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 increased over the past 20 years. Even more important,
it is an increasingly common cause of chronic disability 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 cellular and molecular mechanisms and no therapies
that have been shown to slow the relentless progression of the disease.
COPD is caused by long-term exposure to inhaled noxious gases and particles; cigarette smoke
accounts for more than 90 percent of cases in developed countries. In developing countries, the inhalation of smoke from biomass fuels is also an important cause of COPD, particularly among women
who cook in poorly ventilated homes. COPD develops 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 disability from COPD were related to an accelerated decline 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.
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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 mechanisms have been implicated (see Figure). The first
is a loss of elasticity and the destruction of the alveolar attachments of airways within the lung as a
result of emphysema, which results in a loss of support 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 interact 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 2645–2653) provide new information about
the role of small airways in the progression of
COPD, obtained by carefully quantifying the histologic changes in small airways at different stages in
the disease and relating these changes to the impairment in FEV1. A major finding of their study is
the significant association between the severity of
disease, as measured by the percent of the predicted value for FEV1, and the thickness of the walls of
small airways. The increased airway thickness results from infiltration by inflammatory cells (macrophages, 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 association was found between the severity of disease and
the degree of occlusion of the lumen by mucous secretions from surface goblet cells and an inflammatory exudate. A striking feature of the most severe
disease was the presence of lymphoid follicles composed of B lymphocytes surrounded by T lymphocytes, suggesting an acquired immune response,
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Small Airways in COPD
PERSPECTIVE
Chronic Obstructive Pulmonary Disease
Luminal occlusion by secretion
of mucus glycoproteins and
inflammatory exudate
Fibrosis
Loss of elasticity and
disrupted alveolar
attachments
Thickening of
airway wall
Lymphoid follicles in
severe disease
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 attachments 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 follicles. 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 inflammation in small airways as a determinant of the
progression and severity of disease. The inflammatory response in patients with COPD represents an
amplification of the inflammatory response to irritants that is seen in normal smokers.3 The molecular mechanisms underlying this amplification are
uncertain, but they may result from gene polymor-
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phisms. What is remarkable is that the inflammatory 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 rheumatoid 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.
n engl j med 350;26
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Small Airways in COPD
PERSPECTIVE
The study by Hogg et al. also confirms previous
reports that the inflammatory response in the airways of patients with COPD does not resolve on the
cessation of smoking: all the patients with very severe 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 inflammation is unknown, but a clue may be provided
by the increased numbers of activated T lymphocytes, which may include memory T cells that may
perpetuate the chronic inflammatory response. This
hypothesis suggests that immunosuppressant therapies may be of value. The airway inflammation in
COPD appears to be resistant to corticosteroids,
and there appears to be an active cellular mechanism 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
difficult to quantify the narrowing of small airways:
imaging techniques have inadequate resolution,
and physiological measurements are difficult to interpret 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 research.
From the National Heart and Lung Institute, Imperial College,
London.
1. Lopez AD, Murray CC. The global burden of disease, 19902020. Nat Med 1998;4:1241-3.
2. Fletcher C, Peto R. The natural history of chronic airflow obstruction. 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.
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-replacement therapy. Now, most can expect to live for many
years. The time course of this improvement in prognosis is reflected in the data from the Australia and
New Zealand Dialysis and Transplant Registry presented by McDonald and Craig in this issue of the
Journal (pages 2654–2662). These authors examined the long-term survival of children and adolescents who were less than 20 years of age when renalreplacement therapy was provided, and their report
chronicles the marked improvement in expected
survival during the past four decades. Similar improvement in prognosis has been evident throughout the developed world.
n engl j med 350;26
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Renal failure during childhood has profound effects. 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 normal level. A successful transplantation is followed
by improved linear growth, particularly in younger children; improved cognitive performance, as reflected by standardized neurocognitive testing and
school attendance; enhanced psychosocial development; and an improved quality of life for the
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