COPD Spotlight

As coronavirus disease 2019 (COVD-19) deaths and cases continue to climb in the United States, patients with conditions that can exacerbate COVID-19 severity, such as chronic obstructive pulmonary disease (COPD), have had to adjust to transitions in care delivery and maintenance.

Although the prevalence of comorbid COPD among those hospitalized with COVID-19 is lower than that of the general population, patients with COPD are 3 times more likely to die from a COVID-19 infection.

In an effort to protect these patients, telemedicine utilization has become paramount to ensuring individuals receive quality and timely care while adhering to pandemic guidelines.

However, as Meilan King Han, MD, a professor of internal medicine in the Division of Pulmonary and Critical Care at the University of Michigan explained, because patients with COPD knew they were at increased risk of COVID-19 complications, many experienced fewer exacerbations over the course of the pandemic due to less exposure from external triggers.

In an interview with The American Journal of Managed Care®(AJMC®) Han laid out how her practice has altered patient care to adapt to the ongoing pandemic and elaborated on challenges patients with COPD and their providers face when dealing with a highly contagious airborne respiratory virus.

Han is a physician and researcher with a focus on chronic lung disease and COPD. She is also a national volunteer spokesperson for the American Lung Association.

The following interview has been edited for length and clarity.

AJMC®: The CDC classified individuals with COPD as being at a higher risk of experiencing more severe COVID-19 symptoms. Nearly a year into this pandemic, what do we know about how these 2 conditions interact?

Han: I think it's really interesting because one thing that has happened is that many patients with COPD got the message that they were at increased risk and have been doing, I would say overall, a fairly good job of staying at home. What I would say, on the ground, at least in my own practice, as well as with talking to other physicians around the country, is that one odd thing that we're seeing is that patients with COPD in general are having fewer exacerbations of their disease than we would normally see. We know that in normal times, exacerbations would be due to things like normal colds, and other non-COVID-19 viruses. The interesting thing is that overall, we're seeing patients having fewer exacerbations simply because they're heeding the CDC guidance and staying at home.

Now, this does not mean that no one is getting sick. I have more recently seen several of my patients with both things like COPD as well as asthma become sick with COVID-19. The studies really do indicate that patients who are either older—which COPD patients tend to be, we know that the prevalence increases with age—as well as have underlying conditions such as COPD, truly are at increased risk for poorer outcomes. Certainly, I've had some of my own clinic patients, unfortunately, do poorly when they've contracted COVID-19. For every patient, there's still a wide range of disease severity, even within the group of patients who have COPD. But we know that as a group, they are at increased risk for more severe COVID-19.

AJMC®: What extra pressures or challenges do patients with COPD face during a pandemic that is wrought by a respiratory virus?

Han: We're seeing tons of challenges. One of them is just attaining regular medical care. Many patients with COPD live in rural areas, and they also tend to be, as a group, more socioeconomically disadvantaged. They're also afraid. What this means is that in a pandemic they're less willing to travel. They may not be able, for instance, to get someone to drive them because of the risk of that, and so they're having a harder time making it to in-person appointments when that's an option. They're also having a harder time doing virtual visits, because I'm finding a lot of them don't have the appropriate technical equipment that would require. We still are allowed to do phone visits, but it's unclear how long that those will continue to be reimbursed for.

I will also say, I've had one patient in particular that I did a video visit with who then was admitted to the hospital not long afterwards. And I wondered whether if I'd actually seen her, I would have realized perhaps how sick she was. But it's just difficult, even with video, to not be in the same room with a patient and observe how they're breathing and to listen to them and talk to them and watch them walk around. It's just not the same overall experience.

The other thing I'm finding a challenge is even how to do things like patient education. Normally, my nurses would go into the patients' rooms and would review inhaler techniques with them. We've never really tested this system out virtually. Like I said, many of my patients don't even have video as an option, so that's getting harder and harder.

The other problem that we've noticed is that many of the pulmonary rehabilitation centers closed during the pandemic. Many of them are back open, and are taking significant precautions, but these are intended to be shared spaces. Rehab is often performed in groups. So, getting patients in pulmonary rehabilitation has been hard.

Other things that have been challenging include things like some of the treatments that many of our patients receive. Things like nebulizers, which are aerosol generating procedures, can be challenging, because if a patient has COVID-19, they could be aerosolizing COVID-19 particles to anyone that they might be sharing a home with, for instance. We had developed specific guidance for patients if they already become infected about trying to isolate when using nebulizers. The same thing goes for continuous positive airway pressure (CPAP) machines. Those also can generate aerosols and spread virus. So, if you have an actively infected patient they need to be sleeping alone, for instance, when using the CPAP machine. I think almost every aspect of life for COPD patients has been affected by the pandemic.

AJMC®: In your practice how has the pandemic altered care? Are you doing predominantly telehealth visits or phone visits with patients?

Han: I've been doing a mix depending on how bad the surge is. In Michigan, where I live, the surge was really bad in the spring, and at that point, the hospital encouraged us to move to almost all virtual visits. Things were much better in Michigan over the summer. I was able to get many of my patients back in for in-person visits and check their spirometry and tried to get issues sorted out in person.

We're now in the middle of a second surge. I have re-transitioned many of my visits back to virtual and we're kind of doing a mix. One thing that's been really challenging is just even doing pulmonary function testing on patients because this is also an aerosol generating procedure. Health systems have taken 1 of 2 approaches. Either they will test for COVID-19 first, or they will not test but the technicians and therapists that are doing pulmonary function testing have to wear full personal protective equipment (PPE) and will try to even do those in a negative pressure room if it's available. Even bringing people in when things were better was still more cumbersome than it typically would be.

Right now, I'm doing a mixture both in-person and virtual. The question on all my patients' minds right now is "When can I get the vaccine?" As we know the government and CDC have recommended currently individuals over 65 and individuals with conditions that would put them at increased risk [of COVID-19 complications should be vaccinated]. I think the majority of COPD patients would fall into that group that really should be prioritized for vaccination.

In Michigan and at Michigan Medicine, they started rolling that [protocol] out and scheduling this week, but then put a halt on it because we did not get a shipment of vaccine that we were expecting. I'm kind of just sitting here waiting to see what's going to happen with that. I know that at a national level, we've been told there's plenty of vaccines, but Michigan did not get an expected shipment this week. I really have yet to see any of my COPD patients receive the vaccine yet.

AJMC®: Are most of your patients eager to get the vaccine or are you confronting any hesitancy?

Han: I would say the majority of patients are eager to get the vaccine and are trying to sign up in as many places as they can think of; if they've seen physicians at 2 health systems, they're signing up with both health systems. They're signing up with multiple pharmacies. I have received some patients that have concerns. Patients, for instance, that might be on immunosuppressive medications, or have had other specific questions. Some younger patients, not my COPD patients, have had concerns or they may have seen in the media, for instance, things about pregnancy. But I would say for the most part, my COPD patients have been quite eager to be vaccinated.

AJMC®: How do you think the pandemic will affect treatment paradigms moving forward? Do you think there will be any long-term impacts?

Han: I do, and I'm hoping that they're for the better. I know that getting into the health system for care has always been a challenge for COPD patients, even outside the pandemic. I'm hoping that we can make at least some version of virtual [care] work for patients and figure out how to do that.

But in order to do so we've got to solve some of the technology problems. We need to figure out how to better deliver patient education virtually. We also need to figure out how better to deliver pulmonary rehabilitation, I think in a virtual format. Certainly, there are pulmonary rehab programs that are virtual that exist but trying to figure out how to help patients access that has been a challenge. Another thing that we've seen is, there are portable spirometers that are available. There are companies that manufacture these. They exist and the platforms exist to get these into the hands of patients, but how to bill for them, how to monitor, how to use that information, how to get that information into the electronic medical record, such as EPIC that we're on at the University of Michigan, and I think many health systems are on, those details have not yet been sorted out.

I think this is an opportunity to try to figure out all of these issues, such that we can better deliver care in a way that patients most need it in the future. Interestingly, before the pandemic The University of Michigan had as a goal to transition roughly 30% to 35% of all patient visits to virtual…just to increase access. I would envision that, in the future, I will have better ability to provide care virtually for patients, including patient education and rehab and mobile spirometry, if that makes sense for the patient.

But I don't think this means in-person visits will go away. I think in the future, we will probably be looking at a hybrid approach where patients might do virtual visits, for instance, alternating with in-person visits or perhaps, doing urgent add-on visits virtually if that's the most convenient for both the patient and the provider. My hope is that this will sort of improve options to optimize patient care moving forward because we've been forced to figure out how to deliver care in different ways during the pandemic.

AJMC®: Is there anything that we haven't covered that you would like to discuss, or do you have any final thoughts you'd like to share?

Han: The best final wrap-up thought would be just encouraging patients who do have COPD to get vaccinated as soon as they are able. I have no reason at this point to believe that the vaccines are not safe or effective in the patient population that we're discussing. And I am strongly recommending that all of my COPD patients get the vaccine as soon as they can.

Each year the Global Initiative for Chronic Obstructive Lung Disease (GOLD) releases a report on updated guidelines for chronic obstructive pulmonary disease (COPD) treatment and disease management. In the 2021 GOLD report, changes mainly reflected treatment recommendations for patients with COPD who develop coronavirus disease 2019 (COVID-19), explained Antonio Anzueto, MD, in an interview with The American Journal of Managed Care®(AJMC®).

In addition to recommendations on COVID-19, the updated report highlights new research on COPD therapies, diagnosis, and rehabilitation programs. In this interview, Anzueto discusses the benefits of triple therapy for COPD, adherence issues patients may face, and the importance of correctly diagnosing the disease.

Anzueto, a professor of medicine at the University of Texas Health in San Antonio and clinician practicing pulmonary and clinical care, also serves as a member of the GOLD Science Committee.

The following interview has been edited for length and clarity.

AJMC®: What are some of the key updates made to the GOLD 2021 report, and why are they important?

Anzueto: Probably the main update in the report is having a section related to how COPD patients should be managed in the COVID-19 area. In this document, we emphasize the need to continue their current appropriate medication, to do the evaluations and diagnostic procedures. We recognize there are limitations in the use of spirometry due to COVID-19 and the risk for contamination. But that doesn't mean patients should not continue their appropriate therapies, as well as the prevention measurements, such as smoking cessation and pulmonary rehab. We specifically also recognize that COVID-19 may not finish the day the patient starts feeling better, that patients may have some long-term effects as part of COVID-19. We have a section on follow-up assessment for COPD patients after they develop COVID-19. The main areas are related to the management of COPD patients during the COVID-19 pandemic.

AJMC®: What are the goals for this year's GOLD report?

Anzueto: I think one of the main goals is going to be to fully understand how the pandemic is impacting our COPD patients. More importantly, how the vaccine will be able to protect these patients. We're looking forward as the vaccination is being implemented in older individuals, individuals with comorbid conditions, to understand the efficacy as well as the safety of the vaccine to protect our patients with COPD or with chronic lung disease.

AJMC®: What are some of the benefits of triple therapy in patients with COPD, and can you discuss any potential risks of pneumonia?

Anzueto: I think it's important to recognize that COPD today is a treatable condition. It's crucial to make a diagnosis to know what the disease is. And once we recognize the diagnosis, the important thing is to implement pharmacotherapy for these patients. Since the 2000s, beginning in 2010 to 2015, the standard of care has become the use of inhaled corticosteroids [ICS]/long-acting β2-agonist [LABA] in a fixed combination and the long-acting anticholinergics. Since triple therapy has become available in a single inhaler—first as a once-a-day with a combination of fluticasone, vilanterol, and formoterol, and later on with a twice-a-day formulation of budesonide, formoterol, and glycopyrrolate—we clearly have better opportunities for the management of our patients with COPD.

We have recognized also, for the last 15 years, that patients who receive inhaled corticosteroids are at an increased risk to develop pneumonia. Further studies in that area clearly recognized that the individuals who are sicker, and individuals who have very low eosinophil counts, are the ones at an increased risk of developing pneumonia. The clinical trials in patients on the triple therapy, the ICS/LABA/LAMA [long-acting muscarinic antagonist], versus the dual therapy LABA/LAMA without inhaled corticosteroids, demonstrated that there is an increased risk of pneumonia.

What I tell my patients is, yes, the potential risks have increased for pneumonia, but I'm doing everything that I can to prevent pneumonia. I try to be sure patients get up-to-date on influenza vaccinations. I try to keep them up-to-date on pneumococcal vaccinations both for the conjugated vaccine as well as the polysaccharide vaccine and [make sure] they are given at the appropriate time. Today we also understand that the diphtheria, pertussis, and tetanus [DPT] vaccine should be included in the management of patients with chronic lung diseases.

In a lot of the data on the risk of pneumonia and inhaled corticosteroids, the piece of data that is missing is the history of vaccination, especially pneumococcal vaccination. Clinical studies have demonstrated that pneumococcal vaccinations can give a significant protection especially to the serotypes included in the vaccine. I tell my patients, yes, you are at risk to develop pneumonia, but I'm trying to do everything that I can...This is a matter of risk/benefit. I believe that the benefit [of triple therapy] outweighs the risk primarily with the protection in reduction in exacerbations, improvement in quality of life, as well as improvement in lung function.

AJMC®: Studies on triple therapy have indicated it can result in a reduction in all-cause mortality when compared with dual and monotherapies. Is this finding a class effect?

Anzueto: I think it's hard to say if there is a class effect, if this is an effect of inhaled corticosteroids alone or this is an effect of the combination of medications. If we go back to 2000, there was a study called UPLIFT, and there were patients who were on ICS/LABA and they had the long-acting anticholinergic tiotropium added to the regimen. That study was versus placebo. There was a group of patients who were on ICS/LABA and placebo and patients who were on ICS and LAMA tiotropium. There was a significant reduction in mortality in the triple therapy group. I think, at the end of the day, there may be some effect with inhaled corticosteroids in the decreased mortality. But the benefit is being obtained and having the triple therapy, having the dual bronchodilators given together with inhaled corticosteroids, that would give the largest protection to the patients.

AJMC®: What are the main adherence challenges to triple therapy that your patients face?

Anzueto: For COPD, we have great medications available. As a matter of fact, 28 different medications have been developed over the last 15 to 20 years. And we can have the best medication in the world, but the patient cannot get it. That's a tremendous challenge. We are beginning to recognize that there are factors related to the individual, like their ability to generate enough inspiratory force to have a medication penetrate into the lungs, that is a very significant element, as well as coordination with the delivery systems, that [impact whether] they are able to get their medication. The GOLD committee has recognized, since 3 years ago we proposed in the algorithm of management that when the patient comes back to us for follow-up, and the patient tells us "I don't feel fine, I'm not doing well," before we jump into changing medication, adding or removing medications, we should address their ability to take the medication and their techniques. Having medications from different delivery systems—some dry powder, some are hydrofluoroalkane [HFA] formulation, some are soft mist, some are nebulized—these give us a very unique opportunity to tailor that delivery system to the patient's actual needs.

AJMC®: Can you elaborate on the role of critical errors in inhaler use and how these may impact patient outcomes?

Anzueto: When using the delivery systems and using the medication, certainly, there is a series of steps that the patient has to take in order to have the medication get into the lungs. Some of the challenges that we have are patients have to follow all those critical steps, because if they exhale too fast or inhale too slow, they don't follow those steps, they are at an increased risk of not getting the medication they need into the lungs.

One of the big challenges that we have today is trying to match the medication delivery to give them the appropriate medications…Some patients cannot do it in the powder form, it may be easy for them to do in an HFA form and vice versa. But it's very important, every time we assess our patients in our follow-up, to have them show us how they use the delivery system and remind them the appropriate way to use the delivery system.

AJMC®: According to the CDC, in 2011, about 5.4% of Texas residents surveyed had been told by a health care professional that they have COPD. In your experience, have you seen any trends in diagnoses in the state with the rising popularity of vaping or any external environmental hazards?

Anzueto: We have seen [trends] primarily from policies more related to cigarette smoking. We have seen a significant increase of patients diagnosed with COPD, because we are doing more spirometry [testing]. We're looking more at the management of their condition. So yes, we do see an increase in diagnosis of these patients.

AJMC®: Is there anything we didn't touch on that you'd like to include, or do you have any final thoughts you'd like to share?

Anzueto: It's very important to remind you that COPD is a treatable disease, but in order to treat it, we need to know what the patient has. One of the major concerns that I have is that many people have been labeled to have COPD never having [completed] spirometry, and if you do a spirometry test, they don't have COPD. So, the feeling that people happen to smoke, that doesn't mean they can develop or they're going to have COPD. Today, the gold standard is with the spirometry test… The important issue is we have to make a diagnosis of the disease because this is a treatable disease. If you make the right diagnosis, we have a tremendous opportunity to impact this patient's quality of life and lung function. Now we have seen with the recent publications of the triple therapy, you're not only reducing exacerbations, as well as improving quality of life and lung function, you may be reducing mortality, so we may impact the disease in ways we never suspected before.

Although chronic obstructive pulmonary disease (COPD), is among the leading causes of death in the United States, many challenges remain when it comes to diagnosis, treatment, and management. Now, with coronavirus disease 2019 (COVID-19) threatening to damage even healthy lungs that become infected, pulmonologists are concerned the disease could lead to an uptick in COPD diagnoses or other lung related-issues in the long term, said Gerard Criner, MD, FACP, FACCP, an interview with The American Journal of Managed Care^® (AJMC^®).

Criner is a professor and chair of the Department of Thoracic Medicine and Surgery at the Lewis Katz School of Medicine at Temple University. As an active clinical investigator in advanced lung diseases, primary COPD, pulmonary fibrosis, and respiratory failure, Criner offered his thoughts on the next steps for triple therapy, challenges in diagnosing early COPD, and lessons learned from the COVID-19 pandemic.

The following interview has been edited for length and clarity.

AJMC®: Triple therapy can be associated with increased risks of pneumonia. An analysis of IMPACT trial data showed an increased incidence of pneumonia in patients in Asia compared with those outside of Asia. An additional analysis comparing Western Europe and North American regions found an inhaled corticosteroids (ICS) class effect of increased pneumonia incidence in North America but not in Western Europe. What factors contribute to these findings?

Criner: That finding isn't a first finding. That's been demonstrated before in Asian populations. They have a higher increase of pneumonia with ICS use compared to trials that have been done outside of Asia, such as in the United States or in Western Europe. There's a number of factors [contributing to] that.

It might be something to do with the environment, with the prevalence of other types of infections such as tuberculosis that may cause bronchiectasis, or more structural airway abnormalities that lends to colonization with organisms that may predispose to pneumonia. Some might be due to host factors. Childhood illnesses may be different in one part of the world than the other one.

There also could be environmental causes that could contribute to it. It may just be as simple as that some patients in Asia are leaner than patients in non-Asian populations. It could be the relative dose of steroids that the patient receives could be greater because their body mass is lower. It could be just that the clinical care is different, that the use of x-rays in the diagnosis of pneumonia might be more frequent in Asian populations because the clinical paradigm there might be to consider pneumonia based on clinical parameters or the use of radiographs [compared with] other cultures. The exact reasons aren't known.

AJMC®: The IMPACT and ETHOS trials found beneficial effects of triple therapy vs dual therapy on mortality. But this was only in symptomatic COPD patients who had a history of frequent and/or severe exacerbations and who were previously receiving maintenance therapy with triple therapy, long-acting beta2-agonists/ICS, or single or dual long-acting bronchodilators. The GOLD 2021 report stated, "Future analyses or studies may help determine whether other specific patient subgroups demonstrate a greater survival benefit." In your opinion, which patient subgroups ought to be studied next? What are the next steps for research into triple therapy?

Criner: The 2 studies that you just mentioned that showed that there was a survival advantage, those were prespecified analyses, but they weren't the primary outcomes of the studies. The FDA and other regulatory bodies have not approved the use of triple therapy to improve survival in patients who were in those studies. I think that's the first place to start: an approved indication for the use of inhaled triple therapy for patients with COPD. We would like to see that as approved therapy. I think that it's not a stretch now that the 2 studies that you mentioned and the pooled analysis from the TRINITY and TRELEGY studies also showed an improved survival in a pooled analysis of those studies.

We believe that it's true, it's a class effect; that in the appropriate patients, triple therapy improves survival. Those studies, as you mentioned, [were conducted on patients who] were highly symptomatic, people with frequent or severe exacerbations. The other patient groups that would benefit from this are people who aren't as symptomatic, who are still with severe exacerbations.

Should triple therapy be something that every patient who's hospitalized receive on exit from the hospital and remain on therapy for a period of time? Those are the patient groups I think we need to study, people that have severe exacerbations, [who] are hospitalized but may not be as symptomatic. How long should they be placed on triple therapy? I think we also need to solidify the patient groups that were studied in ETHOS and IMPACT to get an approved indication for triple therapy.

AJMC®: Can you elaborate on some of the limitations of using the forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) ratio to diagnose COPD?

Criner: COPD is more than just an airways disease. There's a lot of symptomatology, morbidity, and mortality that's outside of what can be measured from the FEV1, such as comorbid clinical conditions and important changes COPD [has] on musculoskeletal strength activity. That's one limitation: that any spirometric measure, just not the FEV1/ FVC, is important in characterizing the burden of disease that patients with COPD have. Besides that, the FEV1/FVC just measures the degree of airflow obstruction. We know that some patients can have significant smoke-related or other host factor–related (such as environmental pollutants, etc) changes in lung function and can develop emphysema that may not be reflected by airflow obstruction. That definitely is a trait that patients have that importantly contributes to their outcome.

There are also patients where an absolute cut point of FEV1 to FVC does not identify the burden of their disease or their likelihood of developing COPD later. There are people who surround the border, the threshold variable for FEV1/FVC, which is currently 70%. Patients can still have significant symptoms in outcome; that's been shown in several studies now, where patients can have preserved spirometry and still be symptomatic with COPD-like symptoms and respond to treatment and have a differential outcome. There are several limitations to just using a threshold variable of obstruction identified by the FEV1/FVC ratio.

AJMC®: What are some of the challenges involved in early COPD diagnoses or designating individuals as having pre-COPD?

Criner: There's ups and downs about trying to do that. One of the things that we would like to do is identify patients who have an earlier phase of COPD or a predilection to develop COPD, patients who are at risk, and be able to intercede before they get fixed airflow obstruction. The problem is that not everyone who has symptoms of mucus hypersecretion, or cough, or shortness of breath go on to develop COPD. You don't want to label patients with a disease when they don't have a disease or even a path to develop the disease. Because the stigma and the consequences and the likelihood of overtreatment for that patient group could be worse than having the label of the disease to begin with.

I think, overall, we need better ways to detect patients who are predisposed to develop COPD, that currently we don't have. Patients' symptoms aren't robust enough to do that. Radiographic imaging carries another risk for people who use it at a younger age. That may increase the cost of care, but also, needless exposure to radiation isn't something that we want to do. We don't have a specific and straightforward biomarker that can indicate patients who are at risk for COPD, like we have for patients who may be labeled prediabetic based on a biomarker such as glycosylated hemoglobin.

There's clearly more work that needs to be done to enhance our ability to capture patients who are at risk for developing COPD, before they have intractable airflow obstruction that exists. Currently, we don't have that, but we need to work hard to try to discover that.

AJMC®: Reports of COPD exacerbations have decreased since the pandemic due, in part, to reduction in external exposures. Is there anything that pulmonologists can learn from the lockdown and implement going forward when it comes to improving disease management?

Criner: We've seen that both in clinical trials and also in clinical practice that patients developing acute exacerbations of airflow obstruction, whether they have COPD or asthma, are both less. At our institution so far this year, we've only seen 2 documented cases of influenza, which is markedly different from what we see in any other year. Prevention of aerosol contact with one individual for another one is something that has been the only good benefit that I can see of COVID-19, with social isolation, wearing masks, and better hand hygiene. I think we can learn a lot from that, that [during] peak seasons of the year where populations are at risk, perhaps using those preventative measures would be something that could be very important to lessen the morbidity and mortality associated with viral and bacterial infections that occur throughout the winter months when people are in closer quarters.

AJMC®: It's been proven now that COVID-19 can result in both short- and long-term lung damage. Do you anticipate any long-term impacts of COVID-19 on otherwise healthy lungs that could potentially lead to an uptick in COPD diagnoses or other lung-related issues?

Criner: Yes, unfortunately, I think we will see that, and we have been seeing that. The true magnitude of that problem isn't really clear right now. We thought that, based on the prior experiences with severe acute respiratory syndrome [SARS] 1, that incidence might be 1% to 2% at most, that the likelihood of persistent problems would not be greater than SARS 1. But it appears that it probably is slightly greater. How greater, it isn't known.

For the most part, obstructive airways disease doesn't seem to be as prevalent as parenchymal inflammatory disease with fibrotic changes or with persistent ground glass opacities, which appear to be much more apparent. But I think we'll know a lot more in the next 6 to 12 months [regarding] how many patients have this problem, what the nature of that problem is, and is it only patients with severe COVID-19 infection, hospitalized, or [in] an intensive care unit? Or even in people with milder forms of infection who never were hospitalized? What is the nature of their problem in the long term?

The COVID-19 pandemic has brought social determinants of health into sharp focus in the United States. But for many Americans these factors, which can include food instability, housing, unemployment, and transportation, have hindered access to quality health care for years.

Among individuals with chronic diseases, barriers resulting from social determinants of health can be all the more burdensome. In an interview with The American Journal of Managed Care^® (AJMC^®), Trisha Parekh, DO, discussed her research on the impact social determinants of health, in particular psychological stress, has on low-income patients with chronic obstructive pulmonary disease (COPD).

Parekh is an assistant professor of medicine in the pulmonary, allergy, and critical care medicine division at the University of Alabama at Birmingham.

The following interview has been edited for length and clarity.

AJMC^®: What are some of the social determinants of health commonly associated with poor outcomes among patients with COPD?

Parekh: Specifically with COPD, the most information that we have is in the low-income population. We know that low-income patients who have COPD have higher rates of readmission, higher hospitalizations. They have lower lung function. They also have higher rates of mortality. There's a definite clear association between income and poor outcomes in COPD. Of course, there are so many other social determinants of health.

What drew me to this area of research is realizing that there are all these other factors that really impact our health, but really aren't getting that much attention…One of the problems with our current health care system is that the majority of times, due to time constraints and the need to see a certain number of patients in a day, a lot of us will see a patient, will talk to them about harmful effects of smoking, which they know. You advise them to quit, you give them a prescription for inhalers, and you set them up with pulmonary rehab, and you send them on their way. But without asking anything further, you're not going to know that they don't have transportation to take them to pulmonary rehab…You won't know that they can't afford their inhalers, so they won't be using them. You won't know that they're struggling with social situations at home that are so stressful that smoking becomes the only constant in their life, the only comfort in their life. In those situations, how can we expect someone to be a model patient? Those circumstances are so difficult to deal with…There's a huge interplay between everything else that goes on in our life and our health. It's important for us as physicians and health care providers to look at the patient beyond that 30-minute appointment slot that we have with them to really see what else is going on in their life that could be impacting their health.

AJMC^®: A study you conducted in March 2020 found high-stress groups with COPD had a 2.5-fold increased adjusted odds of acute care use compared with the low-stress group. In the low-income and high-stress group, that was even higher at a 4-fold increase adjusted odds of acute care use. These patients with high stress were also more likely to be female and under the age of 65. Can you elaborate on the significance of these findings?

Parekh: We were interested in one, just looking at social disadvantages in our COPD population. Because I think a big problem with trying to evaluate social determinants of health, address social determinants of health, or determine their impact on COPD outcomes, is the fact that we don't really have that much data. We don't have a lot of large databases that include information about someone's food access, or someone's stress level. That was really a main goal of this project, to develop this cohort.

We did that through a survey study that assessed various social determinants of health as well as COPD outcomes in these patients. What we were interested in looking at initially was, “What does stress do for COPD patients?” We did find in an adjusted model that people who had higher levels of stress more than doubled the odds of utilizing acute care services, either going to the emergency department or getting hospitalized for a COPD exacerbation…We wanted to look at, “Does having low income and high stress interact differently with COPD outcomes, compared to those who are in different situations?” What we did find is that, compared to people who have low stress and high income, those who had high stress and low income had a 4-fold increased risk of utilizing acute care services. The study is limited by its cross-sectional design. It is a relatively small sample size, and it was just at a single center. But there are clear associations that we're seeing between stress and poor outcomes in COPD.

AJMC^®: You're the lead investigator of a community health worker–led stress reduction intervention for low-income patients with COPD. Why did you decide to pursue this model? Can you give an overview of this program and lay out some of your goals?

Parekh: This is an NIH-funded study that is an early career development award, which I'm really excited about. It just started last year. The overall goal of this project is to really understand root causes and clinical implications of stress in a low-income COPD cohort, so as to inform the development of a stress reduction intervention for the COPD patients. That stress reduction intervention is going to be based on a community health worker approach.

Community health workers are trusted, lay health workers. They are the leaders in the community, the trusted advisors, the people that you would turn to for advice. They're kind of a natural born leader in their community. And what we have seen is that through these community health worker interventions—where you take this group of community health workers and you train them in a specific area, whether it's in diabetes education, or stress reduction, or interventions focused on improving depression—these interventions have been very successful, especially in chronic diseases. They've been shown to reduce hospitalizations, lower blood pressure, improve weight loss, increase cancer screening rates, and reduce stress levels.

One of the major pitfalls that we've had thus far in trying to reduce hospitalizations in COPD—which is really what everybody wants, to improve these hospitalizations and readmissions—is that these interventions are not designed with community input, but they're for the community. That, to me, was always baffling, that we are implementing these interventions in the group of people without getting their advice on what would work for them, and how it would best work. I think community health workers are the perfect connection between the health care provider and the patient. There's just an automatic level of trust there that is difficult to build between a physician and a patient who are meeting for the first time.

It's a 5-year project with 3 different parts to it. The initial 2 parts are going to be evaluating sources of stress and really understanding stress in the COPD population. The first aim of the study will be administering surveys to a number of participants in the multicenter SubPopulations and InteRmediate Outcome Measures In COPD (SPIROMICS) study. We'll be administering surveys to participants in this study that would assess various social determinants of health and also assess their stress levels. With that, what we'll be able to do is address one of the limitations of that earlier paper by looking to see if stress levels predict exacerbations prospectively. In the year that follows, if I have high stress levels today, is that associated with increased risk of exacerbations in the next month, or 3 months, or 12 months?

The second part of the study is really going to be understanding these stressful experiences that COPD patients go through. I think this is probably one of my favorite parts of the study because it involves in depth interviews and one on one sittings with a participant to really understand what happens in day-to-day life that's stressful and how [the patient] responds to this stress…We know that chronic stress can impact your pituitary adrenal axis, it can stimulate your sympathetic nervous system, so you end up with these chronically elevated cortisol and inflammatory levels. Over time, that can suppress your immune system leaving you susceptible to infections, which is of course the thing we're trying to avoid. I think this partially explains why we see the higher exacerbation rate in low-income communities. I'm hoping that we really get a more in depth understanding of what's going on as soon as our patients leave the clinic floor.

The final aim of this study is to combine what we learned in those first 2 parts. We're getting a lot of data from that first aim, then we're getting a lot of deeper understanding from that second aim. I want to combine [those 2 components] and develop an intervention that would have stakeholder involvement. We would include community health workers to get their input. We would include participants who have COPD to get their input as well. [The intervention] would work to reduce stress, reduce the negative effects of stress like tobacco use, hopefully improve quality of life and hopefully, down the line, improve acute care use. I think overall, if this intervention could be successful, it could be implemented in a number of sites. It's something that we would want to test outside The University of Alabama at Birmingham as well. Hopefully, it's something that can be replicated in other institutions, so that it can be a strong and solid model that incorporates not just the medical aspects of an individual’s health care, but the social aspects as well.

AJMC^®: It sounds like based on that model, you’re prioritizing local-level interventions, because individuals on the ground have more experience with the certain specific factors contributing to patients' stress. Is there anything that can be done at the systemic level that would ease these social determinants of health?

Parekh: The goal of this is that if we can develop a community health worker intervention that is successful, then eventually it is something that will be supported on a larger scale and something that could be implemented in large institutions. It's something that could be funded by the government.

I think the problem now is a lot of these issues are best addressed at a societal level. But to start, I think that more of these smaller studies are needed to provide that data for larger institutions, or for policy makers, or for different value-based payment models, that could be interested in these innovative solutions.

One aspect is, if we can broaden the implementation of these interventions and if we can get payment for some of these interventions [it may help this process]. Also, going back to data, I think if we can get to a point where on a systems level we are obtaining social determinants of health data, that would probably be the first place to start. Because it's difficult to know what the needs of your community are. Without understanding those needs, it's difficult to address those needs and allocate resources appropriately. When it comes to even thinking about these issues on a larger level, I think policy makers and larger societies are somewhat overwhelmed, because you don't know where to allocate your resources. You don't know who needs what, and I think it's because of that lack of data. The good thing is that there is a larger push to assess social determinants of health. Now the National Academy of Medicine, the American College of Physicians, National Academies of Science, Engineering and Medicine, they're all in support of that. That's something that will hopefully become more routine. Once we have that data and we can start analyzing it and responding to those different needs, I think that's when we'll know how to respond better from a systems level.

AJMC^®: You're based in a rural state, in Alabama, and these states have historically been shown to have higher rates of chronic disease. What are some misconceptions about rural health or COPD in general that you've come across in your career?

Parekh: I'm currently in Alabama, and definitely, the Deep South has worse health outcomes compared to many other places. As far as misconceptions are concerned, I don't think that there is a lack of interest in improving your health from a patient standpoint. I don't think that the drive to get healthier is absent.

The truth is, is that there's effects of systemic racism that we're still dealing with down the line. The disadvantages that a lot of our patients have in the Deep South are caused by years and years of dealing with the effects that systemic racism has had. That's something that is a much larger issue to deal with and to reconcile. But I think that the drive to get better health and to get equal opportunities, of course, is still there. I think that's what everyone wants is the opportunity to have a chance at a better life. That specifically refers to equitable opportunities to achieve…a healthy life for our families, a safe home where we can sleep soundly at night, wanting our kids to grow up safe, healthy, and happy. That's what I see with all of my patients, regardless of where they come from, or what socioeconomic class they come from, or what race they are. Everyone wants those basic rights.

The unfortunate part is that many don't have the opportunity to get even close to this. There's a lot of work to be done, but hopefully research like this in the South, research in disadvantaged communities, will be putting us one more step in the right direction.

AJMC^®: Is there anything we did not touch on that you'd like to include, or do you have any final thoughts you'd like to share?

Parekh: Work in social determinants of health is really, really important. It's an overlooked area that I think we don't have the luxury of overlooking anymore. We’re seeing one example after the next, whether it's in COPD, or with COVID-19, or with natural disasters, or climate change. Communities who are socially disadvantaged will always be hit first and be hit hardest. If you take a look at what's going on in Texas right now, which is where I'm from, the storm hit, and power has been out for several days in some neighborhoods. Now residents are being told they can't use water. Who are the people who are going to be hit hardest here? It's your low-income communities, your predominantly Black and brown neighborhoods, those who have already struggled with feeding their children or keeping them warm. Those who don't have a car to warm up in or family members in nicer neighborhoods to take shelter in. It's a pattern that we see everywhere. I think it's way past time that we start addressing some of these issues, and start focusing on health equity, because it's not going to go away on its own.

Chronic obstructive pulmonary disease (COPD) accounts for substantial societal and economic burdens in the United States. Despite numerous pharmacological and disease management advancements in recent years, studies continue to explore how COPD affects those who suffer from it both physically, mentally, and economically.

In one of their recent investigations, Robert Reed, MD, professor of Medicine and associate medical director of the Lung Transplant Program at the University of Maryland School of Medicine, and Julia Slejko, PhD, assistant professor of pharmaceutical health services research and research core lead at the Patient-Driven Values in Healthcare Evaluation (PAVE) Center at the University of Maryland, among others set out to establish a prioritized set of patient-informed value elements based on the lived experiences of those with COPD.

By highlighting which aspects of COPD treatment patients rank as most important, the study provides a foundation of measured values that can better direct future clinical trials and research into COPD disease management.

In an interview with The American Journal of Managed Care^® (AJMC^®), Reed and Slejko explain how they carried out this study, next steps in this area of research, and potential lessons learned from the COVID-19 pandemic.

The following interview has been edited for length and clarity.

AJMC^®: In one of your latest studies, you both sought to establish a prioritized set of patient-informed value elements elicited from individuals with COPD. Can you describe the impetus behind this investigation and explain how it was carried out?

Slejko: We established the PAVE Center at the School of Pharmacy a few years ago, which was funded by a Center of Excellence grant from the PhRMA Foundation in value assessment. One of the main goals of the center was to really start to lead some establishment of methods for patient-driven value assessment. In brainstorming how we were going to do that and thinking about expertise that we had within the center, another colleague of mine, Susan dosReis, BSPharm, PhD, who is the director of the Center, had a lot of experience in patient preferences and eliciting stated preferences among patients. Thinking about how to bring that into value assessment was really the inspiration for the way that we wanted to conduct patient-driven value assessment by focusing on patient preferences.

Dr. Reed and I had been working together for a couple years at that point on some different ideas around treatment for COPD. [We began] thinking about his expertise in clinical practice and pulmonary treatments and so forth, and about how to bring these 2 things together. We thought COPD would be a really interesting venue for this study, thinking about what [are] COPD patient preferences? How do we find out about COPD patient preferences? How can we put those into economic evaluation? Of course, we really need a clinical expert to help us with that.

We started to work together thinking about the value elements that we had elicited from the first phase of our center's research. These were disease-agnostic value elements, elicited from stakeholders across a number of conditions. Once we had established that list, the idea then was to find out amongst COPD patients which ones were most important. That's where Dr. Reed and I collaborated on putting together some instruments to start to ask patients about these value elements. What does it mean for somebody with COPD, why are they important, and how can we put together some instruments to elicit that?

We also collaborated with the COPD Foundation in this work. We had a person who was in a pretty major leadership role at the COPD Foundation as an author on this study. Her experience with COPD patients over many years and understanding their access issues to medication really helped us to enlist some key patient stakeholders in the study itself and think about how this work would potentially affect COPD patients in terms of accessing medications. That's one really important reason why we conducted the study in the first place and also why we worked with COPD Foundation specifically: to get some of their insight and make sure that we were considering things that were really of importance to these patients.

Reed: From my perspective, it's been really great to work with Dr. Slejko and her group on this project clinically, as well as from a research perspective. Prior to working with Dr. Slejko, I was always struck by the variability that we see in the COPD patients, in terms of what it is that really bothers them and what really impairs their life on a day-to-day basis.

One example that I sometimes give people is hospitalizations. When we do our efficacy testing for various therapies, we usually look at hospitalization as a bad thing. But there are some COPD patients who are so scared and so challenged at home, they actually look at hospitalization during periods where their breathing is really bad as a good thing, as a safety net. So, avoiding hospitalization, while usually reflecting patients doing better, sometimes isn't.

I think it's been really nice to have an opportunity to take a scientific approach to delve into the mindset of a variety of patients that have this problem, and understand what it is that bothers them, so that we can focus on those things to address as we take care of them both in the clinical realm as well as in designing future research studies.

AJMC^®: Which aspects of COPD treatment did the patients rank as the most important? How can these findings be translated into either current or future treatment paradigms?

Slejko: We asked [patients] about a number of what we call value elements. There are about 40 of these. They were distributed among 3 main categories: treatment-related factors, outcome-related factors, and care process factors. As Dr. Reed mentioned, it's really interesting to hear about what patients really care about. Some of those results started to emerge really quickly in the first phase of this. Then, of course, the goal is then to figure out from my perspective, how then can we better fit those into economic evaluations?

If we're thinking about the treatment-related factors that patients talked about the most, or what they ranked to be most important to them, they mentioned side effects as being one of the main things that they cared about when they were thinking about their treatment. Then we asked them about what side effects mean to them, or how does that manifest in the way that they make decisions. That was the second phase of our study: to understand what that means to them. The way that they describe that is that "It might lead to changes in medication" or "Do I have to substitute one medication with another or add something else to my regimen?"

There were some concepts around regimen complexity or substituting things that would have to be done to deal with those side effects that they might be experiencing. Another thing that was really important to them, that overlapped with the care process factors, was relationship with provider. Also, concepts [were] similar to the side effects one, but regarding medication frequencies. So again, "How complex is the regimen?" or "Are there more convenient options that I don't know about? Will I find out about them?"

Reed: An additional thing to point out here is that our research is not done. We've done some good work, and we've taken some initial steps here, but there are future directions that we need to take. Clinically, what we see when we take care of patients with COPD is that lumping all patients with COPD together as a single group is a bit naïve. There are going to be clusters of people that value various elements differently than others.

The obvious [example] here would be a patient who has very advanced COPD and is essentially homebound and a pulmonary cripple. [They’re] going to have a whole different series of life experiences than patients that have COPD that bothers them but they're still functional, they're still able to leave the house and participate in society and have a job. In future steps, looking into these value elements and how they cluster around different types of COPD patients is a direction that we will likely need to go.

AJMC®: The study found that patients with COPD prioritize outcomes that are not typically measured in trials. Can you elaborate on this and explain some of the limitations of patient-reported outcomes?

Reed: In clinical trials, we look at a number of outcomes. There are actually ongoing efforts to evaluate what outcomes would make the most sense to look at in clinical trials […] Historically, things that have been looked at have been survival. Survival always matters. But even before you get to survival, you can look at things like measures of how short of breath you are, assessments of the lung function itself as measured through formal pulmonary function testing. But that doesn't always correlate perfectly with the experience of the patient.

One other factor that's been heavily looked at as an outcome measure in studies, because it's fairly easy to capture, is COPD exacerbation. An exacerbation of COPD is really a symptom change that triggers a treatment response. That treatment response could be to give the patient antibiotics and steroids or to hospitalize them. That exacerbation outcome has been looked at very closely for a number of reasons.

One being that it's fairly obvious that it happened; it's easy to say that someone experienced an exacerbation. Two is quite simple: it does affect people's lives. But it's extremely expensive. COPD is one of the major cost drivers for American medicine expenditures, and exacerbations are the primary driver of those costs. Between direct and indirect costs, it's over $50 billion a year that can be spent in dealing with primarily these exacerbations of COPD. There's a real economic motivation to look at these for the good not only of the patient, but for society in general.

But I think what some of the work we've done here is to show that there may be things that we're missing when we focus on just those outcomes. There may be things that have significant influence on the experience, from day to day, on the lives of folks, that don't translate to those more severe outcomes that we often measure, and may be meaningful, may matter a lot to the lives of people.

Slejko: A couple of really interesting points have been raised there and regarding what patients care about on a day-to-day [basis] versus what's collected in trials. Another aspect of that is then, what makes it into economic evaluation? As Dr. Reed mentioned, there are certain things that are very often collected in trials, like exacerbations, and for good reason: because they are a major economic driver and a big driver of your cost-effectiveness findings.

But then when we do ask patients about what's important to them, some of these outcome-related factors, there's really such a focus on physical abilities, maintaining social activities, fatigue. So of course, those might be intertwined with some of the outcomes that are measured in trials, like lung function. Those 2 things might be very much tied together, physical abilities and fatigue. But the way that we operationalize those in our cost-effectiveness study may not capture all the impacts on patients.

That's really part of the next phase of what we need to do. We found out some really interesting things here, but that work is certainly not done. Because really, what we hope to do is figure out how to translate these things into our value assessment. How that circles back to what's included in trials, I think, is also a very important area of inquiry right now.

To talk a little bit about next steps, there are certainly different types of patients. And that's exactly what the next phase of our study is going to do. We've already worked to put together an instrument to quantify some of the attributes that we asked about, a kind of handful of the most important attributes. We've designed a stated preferences instrument to quantify which ones are more important and how much more important. Through that you can look at groupings based on the heterogeneity of those characteristics as well. We can use the quantified preference data to look at subgroups of patients based on either their preference type and/or some of their other patient characteristics. It really speaks to that heterogeneity of COPD patients.

AJMC®: Can you discuss some of the long-term health and economic burdens of COPD in the United States and how this research addresses some of these challenges?

Reed: COPD is very, very much tied to the COVID-19 pandemic. I think it's really fascinating what kind of a marriage there is here. We looked at our own COPD population in the Maryland system and found something interesting that was observed in other systems as well. That is, during the COVID-19 pandemic, there's been a tremendous decline in people who were admitted for COPD exacerbations.

In my own clinical practice, as well, the patients that I have with COPD are frequently telling me, "I've never breathed this well in my life. I'm paralyzed [by] fear and staying home and hiding and there are aspects of my life that are worse along those lines associated with the pandemic. But from a breathing perspective, I'm great."

When we looked at it closer, it really looked like this was probably because patients with COPD are so frequently bothered by recurrent community respiratory viral infections, and the one thing the pandemic has done is really eliminated those. This is the lightest flu year that we will ever see in our lives most likely. Other respiratory viruses that we typically see, where people are just getting a cold every few months, are just not here.

I think that we're kind of in a new age of breathing without these respiratory viruses going around. It's really changed a lot, the experience of the COPD patient, in particularly in the winter months. [It will be interesting to see] how that's going to change when the limitations that have been imposed on us all and embraced by us all are subsequently lifted.

If we emerge from the COVID-19 pandemic only to enter a new flu pandemic, then I think maybe we've learned nothing. Hopefully we can channel some of the good aspects of breathing and maybe appropriate mask use in the future and translate that into improvements in the care and the health of the COPD patients in general. It may be that the experience is just fundamentally changed now. I think that there's a lot of interesting work that can be done, to look at what it was exactly that drove that change, and where we're going to end in the future, as we come out of the current pandemic.

Slejko: I think going forward, just a little bit of a different angle to Dr. Reed's response, is thinking about the future of value assessment for COPD. As new treatments do come online, thinking about whether our assessments are going to be able to address things that patients derive value from. Maybe that's thinking about how we incorporate measures of physical improvement into our value assessments and some in the clinical trial outcomes as well. Also thinking about things that perhaps aren't commonly included in COPD cost-effectiveness studies.

Side effects are not something that we oftentimes see in cost-effectiveness studies for COPD treatments. But it turns out, this is something that's important to patients. It might really manifest itself later on in terms of adherence to medication and eventual outcomes. I think where we'd like to really focus is then, if treatments aligned better with patients' preferences, are they more adherent to them? Does it work better for them, and does that eventually bring more value by aligning treatment with patients' preferences?

That's something that I'm very interested to continue working on, and really glad that we'll be partnering together on creating this preferences instrument, and working with COPD Foundation to really tackle some of these issues around assessing value that include what's important to patients and supporting their ability to access what they need.

AJMC®: Do you have any final thoughts you'd like to share?

Reed: Working with the COPD Foundation has been great because the COPD Foundation itself has a lot of folks with COPD directly involved. It really allows us to tap directly into the patients themselves as not only participants in the research, but actually functioning almost like engaged researchers.

In the history of research, people involved can be referred to as "research subjects." I think that's a term that we avoid now, particularly in the line of research that Dr. Slejko and I are involved in. We don't look at people who are participating in research as subjects at all; they aren't being subjected to research, they're participating. We call them participants, because we're working directly with them as engaged stakeholders, people who have skin in the game and really care about the research. Without them, we couldn't make any of this work. It's both with them and for them that we do this work that we do.

Slejko: I agree with all of that. I would just emphasize the role of the COPD Foundation in this particular study and going forward. In fact, they have such a huge role in some of the big studies that are going on now. Even pragmatic clinical trials where it's more studying what patients get in the real world. They have patients as co-investigators on those studies. It is a really exciting way to think about conducting research that's going to have an impact in a way that we believe is really important. That's one of the main missions of the PAVE Center […] We want to find out what's important to patients, include them along in the research process, and then think how to circle back and make sure that what they've told us is important is included in economic evaluations and value assessment going forward.

Several studies have demonstrated the benefits of triple therapy in patients with chronic obstructive lung disease (COPD) with a history of frequent and/or severe exacerbations.

Although these trials mark a step in the right direction for patients with COPD, more research needs to be done to understand both the phenotypes and endotypes of the disease, explained Nicola Hanania, MD, MS, a pulmonary critical care physician and director at the Airway Clinical Research Center, Baylor College of Medicine in Houston, Texas.

In an interview with The American Journal of Managed Care^® (AJMC^®), Hanania discusses findings of his most recent analysis investigating the effects of triple therapy among older patients and lays out some potential areas of future research into the disease.

Hanania, who has 26 years of clinical experience, is also an interim section chief of the pulmonary critical care section at Ben Taub Hospital in Houston.

The following interview has been edited for length and clarity.

AJMC^®: You recently coauthored an analysis looking into the effects of age on the efficacy and safety of once-daily, single-inhaler triple therapy in patients with COPD. What did you find?

Hanania: This was an analysis of a large study that looked at the effect of triple therapy in COPD. The study is called IMPACT, which showed the efficacy and safety of triple-inhaler therapy, including inhaled corticosteroid (ICS) when added to long-acting β₂-agonist (LABA)/long-acting muscarinic antagonist (LAMA) in COPD. We were interested to see if a subgroup of patients had a better effect than others. Obviously, with aging, one gets worried about side effects and toxicity of giving medications in older patients. In this subanalysis, we looked at whether the main findings in this study—which showed superiority of triple therapy and exacerbation reduction—were still sustained in a population of older individuals.

Basically, we replicated what we've seen in the younger population and in the general study population, in patients who are 65 and older. We did not find a different response in patients who are older to such a therapy, which is reassuring because although not all patients with COPD are older, some of them are, and these patients have other comorbidities, including cardiovascular [problems] and others. One has to make sure that these patients—although this is a clinical trial, it's not a real-life study—that older patients received the same benefit as the younger patients with no increased risk of adverse effects. That was our main finding.

We also have now looked at a large population of studies, the paper is still in press, in the International Journal of COPD, looking at triple therapy, not just in one device, but in separate devices. [This] replicated very similar findings that in general, in older individuals with COPD, use of triple therapy is a safe and effective. Now obviously this has to be underlined with the fact that not every patient with COPD will need triple therapy, I have to emphasize that.

AJMC^®: Studies have indicated triple therapy can result in a reduction in all-cause mortality compared with dual and monotherapies. Do you believe this finding is class effect?

Hanania: I think very interesting data have come from both the IMPACT study as well as the ETHOS study. These are 2 large clinical trials that looked at 2 different triple combinations of inhalers, LABA/LAMA/ICS, different devices, different chemicals, but similar compounds. [Both used] long-acting beta-agonists, long-acting muscarinic antagonists, and an inhaled steroid. While these effects on mortality were not the primary end points of these studies, when [researchers] looked at the analysis of these trials, effect on mortality was significant, especially in those patients with high risk of exacerbation.

I think we're coming to an era in COPD where we don't have any good drugs to decrease mortality (as you know, COPD is the 3rd leading cause of death around the word and 4th in the United States), to finding some hope, at least on reduction in mortality. But I have to underline the fact that mortality outcomes in both these trials were not the primary outcome of the studies. Scientifically, you have to be very careful. The main outcome of the studies was exacerbation reduction. Both of them achieved that, and triple therapy does decrease exacerbation in patients with high exacerbation risk. Mortality was reduced. It wasn't the primary outcome. I think we have to do a large study looking at it as a primary outcome. But I definitely strongly believe these data are not just a fluke, they are very important data, we cannot ignore them.

AJMC^®: What are the next steps for research on triple therapy?

Hanania: We're in the era with COPD of phenotyping, and of course endotyping. And it's always nice to know who would be the most responsive to triple therapy. I have to underline the fact that ICS in COPD have been overused for many years and continue to do so. We know that the GOLD strategy and American Thoracic Society guidelines for COPD emphasize [them] and inhaled steroids should be entertained in patients with a high risk of exacerbation. There are data that show that patients with high blood eosinophils may be good patients to respond or at least where you can treat them with ICS-containing agents. Those are data are emerging.

What I see in the future is we need more biomarkers to help us subdivide these patients to better personalize the approach for this disease. We are there partly but not completely. I think it would be nice to know which of the phenotypes responds best to triple therapy. If the effect of mortality is correct, should that be taken seriously for patients with moderate COPD? We don't know that. The patients enrolled in these studies all had severe COPD with history of exacerbation. But is there an effect on modifying the disease by giving these patients triple therapy early in the disease? We have no idea whether that's true. Until we do, we shouldn't be rushing into using it as first-line therapy. Disease modification is a big unmet need in COPD, as it is in asthma and other airway diseases. Can we modify the disease? We know smoking cessation does. We have not seen any drugs so far, other than oxygen therapy, that can reduce mortality. Now the triple therapy can in the subpopulation of severe disease. Can they do so in patients with early COPD? We don't know yet. That's a big unmet need. But that requires huge studies, commitment, and long-term follow up. I think that is an unmet need and it answers an important question. Another unmet need is developing more biomarkers in COPD. Now we are looking at not only biomarkers biologically, but also radiologic biomarkers that may help [providers]. If I see a computed tomography (CT) scan, I will decide, well, this patient may respond best to this treatment versus that. Radiologic biomarkers are emerging, I think it's a great tool. It's not ready for primetime use in clinic yet. That's another unmet need, is developing new biomarkers for this disease.

AJMC^®: In your opinion, what does the future of COPD research look like, taking into account the COVID-19 pandemic, and rises in risk factors like vaping and air pollution? What are other priorities in this field?

Hanania: I think you can look at this at different levels. I think for many years, we sort of thought about COPD as the “blue bloaters” and the “pink puffers” and it was a simple disease, one size fits all. But that is not true. In the year 2021 now, we know that this disease has multiple faces, multiple phenotypes and also endotypes. We're still working on those. Endotypes reflect the mechanism of the disease. On a genetic part, there's quite a bit of data accumulating about the potential gene, or susceptible genes for COPD that need to be elaborated upon and continued. On an environmental part, we know that not all COPD patients are smokers. There are other exposures that need to be looked at. But what about the nonsmokers with COPD? We don't know too much about those, but they do exist, [and account for] maybe 20% of patients with COPD. The contribution of other exposures like vaping [should be explored]. Secondhand smoke is something that needs to be looked at.

On a biologic level, we need to look at more the mechanisms, biomarkers, and mediators so that we can target biologics. Right now, there are several studies ongoing to look at biologics in COPD, these are using monoclonal antibodies or small molecule inhibitors. It'd be nice if we shut down the cascade of inflammation in COPD. Can we prevent the disease from progressing? We don't know yet. There are also other targeted therapies to look at mucociliary dysfunction, mucus hypersecretion. We need some drugs to look at remodeling and restructuring of the airway and destruction of the lung. That's another area that needs to be looked at.

On a clinical level, I think we've done quite a bit on phenotyping of this disease. We know some of the clinical tools to divide the patients on exacerbators, or those with chronic bronchitis and those with emphysema. I think more tools to help us as clinicians divide these [cohorts are needed].

You can see that the needs are multilevel and starting from the genetic part, the biologic part, the environmental part, and the clinical part, which is good in a way. It keeps us busy as COPD researchers. But there's a need for investment in these studies, not only from pharma, but also from other entities and foundations and of course, the NIH, to help us. You mentioned COVID-19 and I think that's another area that is of interest. COVID-19 is here to stay. It did affect our patients with COPD. Unfortunately, they are at higher risk of worsening. There are some data to show that some medication like ICS may be helpful in these patients. How does it fit in the equation? We don't know yet. I think that's something that maybe needs to be also added as one of the unmet needs: is to study more the effect of COVID-19 on this population and post COVID-19, what happens to these patients, which we still don't know.

AJMC^®: Is there anything we did not touch on you would like to include, or do you have any final thoughts you'd like to share?

Hanania: People may be interested in nonpharmacological approaches. There are emerging nonpharmacologic approaches for COPD, such as bronchoscopic lung volume reduction. It's something that we're getting more and more acquainted with. FDA approved a couple of valves that can be implanted in patients with emphysema, which may help their dyspnea and shortness of breath. I think we're seeing an expansion of pharmacologic therapies. I'm very pleased that biologic therapies are being looked at. There is a light at the end of the tunnel for these patients. But we're not there yet. We still need to continue to work on how to improve outcomes.