association between small-airway disease and FEV₁ decline was more evident in GOLD 1–2 than in GOLD 3–4. In GOLD 0, PRM^fSAD was significantly associated with FEV₁ reduction, whereas PRM emphysema was not. Additional longitudinal CT analyses suggest that voxels with PRM^fSAD among smokers at risk progress to voxels with emphysema.²⁸

The reduction in total airway count (TAC) may also herald early changes.²⁹ In the CanCOLD cohort, TAC was decreased by 19% and 17% in GOLD 1 and 2 compared to never smokers and participants at risk, respectively. Moreover, TAC had the most significant impact on FEV₁ and FEV₁/FVC than other CT parameters. TAC was also independently associated with FEV₁ decline. Other measures beyond spirometry that may help identify patients with early disease include impaired diffusion capacity²⁹ and forced oscillometry.³⁰

Summary

Early detection of COPD is vital to understand how to modify the course of disease. Small airway is an early lesion that helps to identify patients at increased risk for disease progression. CT imaging and noninvasive physiological tests can help identify these small-airway changes. Remaining challenges include determining the best way to identify patients at risk who should undergo additional testing as well as developing specific therapies for patients with early-stage disease.

Discussion

MacIntyre: Thank you so much for a very nice overview. You showed quite nicely that there are different trajectories for different patients. We don’t have a specific talk on this topic, but maybe you could comment on the role of genetics and analyzing genetic patterns in predicting which person is going to have a fast trajectory versus a slow trajectory.

Han: The COPDGene investigative group has been doing a lot to try to understand the role that genetics play. Obviously alpha-1 antitrypsin is our strongest known genetic risk factor for developing COPD. Outside of this, very few genes have a really strong individual contribution to the development of COPD. Many of the genes that have been identified have much weaker associations with COPD. Some that have been identified are related to factors such as nicotine addiction. So we may need to use multiple genes to develop a genetic risk score that combines information of many, many genes. Having said that, I think the real question is whether genetics in COPD is ready for prime time? We’re not even really very good at screening for alpha-1 antitrypsin deficiency as it is, much less ordering some kind of fancy genetic panel on people. I think at some point we may combine genetic information with CT data and other biomarker data to try to understand which individuals are at risk for decline, for instance. The sad part is that – as I’m sure everyone in the room knows – when we think about simple screening for COPD in people in general, we’ve made little headway. The United States Preventive Services Task Force keep saying there’s no real role for screening. Not even looking at trying to identify early COPD or late COPD, just COPD in general. And some of that argument comes back to the argument, what would you actually do differently other than smoking cessation? Which everyone should do regardless. So, I think in many ways it’s an uphill battle to get the minimal stuff done as opposed to a lot of the fancier stuff. I will say that I think one of the problems of the United States Preventive Services Task Force and other similar recommendations is that they are looking at this from the viewpoint of the physician and the fact that we might not do anything differently. However, would the patient do anything differently? As an example, I talked a little bit about early life risk factors. Recently I saw a 19-year-old who came into my clinic complaining of shortness of breath. With activities like basketball, he couldn’t keep with his peers. He had started vaping 2 or 3 years ago, but initially didn’t offer up a lot more history. But then when I really pressed him and chatted with his mom it turned out that he was born premature and had significant respiratory difficulties in his first year of life but had been lost to follow-up. I’m fairly certain this young man probably had bronchopulmonary dysplasia in childhood, and if he had known that as he was entering his teen years with a significant portion of his lung capacity already gone, he probably wouldn’t have started vaping. I think that’s where we need more data. Whether establishing a diagnosis early makes a difference in long-term outcomes.

MacIntyre: I’ll be a little personal here, I’ve taken care of many chronic bronchitics, emphysema, and COPD patients over my career. But I’d like to comment on my parents. My father was a military fighter pilot, and my mother was a typical military wife. They both smoked like chimneys, at least 2 packs a day of Camels, for probably 50 or 60 years. And neither one of them had clinical COPD. Several years ago, they came to my PFT lab at Duke because they wanted to show me how healthy they were – they had perfectly normal PFTs and they would just smile and say, “we have tough lungs.” I thought that was an interesting response. We have tough lungs. I’m just fascinated what constitutes a tough lung? What is it in the host response of my mother and father that is lacking in people who have rapid declines with equal tobacco exposure? What makes a tough lung and what makes a not so tough lung?

Han: That’s a great question that gets at this concept of resilience. Some individuals are so much more resilient than others. I suspect it’s a combination of factors. A lot has been published in very specific subareas, such as how people handle free radicals and the role of antioxidants and other factors that might limit DNA damage. It’s hard to know for sure why some individuals are more resilient than others, but it is a really interesting question which is being examined in studies such as COPDGene and SPIROMICS.

Haynes: MeiLan, I’m a pulmonary function technologist. We don’t have sophisticated genetic tests, but we do have a patient questionnaire. It’s striking to me how many COPD patients, often younger patients in their 40s and 50s, when you ask them, “do you have a family history of the lung disease?” and almost without exception these folks will inform me that their parents were also diagnosed with COPD. I read a lot of patient histories and very rarely do I see family history of COPD or emphysema mentioned. I see physicians documenting a family history of cancer, diabetes, or heart disease, but it seems to me that simply asking about family history might shed some light on who’s at risk for early COPD.

Han: You’re absolutely right. There are data to suggest that family history is important, but we don’t know if it’s some strong shared genetic risk factor or secondhand smoke exposure in childhood. All of those things could be contributing to excess risk. To be honest, when I’m doing histories on new patients who I see in clinic, I like to start from birth and ask them whether they were premature, did they have respiratory difficulties as a child, frequent respiratory infections, were they ever told they had asthma, did they ever end up in the emergency room because they couldn’t breathe. I think all of those ultimately will increase someone’s risk for lung abnormalities in adulthood.

Criner: Very nice talk. I’m going to ask you somewhat of a pointed question, is it a service or a disservice to create the concept of pre-COPD? And the reason I’m asking is we know how challenging it is for patients to be treated for hypertension when they’re not symptomatic or diabetes when they’re not symptomatic, but we have treatments and we have associations with diabetes and hypertension causing heart disease so there’s a biologic link and we can do something about preventing the cardiovascular consequences of hypertension or diabetes if we treat it early in the course of their disease. But if a patient has incidental emphysema on a CT scan and has stopped smoking or some other structural abnormality, we don’t have exact evidence that they will progress to disease. So we have nothing to do clinically for them now. So outside of the research question, is it clinically relevant or is it a disservice to label someone with a disease who might not progress to a disease that could carry implications for health insurance and other things the rest of their life?

Han: Right. As you know, we’ve gone round and round and round about this issue on GOLD. We’ve also toyed with the whether the definition of COPD itself need to be changed? For instance, there are some patients in that pre-COPD bucket who, for whatever reason, don’t meet our PFT criteria for obstruction, but if you didn’t have PFTs on them you would otherwise be convinced they had COPD. They look and behave like people with COPD. And there certainly are people in that bucket who are at risk for exacerbation and for increased risk of death, but you’re right the question is what are we actually going to do with them? However, I do think it comes back a little bit to this question of, “It’s not just what we as clinicians would do, it’s what the patients would do.” So as a stupid example I have avoided going into to the doctor myself for probably the entire pandemic, and I finally went in recently and they told me that my A1C is borderline which somewhat shocked me, but it’s making me rethink my personal diet and exercise habits. In the same way as the example I gave of that teenager, there are things people can do like paying attention to air quality or not picking up a cigarette, not hanging out at a bar with other people who smoke and making sure they get their immunizations every fall. I do think there are things within an individual’s control that would enable them to potentially make better health choices. And would they make better health choices if they knew they were in this at risk category? Do I necessarily have proof of that? No. There are some data of which I’m sure you’re aware of giving people their PFT results and explaining it to them in terms of lung age and that impacting things like quit rates. That would be an interesting area to get more information. But it’s my personal belief that having that information would allow patients to potentially make better decisions in their own lives. And then the secondary benefit of just identifying those patients so we can study them and potentially develop treatments because most of them are out there wandering around without having that extra information. It’s definitely challenging, we’re in this constant chicken and egg scenario where we don’t have treatments and studies for early COPD because we don’t know who those patients are. However, because we don’t have the treatments nobody wants to go find the patients. At some point we have to figure out how to break that cycle.

MacIntyre: Let me follow-up on that. The flip side of screening with crude tools like FEV₁ is when it comes up normal. One can imagine a patient celebrating their health by having a cigarette. And so the downside of screening is that you might find, at least by crude indices, that they don’t have COPD. We may now have given them a ticket to do things that perhaps they shouldn’t because they have this false impression that they’re healthy.

Criner: Let me support that. Even in lung cancer screening trials in a large general population, the impact of that it doesn’t change smoking habits. And along the lines of what you suggested, Neil, they might get self-reassurance that they’re fine and continue to smoke.

Mike Hess: I wonder as tools like CAPTURE continue to be validated and continue to show us some predictive value, could that break the deadlock? We know the United States Preventive Services Task Force doesn’t like to use spirometry because of the opportunity costs and the opportunity for false results like that, but would a simple screener with some predictive value be of benefit?

Han: You’re right. If you look at what the United States Preventive Services Task Force guidance, they don’t recommend against screening for COPD because of negative evidence, it’s because of lack of evidence. And really what they’re looking for is whether screening impacts long-term outcomes. Are those patients going to have better lung function in a few years or are we going to decrease the number of exacerbations long-term or decrease mortality? And those are really difficult studies to do. In the CAPTURE study,¹ as you know, we do have a third arm that’s going to be exploring some of those longitudinal outcomes, but we really do need a larger study to look at some of those longer-term end points to ultimately combat that. It’s been challenging and unfortunately those studies are large and expensive and would be difficult to get funded.

Mike Hess: That brings up the question: are we not making any difference because early screening doesn’t make a difference or because we simply don’t have the treatment options? We talked about how we don’t have the classes of drugs, so I think you hit it right on the head with the chicken or the egg analogy. How do we break the deadlock?

MacIntyre: I’m going to ask you a question I should have asked Jeff Curtis, and hopefully you can offer some insight. Neither one of you talked about the role of the eosinophil, a cell that has garnered a lot of interest. Where does the eosinophil fit into the pathogenesis and evolution and trajectory of COPD?

Han: I view eosinophilic COPD somewhere between phenotype and bordering on endotype of COPD indicating a specific pathologic process that is also present and contributing to inflammation. The data I’ve seen are split. There are some data to suggest that people in this eosinophilic COPD bucket may be at increased risk for disease progression, but then there are data to suggest that, no, perhaps it’s more indicative of reversible airway inflammation. They may be separate, for instance, from the group of patients with more severe emphysema who ultimately decline the fastest. I think that individuals with eosinophilic COPD benefit from inhaled steroids and may also benefit from biologics targeted against Type 2 inflammation. It’s just trying to find those patients and study them in clinical trials and figure out the best way to identify them is challenging. Eosinophils vary from visit to visit, For now, we do know these patients benefit from inhaled corticosteroids.

MacIntyre: Going beyond bronchodilators and corticosteroids, especially for these small-airway abnormalities and early emphysema, what seems to be promising in your mind that’s on the horizon?

Han: There are a lot of new therapies being investigated. There are some currently in phase 3 like cryotherapies looking to attack chronic bronchitis specifically, there is radiofrequency ablation to try to dilatate the airways and decrease the frequency of exacerbations. There are a lot of companies looking at biologics in particular that may attack certain inflammatory pathways. So there are definitely programs and drugs in the pipeline. I will say that I do worry because of the rigidity of the FDA with respect to what end points they’re willing to look at. For instance, they still have not qualified emphysema as far as I know, and a heavier reliance on FEV₁. The fact that COPD studies, particularly with exacerbation end points are large and difficult to do. Endotyping is challenging to try to identify which patients might benefit from specific biologics. While there are companies who are doing work, just last week a major pharma company pulled out of COPD altogether. So there are things under development, but I’m worried that because of the challenge of studying these patients, we aren’t seeing the level of investment we really need.

MacIntyre: You’ve echoed the comment that was made during an earlier presentation about the rigidity of using the FEV₁, especially to check a response in a disease where the FEV₁ may be normal.

Han: Right.

MacIntyre: It is frustrating.