|
 |
CONTENTS |
|---|
TOP
CONTENTS
CHRONIC OBSTRUCTIVE PULMONARY...
AIR POLLUTION
PULMONARY VASCULAR AND RELATED...
LUNG TRANSPLANTATION
PLEURAL DISORDERS
LUNG CANCER
REFERENCES
|
|---|
Chronic Obstructive Pulmonary Disease (80)
Genetics (3)
Epidemiology (3)
1-Antrypsin Deficiency (1)
Risk Factors (7)
Cellular, Molecular, and Anatomic Abnormalities (7)
Lung Inflammation (7)
Exhaled Markers (2)
Nitric Oxide (1)
Other Markers (1)
Pathophysiology, Radiology, and Airway Narrowing (8)
Pulmonary Vasculature (1)
Control of Breathing and Exercise (9)
Respiratory Muscles (3)
Peripheral Muscles (3)
Nutritional Status (3)
Health Care Delivery (2)
Drug Therapy (9)
-Agonists (3)
Glucocorticoids (5)
Smoking Cessation (1)
Other Therapies (9)
Lung Volume Reduction Surgery (8)
Expectorants and Mucociliary Clearance (1)
Rehabilitation and Oxygen Therapy (1)
Outcome (2)
Air Pollution (19)
General (11)
Ozone (5)
Diesel Exhaust (2)
Environmental Tobacco Smoke (1)
Pulmonary Vascular and Related Disorders (24)
Pulmonary Hypertension (18)
Secondary Pulmonary Hypertension (3)
Molecular and Pathophysiologic Mechanisms (11)
Treatment (4)
Thromboembolic Disorders (2)
Diagnostic Studies (1)
Molecular and Pathophysiologic Mechanisms (1)
High Altitude (1)
Sickle Cell Disease (3)
Lung Transplantation (13)
Lung Preservation (2)
Patient Selection (1)
Obliterative Bronchiolitis (4)
Animal Models (2)
Cellular and Molecular Mechanisms (1)
Early Detection (1)
Rejection (3)
Immunology and Biochemistry (1)
In Cystic Fibrosis (2)
Pleural Disorders (2)
Diagnostic Techniques (1)
Pleurodesis (1)
Lung Cancer (4)
Diagnosis (3)
Molecular Mechanisms (1)
| |
CHRONIC OBSTRUCTIVE PULMONARY DISEASE |
|---|
|
TOP
CONTENTS
CHRONIC OBSTRUCTIVE PULMONARY...
AIR POLLUTION
PULMONARY VASCULAR AND RELATED...
LUNG TRANSPLANTATION
PLEURAL DISORDERS
LUNG CANCER
REFERENCES
|
|---|
Genetics
To investigate the familial risk for chronic obstructive pulmonary disease (COPD) among siblings of probands with severe
COPD, McCloskey and coworkers (1) enrolled 150 subjects
with airway obstruction and low diffusing capacity (but without PiZ 1-antitrypsin deficiency). Complete data were obtained on 173 of 221 (70%) siblings. Of 126 current or ex-smoking siblings, 44 (35%) had airway obstruction (ratio of
forced expiratory volume in one second to forced vital capacity [FEV1/FVC] of less than 70%). The prevalence of airway obstruction in 419 subjects without a family history of COPD
was lower as compared with the siblings (9 versus 32%), with
an odds ratio of 4.7 for airway obstruction among the siblings.
The authors conclude that the risk of airway obstruction is increased among smoking siblings of patients with COPD.
A polymorphism at position 
308 of the promoter region
of the gene for tumor necrosis factor- is associated with altered secretion of the cytokine. When guanine is present at
this position, the allele is denoted as TNF--308*1. When
guanine is replaced by adenine, the rarer allele, TNF--308*2,
occurs and the level of tumor necrosis factor- is higher. To
determine whether this polymorphism is associated with the
development of COPD, Sakao and coworkers (2) studied 106 patients with COPD, 110 asymptomatic smokers or ex-smokers, and 129 blood donors. The frequency of the TNF--308*2
allele was 17% in the patients with COPD and 8% in each of
the two control groups. The authors conclude that a polymorphism in the promoter region of the tumor necrosis factor- gene (designated TNF--308*1/2) is associated with the presence of COPD.
To determine which genes contribute to the severity of
COPD, Sandford and coworkers (3) genotyped two subsets of
subjects from the Lung Health Study: the 283 subjects with the
fastest rate of decline in FEV1 (154 ml per year) and the 308 subjects with no decline (+15 ml per year). MZ heterozygosity
for the 1-antitrypsin Z allele was associated with a rapid decline in FEV1 (odds ratio, 2.8), and the association was stronger when combined with a family history (odds ratio, 9.7). Homozygosity for the His113/His139 haplotype of the gene for
microsomal epoxide hydrolase, an enzyme in the bronchial epithelium that metabolizes epoxides in cigarette smoke, was associated with rapid decline in FEV1 (odds ratio, 2.4). The rate
of decline was not associated with isoforms of vitamin D-binding protein and tumor necrosis factor polymorphisms. The authors conclude that the MZ genotype for 1-antitrypsin and the His113/His139 haplotype for microsomal epoxide hydrolase
are associated with an increased rate of decline in lung function.
Epidemiology
To project the future burden of COPD in the Netherlands, Feenstra and coworkers (4) used a dynamic life table model that takes into account disease duration, aging, population growth, smoking behavior, and comorbidity. Between 1994 and 2015, the prevalence of COPD (per 1,000 of the population) is estimated to increase from 21 to 33 in men and from 10 to 23 in women. Expected changes in smoking behavior will reduce the projected prevalence to 29 in men but will increase the projected prevalence to 25 in women. Loss of life years will increase by more than 60%, and loss of disability-adjusted life years will increase by 75%. Health care costs are projected to rise by 90% over the 21 years, with smoking accounting for 90% of the costs. Most of the increased prevalence of COPD will result from past smoking behavior and aging. The authors conclude that a marked increase in the prevalence and burden of COPD is unavoidable.
To determine the influence of potential factors on the risk
for hospitalization because of an exacerbation of COPD, Garcia-Aymerich and coworkers (5) did a case-control study. The
cases were patients admitted to hospital with an exacerbation
of COPD. The control subjects were stable at the time that the
referent case was hospitalized but they had previously experienced an exacerbation at the same time as the case. Multiple
logistic regression revealed four factors that influenced the
risk of hospitalization: three or more admissions for COPD in
the preceding years (odds ratio, 6.21); low value of FEV1
(odds ratio, 0.96 for each percentage point); under-prescription of oxygen therapy (odds ratio, 22.6); and current smoking, which had a beneficial effect (odds ratio, 0.30). The authors conclude that a limited number of factors
the number
of previous hospital admissions, a lower FEV1, and under-use of oxygen therapyare independent predictors of admission
to hospital for an exacerbation of COPD.
Fibrinogen is an acute phase reactant, and it may reflect inflammation in the airways and lung. To determine whether plasma fibrinogen is associated with lung function and the rate of hospital admission for COPD, Dahl and coworkers (6) analyzed data on 8,955 adults from the Danish general population. Serum fibrinogen was categorized into three tertiles: less than 2.7, 2.7 to 3.3, and greater than 3.3 g per liter. Compared with smokers in the lowest fibrinogen tertile, predicted FEV1 was 7% lower in the smokers in the upper tertile and 2% lower in the smokers in the middle tertile. Nonsmokers in the upper fibrinogen tertile also had a 6% lower predicted FEV1 as compared with nonsmokers in the other two tertiles. The rate of hospital admission for COPD (per 10,000 person-years) was 93 in the upper plasma fibrinogen tertile, 60 in the middle tertile, and 52 in the lower tertile. After adjusting for confounding factors, the relative risks of admission were 1.7 for subjects in the upper tertile and 1.4 for subjects in the middle tertile, as compared with subjects in the lower tertile of plasma fibrinogen. The authors conclude that increased levels of plasma fibrinogen were associated with impaired lung function and increased risk of hospital admission for COPD, and that the risks could not be explained by smoking alone.
1-Antrypsin Deficiency
To determine the relative power of spirometry, exercise capacity, and quantification of emphysema on computed tomography (CT) in predicting health status, Dowson and coworkers
(7) studied 29 patients with 1-antitrypsin deficiency (PiZ).
Peak oxygen consumption during exercise was predicted by
both FEV1 (r = 0.64) and the extent of lower-zone emphysema
on CT (r = 0.64). Health status, as measured by St. George's
respiratory questionnaire, was related to FEV1 (r = 0.43) and
to the extent of emphysema on high-resolution CT (r = 0.37).
Exercise capacity was the best predictor of health status: performance on an incremental shuttle walking test accounted for
up to 55% of the variability in the respiratory questionnaire and
for up to 53% of the variability for physical function on SF-36
generic questionnaire. The authors conclude that exercise testing
provides the best estimate of the limitations in health status in
patients with lower zone emphysema.
Risk Factors
To determine the role of viral infection in exacerbations of COPD, Seemungal and coworkers (8) studied 83 patients with COPD (FEV1, 42% of predicted). Over 16 months, the patients experienced 321 exacerbations (2.9 exacerbations per patient per year). Exacerbations were associated with increased dyspnea (76%), increased sputum volume (62%), increased wheeze (49%), increased cough (48%), increased sputum purulence (39%), and sore throat (18%). In 64% of exacerbations, a cold occurred in the preceding 18 days. Of 168 reported exacerbations in 53 patients, viruses or atypical bacteria were present in 66 (39%) of nasal aspirates. Of viruses found, rhinovirus accounted for 58% of viral exacerbations. Compared with nonviral exacerbations, viral exacerbations were associated with a higher symptom score and a longer time to recovery (13 versus 6 days). The authors conclude that almost 40% of exacerbations in patients with COPD are associated with a viral infection, and that exacerbations associated with viruses are more severe as compared with nonviral exacerbations. An editorial commentary by Hogg (9) accompanies this article.
The frequency of colonization of the lower respiratory tract with nontypeable Haemophilus influenzae is not well defined. In washes or brush specimens on bronchoscopy, Bandi and coworkers (10) found nontypeable H. influenzae in 6 of 23 (26%) patients with stable chronic bronchitis, in 1 of 15 (7%) patients with an acute exacerbation of chronic bronchitis, and in 0 of 26 healthy subjects undergoing elective surgery. The low recovery in the patients with an acute exacerbation probably resulted from the use of parenteral antibiotics. In five of the nine patients with stable chronic bronchitis, molecular typing revealed different strains of nontypeable H. influenzae in the upper and lower respiratory tract. Intracellular nontypeable H. influenzae were found in bronchial biopsy specimens from 13 of the 15 (87%) patients with an exacerbation, 8 of the 24 (33%) stable patients, and 0 of 7 healthy subjects. The authors conclude that the lower airways of patients with stable chronic bronchitis are frequently colonized with multiple strains of nontypeable Haemophilus influenzae, that cultures obtained from the upper airways differ from cultures from the lower airways, and that intracellular infection with H. influenzae contributes to the pathogenesis of acute exacerbations of chronic bronchitis.
To determine the effect of self-reported lower respiratory illnesses on lung function, Kanner and coworkers (11) analyzed data from 5,887 smokers participating in the Lung Health Study. Individuals entered into an intensive program for smoking cessation had a higher rate of quitting smoking and fewer lower respiratory illnesses as compared with the persons who were simply advised to quit smoking. Sustained quitters had fewer lower respiratory illnesses as compared with persons who continued to smoke. Lower respiratory illnesses accelerated the rate of decline in FEV1 only in persons who continued to smoke. Smokers experiencing one lower respiratory illness a year had an accelerated decline in FEV1, averaging 7 ml per year over 5 years. Smokers with more than one lower respiratory illness a year had greater declines in lung function. Chronic bronchitis was associated with an increased frequency of lower respiratory illnesses, but it did not influence the effect of these illnesses on lung function. The authors conclude that lower respiratory illnesses and smoking have interactive effects on FEV1 in people with mild COPD, and that frequent lower respiratory illnesses in smokers may influence the long-term course of the disease.
To determine whether a diet rich in flavonoids protects against the development of COPD, Tabak and coworkers (12) studied 13,651 subjects participating in the MORGEN Study (the monitoring project on risk factors and health in the Netherlands). The average daily intake of catechins, flavonols, and flavones was 58 mg, with tea and apples being the main source. A higher intake of these three flavonoids (expressed as the difference between the fifth and the first quintile of intake) was associated with an increase in FEV1 of 44 ml and inversely associated with chronic cough (odds ratio, 0.80) and breathlessness (odds ratio, 0.74). The intake of solid fruit (apples, pears), but not tea, was associated with fewer clinical manifestations of COPD. The beneficial effect was stronger for catechins as compared with flavonols or flavones. The authors conclude that a high intake of catechins and solid fruit is protective against the manifestations of COPD.
The role of airway infection in accelerating the decline of lung function in patients with COPD is debated by Wedzicha (13) and MacNee (14), with rebuttals from each (15, 16).
Cellular, Molecular, and Anatomic Abnormalities
The adenovirus targets lung epithelium, and adenoviral transactivating protein (E1A) fosters an exaggerated inflammatory response. To determine whether lung inflammation is increased in patients with emphysema, Retamales and coworkers (17) obtained lung tissue from seven patients with severe emphysema, seven patients with mild emphysema, and seven smokers without emphysema. On CT, the proportion of the lung taken up by emphysema was 43% in the patients with severe emphysema, 13% in the patients with mild emphysema, and 2% in the smokers with normal lung function. The patients with severe emphysema had increased numbers of neutrophils, macrophages, eosinophils, CD4 cells, and CD8 cells in lung tissue and airspaces. The extent of emphysema on CT was correlated with the number of inflammatory cells per surface area; for example, r2 = 0.86 for CD8 cells in lung tissue and r2 = 0.63 for CD4 cells in the airspace. The number of alveolar epithelial cells containing adenoviral transactivating protein was increased 5-fold in the patients with mild emphysema and 41-fold in the patients with severe emphysema. The authors conclude that lung inflammation is increased in patients with severe emphysema and that latent expression of adenoviral transactivating protein by alveolar epithelial cells amplifies this process. An editorial commentary by Shapiro (18) accompanies this article.
Transforming growth factor-1 induces fibroblast proliferation, increased production of extracellular matrix proteins,
and decreased collagen degradation. To study the gene expression levels of this growth factor, Takizawa and coworkers
(19) used an ultrathin fiberscope (biopsy channel 0.8 mm) to
do bronchoscopy. In epithelial cells from the small airways,
messenger RNA levels of transforming growth factor-1 were
higher in 17 patients with COPD (FEV1, 65% of predicted)
and in 18 smokers as compared with 15 nonsmokers. The levels were correlated with the pack-years of smoking in both the
patients with COPD (r = 0.65) and the smokers (r = 0.62), and with the degree of small airway obstruction on flow-volume curves in both the patients (r = 0.76) and the smokers
(r = 0.67). The epithelial cells of the patients and the smokers
showed more intense staining for protein of the growth factor
and increased spontaneous release of the protein as compared
with cells from the control subjects. The authors conclude that
the expression of transforming growth factor-1 is increased
in the epithelial cells of the small airways of patients with
COPD and healthy smokers, and that these cells may be involved in the remodeling and obstruction of the small airways.
Kasahara and coworkers (20) determined whether apoptosis contributes to the loss of alveolar structure in emphysema. The number of apoptotic events in epithelial and endothelial cells of the alveolar septa in the lungs of seven patients with emphysema were twofold higher as compared with the lungs of seven subjects with normal lungs and sixfold higher as compared with the lungs of five patients with primary pulmonary hypertension. Apoptotic events did not differ between the healthy nonsmokers and smokers. Emphysematous lungs had increased levels of oligonucleosomal-length DNA fragmentation, and decreased amounts of vascular endothelial growth factor and of its receptor 2. The authors conclude that the death of epithelial and endothelial cells secondary to a decrease of endothelial cell maintenance factors may be part of the pathogenesis of emphysema.
Because emphysema is believed to result from an imbalance between proteolytic enzymes and their inhibitors, Imai and colleagues (21) examined the lung parenchyma of 23 patients with emphysema and eight normal subjects for metalloelastases. Matrix metalloproteinase-1 (a collagenase) was expressed in type II pneumocytes in all of the patients with emphysema (despite them having stopped smoking for at least three months), but in none of the control subjects. Matrix metalloproteinase 12 was not expressed in the samples. The authors conclude that the secretion of matrix metalloproteinase-1 by type II pneumocytes may contribute to the alveolar destruction in emphysema.
Cavarra and coworkers (22) studied the response to cigarette smoking in mice of differing susceptibility. Acute exposure to cigarette smoke caused a decrease in the antioxidant
defenses in the bronchoalveolar fluid of a strain of mice
(C57BL/6J) that has a mild deficiency in its antielastase screen
and also in a strain of mice (DBA/2) that is sensitive to oxidants. Acute smoke exposure caused an increase in the antioxidant defenses in a strain of mice (ICR) that has a normal antielastase screen and is not sensitive to oxidants. More chronic
exposure to cigarette smoke (three cigarettes a day, five days a
week for seven months) produced a decrease in lung elastin
content and emphysema in the C57BL/6J and DBA/2 mice,
but not in the ICR mice. Exposing pallid mice, which have a
severe deficiency of 1-proteinase inhibitor and develop emphysema spontaneously, to cigarette smoke over four months accelerated the development of emphysema. The authors conclude that the sensitivity of mice to cigarette smoke depends on the sensitivity to oxidants and the elastase inhibiting capacity of the strain.
In a pulmonary perspective, Saetta and colleagues (23) discuss the cellular and structural bases of COPD.
Lung Inflammation
Because eosinophilia occurs in nonasthmatic patients experiencing an acute exacerbation of bronchitis, Zhu and coworkers (24) determined which of three eosinophil chemoattractantseotaxin, monocyte chemoattractant protein, or RANTES
(regulated on activation, normal T cell expressed and secreted)is upregulated in this condition. Nine patients with
an exacerbation of chronic bronchitis (FEV1 61% predicted)
had six times the number of activated (that is, EG2-positive)
tissue eosinophils as compared with 11 patients with stable
chronic bronchitis (FEV1 75% predicted) or seven healthy nonsmokers. The number of lymphomononuclear cells expressing messenger RNA for eotaxin was higher in the patients with chronic bronchitis as compared with the healthy
subjects. RANTES was upregulated during an exacerbation,
and it was expressed strongly in both the surface epithelium
and in subepithelial lymphomononuclear cells. Only RANTES
was correlated with the increased number of EG2-positive
cells (r = 0.51). The authors conclude that the recruitment of
tissue eosinophils during an acute exacerbation of chronic bronchitis results primarily from a marked upregulation of epithelial RANTES. An editorial commentary by Costabel (25)
accompanies this article.
To determine whether the inflammatory cells surrounding the mucus-secreting glands of the airways are associated with the expression of the regulatory cytokines, interleukin-4 and interleukin-5, Zhu and coworkers (26) studied tissue surgically resected from 11 asymptomatic smokers, 10 smokers with chronic bronchitis who had normal lung function, and 10 smokers with chronic bronchitis who had COPD (FEV1 65% of predicted). Cells containing messenger RNA for interleukin-4 were three times more plentiful as compared with cells containing messenger RNA for interleukin-5. Cells of the submucosal glands containing messenger RNA for interleukin-4 were 3.4-fold more common in the patients with chronic bronchitis who had normal lung function as compared with the asymptomatic smokers and 2.5-fold more common as compared with the patients with COPD. The number of cells containing messenger RNA for interleukin-4 was correlated with the total number of inflammatory cells in both the subepithelium (r = 0.60) and in the glandular compartment (r = 0.70). The number of CD8+ cells was not correlated with the number of cells containing messenger RNA for either interleukin-4 or interleukin-5. The authors conclude that gene expression for interleukin-4 is increased in the mucus-secreting glands and airway mucosa of smokers with chronic bronchitis, whereas patients with COPD have fewer inflammatory cells and less gene expression for interleukin-4.
Transport of polymeric IgA, the first line of defense in the respiratory tract, into the mucosal lumen requires the expression of the polymeric immunoglobulin receptor (pIgR) on epithelial cells. The extracellular part of this receptor is released after cleavage as secretory component. Compared with a control group of six nonsmokers who had pulmonary hypertension, Pilette and coworkers (27) found that epithelial expression of the secretory component was decreased by 45% in the large airways and by 26% in the small airways of eight patients with COPD. Reduced expression of secretory component in the small airways was correlated with both FEV1 and FVC, and reduced expression in the large airways was correlated with neutrophil infiltration in submucosal glands. Expression of Clara cell protein (CC 16), which has anti-inflammatory actions, was decreased by 38% in the bronchial epithelium of patients with COPD, although it did not correlate with lung function. The authors conclude that reduced expression of secretory protein in the airway epithelium is associated with airway obstruction and neutrophil infiltration in patients with severe COPD.
To determine the role of airway inflammation and infection in an exacerbation of COPD, Aaron and coworkers (28)
enrolled 50 patients with COPD (FEV1 39% predicted) in a
15-month follow-up study. Fourteen patients met predetermined criteria for an acute exacerbation. During an exacerbation, the patients developed a 4-fold increase in tumor necrosis factor- and a 1.8-fold increase in interleukin-8 in their
sputum. Over the subsequent month, the cytokines declined.
Bacterial or viral infection was confirmed in three of the 14 patients (21%), and these patients did not display higher levels of cytokines in their sputum. The authors conclude that
markers of neutrophilic inflammation increase in the airways
of patients with COPD at the time of an acute exacerbation and that the response occurs independently of a demonstrable
viral or bacterial infection.
In 60 patients with COPD (FEV1, 52% predicted), Prieto and coworkers (29) studied alterations in innate (natural) immunity and they also did a double-blind trial of glycophosphopeptical (inmunoferon). Compared with 56 healthy subjects, the patients had decreased cytotoxic activity of natural killer cells in their peripheral blood. The patients also had decreases in phagocytic activity: 60% less for peripheral blood monocytes and 77% less for neutrophils. Treatment with glycophosphopeptical increased the cytotoxic activity of the natural killer cells to a level seen in the healthy subjects, and it produced an 87% increase in the phagocytic activity of monocytes and a 44% increase in the phagocytic activity of neutrophils. The authors conclude that the peripheral blood cells of patients with COPD show deficits in natural immunity that are partially reversed by glycophosphopeptical.
In a state of the art review article, D'Ambrosio and colleagues (30) discuss the role of cytokines and their receptors in guiding the recruitment of T lymphocytes in lung inflammation.
Exhaled Markers
Nitric oxide
To determine the effect of inhaled beclomethasone (500 µg twice daily) on markers of airway inflammation,
Ferreira and coworkers (31) did a double-blind crossover
study in 20 stable patients with COPD (FEV1, 55% of predicted). Median exhaled nitric oxide was 26.2 ppb at baseline,
and the concentration fell by 10.6 ppb after one week and by
6.3 ppb after two weeks of inhaled beclomethasone. The concentration did not change with placebo. The change in exhaled nitric oxide was inversely related to the change in FEV1 (r = 0.50). The concentration of hydrogen peroxide in the breath
condensate did not change with beclomethasone or placebo.
The authors conclude that inhaled beclomethasone decreases
the level of exhaled nitric oxide in stable patients with COPD.
Other markers Heme oxygenases catalyze the degradation of heme to biliverdin, producing free iron and carbon monoxide, and the heme degradation products may protect against oxidant-mediated injury. Maestrelli and coworkers (32) studied the expression of heme oxygenases in lung specimens obtained at surgery. Immunoreactivity for the inducible isoform, heme oxygenase-1 (also termed heat shock protein), was mainly seen in alveolar macrophages. The percentage of macrophages positive for heme oxygenase-1 was 36% in 10 smokers with COPD, 34% in 6 smokers without lung disease, and 13% in 10 nonsmoking subjects. Immunoreactivity for the constitutive isoform, heme oxygenase-2, was distributed more widely, involving the alveolar walls, the adventitia of the pulmonary arteries, and vascular smooth muscle. Cells positive for heme oxygenase-2 were greater in the smokers as compared with the nonsmokers. The authors conclude that lung tissue of smokers has increased expression of inducible heme oxygenase-1 and constitutive heme oxygenase-2, and that the increases may be the result of oxidative stress associated with cigarette smoking.
Pathophysiology, Radiology, and Airway Narrowing
The protease-antiprotease theory for the development of emphysema ignores the contribution of mechanical forces to the destruction of the alveolar walls. To investigate the latter aspect, Kononov and coworkers (33) studied rats with elastase-induced emphysema. In the elastase-treated rats, remodeling produced thickening of the elastin and collagen fibers. Compared with tissue from healthy rats, macroscopic stretching of tissue from elastase-treated rats caused substantially greater distortions of the newly deposited elastin and collagen fibers. The threshold for mechanical failure of collagen was also reduced in the elastase-treated rats. The authors conclude that mechanical forces during breathing are capable of causing failure of the remodeled collagen network at points of stress and may contribute to the progression of emphysema. An editorial commentary by Fessler (34) accompanies this article.
Ninane and coworkers (35) developed a new approach for detecting airflow limitation. They reasoned that manual compression of the abdomen during expiration would not produce an increase in airflow in a patient with flow limitation. In seven healthy seated subjects, manual compression caused a 27% decrease in the anteroposterior dimension of the abdomen, a 15 cm H2O increase in gastric pressure, and a 6 cm H2O increase in esophageal pressure. Expiratory flow was increased over the entire range of expiration as compared with the preceding spontaneous expiration. In 12 seated patients with COPD, compression caused similar changes in abdominal dimensions and pressures, but half of the patients showed no increase in expiratory flow. In the supine posture, abdominal compression failed to increase expiratory flow in 10 of the 12 patients with COPD. In another seven patients with obstructive sleep apnea who had collapsible upper airways, applying negative pressure to the upper airway produced a pattern of airflow limitation in three patients, whereas compressing the abdomen elicited a normal response. The authors conclude that measuring the change in expiratory flow after manually compressing the abdomen is a simple method for detecting airflow limitation.
Stimulation of the M2 muscarinic receptors on postganglionic cholinergic nerves limits the magnitude of bronchoconstriction that results from stimulation of the vagus nerve. On and coworkers (36) assessed the function of the M2 muscarinic receptors in 22 patients with COPD (FEV1 49% of predicted) and 13 control subjects. A cold dry air challenge to the nose, which is known to produce vagally mediated bronchoconstriction, caused airway resistance to increase by 14% in the control subjects and by 9% in the patients with COPD. Pretreatment with ipratropium bromide prevented the bronchoconstriction, indicating that it was vagally mediated. Pretreatment with pilocarpine, a selective agonist of the M2 muscarinic receptor, prevented the bronchoconstriction in both groups, indicating normal function of the M2 receptors. The authors conclude that stable patients with COPD have normal function of the M2 muscarinic receptors.
To determine the relationship between the extent of pulmonary emphysema, assessed by high-resolution CT, and lung
mechanics, Baldi and coworkers (37) studied 24 patients with
COPD (FEV1, 17 to 72% of predicted). The extent of emphysema, defined as areas with Hounsfield Units more negative
than 950, was 21% of total area (range, 1 to 38%). Maximum static recoil pressure was 54% of predicted (range, 20 to
128%). The extent of emphysema on CT was inversely related to
diffusing capacity corrected for alveolar volume (r = 0.84),
but not to either maximal static elastic recoil pressure or to the
exponential constant of the pressure-volume curve. A measure
of the heterogeneity of lung density on CT was related to the
exponential constant of the pressure-volume curve (r = 0.68).
The authors conclude that the extent of emphysema on high-resolution CT is correlated with the reduction in diffusing capacity but not with the elastic properties of lung tissue.
In 43 patients with 1-antitrypsin deficiency of the PiZ phenotype who had never received augmentation therapy, Dowson and coworkers (38) studied the longitudinal changes in
physiologic, radiologic, and health status. Over 2 years, FEV1
decreased by 10% (67 ml per year), diffusing capacity decreased by 12%, and upper zone emphysema on high-resolution CT (voxels with a density below 910 Hounsfield units)
increased by 15%. Health status, measured by the St. George's
respiratory questionnaire, did not change. The decline in FEV1
was related to baseline FEV1 (r = 0.56), reversibility with a
bronchodilator (r = 0.52), and the frequency of exacerbations
(r = 0.38). The authors conclude that the decline in FEV1 in
patients with emphysema caused by 1-antitrypsin deficiency
is dependent on baseline physiology and the frequency of exacerbations, and that high-resolution CT and diffusing capacity are the most sensitive measures of the deterioration.
To determine whether chronic hypoxemia produces increased sympathetic nerve activity, Heindl and coworkers (39) studied 11 patients with PO2 of less than 60 mm Hg (6 had COPD and 5 had lung fibrosis) and 11 healthy subjects. Microneurographic recordings of efferent sympathetic activity in the peroneal nerve revealed 64 bursts per minute in the patients and 34 bursts per minute in the control subjects. Inspiring oxygen at 4 liters per minute caused an 11% decrease in the number of bursts in the patients, and had no effect in the control subjects. The authors conclude that sympathetic activity is increased in patients with chronic respiratory failure and hypoxemia.
To elucidate the mechanisms underlying the adverse response to inhaled hypertonic saline in patients with COPD, Taube and coworkers (40) studied 20 patients (FEV1, 42% of predicted). A concentration of 0.9% saline produced a decrease in FEV1 of 202 ml, a concentration of 3% saline produced a decrease in FEV1 of 363 ml, and albuterol produced an increase in FEV1 of 138 ml. The increase in dyspnea after inhaled saline was correlated with FEV1 (r = 0.62), FIV1 (forced inspired volume in one second; r = 0.73), and inspiratory capacity (r = 0.67). The concentration of histamine in induced sputum was higher with 3% as compared with 0.9% saline: 39 versus 30 ng per ml. The authors conclude that inhaled hypertonic saline causes a deterioration in lung function of patients with COPD and that the deterioration appears to be mediated by activation of mast cells.
Pulmonary Vasculature
To determine the natural history of pulmonary hypertension in patients with mild-to-moderate hypoxemia, Kessler and coworkers (41) prospectively followed 131 patients with COPD (mean PO2, 67 mm Hg) who did not have resting pulmonary hypertension. After 6 years, 25% of the patients developed resting pulmonary hypertension (mean pulmonary artery pressure exceeding 20 mm Hg); the increase in pressure was mild (20 to 43 mm Hg). The patients who developed resting pulmonary hypertension had initially a 13% higher pulmonary artery pressure at rest and an 11% higher pulmonary artery pressure during exercise as compared with the patients who did not develop pulmonary hypertension. The patients who developed pulmonary hypertension also experienced a fall in resting PO2 (64 to 60 mm Hg), whereas PO2 remained constant (69 mm Hg) in the patients who did not develop pulmonary hypertension. On logistic regression, baseline pulmonary artery pressures both at rest and during exercise were independently associated with the subsequent development of pulmonary hypertension. The authors conclude that only about 25% of patients with COPD with mild-to-moderate hypoxemia develop pulmonary hypertension over 6 years of follow-up, and that the risk is associated with pulmonary artery pressure during rest and exercise at baseline.
Control of Breathing and Exercise
To determine to what extent dynamic hyperinflation impairs
exercise performance, O'Donnell and coworkers (42) studied
105 patients with COPD (FEV1, 37% of predicted) and 25 healthy subjects. During incremental exercise on a cycle, 80%
of the patients developed an increase in dynamic hyperinflation
(measured as a fall in inspiratory capacity). The mean decrease
in inspiratory capacity was 0.37 liters, but it ranged from 1.42
to 0.77 liters. The change in inspiratory capacity was inversely
related to the resting inspiratory capacity (r = 0.50). The
peak oxygen consumption during exercise was correlated with
the peak tidal volume during exercise (r = 0.68), which, in
turn, was correlated with inspiratory capacity both at peak exercise (r = 0.79) and at rest (r = 0.75). The authors conclude
that dynamic hyperinflation curtails the ability to increase tidal
volume during exercise in patients with COPD, and that this curtailment contributes to exercise intolerance.
To determine the effect of hyperoxia on exercise performance, O'Donnell and colleagues (43) did a double-blind crossover trial in 11 patients with severe COPD (FEV1 31% of predicted, PO2 52 mm Hg, PCO2 48 mm Hg). After exercise at 50% of maximal capacity, the patients had a PO2 of 46 mm Hg when breathing air and 245 mm Hg when breathing 60% oxygen. Hyperoxia caused endurance time to increase from 4.1 to 8.8 minutes, and it decreased the slopes on plots of dyspnea, minute ventilation, CO2 production and lactate against time. At a fixed time near the end of exercise, hyperoxia caused dyspnea to decrease by 41%, CO2 production to decrease by 12%, minute ventilation to decrease by 13%, and respiratory frequency to decrease by 15%, and it produced a 27% increase in inspiratory capacity. The authors conclude that the improvement in exercise endurance with hyperoxia was explained by decrease in ventilatory demands, a decrease in end-expiratory volume, and the relief of dyspnea.
The antioxidant, reduced glutathione, inactivates reactive
oxygen species by forming oxidized glutathione disulfide as
the oxidation byproduct. The balance between reduced glutathione and oxidized glutathione can be used to assess the
overall redox environment of the cell. In 17 patients with
COPD (FEV1, 38% of predicted; PO2, 69 mm Hg), Rabinovich and coworkers (44) did needle biopsies of the vastus lateralis before and after endurance training (5 days a week for 8 weeks). Before training, the levels of reduced and oxidized
glutathione were equivalent in the patients and the control
subjects both at rest and after 11 minutes of exercise. Training
produced an 89% increase in reduced glutathione in healthy subjects but not in the patients. Training produced a 43% increase in oxidized glutathione in the patients but not in the
control subjects. The increase in peak work rate induced by
training was correlated with the rise in oxidized glutathione in
the patients (r = 0.55) and with the rise in reduced glutathione
in the control subjects (r = 0.83). Concentrations of messenger RNA for 
-glutamyl cysteine synthetase, a key enzyme in
glutathione synthesis, tended to fall in the healthy subjects and
tended to rise in the patients. The authors conclude that exercise training induces an increase in the antioxidant, reduced
glutathione, in the limb muscle of healthy subjects but not in
the muscles of patients with COPD, and that training produces an increase of oxidized glutathione in the muscles of patients with COPD but not in the muscles of healthy subjects.
An editorial commentary by Reid (45) accompanies this article.
To determine the effect of resistive unloading in subjects with mild COPD, Babb (46) studied 10 patients, aged 70 years, with an FEV1/FVC ratio of 61%. The subjects performed graded cycle ergometry to exhaustion, once while breathing air and once while breathing a mixture of helium (79%) and oxygen (21%). While breathing the helium-oxygen mixture, minute ventilation was 12% greater at the ventilatory threshold and 22% greater at maximal exercise. End-tidal PCO2 fell at all levels. The total work done against the lung did not change. The author concludes that a helium-oxygen mixture increases minute ventilation during exercise in patients with COPD because of resistive unloading and the unchanged work of breathing.
To determine whether patients with respiratory disease develop central inhibition of the diaphragm while exercising to exhaustion, Sinderby and coworkers (47) studied 10 patients with COPD (FEV1, 33% predicted). Incremental exercise to exhaustion caused an increase in minute ventilation from 12 to 31 liters per minute. Transdiaphragmatic pressure increased from 9 to 13 cm H2O during early exercise, but it did not change thereafter. Electrical activity of the diaphragm was 24% of maximum at rest, and it increased progressively to 81% of maximum at the end of exercise. Lung volume at the end of inspiration was 86% of total lung capacity at rest and 97% of total lung capacity at the end of exercise. The authors conclude that transdiaphragmatic pressure increases only modestly during maximum exercise in patients with COPD, and that the minor nature of the increase is secondary to the development of dynamic hyperinflation rather than to an inhibition of central drive.
To determine whether measurements other than distance help in assessing patient performance during the six-minute walk test, van Stel and coworkers (48) studied 83 patients with COPD. Of 15 variables, four independent factors accounted for 78% of the variance: endurance capacity, the pattern of heart rate, perceived symptoms, and impairment of oxygen transport. Pulmonary rehabilitation produced an improvement in self-perceived exercise tolerance in 84% of 53 patients, and 29 patients showed improvements in three or four factors. The improvement was explained by a change in walking distance, less desaturation, and less dyspnea (r2 = 0.55). The authors conclude that assessing patient performance during a six-minute walk test is improved when factors other than the distance walked are also measured.
To determine the mechanism for dyspnea during the six-minute walk test, Marin and coworkers (49) studied 72 men with
COPD (FEV1, 45% of predicted). The distance walked in six
minutes was 439 m. The inspiratory capacity decreased from 29%
of total lung capacity before the test to 24% after its completion.
Dyspnea on exertion was correlated with the change in inspiratory capacity (r = 0.49) and with baseline dyspnea (r = 0.59).
The authors conclude that dynamic hyperinflation contributes
to dyspnea during a six-minute walk test, and that it can be
easily detected by measuring inspiratory capacity.
To determine the effect of an acute episode of exercise on cognitive function in patients with COPD, Emery and coworkers (50) studied 29 patients with COPD (FEV1, 43% of predicted) and 29 healthy subjects. Compared with watching a video, exercising to a peak level produced an 8% increase in verbal fluency in the patients but not in the control subjects. Other tests of cognitive performance were not altered. The authors conclude that an acute episode of exercise improves some measures of cognitive performance in patients with COPD.
Respiratory Muscles
To determine whether the diaphragm of patients with COPD
displays ultrastructural evidence of injury and to determine
whether acute loading induces diaphragmatic injury, Orozco-Levi and coworkers (51) obtained biopsies from the costal diaphragm in 18 patients with COPD and 11 healthy subjects during surgery. Electron microscopy revealed sarcomere disruptions
in all samples, and the density and area of disruptions in the
patients were twice that seen in control subjects. The density
of sarcomere disruptions was correlated with FEV1 (r = 0.59) and with the ratio of residual volume to total lung capacity (r = 0.80). Before the surgery, a subset of seven patients with COPD and five control subjects breathed through a threshold resistor until task failure. Compared with the unloaded state, the density of sarcomere disruptions increased
by 89% in the loaded healthy subjects and by 38% in the
loaded patients. The density of disruptions was about three
times greater in the patients with COPD after loading, as compared with the unloaded healthy subjects. The authors conclude that sarcomere disruptions are increased in the diaphragm of patients with COPD, and that acute loading causes
sarcomere disruption in the diaphragm of both healthy subjects and patients with COPD.
To determine whether patients with airflow obstruction experience injury to their diaphragm, MacGowan and coworkers
(52) did partial thickness biopsies of the diaphragm in 21 patients undergoing thoracotomy. The FEV1 of the patients
ranged from 16 to 122% of predicted, mean 74%. The contributions to the cross-sectional area were: normal diaphragm,
66%; abnormal muscle, 18%; and connective tissue, 16%. The
abnormal tissue included fibers with internally located nuclei,
lipofuscin pigmentation, small angulated fibers, and some inflammation. The percent predicted FEV1 was inversely related to the area of abnormal muscle (r = 0.53), but not to the number of macrophages present. The authors conclude that
patients with increasing severity of airway obstruction have a
proportional increase in abnormal tissue in their diaphragm.
Because diaphragmatic dysfunction in emphysema has been attributed to an imbalance between oxygen supply and demand, Poole and coworkers (53) measured oxygen within the diaphragm in hamsters. Microvascular PO2 within the costal diaphragm of hamsters with elastase-induced emphysema was about half the value found in control animals. The value was substantially decreased across inspired oxygen concentrations between 10 and 100%. Decreases in mean arterial pressure from 115 to 40 mm Hg caused proportional decreases in diaphragmatic PO2 (r = 0.98). The authors conclude that microvascular oxygen tension is decreased in the diaphragm of emphysematous hamsters.
Peripheral Muscles
To determine the effect of exercise on amino acid metabolism, Engelen and coworkers (54) obtained arterialized venous blood and quadriceps biopsies before and after 20 minutes of exercise in 14 patients with COPD and eight healthy subjects. In the muscle, the sum of amino acids fell by 20% after exercise in the patients, but it did not change in the healthy subjects. In the plasma, the sum of amino acids rose by 16% after exercise in the patients, and the increases in plasma alanine (61%) and glutamine (21%) were even greater. The authors conclude that patients with COPD experience an increased release of amino acids from the quadriceps muscle during exercise.
Patients with COPD develop fatigue of the quadriceps muscle after exercising to the limits of tolerance. To determine whether a rehabilitation program would increase resistance to muscle fatigue, Mador and coworkers (55) entered 21 patients with COPD (FEV1, 45% of predicted) into a program of supervised exercise training (50% of maximum work was performed three times a week for eight weeks). The program produced a 34% increase in maximum exercise capacity. Before rehabilitation, exercise caused fatigue of the quadriceps as reflected by an 18% decrease in the twitch pressure that resulted from stimulation of the femoral nerve. After completing the rehabilitation program, exercise no longer caused a fall in the twitch pressure of the quadriceps. The authors conclude that supervised rehabilitation increases the resistance of the quadriceps muscle to fatigue in patients with COPD.
In a pulmonary perspective, Debigaré and colleagues (56) discuss wasting of the peripheral muscles in patients with COPD.
Nutritional Status
Leptin, an adipocyte-derived hormone involved in the control of body weight, is decreased in patients with COPD. To determine the circadian rhythm of leptin, Takabatake and coworkers (57) measured serum leptin on eight occasions over 24 hours in nine patients with COPD and cachexia, in eight patients with COPD without cachexia, and in seven healthy subjects. The leptin levels had a diurnal pattern in the control subjects and in the patients without cachexia, but the circadian pattern was blunted, with marked attenuation of the nocturnal peak, in the patients with cachexia. In all three groups, the 24-hour fluctuations in leptin were identical to the fluctuations of heart-rate variability in the very low-frequency band, a measure of autonomic and neuroendocrine control. The authors conclude that patients with COPD free of cachexia have a normal circadian rhythm in serum leptin, which is under autonomic and neuroendocrine regulation, and that the rhythm is lost in patients with COPD who have cachexia. An editorial commentary by Goldberger (58) accompanies this article.
To determine the role of systemic inflammation on body
composition, Eid and coworkers (59) studied 80 stable patients with COPD. Body mass index was normal (greater than
20 kg per m2) in 55 patients (69%). Among the patients with a
normal body mass index, 17 (31%) had a decrease in skeletal
muscle mass, as reflected by a creatinine-height index of less than
80% of predicted. A low creatinine-height index was associated
with increased levels of circulating interleukin-6 (r = 0.40),
tumor necrosis factor- (r = 0.30), soluble receptor for interleukin-6 (r = 0.30), and soluble receptor 2 for tumor-
necrosis factor- (r = 0.40). Patients with a normal body mass
index and low creatinine-height index had equivalent levels of
inflammatory mediators as compared with patients with a low
body mass index and low creatinine-height index. Urinary excretion of nitrogen was 94% higher in patients with a low versus a normal creatinine-height index, although nitrogen balance was equivalent in the two groups. The authors conclude that weight loss, particularly of skeletal muscle mass, in patients with COPD is associated with the host inflammatory response.
Health Care Delivery
In an executive summary from an NHLBI/WHO workshop on a Global Initiative for Chronic Obstructive Lung Disease (GOLD), Pauwels and colleagues (60) outline a challenge to increase the awareness of COPD, to improve its prevention and management, and to encourage renewed research on this subject. An editorial commentary by Gross (61) accompanies this article.
Drug Therapy
-Agonists
In a double-blind study in 780 patients with COPD
(FEV1, 45% of predicted), Dahl and coworkers (62) compared formoterol (12 or 24 µg twice daily), ipratropium bromide (40 µg four times daily), and placebo. After 12 weeks of
treatment, the area under the curve for FEV1 measured over
12 hours was greater for formoterol, 12 µg twice daily (0.223 liter), formoterol, 24 µg twice daily (0.194 liter), and ipratropium (0.137 liter) as compared with placebo. The area under
the curve for both doses of formoterol was greater as compared with ipratropium. Compared with placebo, both doses
of formoterol improved symptoms and the quality of life,
whereas ipratropium did not have a beneficial effect. The authors conclude that formoterol, a long-acting 2-adrenergic agonist, is more effective than ipratropium bromide in the
treatment of patients with COPD.
-agonist, salmeterol, produces bronchodilation in patients with COPD.
-agonist superior to use on an as-needed basis?" All patients received inhaled ipratropium bromide (40 µg four times daily), beclomethasone (500 µg twice daily), and albuterol as needed. The
intervention consisted of scheduled albuterol (200 µg four
times daily) or placebo, each for three months. Consumption
of albuterol was twice as high when patients took it on a
scheduled basis as compared with using it on an as-needed basis (12.8 versus 6.3 puffs per day). The groups showed no differences in FEV1, six-minute walking distance, and health status on a questionnaire. The authors conclude that patients with COPD consume twice as much of an inhaled -agonist
when instructed to use it on a scheduled basis as compared
with using it on an as-needed basis.
Glucocorticoids To determine whether inhaled glucocorticoids influence repeat hospitalization and mortality in elderly patients with COPD, Sin and Tu (65) studied a cohort of 22,620 patients with COPD who were 65 years of age or older. At 1-year follow-up, 25% of the patients had undergone repeat hospitalization and 11% had died. In the 90 days after the first discharge, 51% of the patients received inhaled glucocorticoids. During follow-up, the patients receiving inhaled glucocorticoids had 24% fewer hospitalizations for COPD and a 29% lower mortality. The authors conclude that use of inhaled glucocorticoids is associated with decreased morbidity and mortality in elderly patients with COPD. An editorial commentary by Vestbo (66) accompanies this article.
To determine the cost effectiveness of early treatment with an inhaled glucocorticoid in subjects with previously undiagnosed obstructive airway disease, van den Boom and coworkers (67) entered 82 subjects from a random sample of the general population into a one-year double-blind study of inhaled fluticasone proprionate (250 µg twice daily) versus placebo. Compared with placebo, the group treated with fluticasone developed a 90-ml increase in post-bronchodilator FEV1. At 12 months, subjects with reversible airway obstruction showed an improvement in airway hyperresponsiveness (1.4 steps in the dose of histamine producing a 20% decrease in FEV1). Early treatment resulted in a gain of 2.7 QALYs (quality-adjusted life years) per 100 subjects treated and an improvement in dyspnea. The incremental cost effectiveness ratio was $13,016 per QALY for early treatment and $33,921 per QALY for detection combined with treatment. The mean incremental cost for achieving a relevant decrease in dyspnea in one additional subject was $1,674. The authors conclude that early intervention with fluticasone improves lung function and the quality of life at relatively low financial cost in subjects with manifestations of obstructive airway disease. To determine whether withdrawal of inhaled glucocorticoids would lead to a worsening of lung function, O'Brien and coworkers (68) did a double-blind crossover study in 24 men with COPD (age, 67 years; FEV1, 47% of predicted). After discontinuing inhaled glucocorticoids, the patients were randomized to either six weeks of placebo followed by six weeks of beclomethasone diproprionate (336 µg daily) or the reverse sequence. The patients experienced a 2.4% increase in FEV1 while taking beclomethasone, as compared with a 5.9% decrease in FEV1 while taking placebo. Patients experienced less dyspnea during walking when they were taking beclomethasone. The distance walked during six minutes, sputum cell counts, and subjective assessment on a chronic respiratory disease questionnaire did not differ between the two arms of the study. The authors conclude that the withdrawal of inhaled glucocorticoids in elderly patients with COPD leads to a deterioration in lung function and to an increase in dyspnea while walking. To determine whether change in health status is detectable over time, Spencer and coworkers (69) analyzed data on 387 patients with COPD (FEV1, 50% of predicted) participating in the ISOLDE (inhaled steroids in obstructive lung disease) study. Health status was measured using a generic instrument, the SF-36, and a disease-specific instrument, the St George's respiratory questionnaire, at baseline and every six months for three years. Progressive deterioration in all domains of health (symptoms, physical activity, and psychosocial function) was detectable using either instrument. Deterioration was slower in the patients receiving fluticasone (1,000 µg daily) as compared with the patients receiving placebo. FEV1 was correlated with scores on the respiratory questionnaire at baseline (r =0.25), and the changes in the scores and in FEV1 over
time were correlated (r = 0.24). At baseline, smokers had
poorer scores on the respiratory questionnaire as compared
with the ex-smokers; although this difference was maintained
throughout the study, smoking did not influence the rate of
decline in health status. The authors conclude that measuring
health status is valuable in assessing the effect of a long-term
therapy in COPD, and that inhaled fluticasone reduces the decline in health status.
Smoking cessation In a pulmonary perspective, Britton and colleagues (70) discuss the challenges of treating nicotine addiction.
Other Therapies
Lung volume reduction surgery
On CT scan, emphysema appears to be more extensive in the inner region (core) as compared
with the outer region (rind) of the lung. Because a predominance of emphysema in the outer region may be more accessible during lung volume reduction surgery, Nakano and coworkers (71) determined whether quantifying the distribution of emphysema would predict outcome in 21 patients undergoing surgery. The peripheral 50% of the lung area on CT scan
was defined as the rind, and remainder as the core. (Areas of
lung expansion exceeding 10.2 ml per gram of tissue [equivalent to Hounsfield units more negative than -910] are associated with emphysematous lesions exceeding 5 mm in diameter; areas of lung expansion between 6.0 and 10.2 ml per gram
of tissue [equivalent to 910 to 856 Hounsfield units] are associated with emphysematous lesions of less than 5 mm in diameter; and areas of expansion of less than 6 ml per gram of
tissue are associated with normal lung tissue.) Surgery produced an increase in FEV1 from 29 to 40% of predicted and an
increase in exercise performance from 26 to 44 watts. The amount of lung displaying severe emphysema (expansion beyond 10.2 ml per gram) in the rind of the upper lung predicted
a greater increase in FEV1 and an increase in maximal exercise capacity after surgery. The authors conclude that patients
who have more emphysema in the surgically accessible rind
area of the upper lung show the greatest benefit after lung volume reduction surgery. An editorial commentary by Gevenois
and Estenne (72) accompanies this article.
0.47).
Surgery did not change the area of the dome. The authors conclude that the decrease in lung volume after lung volume reduction surgery causes the dome of the diaphragm to move upwards, and thus it increases the area of the diaphragm that is apposed to the rib cage. An editorial commentary by Hoppin (74) accompanies this article.
To determine whether radiologic and physiologic measurements can predict benefit from lung volume reduction surgery,
Ingenito and coworkers (75) studied 48 patients with emphysema (FEV1, 23% of predicted). Patients were classified as
having homogenous emphysema when the ratio of perfusion
to the upper and lower zones on a radioisotope scan was between 0.75 and 1.25. At six months after surgery, 27 patients
with heterogeneous disease experienced a greater increase in
FEV1 as compared with 21 patients with homogenous disease
(increases of 41 versus 22%). Good airflow on inspiration, as
reflected by a high inspiratory conductance, was correlated with
the improvement in FEV1 at six months (r = 0.53). Conductance identified 11 patients who had a good response to surgery but were missed by the radiologic criteria. On multiple regression analysis, the combination of inspiratory conductance and the
radiologic pattern explained 33% of the improvement in
FEV1. The authors conclude that radiologic and physiologic
measurements are additive in their ability to predict patients
who are likely to benefit from lung volume reduction surgery.
To elucidate the mechanism of improvement in lung function after lung volume reduction surgery, Ingenito and coworkers (76) studied 37 patients. Surgery produced an overall
increase in FEV1 of 28%, and a positive response was defined
as an increase in FEV1 of at least 12%. Nineteen responders
had a mean increase in FEV1 of 60% and 18 nonresponders
had a mean decrease in FEV1 of 6%. The responders experienced a 39% increase in elastic recoil pressure and a 12%
decrease in the time-constant for expiration. Conductance,
transmural pressure at the site of flow limitation, and lung
compliance did not change. An increase in elastic recoil pressure weighted by the preoperative value of conductance upstream of the site of flow limitation accounted for 72% of the
improvement in expiratory flow. The only change in the nonresponders was a 13% increase in the expiratory time-constant.
In the nonresponders, the change in expiratory flow was correlated with a change in conductance weighted by the preoperative
recoil pressure. The authors conclude that the improvement in
expiratory flow after lung volume reduction surgery is mainly
the result of an increase in elastic recoil pressure.
Gelb and coworkers (77) followed 26 patients with emphysema (FEV1 700 ml, 29% of predicted) for 5 years after lung
volume reduction surgery. Mortality caused by respiratory
failure was 4% in the first year, 31% after three years, and
58% after five years. An increase in FEV1 of more than 200 ml
above baseline was noted in 73% of patients at one year, in
35% at three years, and in 8% at five years. Eighteen patients
were initially oxygen dependent. This dependence was eliminated in 78% of patients at one year, in 33% at three years,
and in 0% at five years. In the 11 patients who survived for
five years, the peak increase in FEV1 in the first post-operative
year was 438 ml. The fastest decline was over the subsequent
year, 149 ml, and a decline of 78 ml per year occurred over the
following four years. The authors conclude that lung volume
reduction surgery produced significant improvement in 35%
of patients at three years and in 8% of patients at five years.
In 12 sheep with papain-induced emphysema, Ingenito and
coworkers (78) investigated the effect of a less invasive alternative to lung volume reduction surgery. Dysfunctional regions of the lung were obliterated under bronchoscopic control using both a washout solution and a fibrin-based glue to
collapse, seal, and scar the region. After 8 to 12 weeks, the
bronchoscopic approach produced equivalent decreases in total lung capacity and residual volume as compared with the
sheep undergoing lung volume reduction surgery. Histology
revealed collapse and scarring in 11 of 20 target areas, and
three zones developed sterile abscesses. Complications with
the bronchoscopic approach were less common as compared
with surgery. The authors conclude that the application of a fibrin-based glue through a bronchoscope can achieve similar
reductions in lung volume as those achieved by surgery in
sheep with emphysema.
Expectorants and mucociliary clearance Uridine 5'-triphosphate, an agonist of the purinergic receptors, enhances mucociliary clearance in healthy subjects. In 15 patients with chronic bronchitis, Bennett and coworkers (79) did a double-blind study of the effect of the agonist on the clearance of inhaled technetium particles (99mTc-Fe2O3), which have a mass median aerodynamic diameter of 4 µm. Inhaling 20 mg of uridine 5'-triphosphate produced a 46% increase in the clearance rate of the particles. When the dosage was increased fivefold, clearance was no greater. The authors conclude that a small dose of aerosolized uridine 5'-triphosphate increases mucociliary clearance in patients with chronic bronchitis, presumably by stimulating cilia and hydrating airway secretions.
Rehabilitation and Oxygen Therapy
The optimal flow rate for use with long-term oxygen therapy has not been standardized. In 88 patients with COPD, Guyatt and coworkers (80) studied four protocols for selecting the delivered flow: rest, exercise in hospital, exercise during simulation of the home, and exercise at home. For each protocol, the flow of oxygen was adjusted according to explicit criteria. For four testings done at rest, 63% yielded the same prescription and 94% of the prescriptions were within 1 liter per minute of each other. For four testings done during exercise, 27% yielded the same prescription and 73% of the prescriptions were within 1 liter per minute of each other. During exercise, hospital testing produced a higher prescription as compared with the simulated home testing (2.5 versus 2.0 liters per minute). The authors conclude that the use of explicit protocols for selecting a flow of supplemental oxygen that prevents hypoxemia during exercise achieve a moderate degree of reproducibility when done in a hospital setting and less reproducibility in the home setting.
Outcome
To determine whether undiagnosed airway obstruction has an impact on health, Coultas and coworkers (81) analyzed data from the National Health and Nutrition Examination Survey (NHANES III). Undiagnosed airway obstruction, based on FEV1 and responses to a questionnaire, was more common (12%) as compared with physician-made diagnoses of COPD (3.1%) or asthma (2.7%). The occurrence of undiagnosed airway obstruction (FEV1 less than 75% of predicted) was equivalent among men (5.7%) and women (4.6%). After adjusting for smoking and co-morbid conditions, the risk of impaired general health and the difficulty in walking were associated with the degree of reduction in FEV1. Among women with airflow obstruction, 12 to 35% had never smoked. The authors conclude that undiagnosed airway obstruction occurs in 5% of the general population and is associated with impaired health and functional status.
FEV1 is most accurate in predicting prognosis in patients with COPD when measured after maximal bronchodilation. To assess the power of peak expiratory flow rate (PEFR), after maximizing lung function with bronchodilators and glucocorticoids, in predicting prognosis, Hansen and coworkers (82) studied 491 patients with asthma and 1,095 patients with COPD (baseline FEV1, 49% of predicted). Ten to 15 years after measuring pulmonary function, 26% of the patients with asthma and 66% of the patients with COPD had died. After controlling for age, smoking, sex, and body mass index, the best value of PEFR was at least equally powerful as the best value of FEV1 in predicting prognosis. Despite its close correlation with FEV1, PEFR provided independent information on prognosis. In patients with asthma, the best FEV1 was a better predictor of mortality than the best PEFR. The authors conclude that measurement of PEFR after maximal bronchodilation was at least as powerful as FEV1 in predicting prognosis in patients with moderate-to-severe COPD.
| |
AIR POLLUTION |
|---|
|
TOP
CONTENTS
CHRONIC OBSTRUCTIVE PULMONARY...
AIR POLLUTION
PULMONARY VASCULAR AND RELATED...
LUNG TRANSPLANTATION
PLEURAL DISORDERS
LUNG CANCER
REFERENCES
|
|---|
General
Epidemiologic studies done before the closure of a steel mill
in the Utah Valley in 1986, during closure of the mill, and after
reopening of the mill established that exposure to particulate matter was related to human health. Ghio and Devlin (83)
generated aqueous extracts from filters containing particulate
matter from the three time periods, and instilled the extracts
through a bronchoscope into the lingula of 24 healthy subjects.
When the lingula was lavaged 24 hours later, the bronchoalveolar fluid of the subjects exposed to particulate matter from
the time when the mill was open contained higher levels of
neutrophils, protein, fibronectin, -antitrypsin, interleukin-8,
interleukin-1, tumor necrosis factor, and oxidized products
as compared with the subjects exposed to particulate matter
from when the mill was closed. The subjects exposed to particulate matter from when the mill was open also had lower concentrations of tissue factor and fibrinogen. The authors conclude that mass is not the only important variable when
assessing health effects of air pollution particles, and that the
particle composition also needs to be considered. An editorial
commentary by Beckett (84) accompanies this article.
Van Eeden and coworkers (85) surveyed the cytokines produced by human alveolar macrophages on exposure to ambient
particles of different composition and size. Incubation of macrophages with particle suspensions of latex, inert carbon, or residual oil fly ash produced a 1.5- to 2-fold increase in tumor necrosis
factor-, whereas ambient urban particles (EHC 93) produced a
10-fold increase. Macrophages incubated with ambient urban
particles also produced interleukin-6, macrophage inflammatory
protein-1, and granulocyte-macrophage colony-stimulating factor. Thirty healthy men exposed to air pollutant during the 1997 Southeast Asian forest fires had increased concentrations of interleukin-1, interleukin-6, and granulocyte-macrophage colony-stimulating factor in their serum. The authors conclude that
stimulation of alveolar macrophages by atmospheric particles
causes the production of proinflammatory cytokines, and that
these cytokines are also found in the blood of subjects exposed
to acute atmospheric pollution.
Exposure to airborne particles exacerbates heart and lung disease, but it is not known whether underlying disease predisposes to this effect. To determine whether diabetes increases susceptibility, Zanobetti and Schwartz (86) analyzed Medicare data for the years 1988 to 1994 in the Chicago area. For particulate matter with an aerodynamic diameter of less than 10 µm (PM10), a 10 µg per cubic meter increase in concentration was associated with a 2% increase in admission to hospital for heart disease among patients with diabetes, but only a 0.9% increase in admissions among individuals without diabetes. Exposure did not influence admissions for lung disease. The authors conclude that increased exposure to airborne particles resulted in twice the risk of admission to hospital for heart disease among individuals with diabetes.
To investigate the causal relationship between exposure to
airborne particulate matter and the development of asthma-like manifestations, Walters and coworkers (87) exposed
naïve mice to a single dose of ambient particulate matter, coal
fly ash, or diesel particulate matter. Ambient particulate matter induced increases in bronchoalveolar cellularity and airway hyperreactivity. Exposure to diesel particulate matter induced increases in bronchoalveolar cellularity but did not
increase airway hyperreactivity. Exposure to coal fly ash induced no changes. The airway hyperreactivity induced by airborne particulate matter was sustained over seven days. The
increase in airway hyperreactivity was preceded by a marked
increase in bronchoalveolar eosinophils, whereas the decline in hyperreactivity was associated with an increase in macrophages. A type 2 (Th2) cytokine pattern (interleukin-5, interleukin-13, eotaxin) was observed in the early phase. A type 1 (Th1) pattern (interferon-) response was initially depressed
and increased after 2-3 days. The active component(s) of the
ambient particulate matter was not soluble in water, and the
airway hyperreactivity and inflammation caused by ambient
particulate matter was dose dependent. The authors conclude
that ambient particulate matter can induce sustained asthma-like manifestations in mice.
Although epidemiologic studies show an association between exposure to particulate matter and human morbidity, the clinical presentation is not clear. Ghio and coworkers (88) described a 42-year-old man who was exposed to suspended particles of oily fly ash while cleaning a domestic oil-burning stove. The patient developed cough, dyspnea, and wheezing within 24 hours of exposure. He gradually progressed to hypoxemic respiratory failure and required mechanical ventilation. A lung biopsy revealed particle-laden macrophages and diffuse alveolar damage. The patient's condition improved with systemic glucocorticoids. Ash collected from the patient's furnace was instilled into the trachea of rats and produced similar proinflammatory and biological effects. The authors conclude that exposure to particulate matter from an emission source can cause acute respiratory failure.
Ultrafine particles, having diameters of 0.1 µm or less, represent a substantial fraction of particulate matter with a diameter below 10 µm (PM10). Because the mechanism whereby particulate pollution causes cardiovascular mortality is poorly understood, Nemmar and coworkers (89) studied the extent to which ultrafine particles pass into the circulation. Hamsters received a single intratracheal instillation of particles of less than 80 nm in diameter, which were labeled with technetium-99m. In the blood, 2.9% of the dose per gram of blood was detectable at 5 minutes and the percentage gradually decreased over the subsequent 45 minutes. Lower percentages were found in the liver, heart, spleen, kidneys, and brain. The authors conclude that a substantial proportion of ultrafine particles instilled into the trachea pass into the circulation of hamsters.
To determine the association between particulate air pollutions and emergency admission to hospital for respiratory problems, Atkinson and coworkers (90) analyzed data from participants in the APHEA2 (Air Pollution and Health: a European Approach) project, which was conducted in eight European cities. After controlling for environmental factors and temporal patterns, an increase in PM10 (particles with an aerodynamic diameter of less than 10 µm) of 10 µg per cubic meter was associated with a 1.2% increase in the number of daily admissions to hospital for asthma in subjects aged 0 to 14 years old, a 1.1% increase in admissions to hospital for asthma in subjects aged 15 to 64 years old, and a 1.0% increase in admissions to hospital for all respiratory problems. The combined effect for black smoke was smaller. In subjects older than 65 years, ozone accounted for a large proportion of the effect of particles. The authors conclude that admission to hospital for respiratory problems increases by about 1% for an increase of 10 µg per cubic meter in particles of less than 10 µm in diameter.
To determine whether changes in air pollution might affect lung function during adolescence, a time of rapid lung growth, Avol and coworkers (91) studied 110 children who had moved between communities. The children were aged 10 years at enrollment and 15 years at follow-up. Across the six western states in the study, the annual levels of PM10 (particulate matter with a mean diameter of 10 µm) varied from 15 to 66 µg per cubic meter. An increase of 10 µg per cubic meter in the annual average of PM10 was associated with a decrease in annual growth of both maximal midexpiratory flow (16.6 ml per year) and peak expiratory flow (34.9 ml per year). Children moving to communities with lower PM10 experienced an increase in the growth of lung function, and children moving to communities with higher PM10 experienced a decrease in the growth of lung function. The trend was stronger in children who had moved their community for three years or longer before the follow-up visit, as compared with children who had moved within 1 to 2 years. The authors conclude that a change in the level of air pollution affects the growth of lung function during adolescence.
To assess the association between short-term variations in air pollutant levels and lung function, Schindler and coworkers (92) studied a random, cross-sectional sample of 3,912 adults who had never smoked and who lived in eight areas of Switzerland. After controlling for sex, age, height, weight, and seasonal fluctuations in meteorological factors, 10-µg per cubic meter increments in the daily level of nitrogen dioxide, total suspended particulates, and ozone were associated with respective decrements in FEV1 of 0.67%, 0.46%, and 0.51%. Increments in nitrogen dioxide and total suspended particulates of 10 µg per cubic meter were associated with respective decrements in FVC of 0.73% and 0.36%. An increment in ozone of 10 µg per cubic meter was associated with a decrement in FEF25-75 of 1.04%. The authors conclude that daily concentrations of nitrogen dioxide, total suspended particulates, and ozone have a significant effect on lung function.
Exposure to ambient particulate matter is associated with
increased morbidity and mortality. In rabbits exposed to particles smaller than 10 µm (PM10) twice a week for three weeks,
Mukae and coworkers (93) used the thymidine analog, 5'-bromo-2'-deoxyuridine, to study the bone-marrow response. Exposure
to particulate matter caused a persistent increase in circulating
band cells, a 13% decrease in the transit time of neutrophils
through the post-mitotic pool in the marrow, and an increase
in the marrow pool of neutrophils (especially the mitotic
pool). The particles were diffusely distributed in the lung and
they caused a mild mononuclear inflammation. The percentage of macrophages containing particles less than 10 µm correlated with the size of the total marrow neutrophil pool (r2 = 0.56), the mitotic pool (r2 = 0.61), and the transit time of neutrophils through the postmitotic pool (r2 = 0.42). The authors conclude that particulate air pollution stimulates the
bone marrow to produce more neutrophils and to release immature neutrophils into the circulation, and that these occurrences are related to the degree to which particles are phagocytosed by alveolar macrophages.
Ozone
The inflammatory response to ozone is associated with the
induction of enzymesnicotinamide adenine dinucleotide phosphate:quinone oxidoreductase (NAD[P]:NQO1) and glutathione-S-transferases (GSTs)that protect against oxidative stress.
To determine whether polymorphism of these enzymes accounts
for the interindividual variability to ozone, Bergamaschi and
coworkers (94) studied 24 healthy subjects during two-hour
bicycle rides at ambient ozone concentrations between 32 and
103 ppb. Rides at ozone concentrations exceeding 80 ppb
caused decrements in lung function and increases in the serum
levels of Clara cell protein CC 16 (an indicator of increased permeability of the lung epithelial barrier). These changes
were largely confined to a subgroup of subjects bearing both
the NQO1wt and GSTM1null genotypes. Other haplotypes
developed a rise in Clara cell protein CC16 but no change in
lung function. In the subjects carrying both the NQO1wt and
GSTM1null genotypes, the increase in Clara cell protein CC16
was related to ambient ozone (r2 = 0.48), and the increase in
this protein was related to fall in FEV1 (r2 = 0.67). The authors conclude that the adverse affects of ozone on lung function and on the lung epithelial barrier are most apparent in individuals with a combination of the NQO1wt and GSTM1null genotypes, who are susceptible to developing increased free radicals.
To determine whether tumor necrosis factor contributes to the airway hyperresponsiveness induced by ozone, Shore and coworkers (95) studied wild-type mice and knockout mice deficient in the p55 receptor for tumor necrosis factor, deficient in the p75 receptor for tumor necrosis factor, or deficient in both receptors. Three hours after exposure to ozone, the airway response to methacholine underwent a 1.2 log shift to the left in the wild-type mice, indicating hyperresponsiveness. The shift was only 0.5 log in the mice genetically deficient in the two tumor necrosis factor receptors; the results were similar in the mice deficient in the p75 receptor. Ozone caused an equivalent increase in neutrophils in the bronchoalveolar fluid of both the wild-type mice and the mice deficient in the two receptors. The authors conclude that tumor necrosis factor contributes to the airway hyperresponsiveness but not to the neutrophil migration induced by ozone.
Samet and coworkers (96) studied susceptibility to ozone in two groups of subjects: one group was relatively well supplemented in ascorbate,