Critical Challenges and Compelling Questions for Chronic Obstructive Pulmonary Disease. Moving the Field Forward: A National Heart, Lung, and Blood Institute Perspective

Abstract

Although the National Heart, Lung, and Blood Institute (NHLBI) supports an active and varied portfolio of research pertaining to chronic obstructive pulmonary disease (COPD), there remain several research gaps that, when filled, could significantly help ease the burden of this disease. I use the NHLBI Strategic Vision in this article to identify opportunities for COPD research over the next decade. Filling these gaps will require collaboration between NHLBI, funded investigators, and various other stakeholders. Recent advances, including the development of powerful research technologies and the completion of the COPD National Action Plan, offer new tools that will one day improve the lives of patients with COPD and their families.

The National Heart, Lung, and Blood Institute (NHLBI) has a long history of supporting lung disease research. The bulk of support is through research project grants that are initiated by the research community. When there are barriers to investigator-initiated research, NHLBI is sometimes able to support research enterprises through more directed focusing of funds. Over the past several decades, NHLBI has used targeted funding opportunities to shape the course of research on chronic obstructive pulmonary disease (COPD) (1), the fourth leading cause of death in the United States. Ongoing programs funded by NHLBI continue to produce critically important results that inform the COPD research community, particularly in the areas of genetic contributions, biomarkers and mechanisms of pathogenesis, subpopulations and endotypes, and therapeutic approaches.

In an effort to focus and accelerate heart, lung, blood, and sleep research, including research on COPD, over the next decade, NHLBI recently embarked on a strategic visioning process, soliciting input from a wide range of stakeholders regarding research and training priorities (2). The process resulted in the NHLBI Strategic Vision (3), which includes compelling questions and critical challenges that were submitted by the research community and others. Applying this strategic vision to the issues that are currently of great importance in pulmonary, critical care, and sleep research, the NHLBI Division of Lung Diseases has identified several high-priority goals for research. These generally fall into five broad categories: prevention, disparities, precise treatments, regeneration, and implementation. In the discussion that follows, I use these strategic categories as a framework to highlight important gaps that still exist in the understanding of COPD and discuss how emerging research platforms and tools may be used to fill those gaps over the coming decade (Figure 1). Although this is by no means a comprehensive discussion of gaps related to COPD, the intention of this article is nevertheless to spark discussion on the numerous and, in some cases, underappreciated ways that scientific research can touch fundamental unanswered questions relevant to this disease.

Figure 1.

A model for adapting the NHLBI Strategic Visioning process to identify gaps in COPD research. Compelling questions and critical challenges were submitted by stakeholders in heart, lung, blood, and sleep research and were used to develop the NHLBI Strategic Vision. The NHLBI Division of Lung Diseases applied the Strategic Vision to questions of importance to pulmonary, critical care, and sleep research and identified five overarching themes: prevention, disparities, precise treatments, regeneration, and implementation. COPD-relevant research gaps within these themes are highlighted and discussed further in the text. COPD = chronic obstructive pulmonary disease; NHLBI = National Heart, Lung, and Blood Institute.

Prevention

It is increasingly appreciated that two factors regulate the susceptibility to COPD late in life: the peak lung function obtained in early adulthood and the rate of decline in lung function as the individual ages (4). Both are potentially modifiable in an effort to prevent disease, such as through limiting inhaled environmental exposures. This might be accomplished via behavioral interventions (e.g., smoking cessation treatments) or policy changes (e.g., clean air or indoor smoking laws). Justification for either requires extensive scientific evidence. Although the overwhelming role of smoking in COPD prevalence is well understood (5), and though addressing this remains the most important element of COPD prevention, data derived from Behavioral Risk Factor Surveillance System surveys indicate that a significant fraction of patients with COPD, up to 25%, have never smoked (6). Indeed, other contributions, such as childhood and adult exposure to secondhand smoke, are becoming increasingly appreciated (7). Similarly, recent population-wide changes in behavior, including the growing popularity of electronic cigarettes (8) and changes to the legal status of cannabis, increase the urgency for understanding the health effects of these activities, particularly whether their long-term use predisposes to COPD.

Disparities

Most large studies underway in COPD research are limited to studying patients who receive care through academic medical research centers with strong COPD clinical research programs. In fact, the prevalence and mortality of COPD are also found elsewhere, especially in poorer and more rural communities. Behavioral Risk Factor Surveillance System data show a striking overrepresentation of both COPD diagnosis and mortality in rural counties (9). Several factors likely contribute to this disparity. In addition to a greater prevalence of cigarette smoking, there is reason to believe that socioeconomic factors, occupational exposures, and other environmental exposures encountered in these regions likely contribute (10). Furthermore, rural populations might have less access to medical care and pulmonary rehabilitation facilities. More research is clearly needed to better understand factors relevant to COPD that come into play among rural populations.

Precise Treatments

Precision medicine was defined in the Precision Medicine Working Group 2015 report as “an approach to disease treatment and prevention that seeks to maximize effectiveness by taking into account individual variability in genes, environment, and lifestyle” (11, page 1). Because the ways in which COPD presents itself differ so drastically among patients, this disease is a strong candidate for precision medicine approaches. However, there are two broad gaps in the COPD research portfolio that hinder progress in precision medicine: limited understanding of early disease mechanisms and a general lack of animal models that reproduce the disease with fidelity and can be used with confidence for hypothesis testing and drug development. These gaps suggest two interrelated goals: 1) knowledge gained from clinical studies of early disease can be used to develop relevant animal models, and 2) better animal models can be used to test disease-relevant hypotheses. To fill these gaps, investigations are needed at the molecular, cellular, organ, and multiorgan systems levels. The future is bright for these studies. Emerging technologies such as single-cell RNA sequencing, CRISPR/Cas9-based gene manipulations, and novel imaging tools all promise to provide an unprecedented level of clarity regarding disease development mechanisms and to better enable the generation of relevant model systems.

Regeneration

These new tools may also one day help researchers obtain the holy grail of emphysema treatment: enabling the lung to heal and regenerate its disrupted structures. Repair of emphysematous lungs through regeneration has been observed in rodents (12), but this has not yet been reproduced clinically. Why is lung regeneration possible in experimental rodent models but not in humans? Age may be a factor. Patients generally are not diagnosed with COPD until middle age at the earliest; yet, studies using model organisms frequently use animals of an age equivalent to young adults. It has been posited that COPD represents a disease of accelerated aging and that understanding COPD will require understanding the role of cellular senescence and other aging mechanisms in the lung (13) in combination with a thorough understanding of lung cell proliferation and differentiation pathways. Understanding how these pathways govern regenerative processes in the lung may be an especially productive research area in the coming years for COPD and other aging-related lung diseases.

Implementation

Therapeutic approaches and treatments developed through research must be made available to patients and be used if they are to be of value. Unfortunately, there are many hurdles that must be overcome by patients with COPD, their families, and their providers to ensure that optimal care is achieved. For this reason, NHLBI, with considerable input from federal and nonfederal stakeholders, developed the COPD National Action Plan (14). The plan is a blueprint that provides a framework for action by those affected by and interested in the disease. It contains five goals: 1) to empower the people affected by COPD with better knowledge of the disease; 2) to increase healthcare providers’ capability to prevent, diagnose, treat, and manage COPD; 3) to collect, analyze, disseminate, and report COPD-related public health data; 4) to increase and sustain research to better understand COPD; and 5) to translate national policy, educational, and program recommendations into action. By working together to implement the plan, different individuals, societies, agencies, and others can help reduce the burden of COPD.

Conclusions

COPD is a complex, slowly developing disease with varying phenotypes and rates of progression. Each of these factors makes it exceedingly challenging to study and develop novel therapies. This article reports on some of the major gaps in COPD research and positive actions being taken by NHLBI to reduce the burden of this disease. Guided by the NHLBI Strategic Vision and the COPD National Action Plan, major advances are anticipated over the coming decade in understanding the causes and mechanisms of COPD and the development and testing of novel approaches for both treatment and prevention.