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Understanding Breathlessness in Mild Chronic Obstructive by yaohongm

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									564                                                  AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 177                           2008


Understanding Breathlessness in Mild Chronic
Obstructive Pulmonary Disease
Dyspnea remains the symptom most feared by patients with               discomfort stopped exercise in the control subjects. The patients
chronic obstructive pulmonary disease (COPD). It limits their          with COPD stopped sooner, had a lower anaerobic threshold, and
ability to exercise, can precipitate hospitalization, and is an        exhibited a significant fall of inspiratory capacity by end-exercise
independent marker for premature death (1). In the last decade,        of over 0.5 L, although there was some intersubject variability
we have made significant progress in understanding the factors that     in this result. By contrast, inspiratory capacity was unchanged
lead to dyspnea, particularly during exercise, in moderate to severe   in the healthy control subjects. The patients with COPD had
COPD. Building on ideas developed in the early 1970s (2),              higher minute ventilation for any given degree of carbon dioxide
O’Donnell and colleagues demonstrated that end-expiratory lung         production and adopted a more rapid shallow breathing pattern
volume rises progressively during exercise in patients with COPD       during exercise. However, their cardiovascular response to exer-
rather than remaining constant or falling, as is the case in healthy   cise was normal and they did not show oxygen desaturation.
subjects (3, 4). As a result of this dynamic hyperinflation (DH), the       The authors reasonably conclude that increased breathless-
work of breathing is greater and the respiratory muscles in the        ness in mild COPD is multifactorial, reflecting a combination of
chest wall operate less efficiently, contributing to the neurome-       increased ventilatory demand, dynamic hyperinflation, and the
chanical disassociation that these authors have proposed as the        impact of a rapid shallow breathing pattern, although this is
principal mechanism for breathlessness in COPD (5). Changes in         more likely to be the consequence of the former factors rather
end-expiratory lung volume at rest after bronchodilators explain       than an independent cause of breathlessness. Some of the mech-
the improved exercise performance with these drugs, although the       anisms identified have been recognized before. The lower an-
rate of increase of DH is generally not affected (6). This is in       aerobic threshold of the patients with COPD may be associated
contrast to situations in which respiratory drive and the metabolic    with a lower level of physical activity and this has certainly been
load on the respiratory system are reduced—for example, after          demonstrated in patients with more severe disease. Ventilation–
oxygen treatment, where baseline mechanics are unaffected but          perfusion abnormalities and the effects of increased dead space
hyperinflation is delayed. Combining these treatments has addi-         help explain the higher ventilatory equivalent during exercise,
tive beneficial effects that were again associated with improved        which was clearly sufficient to prevent oxygen desaturation. How-
lung mechanics during exercise (7). Studies measuring chest wall       ever, the striking abnormality resulting from all these factors
volume noninvasively have complemented and confirmed these              which increased minute ventilation for a given workload was the
findings. However, sometimes lung mechanics can improve but             increase in end-expiratory lung volume, which, by the end of
the patient may adopt a less effective breathing pattern, and this     exercise, was similar to that in patients with much more severe
may explain why they become breathless prematurely and stop            disease. The patients with COPD studied here did have evi-
exercising (8). Changes in lung volume track breathlessness during     dence of small airway disease; such small airway disease, to-
the recovery from exacerbation (9), but the degree of hyper-           gether with accompanying emphysema, may explain the pro-
inflation is not as predictive of the degree of breathlessness in the   longed mechanical time constant necessary to favor dynamic
recovery period from exercise (10).                                    hyperinflation. Previous data suggest that true expiratory flow
    All of these observations have been made in relatively             limitation is uncommon in patients with such well-preserved
severe COPD, and specifically in individuals with significant            spirometry; this should be formally tested in patients, such as
resting hyperinflation of the lungs. There is a paucity of data in      those reported here, using more robust methods of detection (14).
patients with less severe disease. The basis of breathlessness             It is important not to overstate findings of this study. They do not
in milder COPD is not a trivial issue as there are real concerns       demonstrate that all patients with mild COPD show these abnor-
in identifying patients with only modest spirometric abnormal-         malities and would have limited exercise performance. In general
ities, specifically GOLD (Global Initiative for Chronic Obstruc-        clinical practice, other factors could be contributory and there are
tive Lung Disease) stage I, where the FEV1 is above 80%                good data suggesting that heart failure, in particular, is under-
predicted (11). There is a risk of believing disease to be present     diagnosed in patients with milder COPD managed in the community
when this is not the case, a particular problem in the elderly in      (15). Nonetheless, the present results provide clear evidence that
whom the FEV1/FVC ratio in healthy subjects tends toward 0.7           even mild airflow obstruction can be associated with considerable
(12). The article by Ofir and colleagues in this issue of the           physiological abnormalities during exercise and that such abnormal-
Journal (pp. 622–629) is particularly welcome as it presents for the   ities are present early in the natural history of COPD, with worsening
first time a detailed analysis of the mechanisms contributing to        disease severity serving to accelerate the speed with which hyper-
breathlessness in a group of patients with very mild COPD (13).        inflation occurs. Understanding these mechanisms helps us explain
    Twenty-one patients with a mean age of 64 years and an FEV1        to our patients why symptoms occur and plan more sensibly the
of 91% predicted (FEV1/FVC, 0.6) were recruited into Ofir and           management strategies we adopt. Future studies investigating the
colleagues’ study. All complained of some degree of breathless-        relative efficacy of treatment in patients with COPD, such as those
ness, with most having a Medical Research Council rating of 2          described by Ofir and colleagues, are clearly justified.
without another condition that could explain this. Although the
                                                                       Conflict of Interest Statement: P.C. has received funding from GlaxoSmithKline
patients’ spirometry was preserved, the residual volume was            (GSK), Altana, and Chiesi to conduct clinical research trials for COPD; has led
somewhat increased as was the functional residual capacity, and        several large sponsored studies including those by GSK, Roche, Chiesi and Altana;
some showed evidence of emphysema. These patients underwent            and has spoken at meetings supported by these companies and by AstraZeneca,
                                                                       Pfizer/Boehringer Ingelheim, and BOC/Linde.
an incremental cardiopulmonary exercise test recording symptoms
of leg discomfort and breathlessness every minute and measure-
ment of inspiratory capacity at the end of each 2-minute interval.                                              PETER CALVERLEY, M.B. CH.B.
The data were compared with an age-matched group of healthy                                                     Clinical Sciences Centre
subjects who completed the same protocol. The patients with                                                     University Hospital Aintree
COPD tended to be limited by breathlessness, whereas leg                                                        Liverpool, United Kingdom
Editorials                                                                                                                                             565

References                                                                     9. Stevenson NJ, Walker PP, Costello RW, Calverley PMA. Lung mechanics
 1. Rabe KF, Hurd S, Anzueto A, Barnes PJ, Buist SA, Calverley P,                    and dyspnea during exacerbations of chronic obstructive pulmonary
      Fukuchi Y, Jenkins C, Rodriguez-Roisin R, van Weel C, et al. Global            disease. Am J Respir Crit Care Med 2005;172:1510–1516.
      strategy for the diagnosis, management, and prevention of chronic       10. Stevenson NJ, Calverley PM. Effect of oxygen on recovery from maximal
      obstructive pulmonary disease: GOLD executive summary. Am J                    exercise in patients with chronic obstructive pulmonary disease. Thorax
      Respir Crit Care Med 2007;176:532–555.                                         2004;59:668–672.
 2. Potter WA, Olafsson S, Hyatt RE. Ventilatory mechanics and expiratory     11. Enright PL. GOLD stage I is not a COPD risk factor. Thorax 2007;62:
      flow limitation during exercise in patients with obstructive lung               1107–1109.
      disease. J Clin Invest 1971;50:910–919.                                 12. Hardie JA, Buist AS, Vollmer WM, Ellingsen I, Bakke PS, Morkve O.
 3. O’Donnell DE, Revill SM, Webb KA. Dynamic hyperinflation and                      Risk of over-diagnosis of COPD in asymptomatic elderly never-
      exercise intolerance in chronic obstructive pulmonary disease. Am J            smokers. Eur Respir J 2002;20:1117–1122.
      Respir Crit Care Med 2001;164:770–777.                                  13. Ofir D, Laveneziana P, Webb KA, Lam Y-M, O’Donnell DE. Mecha-
 4. O’Donnell DE, Parker CM. COPD exacerbations. 3: Pathophysiology.                 nisms of dyspnea during cycle exercise in symptomatic patients with
      Thorax 2006;61:354–361.                                                        GOLD Stage I chronic obstructive pulmonary disease. Am J Respir
 5. O’Donnell DE, Laveneziana P. The clinical importance of dynamic lung             Crit Care Med 2008;177:622–629.
      hyperinflation in COPD. COPD 2006;3:219–232.                                        `
                                                                              14. Dellaca RL, Duffy N, Pompilio PP, Aliverti A, Koulouris NG, Pedotti
 6. O’Donnell DE, Voduc N, Fitzpatrick M, Webb KA. Effect of salmeterol              A, Calverley PM. Expiratory flow limitation detected by forced
      on the ventilatory response to exercise in chronic obstructive pulmo-          oscillation and negative expiratory pressure. Eur Respir J 2007;29:
      nary disease. Eur Respir J 2004;24:86–94.                                      363–374.
 7. Peters MM, Webb KA, O’Donnell DE. Combined physiological effects          15. Rutten FH, Moons KGM, Cramer M-JM, Grobbee DE, Zuithoff NPA,
      of bronchodilators and hyperoxia on exertional dyspnoea in normoxic            Lammers J-WJ, Hoes AW. Recognising heart failure in elderly
      COPD. Thorax 2006;61:559–567.                                                  patients with stable chronic obstructive pulmonary disease in primary
 8. Aliverti A, Rodger K, Dellaca RL, Stevenson N, Lo MA, Pedotti A,                 care: cross sectional diagnostic study. BMJ 2005;331:1379–1385.
      Calverley PMA. Effect of salbutamol on lung function and chest wall
      volumes at rest and during exercise in COPD. Thorax 2005;60:916–924.    DOI: 10.1164/rccm.200712-1792ED




Thinking Longitudinally in a Cross-sectional World
Asbestos exposure is widely recognized to cause serious and                   fibers. The investigators estimated cumulative fiber exposures
often deadly health effects (1). The World Health Organization                for each worker based on job history and historical records
and the International Labour Organization have called for as-                 of plant industrial hygiene evaluations. As expected, workers
bestos bans worldwide, and more than 40 countries have either                 with the most exposure had the greatest probability of pleural
banned or severely restricted asbestos use (2, 3). The U.S.                   abnormalities. What is striking, however, is the level of adverse
Congress is currently considering legislation entitled the ‘‘Ban              effects in the low-exposed group: 13.9% of workers with cu-
Asbestos in America Act of 2007’’ (4). In this issue of the Journal           mulative exposures estimated between 0.25 and 0.74 fibers/cc-
(pp. 630–637), Rohs and colleagues report dose-dependent pleu-                years showed pleural abnormalities. This compares with a
ral changes identified in a cross-sectional follow-up study of a               current legal permissible exposure limit (PEL) in the United
cohort of workers exposed to asbestos-contaminated vermiculite                States that limits asbestos exposures to 0.45 fibers/cc-years over
originating in Libby, Montana (5). The study has particular rele-             a 45-year working lifetime (8), indicating that a significant
vance to current national and international efforts to control risk           number of workers exposed at the current exposure limit would
from exposure to durable fibers.                                               experience pleural abnormalities. Although arguments persist
   Vermiculite is a mineral that expands when rapidly heated.                 about the extent to which pleural abnormalities are inherently
Expanded vermiculite is used in both industrial and consumer                  harmful, it is clear that the presence of pleural changes demon-
products, such as loose-fill attic insulation, gardening and agri-             strates a physiologic response to durable fibers and is associated
cultural products, and automobile brakes. Between 1925 and                    with increased risk of pulmonary fibrosis, lung cancer, and
1990, the majority of the world’s vermiculite was mined in Libby,             mesothelioma (1).
Montana. Amphibole minerals, including tremolite asbestos,                        A notable aspect of this study is the contemporary classi-
contaminated the Libby vermiculite products (6).                              fication of the fibers contaminating the Libby vermiculite. In
   In 1980, following reports of bloody pleural effusions at one              1980, these fibers were classified as ‘‘tremolite asbestos’’ and, as
industrial site, Lockey and colleagues examined 513 workers                   such, fit within the definition of regulated asbestos fibers (8).
exposed to Libby vermiculite; 2.2% showed radiographic evi-                   (U.S. regulations define asbestos as one of six specific mineral
dence of either interstitial fibrosis or pleural changes consistent            fibers that are or have been of commercial value.) The current
with asbestos effects (7). This was an important finding at the                study notes that the primary durable fibers contaminating the
time, especially since exposure to vermiculite had been thought               vermiculite are winchite and richterite with perhaps 10% trem-
by many to be essentially benign and knowledge of the contam-                 olite asbestos; however, winchite and richterite are not explicitly
ination of Libby vermiculite was limited. The Rohs and col-                   regulated as asbestos. This investigation does not prove that the
leagues’ study examines the same cohort of workers 25 years                   health effects of these fibers are identical to tremolite; however,
later. The proportion of affected workers has risen to 28.7% for              their chemical and physical properties are virtually identical to
pleural changes and 2.9% for fibrosis, despite no known interim                tremolite, indicating the importance of evaluating potentially
exposure to asbestos. These findings are consistent with the well-             harmful fibers not only on whether they meet a mineralogical
known capability of asbestos to cause both malignant and non-                 definition of asbestos but also on their biologically relevant
malignant changes years after an original exposure—effects that               features of durability, biopersistence, shape, size, and surface
increase as residence time of the inhaled, biopersistent fibers                characteristics. The Ban Asbestos Act explicitly expands the
lengthens (1).                                                                definition of asbestos to include winchite and richterite (4). The
   The current study makes important new contributions to                     U.S. National Institute for Occupational Safety and Health has
our understanding of the consequences of exposure to durable                  circulated a draft ‘‘Roadmap for Scientific Research’’ proposing

								
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