Clinical Correlates of an Elevated Diffusing Capacity for Carbon Monoxide Corrected for Alveolar Volume

Clinical Correlates of an Elevated Diffusing Capacity for Carbon Monoxide Corrected for Alveolar Volume PETER BAYLOR, MD,

PAUL GOEBEL, MD

ABSTRACT: The diffusing capacity for carbon monoxide is partially dependent on lung volume at which it is measured. As a consequence, the diffusing capacity for carbon monoxide is often indexed to the simultaneously measured lung volume (VA), giving rise to the term DL/V A. This reflects the diffusing capacity of carbon monoxide per unit area of lung parenchyma. The authors investigated the pulmonary function of 18 patients who had an elevated DL/V A in order to identify factors that could account for this abnormality. Sixteen of the 18 had a reduction in vital capacity. The vital capacity was reduced because of obesity, pleural disease, and diaphragmatic dysfunction. Eight of nine patients with a body mass index > 30 kg/m 2 had a reduction in vital capacity. On the basis of these findings, we believe that an elevated DL/V A should alert the physician to the possibility of 1) an increase in pulmonary capillary blood volume (Vc) (obesity, polycythemia, negative pleural pressure), and 2) reduced VA that does not directly affect the pulmonary capillary bed (pleural disease, neuromuscular disease). KEY INDEXING TERMS: High DL/V A; Clinical correlates. [Am J Med Sci 1996;311(6):266-271.]

T

he diffusing capacity for carbon monoxide corrected for alveolar volume (DL/VA) is a commonly performed test of pulmonary function. The diffusing capacity for carbon monoxide (DLCO) is derived from the product of DL/VA and the alveolar volume (VA). Lung volume is one of several variables that affect the DLC0. 1- 6 This was first noted by Krogh. 7 The diffusing capacity for carbon monoxide has been inFrom the Veterans Affairs M edical Center, Fresno, California. S ubmitted N ovember 23, 1994; accep ted in revised form February 8, 1996. Corresp ondence: Peter Bay lor, MD, Veterans Affairs M edical Center, 2615 E ast Clin ton Avenue, Fresno, CA 93703.

266

de xed to the VA as measured by helium dilution during the procedure to index the DLCO for lung volume; 8 •9 this is called the specific diffusing capacity, or DL/VA. Causes of decreased DL/VA include pulmonary fibrosis, anemia, emphysema, and pulmonary vasculitis.9 Because there is a paucity of literature on high DL/ VA values, we decided to investigate its significance. Materials and Methods Patient Selection. A retrospective survey of all pul-

monary function tests performed at V AMC Fresno during 1989 was performed. Eight hundred and eighty tests were performed. We identified 18 patients who had an elevated DL/VA (greater than 95% confidence interval) using Miller's predicted normal values, 10 a prevalence of 2%. One of us (P.B.) interviewed all of these patients, who formed the study group. The most common indication for pulmonary function testing was dyspnea. Measurements. The Medical Graphics Corporation system was used to measure pulmonary function. The Medical Graphics Corporation method used meets the American Thoracic Society (ATS) equipment standards.11 We followed the ATS recommended technique using the Jones and Meade 12 time and the Cotes13 hemoglobin correction factor. All 18 patients had less than 1.5% carboxyhemoglobin as measured by a cooximeter analysis of arterial blood [Corning Co-oximeter model2500 (Ciba-Corning, Medfield, MA)]. All pulmonary function tests were performed by the same technician. Predicted values for total lung capacity (TLC) , forced vital capacity and forced expiratory volume in one second were calculated using the data of Morris et al. 14 Eight patients had TLC measurement by plet hysmography, and 10 had TLC measurement by the nitrogen washout method; the TLC was calculated by adding the inspiratory capacity to the measured FRC. The lower limit of normal for TLC was found by subtracting the 95% confidence limit from the predicted value. We used 50 kg for 5 feet and 2.3 kg for every inch over 5 feet as the ide~~ body weight. Lung Volume and DLCO Interpretation. Pulmonary function was interpreted according to the recommenJune 1996 Volume 311 Number 6

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dations of the Intermountain Thoracic Society. 14 When the vital capacity was less than predicted by more than the 95% confidence interval, it was classified as being low. An obstructive defect was diagnosed if the forced expiratory volume in one second to forced vital capacity ratio was less than the predicted value by greater than the 95% confidence interval. We categorized DL/VA according to the difference between measured and predicted DL/VA; the greater the difference, the more abnormal the DL/VA. The 95% confidence intervals for DLCO and DL/V A from Miller's 10 data are 8.0 and 1.2, respectively. We defined an increase in DL/VA if the patient's measured DL/ VA was greater than the predicted DL/VA by 1.2 or more. Although we used different reference values for lung volumes and alveolar volumes, this practice is not uncommon.

2

•

1.9

1.8 1.7

~~

1.6

co 1.5 co

a: ... "'"' :>!,1

1.4

i:li"' ::.g:

1.3


~ ~

1.2 1.1

0.2

0

0.4

0.6

0.8

1.2

MEASURED VA PREDICTED VA

Figure 1. Relation between measured DL/VA/predicted DL/VA and measured VA/predicted VA. DL/VA = diffusing capacity for carbon monoxide corrected for alveolar volume.

Results

We identified 18 patients who met the entry criteria. All were Caucasian men; their age ranged between 35 and 75 years (mean, 59 years). The mean patient height was 178 em; mean weight was 97 kg. There was a correlation of 0.64 (P = 0.003) between the forced vital capacity and VA. Of patients 1-12 (Table 1), there was a correlation of 0. 70 (P = 0.007) between the TLC and VA. There was an inverse correlation of r = -0.53, P = 0.02, between :q1easured DL/V A/predicted DL/V A and measured VA/predicted VA (Figure 1). Sixteen of

the 18 subjects had a reduction in vital capacity; this was not significant by chi-square analysis (P = 0.14) . A summary of lung volume measurements and DLCO values is shown in Table 2. Of the 9 patients with a body mass index greater than 30 kg/m 2 , 2 (patients 2 and 7) had a reduction in vital capacity and total lung capacity, 6 of these 9 subjects (patients 3, 4, 10, 11, 13,

Table 1. Clinical and Pulmonary Function Findings in 18 Patients With Elevated DL/VA

No.

Age

%1BW

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 MN

55 69 55 64 67 64 41 70 64 55 58 52 54 53 64 71 49 55 59

116 132 143 168 125 104 158 117 104 140 140 110 140 140 100 110 116 171 130

TLC Liters Meas./Pred

FVC Liters Meas./Pred

5.60 4.97 6.22 5.65 4.10 4.94 4.90 3.67 6.48 5.79 5.83 5.97 6.14 7.83 6.59 7.93 8.30 6.56 5.97

3.84 2.34 3.35 2.64 2.44 2.84 3.67 2.20 3.13 2.65 3.08 3.61 3.17 2.36 3.06 2.19 4.43 5.05 3.11

7.18 6.62 7.38 7.21 6.41 7.21 7.57 7.48 7.21 6.78 6.58 6.77 6.97 7.17 7.21 6.42 7.16 7.38 7.03

4.99 4.24 5.15 4.80 4.13 4.80 5.60 5.17 4.80 4.69 4.47 4.75 4.86 5.04 4.80 4.04 5.12 5.19 4.81

FEV 1 Liters Meas./Pred 3.16 1.99 2.62 2.12 1.91 2.38 3.00 1.93 2.44 1.95 2.65 2.87 2.20 1.27 1.77 1.16 3.36 4.32 2.34

3.93 3.28 4.04 3.71 3.22 3.71 4.49 3.93 3.71 3.72 3.55 3.80 3.85 3.98 3.71 3.12 4.08 4.09 3.77

FEV 1% Meas./Pred 82 85 78 80 78 84 82

88 78 74 86 79 69 54 58 53 76 85 76

79 78 78 77

78 77 80 76 77 79 79 80 79 79 77 78 80 79 78

DL mlfmin/ Hg Meas./Pred

VA Liters Meas./Pred

DL/VA Meas./Pred

40.35 28.74 43.12 31.85 23.46 29.51 37.86 17.86 28.34 40.16 34.95 38.33 32.65 35.69 33.95 29.91 45.57 37.34 33.87

5.78 5.20 5.36 4.62 3.93 5.24 5.29 2.94 4.74 5.54 6.05 6.31 5.49 5.81 5.86 5.59 7.45 6.33 5.41

6.98 5.53 8.05 6.89 5.97 5.64 7.15 6.01 5.98 7.25 5.78 6.08 5.95 6.14 5.80 5.35 6.11 5.90 6.25

29.99 25.53 30.41 27.93 25.57 27.93 34.04 27.81 27.93 29.16 28.05 29.85 29.81 30.45 27.93 24.66 31.37 30.87 28.84

7.01 6.43 7.21 7.01 6.24 7.01 7.40 7.59 7.01 6 .63 6.43 6.63 6.82 7.01 7.01 6.24 7.01 7.21 6.88

4.27 3.97 4.21 3.98 4.10 3.98 4.60 3.66 3.98 4.40 4.36 4.50 4.37 4.34 3.98 3.95 4.47 4.28 4.18

Patients 1-12 had low vital capacity. Patients 13-16 had a low vital capacity with moderate airflow obstruction. Patients 17-18 had normal pulmonary function . Abbreviations: %1BW =percent ideal body weight; FVC = forced vital capacity; FEVI =forced expiratory volume; DL =diffusing capacity for carbon monoxide; VA = alveolar volume as measured by neon dilution; TLC = total lung capacity. Patients: 2, 3, 4, 7, 10, II, 13, 14, and 18 had a body mass index> 30 kg/m 2 THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES

267

Elevated DLIV A

Table 2. Pulmonary Function Changes in 18 Patients With Elevated DL/VA Values

Pulmonary Function

No. Patients

Reduction in VC and TLC Reduction in VC and normal TLC Reduction in FEV 1% Normal VC, TLC, and FEV 1%

5 11 4 2

VC = vital capacity; TLC exhaled in first second.

=

total lung capacity; FEV 1%

=

No. Patients 4 2 1 11

(Patients 5, 8, 12, and 15) (Patients 6 and 9) (Patient 14) (remainder)

volume

and 14) had a reduction in vital capacity alone. One (patient 1) of our patients had polycythemia rubra vera (hemoglobin 20.5 g/dL, hematocrit 55.7%) . The chest radiographs of the 18 patients were reviewed by an attending radiologist who was aware of the clinical history but unaware of the pulmonary function test report. Only one had parenchymal lung disease (patient 14). Of the remaining 17 patients, the only radiographic abnormality present was confined to the pleura or diaphragm, as shown in Table 3. Three patients (8, 12, and 15) had radiographic evidence of pleural thickening, patient 8 had bilateral pleural thickening associated with pleural calcification and a history of asbestos exposure, patient 12 had an open lung biopsy which was diagnosed as sarcoidosis, and patient 15 had pleural thickening that was unexplained. Patient 5 had a history of asbestos exposure and had pleural calcification. Patients 6 and 9 had paralyzed hemidiaphragms (fluoroscopic diagnosis). Patient 14 had radiographic evidence of bullous emphysema. The clinical disorders associated with high DL/V A values are shown in Table 4. Miller et al 10 demonstrated that the DLCO values predicted by various authors are often different. As a result, the same patient may be regarded as normal using one equation and abnormal using another. He stated that this discrepancy was due to the small number of subjects accessible for each study. To correct this deficit, he provided a new prediction equation based on data representative of a cross-section of the general population of the state of Michigan. We used the (nonsmokers) predicted equations of Miller et al 10 for DLCO and DL/VA as our reference. It is one of the largest series available for adults and is based on subjects with normal hemoglobin concentrations. Miller et al's 10 method of measuring DLCO differs slightly from the method used by the Medical Graphics system. Miller et al 10 used a dead space of 1,000 mL for most of his patients, and an electrochemical cell to analyze exhaled gas. Medical Graphics uses a gas chromatograph to measure exhaled gas.

268

Radiographic Changes 1. Pleural disease 2. Paralyzed diaphragm 3. Bullous disease 4. No radiographic abnormality

Patients 1, 3, 4, 9- 18, had normal TLC. Patients 2, 5, 6, 7, and 8 had a low TLC. Patients 1, 3, 10, 12, and 17 had a high DLCO. Patient 8 had a low DLCO.

Discussion

Table 3. Radiographic Changes in 18 Patients With Elevated DL/VA Values

Miller et al's 10 regression equation for DLCO values for male nonsmokers is slightly higher (by approximately 7%) than those of other workers, 15- 17 but lower (by as much as 30%) than those of Crapo and Morris 18 and those of Paoletti and colleagues.19 Had we chosen the predicted values of Crapo and Morris 18 or Paoletti and colleagues, 19 we possibly would have found a lower prevalence of elevated DL/V A. Other technical factors that could account for high DL/VAs include difference in equipment and test performance, but both our equipment and our test performance followed ATS standards and are unlikely to contribute to falsely high DL/VA. Because the incidence of elevated DL/VA was less than the 2.5% implied in the 95% confidence intervals, it is possible that our data reflect a random event and that all the subjects are normal. This may be true for subject 17, but all other subjects are unlikely to be normal. Why was a low vital capacity a more important predictor of a high DL/V A than either TLC or VA? It may be because a low vital capacity is multifactorial in nature in that it can reflect a reduced TLC from inspiratory muscle, parenchymal, or extrapulmonary dysfunction; it can also reflect an elevated residual volume (RV) due to airtrapping or airflow obstruction. A high DL/VA reflects either a high DL or a low VA. We do not have strong evidence of a high D L but we do have evidence of a low VA. From the RoughtonForster20 equation, we see that 1/DL = 1/Dm + 1/0Vc (where Dm refers to membrane diffusing capacity,() refers to specific uptake of carbon monoxide, Vc refers to pulmonary capillary blood volume), it would follow that 1/DL/VA = 1/Dm/VA + 1/0Vc/VA. Although Dm falls somewhat with VA, it is offset by an increase in ()Vc/VA. An increase in OVc/VA means either an increase in Vc or a fall in VA that does not cause a co-

Table 4. Clinical Abnormalities in 18 Patients With Elevated DL/VA Values Clinical Disorder

No. Patients

Asbestos related pleural disease Paralyzed diaphragm Unexplained pleural disease Sarcoid pleural disease Bullous emphysema

2 2 1 1 1

(Patients 5 and 8) (Patients 6 and 9) (Patient 15) (Patient 12) (Patient 14)

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existing drop in Vc; the latter condition would occur in pleural diseases or muscular disorders. Lipscomb et al 21 also demonstrated an inverse relation between DL/ VA and measured VA/predicted VA. Although the data are not shown, the patients' high DL/V A values also exceeded the high DL/VA values of Lipscomb and colleagues' 21 healthy subjects; whether this is due to compensatory overdistension of the remaining capillaries is unclear. Increased DL/VA calculations have been recorded in those with a reduced vital capacity. Conditions where this might occur include poor effort, pneumothorax, pleural mesothelioma, postresectional lung surgery, diaphragmatic weakness, 21 and diffuse pleural thickening.22 The DL/VA may be increased in those with increased pulmonary capillary blood volume or hemoglobin concentration-these include pulmonary hemorrhage, 21·23 obesity, 21·24 or polycythemia rubra veraY Finally, an increase in DL/VA was reported in those with airflow obstruction-these conditions include asthma 25-31 and cystic fibrosis. 27 The fact that we did not identify many of these conditions may be due to our patient population. Our small sample size is a statistical limitation. A major concern in measuring diffusing capacity for carbon monoxide is the performance variability of this test by different laboratories, slightly different techniques and possibly different hardware. Clausen et al 32 found differences in excess of 50% when the DLCO was measured on the same subject in different laboratories, which emphasized the potential significance of the measurement problem. In those with a low vital capacity, the main factor associated with a high DL/VA was a low VA. In those with airflow obstruction, the postulated mechanism to increase the DL/V A is increased negative pleural pressure, which increases pulmonary capillary blood volume.27·31 In those with pulmonary hemorrhage or polycythemia, the postulated mechanism is an increase in intrapulmonary erythrocyte volume. 23 The most common cause of an elevation in DL/VA is poor effort. 33 The measurement of alveolar volume is effort dependent (apart from satisfactory distribution of ventilation and mixing), and poor effort can introduce the greatest variability. We believe that all the patients had a good effort, because each demonstrated ATS level reproducibility when performing the spirogram. When performing the inspiratory effort during the diffusing capacity measurement, the technologist is alerted if the inspiratory vital capacity is less than 90 % of the slowly exhaled vital capacity. The test is repeated until the patient could fulfill this requirement. This alert system is built into the software of the Medical Graphics System 1070. Obesity is known to be associated with an increase in cardiac output, pulmonary blood volume,34 DLCO, and DL/VA. 24 Ray et al 24 investigated the pulmonary function of patients with obesity and found that the THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES

DL/V A was increased in some of those in whom the weight/height ratio (kg/em) exceeded 1.0. None of our patients exceeded this weight/height ratio. The mean weight of all the patients was 97 kg. This was below the lower limit (103 kg) in the group of obese patients described by Ray et al 24 ; they, however, used different predicted values than we did. The effect of the weight/ height ratio on the vital capacity and DL/V A is seen in Table 5. McGrath and Thompson, 35 studying eight healthy individuals, found that the DL/VA was inversely related to VA, but nonlinearly. They showed that DLCO was dependent on lung volume when lung volume exceeded functional residual capacity, and that the DL/ VA was inversely related to VA when the VA was less than predicted by 2 L or more. McGrath and Thompson 35 deliberately varied lung volume, whereas our patients' DLCO values were measured at TLC. Of Lipscomb et al's 21 seven patients who had an elevated DL/VA in the absence of pulmonary hemorrhage, almost all had a reduction in vital capacity. This suggested that as pulmonary capillary blood volume remains the same at all lung volumes, 2 a reduction in vital capacity would usually result in elevation in DL/ VA. In a group of six patients studied by Wright et al, 36 all of whom had asbestos pleural disease with reductions in inspiratory capacity, an elevation in DL/ VA was also noted in two cases. (Data on the other four were not given.) Sixteen of our eighteen patients had a reduction in vital capacity. In keeping with other studies, it is expected that a reduction in vital capacity would be associated with an increase in DL/VA as we found. Two of the patients (17 and 18) had normal pulmonary function and an increase in DL/VA, one of whom (18) was among the heaviest of the group. Therefore, obesity, by increasing pulmonary capillary blood volume, may have played a role in one of these cases. Interestingly, patients 11 and 18, the VAs of whom were not reduced from that predicted by more than 2 L, both had an increase in DL/VA. The patient's DL/V A ratio cannot effectively be compared with the predicted DL/VA if the patient's VA is widely different from the predicted VA value. Ideally, one should compare the measured DL/VA with Table 5. Effect of Weight/ H eight Ratio (kg/em) on VC and DL/ VA Weight/ Height Ratio (kg/ em)

VC (% pred) DL/ VA ( % pred )

0.40-0.49 n = 7

0.50-0.59 n = 7

0.60- 0 .69 n = 1

0.70- 0.79 n= 3

63

64 146

47 140

71 153

140

VC = vital capacity; DL/ VA =diffusing cap acity for carbon monoxide corrected for alveolar volume.

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Elevated DLIV A

the predicted DL/VA only in those patients with normal VA values. It is suggested that if the VA is normal and there is a high DL/VA, this represents a true high diffusing capacity per unit area. If the VA is reduced by 2 L or more from predicted in the presence of a high DL/VA, extra pulmonary (ie, muscle weakness) or pleural disease may exist. Pulmonary fibrosis that causes restriction alone and that does not interfere with gas exchange at rest could also increase the DL/V A. In a group of 38 patients with interstitial disease, Kanengiser et al37 found that the highest DL/V A values were found among those with the smallest VA values. One must not forget that a normal DL/VA by itself, in a patient with a low DL and a low VA, does not ensure normal overall gas exchange. A normal DL/VA (ie, not increased) in the presence of a low vital capacity due to obesity, pleural disease, or diaphragmatic dysfunction, may indicate an associated gas exchange defect. Our aim was to identify factors that caused a high DL/V A. Most of our patients were obese. Obesity is known to be associated with an increase in pulmonary blood volume and, therefore, DL/V A. Eighty-eight percent had a reduction in vital capacity. Because pulmonary capillary blood volume is independent of lung volume in the healthy subject, a reduction in VA can increase the DL/VA. The low alveolar volume in those with a high DL/VA is often caused by a condition that does not interfere with gas exchange, such as pleural, chest wall, or diaphragmatic disease. Twenty-two percent of our patients had evidence of airflow obstruction that could result in either redistribution of blood to the lung apex because of basal vasoconstriction or because of elevated negative intrapleural pressure resulting in higher pulmonary capillary blood volume. In only 1 (patient 5) of the 18 cases was obesity found in association with pleural or diaphragmatic dysfunction. These conclusions are applicable in our patients when using the reference values of Miller et al 10 for DL/VA and those of Morris et al 14 for vital capacity and total lung capacity. The high DL/VA in the presence of a low alveolar volume and a low vital capacity is presumably an attempt to ensure normal overall gas exchange. The clinical use of a high DL/VA in our patients was limited to identification of those with a) high intrapulmonary blood volume, (ie, obesity, polycythemia, and those with high negative pleural pressure), and those with b) a low alveolar volume that does not affect the pulmonary capillary bed (pleural disease, muscle disease). There was a statistically significant increase in DL/VA as the alveolar volume falls, which suggests that the lung constricts by infolding so that the surface area to volume ratio (DL/VA) increases as alveolar volume falls. In obesity, the increase in intrapulmonary blood volume may increase the DL, and in extrapulmonary restriction, the alveolar volume is decreased; some patients may have a combination of both factors.

270

These data also suggest that in nonparenchymal reduction in lung volume, the pulmonary capillary blood volume is preserved, or in the case of obesity, possibly increased. The ratio of pulmonary capillary blood volume to alveolar volume increases as alveolar volume decreases-this may be the main cause of an increase in DL/VA as alveolar volume falls, as was suggested by Lipscomb et al 21 and Starn et al. 38 An increase in extracapillary blood also causes an increase in DL/VA, but none of our patients had recent intrapulmonary hemorrhage. Acknowledgments

The authors thank Joseph Ollivier, BA, RRT, for technical assistance. References 1. Hamer NAJ. Variation in the components of the diffusing capacity as the lung expands. Clin Sci. 1963;24:275-85. 2. Miller JM, Johnson RL Jr. Effect of lung inflation on pulmonary diffusing capacity at rest and exercise. J Clin Invest. 1966;45:493-500. 3. Rose Gl, Cassidy SS, Johnson RL Jr. Diffusing capacity at different lung volumes during breath holding and rebreathing. J Appl Physiol. 1979;47:32-7. 4. Cadigan JB, Marks A, Ellicott MF, Jones RH, Gaensler EA. An analysis of factors affecting the measurement of pulmonary diffusing capacity by the single breath method. J Clin Invest. 1961;40:1495-1514. 5. Mittman C, Burrows B. Uniformity of pulmonary diffusion: Effect of lung volume. J Appl Physiol. 1959;14:496-8. 6. Ogilvie CM, Forster RE, Blakemore WS, Morton JW. A standardized breath holding technique for the clinical measurement of the diffusing capacity of the lung for carbon monoxide. J Clin Invest. 1957;36:1-17. 7. Krogh M. The diffusion of gases through the lungs. J Physiol (Lond). 1915;49:271-300. 8. Forster RE, Fowler WS, Bates DV, Van Lingen B. The absorption of carbon monoxide by the lungs during breath holding. J Clin Invest. 1954;33:1135-45. 9. Ayers LN, Ginsberg ML, Fein J, Wasserman K. Diffusing capacity, specific diffusing capacity and interpretation of diffusion defects. West J Med. 1975;123:255-64. 10. Miller A, Thornton JC, Warshaw R, Anderson H, Teirstein AS, Selikoff IJ. Single breath diffusing capacity in a representative sample of the population of Michigan, a large industrial state. Am Rev Respir Dis. 1983;127:270-7. 11. Crapo RO, Gardner RM. Single breath carbon monoxide diffusing capacity (transfer factor). Official statement of the American Thoracic Society, March 1987. Am Rev Respir Dis. 1987;136: 1299-307. 12. Jones RS, Meade F. A theoretical and experimental analysis of anomalies in the estimation of pulmonary diffusing capacity by the single breath method. Q Rev Exp Physiol. 1961;46:13143. 13. Cotes JE. Measurement of the transfer factor for the lung and its subdivisions. In: Lung Function, 4th ed. Oxford: Blackwell Scientific Publications; 1979:230-50. 14. Morris AH, Kanner RE, Crapo RO, Gardner RM. Clinical pulmonary function testing: A manual of uniform laboratory procedures. 2nd ed. Salt Lake City: Intermountain Thoracic Society; 1984. 15. Van Ganse WF, Ferris BG Jr, Cotes JE. Cigarette smoking and pulmonary diffusing capacity (transfer factor). Am Rev Respir Dis. 1972;105:30-41. 16. Marcq M, Minette A. Lung function changes in smokers with normal conventional spirometry. Am Rev Respir Dis. 1976;114: 723-38. June 1996 Volume 311 Number 6

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17. Fridriksson HV, Malmberg P, Hedenstrom H, Hillerdal G. Reference values for respiratory function tests in males. Prediction formulas with tobacco smoking parameters. Clin Physiol. 1981;1:349-64. 18. Crapo RO, Morris AH. Standardized single breath normal values for carbon monoxide diffusing capacity. Am Rev Respir Dis. 1981;123:185-9. 19. Paoletti P, Viegi G, Pistelli G , DiPede F, Fazzi P, Polato R, et aL Reference equations for the single breath diffusing capacity. Am Rev Respir Dis. 1985;132:806-13. 20. Roughton FJW, Forster RE. Relative importance of diffusion and chemical reaction rates in determining rate of exchange of gases in the human lung, with special reference to true diffusing capacity of pulmonary membrane and volume of blood in the lung capillaries. J Appl Physiol. 1957;11:290-302. 21. Lipscomb DJ, Patel K, Hughes JMB. Interpretation of increases in the transfer coefficient for carbon monoxide (T1co/ VA or Kco). Thorax. 1978;33:728- 33. 22. Corris PA, Best JJK, Gibson GJ. Effects of diffuse pleural thickening on respiratory mechanics. Eur Respir J . 1988;1:24852. 23. Ewan PW, Jones HA, Rhodes CG, Hughes JMB. Detection of intrapulmonary hemorrhage with carbon monoxide uptake: Application in Goodpasture's syndrome. N Eng! J Med. 1976;295: 1391-6. 24. Ray CS, Sue DY, Bray G, Hansen JE, Wasserman K. Effect of obesity on respiratory function . Am Rev Respir Dis. 1983;128: 501- 6. 25. Meisner P, Hugh-Jones P. Pulmonary function in bronchial asthma. BMJ. 1968;1:470-5. 26. Ogilvie CM. Pulmonary function in asthma. BMJ. 1968;1:768. 27. Keens TG, Mansell A, Krastins IRB, Levison H, Bryan AC, Hyland RH, Zamel N. Evaluation of single breath dif-

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