PERSPECTIVE
Small Airways in COPD
Peter J. Barnes, D.M., D.Sc.
Chronic obstructive pulmonary disease (COPD) is a
major and growing global health problem. It ranked
as the sixth most common cause of death worldwide
in 1990, and the Global Burden of Disease Study
predicted that it would become the third most
common cause by 2020.1 COPD has already risen
to fourth place and is the only common cause of
death in the United States whose prevalence has in-
creased over the past 20 years. Even more important,
it is an increasingly common cause of chronic dis-
ability and is predicted to become the fifth most
common cause of disability in the world by 2020.
COPD is also an increasingly common cause of
hospital admissions and loss of time from work,
resulting in a major health care expenditure that
now exceeds the costs associated with asthma by
more than a factor of three. Yet among common
diseases, COPD has been relatively neglected, with
less investment in research on its underlying cellu-
lar and molecular mechanisms and no therapies
that have been shown to slow the relentless pro-
gression of the disease.
COPD is caused by long-term exposure to in-
haled noxious gases and particles; cigarette smoke
accounts for more than 90 percent of cases in devel-
oped countries. In developing countries, the inha-
lation of smoke from biomass fuels is also an im-
portant cause of COPD, particularly among women
who cook in poorly ventilated homes. COPD devel-
ops in only a minority of heavy smokers (10 to 20
percent), indicating that there are differences in
individual susceptibility to the effects of cigarette
smoking. The classic epidemiologic studies of
Fletcher and Peto demonstrated that death and dis-
ability from COPD were related to an accelerated de-
cline in lung function over time, with a loss of more
than 50 ml per year in the forced expiratory volume
in one second (FEV1), as compared with a normal
loss of 20 ml per year.2 The progressive reduction
in FEV1 and increasing severity of disease over time
result in increasing shortness of breath on exertion
that slowly advances to respiratory failure.
n engl j med 350;26 www.nejm.org june 24, 2004
Downloaded from www.nejm.org on June 14, 2010 . Copyright 2004 Massachusetts Medical Society. All rights reserved.
There has been much debate about the reasons
for this accelerated loss in FEV1 and its relation to
the pathogenesis of the disease. Three major mech-
anisms have been implicated (see Figure). The first
is a loss of elasticity and the destruction of the alve-
olar attachments of airways within the lung as a
result of emphysema, which results in a loss of sup-
port and closure of small airways during expiration.
The second is the narrowing of small airways as a
result of inflammation and scarring, and the third
is the blocking of the lumen of small airways with
mucous secretions. These three mechanisms inter-
act with one another, and all may be induced by
cigarette smoking and the inhalation of noxious
agents, but the contribution of each mechanism
may vary from person to person. The narrowing of
small airways results in hyperinflation of the lungs,
which are unable to empty; this effect, in turn, results
in dyspnea on exertion and, eventually, even at rest.
Hogg and colleagues in this issue of the Journal
(pages 26452653) provide new information about
the role of small airways in the progression of
COPD, obtained by carefully quantifying the histo-
logic changes in small airways at different stages in
the disease and relating these changes to the im-
pairment in FEV1. A major finding of their study is
the significant association between the severity of
disease, as measured by the percent of the predict-
ed value for FEV1, and the thickness of the walls of
small airways. The increased airway thickness re-
sults from infiltration by inflammatory cells (macro-
phages, neutrophils, and lymphocytes), as well as
from structural changes, including increases in
smooth muscle and fibrosis under the epithelium
and in the outer part of the wall. A weaker associa-
tion was found between the severity of disease and
the degree of occlusion of the lumen by mucous se-
cretions from surface goblet cells and an inflamma-
tory exudate. A striking feature of the most severe
disease was the presence of lymphoid follicles com-
posed of B lymphocytes surrounded by T lympho-
cytes, suggesting an acquired immune response,
2635
PERSPECTIVE Small Airways in COPD

Chronic Obstructive Pulmonary Disease

Luminal occlusion by secretion

of mucus glycoproteins and
inflammatory exudate

Fibrosis

Loss of elasticity and

disrupted alveolar
attachments

Lymphoid follicles in
Thickening of severe disease
airway wall
Goblet cells

Figure. Small-Airway Obstruction in Chronic Obstructive Pulmonary Disease (COPD).

Airflow in small airways (internal diameter, <2 mm) may be limited in COPD by three mechanisms. First, alveolar attach-
ments may have reduced elasticity and become disrupted as a result of emphysema. Second, the airway wall may be
thickened by an inflammatory-cell infiltrate (composed of macrophages, neutrophils, and B and T lymphocytes), by
structural changes (increased thickness of airway smooth muscle and fibrosis), and in severe disease, by lymphoid folli-
cles. Third, the airway lumen may be occluded by mucous secretions (mucus glycoproteins secreted from surface goblet
cells and inflammatory exudate).

possibly to bacterial antigens arising from the
chronic bacterial colonization that is a feature of
severe disease.
This study highlights the importance of inflam-
mation in small airways as a determinant of the
progression and severity of disease. The inflamma-
tory response in patients with COPD represents an
amplification of the inflammatory response to irri-
tants that is seen in normal smokers.3 The molecu-
lar mechanisms underlying this amplification are
uncertain, but they may result from gene polymor-
phisms. What is remarkable is that the inflamma-
tory response in COPD appears to increase with the
severity of disease and therefore with time, rather
than burning out, as it has been shown to do in
other chronic inflammatory diseases such as rheu-
matoid arthritis and interstitial lung disease. This
observation has important implications for future
therapy for COPD and suggests that treatments
directed at these mechanisms should be of value at
all stages of the disease, even in patients with the
most severe illness.

2636 n engl j med 350;26 www.nejm.org june 24, 2004

Downloaded from www.nejm.org on June 14, 2010 . Copyright 2004 Massachusetts Medical Society. All rights reserved.
PERSPECTIVE
The study by Hogg et al. also confirms previous
reports that the inflammatory response in the air-
ways of patients with COPD does not resolve on the
cessation of smoking: all the patients with very se-
vere disease and most of those with severe disease
had stopped smoking many years previously. This
finding suggests that the inflammation, at least in
severe disease, becomes independent of the causal
mechanism. The reason for the persistence of in-
flammation is unknown, but a clue may be provided
by the increased numbers of activated T lympho-
cytes, which may include memory T cells that may
perpetuate the chronic inflammatory response. This
hypothesis suggests that immunosuppressant ther-
apies may be of value. The airway inflammation in
COPD appears to be resistant to corticosteroids,
and there appears to be an active cellular mecha-
nism of corticosteroid resistance.4 New therapies
must target the inflammation in small airways as
well as emphysema in the lung parenchyma.5
Although emphysema is now detectable with the
use of high-resolution computed tomography, it is
Pediatric Renal-Replacement Therapy Coming of Age
Dawn S. Milliner, M.D.
Before the middle of the 20th century, the prospect
that a child with end-stage renal disease (ESRD)
would reach adulthood was essentially nil. Once
dialysis and transplantation became available, that
death sentence was lifted, as increasing numbers
of children with ESRD were offered renal-replace-
ment therapy. Now, most can expect to live for many
years. The time course of this improvement in prog-
nosis is reflected in the data from the Australia and
New Zealand Dialysis and Transplant Registry pre-
sented by McDonald and Craig in this issue of the
Journal (pages 26542662). These authors exam-
ined the long-term survival of children and adoles-
cents who were less than 20 years of age when renal-
replacement therapy was provided, and their report
chronicles the marked improvement in expected
survival during the past four decades. Similar im-
provement in prognosis has been evident through-
out the developed world.
n engl j med 350;26 www.nejm.org june 24, 2004
Downloaded from www.nejm.org on June 14, 2010 . Copyright 2004 Massachusetts Medical Society. All rights reserved.
Small Airways in COPD
difficult to quantify the narrowing of small airways:
imaging techniques have inadequate resolution,
and physiological measurements are difficult to in-
terpret because there is abnormal airflow in larger
airways. Therefore, it will be difficult to assess the
effects of new treatments on small-airway function,
and it will be important to develop new techniques
in order to do so. For now, the data presented by
Hogg et al. focus our attention on the inflammatory
response of small airways, a neglected area of re-
search.
From the National Heart and Lung Institute, Imperial College,
London.
1. Lopez AD, Murray CC. The global burden of disease, 1990-
2020. Nat Med 1998;4:1241-3.
2. Fletcher C, Peto R. The natural history of chronic airflow ob-
struction. BMJ 1977;1:1645-8.
3. Barnes PJ. New concepts in chronic obstructive pulmonary
disease. Annu Rev Med 2003;54:113-29.
4. Barnes PJ, Ito K, Adcock IM. Corticosteroid resistance in
chronic obstructive pulmonary disease: inactivation of histone
deacetylase. Lancet 2004;363:731-3.
5. Barnes PJ. New treatments for COPD. Nat Rev Drug Discov
2002;1:437-46.
Renal failure during childhood has profound ef-
fects. Abnormalities of skeletal development, with
associated growth retardation, affect most patients.
Abnormal neurocognitive development, pubertal
delay, and disordered psychosocial maturation also
occur. Renal-replacement therapy in the form of
dialysis provides only a small fraction of normal
renal clearance. Dialysis alleviates but does not
eliminate uremic symptoms such as fatigue and
anorexia and does not address the nearly universal
abnormalities of growth and development.
In contrast, renal transplantation can provide
renal function that is 40 to 80 percent of the nor-
mal level. A successful transplantation is followed
by improved linear growth, particularly in young-
er children; improved cognitive performance, as re-
flected by standardized neurocognitive testing and
school attendance; enhanced psychosocial devel-
opment; and an improved quality of life for the
2637