Am J Physiol Lung Cell Mol Physiol 321: L983–L987, 2021.

First published October 6, 2021; doi:10.1152/ajplung.00400.2021

PERSPECTIVES

A rapidly changing understanding of COPD: World COPD Day from the COPD
Foundation
Byron M. Thomashow,1,2 David M. Mannino,1,3 Ruth Tal-Singer,1 and James D. Crapo1,4
1
COPD Foundation, Miami, Florida; 2Department of Medicine, Columbia University, New York, New York; 3Department of
Medicine, University of Kentucky College of Medicine, Lexington, Kentucky; and 4Department of Medicine, National Jewish
Health, Denver, Colorado

Abstract
World COPD Day raises awareness about chronic obstructive pulmonary disease (COPD). COPD accounts for over 150,000 US
deaths per year. A major challenge is that COPD receives only a fraction of the research funding provided to other major dis-
eases. Control of COPD is dependent on developing new approaches to diagnose the disease earlier with a recognition of ei-
ther pre-COPD or established COPD based on symptoms, lung structural change and/or loss of lung function that occurs before
meeting long established criteria for a population-based definition of obstruction. Optimization of current therapies improves
lung function, exercise capacity, quality of life, and survival. New pathways of disease progression are being identified creating
new opportunities for development of therapies that could stop or cure this disease.

classification; COPD; definition; editorial; treatment

INTRODUCTION EXPANDING THE PATHOGENESIS OF COPD

World COPD Day was organized by the Global Initiative
for Chronic Obstructive Lung Disease (GOLD) and launched
in 2002. The objective of World COPD Day is to raise aware-
ness about chronic obstructive pulmonary disease (COPD)
and to improve COPD care globally (1). This year it will be
held on November 17 and its theme is “Healthy Lungs–Never
More Important.” This year’s aim is to highlight the ongoing
high burden of COPD in the midst of the COVID-19 pan-
demic. Over 15 million Americans have been diagnosed with
COPD with an equal number suspected of having COPD
but undiagnosed. Worldwide estimates suggest over 300 mil-
lion are affected. In 2019, data from the World Health
Organization listed COPD as the third leading cause of death
worldwide trailing only ischemic heart disease and stroke
(2). Recent data report COPD as the sixth leading cause of
death in the United States, decreased from a prior listing of
fourth, but this change appears to reflect increased deaths
from COVID-19, unintentional drug overdoses, and stroke
(3). COPD still accounts for over 150,000 US deaths per year
and remains a major cause of morbidity and disability.
COPD is almost always preventable and despite common
misconceptions, almost always treatable.
Leading groups across the world are calling for an
expanded approach to diagnose and treat COPD. The mission
of the COPD Foundation includes finding a cure for COPD,
and the Foundation supports multiple research programs to
better understand and treat patients at risk for or with COPD.
Celli and Agusti (4) pointed out that it is no longer tenable
to consider COPD as a single disease simply defined by a pro-
gressive loss of lung function and recommended expanding
the taxonomy of the disease to include principles outlined in
the 1980s by J. G. Scadding—i.e., 1) symptoms, 2) structure,
3) function, and 4) causation. They also recognize the impor-
tance of understanding the early stages of COPD that they
term pre-COPD (Fig. 1).
DIAGNOSING COPD EARLY AND
IDENTIFYING PRE-COPD
One of the critical issues in managing COPD is that the dis-
ease is commonly diagnosed late when impairment is severe
and treatments are primarily palliative other than recom-
mendations to stop smoking, control respiratory infections,
and/or limit exposures to other offending conditions.
Finding a cure for this disease will require identifying it in
its earliest stages and characterizing the primary pathways
that underlie progression and that can provide targets for
therapeutic interventions. Identifying the early beginning of
COPD, particularly in the subset of people who are at high
risk for rapid progression, is critical. Individuals in the early
stages of COPD do not commonly have a low forced expira-
tory volume in the first one second (FEV1)/forced vital
capacity of the lungs (FVC), which is the current definition
of obstruction. They may develop an airway or alveolar

Correspondence: J. D. Crapo (crapoj@njhealth.org).

Submitted 29 September 2021 / Accepted 29 September 2021

http://www.ajplung.org 1040-0605/21 Copyright © 2021 the American Physiological Society. L983

 A RAPIDLY CHANGING UNDERSTANDING OF COPD
Figure 1. Proposed taxonomy of chronic obstructive pulmonary diseases
(COPDs) using the principles of Scadding. Different etiologies can be re-
sponsible for the expression of COPDs with or without airflow limitation.
[From Celli and Agusti (4). Reproduced with permission of the ©ERS 2021:
ERJ Open Research.]
inflammatory process and can have significant symptoms
and disease progression long before they show a fall in the
FEV1/FVC to meet the classic definition of airway obstruc-
tion and COPD.
It is well established that chronic airway obstruction,
defined as the ratio of the forced expiratory volume in the
first one second to the forced vital capacity of the lungs
(FEV1/FVC) below 0.7, has a strong positive correlation with
COPD-related hospitalization and mortality. This hard defi-
nition of obstruction, however, is based on a population
range of normal and ignores both individual variability and
a disease process that involves concurrent loss of both FEV1
and FVC resulting in preserved ratio impaired spirometry
(PRISm) physiology (5). Many cohorts worldwide have
described signs and symptoms of COPD in people who have
no obstruction (FEV1/FVC above 0.7). Han et al. (6) in 2021
proposed defining these subjects (previously defined as nor-
mal or GOLD 0) as “Pre-COPD” (Fig. 2). This approach should
stimulate important new findings and enable development
of therapies to control or eliminate COPD early in its develop-
ment. The Copenhagen General Population Study (7) recently
Figure 2. Conceptualized understanding of the relationships among
symptoms, structure, and function with respect to pre-COPD. COPD,
chronic obstructive pulmonary disease; CT, computed tomography. [From
Han et al. (6). Reprinted with permission of American Thoracic Society.
Copyright © 2021 American Thoracic Society. All rights reserved.]
L984 AJP-Lung Cell Mol Physiol  doi:10.1152/ajplung.00400.2021  www.ajplung.org
demonstrated that chronic respiratory symptoms and a his-
tory of asthma, bronchitis, or pneumonia identified sub-
groups of young smokers with the highest risk of progression
to COPD.
EXPANDING THE DIAGNOSIS OF COPD
The COPDGene project includes a focus on diagnosing this
disease early and identifying study participants who are at
the greatest risk of disease progression. In 2019, a special issue
of the Journal of the COPD Foundation proposed an expanded
diagnosis of COPD that would take advantage of clinical infor-
mation in four areas: exposure, symptoms, lung function, and
lung imaging. To identify these individuals, expanded criteria
for diagnosis have been applied as shown in Fig. 3 (8).
The proposed expansion of the diagnosis of COPD using
COPDGene 2019 criteria would include a low FEV1/FVC as
only one contributing factor and recognize the important
impact of symptoms and structure in making this diagnosis.
It incorporates additional clinical considerations including
symptoms, lung structure, and loss of FEV1 without requir-
ing a low FEV1/FVC. Pre-COPD would be defined by the
strength of multiple elements of diagnosis. A diagnosis of
COPD would appropriately be assigned as the disease pro-
gresses in expression of all factors in the diagnosis. Although
not all patients progress to COPD as defined by a low FEV1/
FVC, many individuals in this expanded category have poor
health status and experience worsening exacerbation epi-
sodes requiring emergency room visits or hospitalization (9).
Patients showing PRISm physiology and who are smokers
have been shown to have a substantial risk of COPD disease
progression and mortality (10, 11). Already in general medical
care, a form of this approach to the diagnosis and treatment
of COPD is common as demonstrated by the fact that a sub-
stantial portion of patients with a smoking history but an
FEV1/FVC above 0.7 are receiving bronchodilator and/or
Figure 3. Proposed expanded criteria for diagnosing chronic obstructive pul-
monary disease (COPD). Four major criteria are used as important contribu-
tors to a diagnosis of COPD: 1) exposure includes both current and former
cigarette smoking and occupational and environmental exposures; 2) symp-
toms include chronic bronchitis and dyspnea that would be grade 2 by
mMRC (modified Medical Research Council); 3) computed tomography (CT)
imaging with a finding of >5% emphysema, airway wall thickening, or >15%
gas trapping; and 4) spirometry with a demonstration of a forced expiratory
volume in the first one second (FEV1) below 80% predicted or a ratio of FEV1
to forced vital capacity of the lungs (FEV1/FVC) below 70% predicted.
Definitions of Pre-COPD or COPD require exposure and one to three addi-
tional factors. [From Lowe et al. (8). Modified with permission from Chronic
Obstructive Pulmonary Diseases: Journal of the COPD Foundation.]
 A RAPIDLY CHANGING UNDERSTANDING OF COPD
inhaled corticosteroids (ICS) therapy (which are only studied
and approved for COPD and asthma). The most common
clinical criterion used for prescribing a bronchodilator is
dyspnea rather than the results of lung function assessment
demonstrating low FEV1/FVC.
EXPLORING NOVEL PATHWAYS FOR COPD
PROGRESSION
Machine learning applied to data in the COPDGene cohort
after more than 7 years of follow-up for disease progression
and mortality has identified unique patterns of disease pro-
gression (12, 13). This study included both current and for-
mer smokers with a substantial history of smoking. Two
patterns of disease progression that showed strong associa-
tions with mortality are an emphysema-predominant path-
way (EPD) and an airway-predominant pathway (APD).
Subjects in the EPD pathway developed emphysema early,
often while still in the range that is considered to have nor-
mal physiology, and are shown in the right upper quadrant
in Fig. 4. These subjects progressed in a classically defined
pattern with a falling FEV1/FVC and then being present in
GOLD categories 1, 2, 3, and 4. In contrast, patients with air-
way-predominant disease (APD) initially developed little
emphysema and progressed primarily by a concurrent loss
of both FEV1 and FVC, which would place them in the left
upper quadrant of Fig. 4, which has been determined as
PRISm. Current data suggest that many of these patients de-
velop emphysema late but have a highly aggressive form of
COPD, commonly progressing directly to GOLD 2, 3, or 4. A
serious limitation of accepting a low FEV1/FVC as an abso-
lute requirement to diagnose chronic lung obstruction is
that patients having PRISm physiology have been largely
ignored in clinical studies. To date, there have been no
Figure 4. Primary pathways for chronic obstructive pulmonary disease
(COPD) progression. Principal components analysis of smokers identifies
two major distinct pathways for disease progression and of mortality.
Subjects in the highest 20% mortality risk in the emphysema-predominant
pathway (EPD) are shown in blue. Subjects in the highest 20% mortality
risk in an airway-predominant pathway (APD) are shown in red. Subjects
that are in the highest 20% mortality in both the EPD and APD pathways
are shown in yellow. [From Young et al. (12). Modified with permission
from Chronic Obstructive Pulmonary Diseases: Journal of the COPD
Foundation.]
AJP-Lung Cell Mol Physiol  doi:10.1152/ajplung.00400.2021  www.ajplung.org
clinical trials involving patients who smoke and who develop
PRISm physiology.
OPTIMIZING THERAPY FOR COPD
There are increasing efforts to move away from viewing
and treating all COPD the same. The concept of “treatable
traits” appears to be gaining popularity (14). These treatable
traits include symptoms, exacerbations, reactive airways,
oxygenation requirements, the presence of emphysema,
chronic bronchitis, and polymorbidity. Bronchodilators
remain the mainstay of COPD therapy. Evidence suggests
that combining bronchodilators, long-acting muscarinic
antagonists (LAMA), and long-acting b-2 agonists (LABA), is
more effective than monotherapy alone with no greater risk
of side effects (15). Increasing evidence suggests the impor-
tance of adding inhaled corticosteroids (ICS) for frequent
exacerbators, particularly those requiring hospitalization
(16, 17). Combinations of LAMA, LABA, and ICS are now
available in single devices easing delivery. Pulmonary reha-
bilitation improves dyspnea, health status, and exercise tol-
erance, reduces symptoms of anxiety and depression, and
appears to reduce rehospitalization in those recently hos-
pitalized with exacerbations (18). Noninvasive ventilation
decreases the need for intubation in those with severe
exacerbations and appears to reduce readmission rates in
selected patients with hypercarbia (19). Oxygen can
improve mortality in patients with hypoxemia (20). And,
in carefully selected patients with emphysema, lung vol-
ume reduction surgery has been shown to improve lung
function, exercise tolerance, quality of life, and survival
(21). More recently, bronchoscopic lung volume reduction
has been shown to improve lung function and quality of
life in selected patients (22).
Important challenges remain in COPD. Although diagnos-
ing COPD continues to require spirometric confirmation,
many if not most with COPD are diagnosed without spirome-
try. And confirmation of postbronchodilator obstruction is
even less commonly obtained. If the ongoing large validation
study of CAPTURE (COPD Assessment in Primary Care to
Identify Undiagnosed Respiratory Disease and Exacerbation
Risk) confirms earlier results, the CAPTURE approach, which
includes a short questionnaire and peak flow testing, could
provide a better way to determine who needs spirometry
(23). A recent study in general practice in Okinawa, Japan
has demonstrated the utility of CAPTURE in identifying
undiagnosed PRISm and COPD (24). Although bronchodila-
tors can often be very effective and well tolerated, many
patients do not renew prescriptions, whether out of conven-
ience or to decrease cost, preferring to limit their dyspnea by
cutting back their activity, an approach often doomed to fail.
We need to do a better job choosing the right device for the
specific patient and instructing patients on how to use the
inhalers correctly, using “Teach-Back” approaches (25, 26).
Although ICS have an important additive role in COPD, evi-
dence suggests ICS are overused in patients with high grades
of emphysema and COPD such as GOLD 3 and GOLD 4
patients. Overuse of ICS in this population increases the risk
for pneumonia, cataract, and osteoporosis (27). ICS or other
anti-inflammatories have not been studied in patients who
L985
 A RAPIDLY CHANGING UNDERSTANDING OF COPD
have a predominate airway inflammatory disease and who
are progressing through the PRISm pathway.
Although overwhelming data suggest the effectiveness of
pulmonary rehabilitation, only a small percentage of patients
with COPD ever undergo pulmonary rehabilitation, and the
number of pulmonary rehabilitation programs continues to
decrease (28). Efforts are underway to develop validated vir-
tual pulmonary rehabilitation programs that could provide
important options even after the COVID-19 pandemic hope-
fully resolves. Portable oxygen concentrators should allow
more patients with severe COPD to be more active and inter-
active, but these concentrators tend to be expensive, are not
available for all who could benefit, and have limited flow
capacity. COVID-19 has exposed major gaps in oxygen avail-
ability, an issue that has to be resolved. Lung volume reduc-
tion continues to be underutilized. Most with COPD, certainly
almost all with “early” COPD, are diagnosed and treated in
primary care and rarely if ever see pulmonologists unless or
until symptoms and severe acute exacerbations have pro-
gressed. Optimized COPD diagnosis and treatment in primary
care need to be important goals moving forward.
Cigarette smoking remains the most common cause of
COPD and a key driver of susceptibility to poor outcomes
from COVID-19 in individuals with or without COPD, so
smoking cessation and improved control of tobacco products
associated with nicotine addiction and the vaping epidemic
are key priorities for healthcare organizations (29, 30).
However, estimates suggest that more than a quarter of
COPD cases are never smokers. Other risk factors including
biomass smoke and occupational dust exposure are poten-
tially important factors. We continue to know surprisingly
little about nonsmoking COPD and the effectiveness of
therapies in that setting (31).
TOWARD A BETTER FUTURE
Major studies including COPDGene and SPIROMICS
(Study of COPD Subgroups and Biomarkers) suggest that spi-
rometric confirmation of obstruction (required for a COPD
diagnosis) underestimates the presence of emphysema and
airway disease visualized on computed tomography (CT)
scanning (8, 32). An expanded view of COPD and new case
finding tools such as CAPTURE offer the potential to find
patients at an earlier point in their disease course when the
disease may be more modifiable. Unfortunately, despite the
impact of COPD, only one drug of a new class has been
approved for COPD in the past 20 years and that was over 10
years ago. COPD continues to receive only a fraction of the
research funding provided to other major diseases; for exam-
ple, in 2020, COPD funding by the US National Institutes of
Health (NIH) for COPD was $121 M, whereas diabetes was
$1,156 M, dementia funding was $2,795 M, and the rare respi-
ratory disease cystic fibrosis was $95 M (33), which seems
disproportionate with the prevalence and burden of COPD in
the United States. This must change if real progress is to be
made. The COPD Foundation is a patient advocacy not-
for-profit organization dedicated to preventing COPD,
bronchiectasis, and nontuberculous (NTM) lung disease,
improving the lives of those affected, and seeking cures.
The COPD Foundation is partnering with international
stakeholders to advocate for innovation supporting better
L986 AJP-Lung Cell Mol Physiol  doi:10.1152/ajplung.00400.2021  www.ajplung.org
diagnosis, prevention, and care. The COPD Biomarker
Qualification Consortium (CBQC) was created in 2011 (34)
to help fast track regulatory acceptance of new drug devel-
opment tools to enable the development of better treatments.
In 2020, the consortium was expanded to include other
chronic lung diseases. The COPD Foundation’s Digital Health
and Therapeutics Accelerator Network COPD360Net supports
the development and adoption of novel digital health tools,
medical devices, and therapeutics. COPD360Net is raising
funds to support innovative clinical trials that would address
the neglected populations, which are currently excluded from
drug development efforts for COPD.
Advances in the understanding and diagnosis of COPD
open multiple new challenges and opportunities to improve
care. Criteria for the management of disease burden and pre-
vention of disease progression in these groups of patients is
essential. The expanded definition that includes symptoms,
lung structure abnormalities, and PRISm physiology will
increase the number of individuals diagnosed with COPD.
Applying the abovementioned expanded criteria of COPD
should allow earlier diagnosis before irreversible damage has
occurred. It should incentivize funding of research and evi-
dence generation studies to ensure optimal therapies that
address disease burden and disease progression in a popula-
tion that is currently excluded from most clinical trials (35).
DISCLOSURES
D. M. Mannino is a former employee and current shareholder
of GlaxoSmithKline and receives royalties from Up to Date. R. Tal-
Singer is a retiree and current shareholder of GlaxoSmithKline.
She reports personal fees from Teva, ImmunoMet, Vocalis Health,
and ENA Respiratory before 2021. She is a member of the ENA
Respiratory Board of Directors. B. M. Thomashow has served as a
consultant for GlaxoSmithKline and served on Advisory Board for
Boehringer Ingelheim. J. D. Crapo has no conflicts of interest, fi-
nancial or otherwise, to disclose.
AUTHOR CONTRIBUTIONS
B.M.T., D.M.M., R.T.-S., and J.D.C. prepared figures; drafted
manuscript; edited and revised manuscript; and approved
final version of manuscript.
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