Editorials
Chronic Obstructive Pulmonary Disease
Does Occupation Matter?
In the current issue of the Journal (pp. 994–1000), Harber and
colleagues present a longitudinal analysis of participants in the
Lung Health Study with chronic obstructive pulmonary disease
(COPD), which showed that ongoing occupational exposure to
fumes was associated with an increased rate of decline of FEV1
(1). The increased decline was restricted to men. These results
underscore that, in addition to causing COPD, occupational
exposures to inhaled irritants can cause an accelerated rate of
decline in FEV1 in patients who already have COPD.
The importance of occupational exposures as a risk factor for
COPD was observed in the 1950s by Fletcher and other
pulmonary epidemiologists (2). Unfortunately, in the ensuing
several decades, the impact of smoking as a risk factor for
COPD was perceived as so overwhelming that interest in other
risk factors faded away. During the 1970s and 1980s, however,
several general population studies and occupational cohort
studies were published in which occupational exposure to gases,
dusts, and fumes was demonstrated to be a risk factor for
COPD and/or accelerated decline of FEV1 (3, 4). In 2002, this
work was summarized in an official American Thoracic Society
(ATS) statement, which concluded that the attributable fraction
of COPD due to occupational exposures was 15 to 20% (5). The
data reviewed suggest that occupational exposures add an extra
decline in FEV1 of 7 to 8 ml/year.
Since the ATS document was published, at least four addi-
tional studies have been published that support occupational
exposures as an important risk factor for COPD (6–9). In a
cross-sectional study of the United States’ general population
(Third National Health and Nutrition Examination Survey),
significantly increased risks for COPD (defined as FEV1/FVC ,
70% and FEV1 , 80%) were found among workers in a number
of industries, including plastic, textile, rubber and leather
manufacturing; food products manufacturing; transportation
and trucking; automotive repair; agriculture; construction; office
services (e.g., professional cleaning); personal services (e.g.,
beauty care); the armed forces; and health care (6). The attrib-
utable fraction for occupation was estimated to be 19% (31%
among never-smokers). In another population-based study from
the United States, the attributable fraction for occupational
exposure to gas, dust, and fumes was again estimated at 20%
(7). In a longitudinal study from Sweden, mortality data were
investigated for 300,000 construction workers, and those
exposed to fumes and mineral dust had significantly higher risk
of death due to COPD (8). In an Australian cross-sectional
study, occupational exposure to biological dust was associated
with increased risk of COPD (different definitions were used),
with risks being higher in women than in men (9).
In the study by Harber and colleagues, men with COPD who
had continuing occupational exposure to fumes had an accel-
erated rate of loss of ventilatory function. After adjusting for
baseline FEV1, age, bronchial hyperresponsiveness, and yearly
smoking status, the annual additional decline was 0.25% of
Am J Respir Crit Care Med Vol 176. pp 951–953, 2007
Internet address: www.atsjournals.org
predicted, roughly corresponding to about 10 ml/year. At this
rate, after 30 years of fumy work, the cumulative loss would be
300 ml or about 7.5% of predicted FEV1, a loss that could be of
clinical relevance. This estimated loss is based on the mean
effect observed in the Lung Health Study population. For some
individuals, the amount of ventilatory function lost would be
much greater.
The main lesson for the clinician from the work of Harber
and colleagues is that when caring for patients with COPD of
working age, one must consider ongoing occupational exposures
to inhaled irritants. A critical question to ask these patients is
whether they are working in jobs with exposures to fumes, such
as those in agriculture, metal fabrication, construction, profes-
sional cleaning, and beauty care.
Should a patient with COPD remain in his/her usual job if it
involves exposures to gases, dusts, or fumes? We lack adequate
data to fully answer this question. The results of one study
showed that subjects with COPD and ongoing occupational
exposure to gases, dusts, and/or fumes have increased disability
and health care utilization compared with unexposed subjects
with COPD (10). To remove someone from his/her job can have
devastating psychological, social, economic, and physical health
consequences. Reduction of exposure to inhaled irritants
through engineering controls (e.g., process enclosure or local
exhaust ventilation) or respiratory protective equipment (e.g.,
masks or respirators) is preferable. Our judgment based on
clinical experience is that workers with COPD as far as possible
should remain at their workplaces. However, such a decision
must be combined with efforts to reduce exposures to irritants
and monitor clinical status over time to ensure that disease
management is not being compromised.
Conflict of Interest Statement: Neither author has a financial relationship with a
commercial entity that has an interest in the subject of this manuscript.
KJELL TORÉN, M.D., PH.D.
Göteborg University Göteborg, Sweden
JOHN BALMES, M.D.
University of California, San Francisco
San Francisco, California
References
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Katz PP, Blanc PD. The occupational burden of chronic obstructive
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Daily Cyclophosphamide for Scleroderma
Are Patients with the Most to Gain Underrepresented in this Trial?
In diffuse fibrosing lung disease, therapeutic studies have been
inconclusive. Statistically significant treatment effects are re-
ported in a number of placebo-controlled studies (1–3). How-
ever, the clinical benefits of these effects have been uncertain in
idiopathic pulmonary fibrosis (1), sarcoidosis (2), and, until
now, pulmonary fibrosis in scleroderma (SSc) (3). In particular,
it is not known whether apparent benefits after a limited period
of treatment translate into changes in longer term outcome.
Tashkin and colleagues make a radical and very welcome
departure from usual practice in this field. They had previously
reported the first placebo-controlled evidence of a therapeutic
effect with cyclophosphamide in patients with SSc and lung
disease (3). Their follow-up data, reported in this issue of the
Journal (pp. 1026–1034) (4), show clearly that the beneficial pul-
monary effects of oral cyclophosphamide persist for 6 months after
cessation of treatment but are largely lost at 1 year. The internal
consistency of the observations is reassuring—the trends with
regard to the primary endpoint (FVC) and a number of secondary
endpoints were strikingly similar at all time points. There was
uniformity in the lack of a treatment effect on measures of gas
transfer (which are notoriously subject to confounding by pulmo-
nary vascular disease in SSc). The findings, including those during
follow-up, were robust when an alternative logistic analytic strat-
egy was used. Overall, the follow-up data reinforce the credibility
of the earlier report and establish that therapeutic benefits from
short-term oral cyclophosphamide do not endure for very long.
Taken together, the two reports clearly show that the treat-
ment effect amounts largely to the prevention of progression of
fibrotic disease. During the first year, group differences were
ascribable to declines in FVC in the placebo group, and par-
ticularly in patients with more extensive fibrosis on computed
tomography. After cessation of cyclophosphamide, the thera-
peutic effect was lost because disease progression occurred se-
lectively in previously treated patients with more advanced
disease. The observations amply justify the pathogenic concept
of an alveolitis in SSc—that inflammation precedes and leads to
fibrosis— but, paradoxically, it appears that treatment benefits
across SSc apply more to predominantly fibrotic than to inflam-
matory disease. If so, the notion that reversible pulmonary dis-
ease must be present, to justify prolonged therapeutic interven-
tion in SSc, is incorrect. The findings of Tashkin and colleagues
are consistent with the view that, for patients with progressive
pulmonary fibrosis, stability is tantamount to therapeutic success.
Herein lies the problem. It is correct to question whether the
average absolute effect on FVC of 2.5% is worth the price of
cyclophosphamide toxicity, especially if the benefit of treatment
is transient. However, it can be argued that an ‘‘average treat-
ment effect’’ is a meaningless mean value when extrapolated to
individual patients in clinical practice. Conventionally, the great
desideratum in therapeutic studies is placebo-controlled evalu-
2007
9. Matheson MC, Benke G, Raven J, Sim MR, Kromhout H, Vermeulen
R, Johns DP, Walters EH, Abramson MJ. Biological dust exposure in
the workplace is a risk factor for chronic obstructive pulmonary
disease. Thorax 2005;60:645–651.
10. Blanc PD, Eisner MD, Trupin L, Yelin EH, Katz PP, Balmes JR. The
association between occupational factors and adverse health outcome
in chronic obstructive pulmonary disease. Occup Environ Med
2004;61:661–667.
DOI: 10.1164/rccm.200707-1003ED
ation. In reality, placebo-controlled studies are subject to major
selection biases, especially when open therapy is available. In a
recent placebo-controlled study of intravenous cyclophospha-
mide in SSc (5), patients and referring physicians preferred open
therapy when disease was overtly severe or progressive (personal
communication, R. K. Hoyles). In the studies of Tashkin and
colleagues, the FVC at baseline exceeded 70% of predicted in
approximately half the cohort and, during the follow-up period,
open therapy was thought by the primary treating physician to be
necessary in only 24 of 113 patients. If severe, more progressive
disease is indeed seriously underrepresented, the attainment of
complete stability with treatment should not be discounted, sim-
ply because an average treatment effect is small. For these rea-
sons, the small but significant benefits of infliximab in sarcoidosis
(2), and marginally significant benefits of intravenous cyclo-
phosphamide in SSc (5), should not be dismissed too readily.
How, then, can clinicians apply the findings of this study to
routine practice? Crucially, the treatment effect was largely
confined to patients with more advanced disease, and was there-
fore much larger in this subgroup. In SSc, an FVC benefit of
approximately 9% was reported in open trials of oral cyclo-
phosphamide (6). If patients with less extensive and progressive
disease are selectively enrolled in a placebo-controlled study, those
with aggressive disease, justifying vigorous therapeutic measures,
may be overrepresented in pilot reports of open treatments. If so, it
can be argued that the true ‘‘average treatment effect’’ of oral
cyclophosphamide is likely to lie somewhere between that in the
study of Tashkin and colleagues and that reported in open pilot
studies: clinicians should, therefore, reasonably hope for a much
larger benefit in patients with severe or overtly progressive disease.
The follow-up data provided by this study are also highly
informative when the balance between therapeutic efficacy and
toxicity is considered. In patients with more extensive fibrosis and a
higher likelihood of disease progression, early benefits from treat-
ment are more likely to outweigh the cumulative risk of long-term
complications, such as malignancy. However, the dissipation of
most benefits of cyclophosphamide after 18 months strongly
suggests that prolonged immunosuppression is needed to main-
tain stabilization. Previous studies of long-term daily oral cyclo-
phosphamide treatment of lupus nephritis and Wegener’s gran-
ulomatosis, conditions that have a high relapse rate when treated
for only 1 year, document increasingly unacceptable levels of
toxicity associated with longer treatment duration (6, 7). In the
long-term National Institutes of Health trial of immunosuppres-
sion for lupus nephritis, daily oral cyclophospamide treatment,
when compared with monthly intravenous cyclophosphamide (which
markedly reduces cyclophosphamide exposure), was associated
with a higher 20-year mortality (0.58% vs. 0.20%) (8). In Wegener’s
patients treated with daily cyclophosphamide for 2 to 3 years, with
cumulative doses sometimes exceeding 100 g, severe complications