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Clinical Investigations: COPD |

Patterns of Lung Disease in a “Normal” Smoking Population*: Are Emphysema and Airflow Obstruction Found Together? FREE TO VIEW

Kimberley D. Clark, BSc; Nigel Wardrobe-Wong, BSc; John J. Elliott, HDCR; Peter T. Gill, MBBS; Nicholas P. Tait, MD; Phillip D. Snashall, MD
Author and Funding Information

*From the School of Clinical Medical Sciences, University of Newcastle upon Tyne, and Departments of Cardio-respiratory Medicine and Radiology, University Hospital of North Tees, Stockton on Tees, Cleveland, UK.

Correspondence to: P D. Snashall, MD, Department of Medicine, University Hospital of North Tees, Stockton on Tees, Cleveland, TS19 8PE, UK; e-mail: snashall@ukgateway.net



Chest. 2001;120(3):743-747. doi:10.1378/chest.120.3.743
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Published online

Study objectives: We determined whether emphysema demonstrated on high-resolution CT (HRCT) scanning in apparently well smokers is associated with airflow obstruction.

Interventions: Lung function testing and limited HRCT scanning.

Design: Lung function measurements and scans were analyzed independently of each other. We used analysis of covariance to compare FEV1 and maximum expiratory flow at 50% of vital capacity (MEF50) values after suitable corrections, between subjects with and without parenchymal damage (emphysema and/or reduced carbon monoxide transfer coefficient[ Kco]), and to compare indexes of parenchymal damage between subjects with and without airflow obstruction.

Setting: Radiology and lung function departments of a district general hospital.

Participants: Eighty current cigarette smokers and 20 lifetime nonsmoking control subjects (aged 35 to 65 years) who volunteered following publicity in local media. In all subjects, FEV1 was > 1.5 L; no subjects were known to have lung disease.

Measurements and results: FEV1 and MEF50 were measured spirometrically; static lung volumes were measured by helium dilution and body plethysmography; Kco was measured by a single-breath technique. HRCT scans were analyzed for emphysema by two radiologists. Of smokers, 25% had HRCT emphysema, generally mild; 16.3% and 25% had reduced FEV1 and MEF50, respectively; 12.5% had reduced Kco. Smokers with airflow obstruction were not more likely to have parenchymal damage. Smokers with parenchymal damage did not have reduced airway function. Nonsmokers generally had normal airways and parenchyma.

Conclusions: “Normal” smokers with lung damage had either airflow obstruction or parenchymal damage, but not generally both.

Using lung CT, emphysema is sometimes found unexpectedly in otherwise normal lungs.13 It is commonly thought that emphysema and the associated loss of lung elastic recoil pressure leads to expiratory airflow limitation. In severe COPD, emphysema is usually associated with airflow obstruction,4but the coexistence of these conditions is not inevitable.5Previous studies suggest that loss of lung elastic recoil may result in airway obstruction67 or have no such effect.8 The relationship between emphysema and airflow obstruction is therefore more complex and less clearly defined than often taught.

High-resolution CT (HRCT) is a highly sensitive method for demonstrating and quantifying emphysema2,4,910 and has demonstrated mild degrees of emphysema in symptomless smokers,11in whom COPD might therefore be thought to be developing. Radiographic and pathologic correlations demonstrate the sensitivity of the CT technique.12The present study addresses the question of whether mild emphysema demonstrated by HRCT in symptomless smokers is associated with airflow obstruction. We have analyzed lung function and radiographic data from a cross-sectional study13 of current cigarette smoking and never-smoking volunteers, none of whom were known to have COPD or other obstructive lung diseases.

Subjects

Eighty current cigarette smokers (five or more cigarettes per day) aged 35 to 65 years (mean [SD] age, 51 [7.7] years; 41 men and 39 women) and 20 lifetime nonsmokers (not more than one cigarette per day for 1 year; mean [SD] age, 50 [8.1] years; 7 men and 13 women) volunteered after publicity in local media. All subjects were white. Exclusion criteria were an FEV1 > 1.5 L, asthma, bronchodilator or corticosteroid medications, and use of other tobacco products.

The study was approved by the North Tees Local Research Ethics Committee. Subjects consented in writing after reading a description of the study and possible risks. At the end of the study, all subjects were informed of their results via their general practitioner. Smokers were offered information and help on smoking abstinence. Subjects also completed a Medical Research Council Respiratory Health Questionnaire.

HRCT scanning was performed (IGE Sytec 3000i CT scanner; GEC; Milwaukee, WI). Three 1-mm cuts from the upper, middle, and lower zones of the right lung were obtained at total lung capacity (TLC). The images were examined by two radiologists who worked independently and were unaware of the subjects’ smoking status. They primarily examined for areas of emphysema, characterized as areas of abnormally low radiographic density, lacking a well-defined wall, and where marked, associated with a disruption of the normal vascular markings. When they disagreed, they viewed the images together and came to an agreed decision. Emphysema was graded using criteria of Remy-Jardin et al,11, ie, grade 1, ≤ 25% of lung fields affected by emphysema; grade 2, > 25%, ≤ 50%; grade 3, > 50%,≤ 75%; and grade 4, > 75%.

Lung Function

Forced spirometry, lung volumes (helium dilution), and carbon monoxide transfer were measured using automated apparatus (model TTUSA; P.K. Morgan; Chatham, Kent, UK). Lung volumes were also measured using a constant volume body plethysmograph (model 1190; P.K. Morgan). All measurements were adjusted to body temperature and pressure, saturated. Measurements of residual volume (RV), functional residual capacity (FRC), and TLC were repeated until duplicate measurements of TLC were within 7%. In subjects in whom satisfactorily reproducible volume measurements were made by both helium dilution and body plethysmographic methods, the quoted value is the mean of the two methods. Where only one method yielded adequately reproducible results, the quoted value is for that method alone. Calibration checks on all instruments were carried out daily.

Expiratory flow-volume curves were recorded from a computerized dry rolling-seal spirometer. Forced expiratory maneuvers were repeated until duplicate estimates of FVC and FEV1 were within 5% of each other. Maximum expiratory flow at 50% of vital capacity (MEF50) was derived automatically from the expiratory flow volume curve. Carbon monoxide transfer was measured by the single-breath method14 using a 9-s breath-hold time. Duplicate measurements were accepted where estimates of carbon monoxide transfer factor (Tlco) and effective alveolar volume (Va) were within 5%; carbon monoxide transfer coefficient (Kco) was derived (Kco = Tlco/Va). Four smokers achieved unacceptable Kco reproducibility. Hemoglobin was measured and in all cases was within the normal range.

Statistics

Data were analyzed using a statistical package (SPSS Inc.; Chicago, IL). We assumed that lung function measures were normally distributed. We used analysis of covariance (ANCOVA) to compare FEV1 and MEF50 (corrected for pack-years, age, height, and sex) between grades of HRCT emphysema, and in subjects with and without significantly low Kco. We similarly compared Kco (corrected for pack-years) between subjects with and without a significantly low FEV1, and we compared emphysema grade (corrected for age, sex, smoking status, and height) in subjects with and without significantly low Kco and subjects with and without significantly low FEV1. A p value of < 0.05 was accepted as significant. Predicted lung function values used were derived from a nonsmoking, white, urban British population,15 and we adopted (mean − 1.645 SD) as the lower limit of normal for FEV1 and Kco. Values below this will occur by chance on 5% of occasions in a normal population.,15 We used theχ 2 statistic to compare the actual frequency of coexistence of parenchymal and airway abnormalities with frequencies expected by chance.

Lung Function

In nonsmokers, mean values were close to predicted,15 but one subject had a low Kco and another subject had a low MEF50. Mean FEV1, MEF50, and Kco were significantly lower in smokers than in nonsmokers; mean FRC and RV were higher (Table 1 ). Of smokers, 13 subjects (16.3%) had a significantly reduced FEV1 and 20 subjects (25%) had a significantly low MEF50. Kco was reduced in 10 smokers (12.5%).

HRCT Scans

In their first examination of the scans, the radiologists agreed on the presence of emphysema in 14 smokers and its absence in 54 smokers. In 12 subjects, they disagreed over the presence of minor emphysema, but after viewing these images together, they agreed that 6 subjects had emphysema and 6 subjects did not. No emphysema was detected in nonsmokers by either radiologist. Emphysema was found as grade 1 in 14 smokers, grade 2 in 5 smokers, and grade 3 in 1 smoker.

Of 20 smokers with radiographic emphysema, 5 subjects had airflow obstruction (low FEV1 and/or low MEF50), as would be expected by chance. Six smokers had a significantly low Kco; two or three smokers would have had a significantly low Kco expected by chance (p < 0.025).

Relationships Between Lung Function and Emphysema

ANCOVA demonstrated several significant relationships among lung function and radiographic variables (Table 2 ). A low FEV1 was associated with high RV and FRC, but with no significant changes in carbon monoxide transfer or with HRCT emphysema score. A low Kco was associated with high TLC and FRC and with an increased emphysema score, but with no significant change in FEV1 or MEF50. The presence of HRCT emphysema was associated with reduced Kco and Tlco, but with no significant changes in FEV1, MEF50, or lung volumes. In emphysema grades 0 to 3, FEV1 averaged 2.89 L, 3.19 L, 3.07 L, and 2.91 L, respectively (p = 0.20).

Symptoms and History

Two nonsmokers were breathless when hurrying on a flat surface or walking up a slight hill. One subject had a productive cough for > 3 mo/yr. Two subjects (10%) recollected nonasthmatic childhood chest trouble.

Twenty-one smokers were breathless when hurrying on a flat surface or walking up a slight hill, and 16 smokers had a productive cough for> 3 mo/yr. FEV1 was reduced in breathless smokers compared with nonbreathless smokers (p < 0.01) and in those with productive cough compared with those without cough (p < 0.01). There was no significant relationship between breathlessness and emphysema or a reduced Kco. Seventeen smokers (21%) recollected nonasthmatic childhood chest trouble; 4 of these smokers had emphysema and 3 smokers had a reduced FEV1.

Of this group of smokers, with a mean lifetime cigarette exposure of 35 pack-years, 25% had HRCT emphysema, 12.5% had a significantly reduced Kco, and 25% and 16.3% had significant reductions of MEF50 and FEV1, respectively. Airway obstruction and parenchymal damage were not significantly associated with each other. It is important to stress both aspects of this lack of association. Neither early emphysema nor reduced carbon monoxide transfer was associated with airway obstruction more than expected by chance. Similarly, subjects with significant airflow obstruction did not have an excess of emphysema or reduced carbon monoxide transfer.

This lack of relationship, which has also been shown by others,12 argues against a causal relationship between parenchymal destruction and airflow obstruction as measured by FEV1 and MEF50. Early in its genesis, smokers’ airflow obstruction is due either to intrinsic airway disease or to loss of lung elastic recoil pressure, independent of detectable emphysema.3 In established COPD, however, there is a significant correlation between extent of emphysema and severity of airflow obstruction4 and it is probable that emphysema aggravates airway narrowing.67

A previously published analysis13 of these data, taken with indexes of smoke inhalation, suggested that different patterns of smoke inhalation may result in different patterns of lung damage. We found indirect evidence that deep or prolonged smoke inhalation predisposes to emphysema.

Looking at the lung function of the groups as a whole, we see that the effect of smoking is to cause airway obstruction, a loss of carbon monoxide transfer capacity, and an increase in the lower divisions of lung volume, RV, and FRC. There was no significant effect on TLC for reasons that are not clear.

We found a clear association between HRCT emphysema and reduced carbon monoxide transfer, as have others.2,4 Kco was lower in subjects with HRCT emphysema, and emphysema grade was higher in subjects with a low Kco. Thus, although emphysema was generally minor and focal and was not associated with an increase in lung volume, it was associated with a general defect in parenchymal function. In subjects with a significantly reduced Kco, lung volume, particularly at TLC, was elevated, suggesting a loss of lung elastic recoil pressure. A low Kco therefore indicated more severe or generalized parenchymal damage than HRCT emphysema alone. Because maximal expiratory flow depends on elastic recoil pressure, one might expect to have found reduced expiratory flows in those with low Kco, but there was no hint of this. We assume that hyperinflation maintained recoil pressure at near normal values.

Subjects with a significantly low FEV1 had a raised RV, suggesting air trapping at low lung volumes, presumably due to intrinsic small airway disease. The HRCT emphysema score was not increased, nor was there any hint of a reduction of Kco.

The study population showed a surprisingly high incidence of abnormalities, particularly emphysema. In total, of 80 “normal” smokers, 39 subjects (49%) had a lung function or HRCT abnormality or both. Admittedly, most of the HRCT emphysema was minor (grade 1), as were most of the airway abnormalities. By contrast, only two nonsmoking subjects (10%) had minor abnormalities of lung function, and no emphysema was detected. Some smoking subjects volunteered because of concerns about their health, and the group may therefore have an excess of subjects with developing lung disease. Conversely, we may have underestimated the prevalence of emphysema by restricting HRCT scanning to three slices, which was done to limit radiographic exposure. Our findings are in line with an earlier study11 of younger smokers, 21% of whom had mild HRCT emphysema.

We found that volunteers with mild, generally asymptomatic, smoking-induced lung damage had either airflow obstruction or emphysema, not both. The study therefore lends no support to the hypothesis that emphysema causes expiratory flow limitation.67 In their early stages, emphysema and airflow obstruction appear to occur independently, although both are linked to the smoking habit.8,16

Abbreviations: ANCOVA = analysis of covariance; FRC = functional residual capacity; HRCT = high-resolution CT; Kco = carbon monoxide transfer coefficient; MEF50 = maximum expiratory flow at 50% of vital capacity; RV = residual volume; SR = standardized residual; TLC = total lung capacity; Tlco = carbon monoxide transfer factor; Va = alveolar volume

Funded by grants from the Northern and Yorkshire Regional Health Authority and North Tees Health (NHS) Trust.

Table Graphic Jump Location
Table 1. Lung Function Values*
* 

Data are presented as percentage of predicted values (SD).

 

< 0.05 ≥ 0.01 comparison p values between smokers and nonsmokers.

 

< 0.01 ≥ 0.001 comparison p values between smokers and nonsmokers.

Table Graphic Jump Location
Table 2. Lung Function Variables and HRCT Emphysema Score in Subjects With and Without Three Categories of Lung Abnormalities Adjusted Using ANCOVA
* 

p < 0.05.

 

p < 0.01.

Petty, TL, Silvers, GW, Stanford, RE (1987) Mild emphysema is associated with reduced elastic recoil and increased lung size but not with air-flow limitation.Am Rev Respir Dis136,867-871. [PubMed] [CrossRef]
 
Klein, JS, Gamsu, G, Webb, WR, et al High-resolution CT diagnosis of emphysema in symptomatic patients with normal chest radiographs and isolated low diffusing capacity.Radiology1992;182,817-821. [PubMed]
 
Hogg, JC, Wright, JL, Wiggs, BR, et al Lung structure and function in cigarette smokers.Thorax1994;49,473-478. [PubMed]
 
Gelb, AF, Hogg, JC, Muller, NL, et al Contribution of emphysema and small airways in COPD.Chest1996;109,253-259. [PubMed]
 
Gelb, AF, Zamel, N, Hogg, JC, et al Pseudophysiologic emphysema resulting from severe small-airways disease.Am J Respir Crit Care Med1998;158,815-819. [PubMed]
 
Colebatch, HJH, Finucane, KE, Smith, MM Pulmonary conductance and elastic recoil relationships in asthma and emphysema.J Appl Physiol1973;34,143-153. [PubMed]
 
Leaver, DG, Tattersfield, AE, Pride, NB Bronchial and extrabronchial factors in chronic airflow obstruction.Thorax1974;29,394-400. [PubMed]
 
Pride, NB, Ingram, RH, Jr, Lim, TK Interaction between parenchyma and airways in chronic obstructive pulmonary disease and in asthma.Am Rev Respir Dis1991;143,1446-1449. [PubMed]
 
Thurlbeck, WM, Muller, NL Benjamin Felson lecture: emphysema; definition, imaging and quantification.AJR Am J Roentgenol1994;163,1017-1025. [PubMed]
 
Coxon, HO, Rogers, RM, Whittal, KP, et al A quantification of the lung surface area in emphysema using computerized tomography.Am J Respir Crit Care Med1999;159,851-856. [PubMed]
 
Remy-Jardin, M, Remy, J, Boulenguez, C, et al Morphologic effects of cigarette smoking on airways and pulmonary parenchyma in healthy adult volunteers: CT evaluation and correlation with pulmonary function tests.Radiology1993;186,107-115. [PubMed]
 
Hruban, RH, Meziane, MA, Zerhouni, EA, et al High resolution computed tomography of inflation-fixed lungs: pathologic-radiologic correlation of centrilobular emphysema.Am Rev Respir Dis1987;136,935-940. [PubMed]
 
Clark, KD, Wardrobe-Wong, N, Elliott, JJ, et al Cigarette smoke inhalation and lung damage in smoking volunteers.Eur Respir J1998;12,395-399. [PubMed]
 
Ogilvie, CM, Forster, RE, Blakemore, WS A standardized breath holding technique for the clinical measurement of the diffusing capacity of the lung for carbon monoxide.J Clin Invest1957;36,1-17
 
Roberts, CM, MacRae, KD, Winning, AJ, et al Reference values and prediction equations for normal lung function in a non-smoking white urban population.Thorax1991;46,643-650. [PubMed]
 
Thurlbeck, WM Smoking, airflow limitation, and the pulmonary circulation.Am Rev Respir Dis1980;122,183-186
 

Figures

Tables

Table Graphic Jump Location
Table 1. Lung Function Values*
* 

Data are presented as percentage of predicted values (SD).

 

< 0.05 ≥ 0.01 comparison p values between smokers and nonsmokers.

 

< 0.01 ≥ 0.001 comparison p values between smokers and nonsmokers.

Table Graphic Jump Location
Table 2. Lung Function Variables and HRCT Emphysema Score in Subjects With and Without Three Categories of Lung Abnormalities Adjusted Using ANCOVA
* 

p < 0.05.

 

p < 0.01.

References

Petty, TL, Silvers, GW, Stanford, RE (1987) Mild emphysema is associated with reduced elastic recoil and increased lung size but not with air-flow limitation.Am Rev Respir Dis136,867-871. [PubMed] [CrossRef]
 
Klein, JS, Gamsu, G, Webb, WR, et al High-resolution CT diagnosis of emphysema in symptomatic patients with normal chest radiographs and isolated low diffusing capacity.Radiology1992;182,817-821. [PubMed]
 
Hogg, JC, Wright, JL, Wiggs, BR, et al Lung structure and function in cigarette smokers.Thorax1994;49,473-478. [PubMed]
 
Gelb, AF, Hogg, JC, Muller, NL, et al Contribution of emphysema and small airways in COPD.Chest1996;109,253-259. [PubMed]
 
Gelb, AF, Zamel, N, Hogg, JC, et al Pseudophysiologic emphysema resulting from severe small-airways disease.Am J Respir Crit Care Med1998;158,815-819. [PubMed]
 
Colebatch, HJH, Finucane, KE, Smith, MM Pulmonary conductance and elastic recoil relationships in asthma and emphysema.J Appl Physiol1973;34,143-153. [PubMed]
 
Leaver, DG, Tattersfield, AE, Pride, NB Bronchial and extrabronchial factors in chronic airflow obstruction.Thorax1974;29,394-400. [PubMed]
 
Pride, NB, Ingram, RH, Jr, Lim, TK Interaction between parenchyma and airways in chronic obstructive pulmonary disease and in asthma.Am Rev Respir Dis1991;143,1446-1449. [PubMed]
 
Thurlbeck, WM, Muller, NL Benjamin Felson lecture: emphysema; definition, imaging and quantification.AJR Am J Roentgenol1994;163,1017-1025. [PubMed]
 
Coxon, HO, Rogers, RM, Whittal, KP, et al A quantification of the lung surface area in emphysema using computerized tomography.Am J Respir Crit Care Med1999;159,851-856. [PubMed]
 
Remy-Jardin, M, Remy, J, Boulenguez, C, et al Morphologic effects of cigarette smoking on airways and pulmonary parenchyma in healthy adult volunteers: CT evaluation and correlation with pulmonary function tests.Radiology1993;186,107-115. [PubMed]
 
Hruban, RH, Meziane, MA, Zerhouni, EA, et al High resolution computed tomography of inflation-fixed lungs: pathologic-radiologic correlation of centrilobular emphysema.Am Rev Respir Dis1987;136,935-940. [PubMed]
 
Clark, KD, Wardrobe-Wong, N, Elliott, JJ, et al Cigarette smoke inhalation and lung damage in smoking volunteers.Eur Respir J1998;12,395-399. [PubMed]
 
Ogilvie, CM, Forster, RE, Blakemore, WS A standardized breath holding technique for the clinical measurement of the diffusing capacity of the lung for carbon monoxide.J Clin Invest1957;36,1-17
 
Roberts, CM, MacRae, KD, Winning, AJ, et al Reference values and prediction equations for normal lung function in a non-smoking white urban population.Thorax1991;46,643-650. [PubMed]
 
Thurlbeck, WM Smoking, airflow limitation, and the pulmonary circulation.Am Rev Respir Dis1980;122,183-186
 
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