Radioaerosol Lung Imaging in Chronic Obstructive Pulmonary Disease

Radioaerosol Lung Imaging in Chronic Obstructive Pulmonary Disease* Comparison with Pulmonary Function Tests and Roentgenography Lalitluz Ramanna, M.D.; 00 Donald P. Tashkin, M.D.;t George V . Taplin, M .D .;:j: Dennis Elam;§ Roger Detels, M .D.; [[ Anne Coulson;n and Stanley N. Rokaw, M.D., F.C.C.P.#

Seventy subjects with either no, mild, or definite evidence of pulmonary abnormality on screening studies volunteered to have detailed pulmonary function tests (PFfs), respiratory questionnaires, physical examinations, and I13"'indium aerosol-inhalation lung imaging performed. Also, 22 and 52 of these subjects underwent 133xenon ventilation and lung perfusion imaging with 99mtechnetium-labelled macroaggregated albumin, and 56 had chest x-ray examinations performed. Results of the radionuclide lung-imaging procedures were compared with those of conventional PFfs and other clinical diagnostic procedures used to identify chronic obstructive pulmonary disease (COPD). Abnormal radioaerosol patterns were found in 32 of 33 subjects with abnormal findings

sol lung images were abnormal more frequently than respiratory questionnaire responses, findings on physical examination, chest x-ray films, and perfusion lung images and with approximately the same frequency as 133xenon ventilation scintiscans. These results suggest that radioaerosol lung imaging may be a more sensitive indicator of early COPD than other diagnostic procedures, including maximal midexpiratory flow rates, single-breath nitrogen washout, and closing volume. Further studies are required to determine the physiologic and pathologic significance of isolated aerosol lung-imaging abnormalities.

Chronic obstructive pulmonary disease ( COPD) is one of the major and most rapidly increasing causes of disability in the United States. 1 •2 Diagnosis in the early stages is essential for effective medical management and for the prevention of progres-

sive involvement and associated disability. Certain pulmonary function tests ( PFTs), such as the maximum midexpiratory flow rate ( MMFR ) , the singlebreath oxygen ( SBO:!) test, and closing volume ( CV), are considered to be practical sensitive indi-

°From the School of Medicine, the School of Public Health, and the Laboratory of Nuclear Medicine and Radiation Biology, University of California, Los Angeles. This study was supported by the California Research and Medical Education Fund of the California Lung Association, grant HR4-2913 from the National Heart and Lung Institute, USAEC Gen-12 contract between the Atomic Energy Commi~sion and the University of California, and grants-in-aid and radionuclides supplied by Mallinkrodt's Radiopharmaceutical Division and E. R. Squibb and Sons. 0 0 lnternational Atomic Energy Agency Fellow in Nuclear Medicine. t Assistant Professor of Medicine, Pulmonary Disease Division. :j:Professor of Nuclear Medicine and Radiological Sciences, Director, Nuclear Medicine Research Laboratory, Department of Radiological Sciences, and Associate Director, Laboratory of Nuclear Medicine and Radiation Biology. §Senior Staff Research Associate, Laboratory of Nuclear Medicine and Radiation Biology. !!Professor of Epidemiology, School of Public Health. I! Senior Statistician, School of Public Health. # Associate Clinical Professor of Medicine. Manuscript received January 27; revision accepted May 19. Reprint requests: Dr. Taplin, Laboratory of Nuclear Medicine, 900 Veteran Avenue, Los Angeles 90025

634 RAMANNA ET AL

on PFTs, whereas results of PFfs were abnormal in only 32 of 46 subjects with abnormal aerosol deposition. Aero-

For editorial comment, see page 613

cators of small-airway obstruction. 3· 5 However, such tests do not reveal the site ( s) of either partial or complete airway obstruction6 and may fail to identify regional abnormalities in airway dynamics. Radioaerosol and xenon-gas inhalation scintiscanning has the unique capability of detecting and localizing abnormal patterns of air flow distribution on a regional basis. 7 •8 The present study was undertaken in an attempt to assess the value of the aerosol radionuclide lung-imaging procedure in the detection of COPD by correlating the results of this procedure with respiratory questionnaire responses, physical findings, tests of overall lung function, chest roentgenography, and other radionuclide lung studies in individuals participating in a population study designed to determine the prevalence of COPD.9 CHEST, 68: 5, NOVEMBER, 1975

MATERIALS AND MITHODS

Subjects were selected from residents of two census tracts (Burbank, Calif, and Lancaster, Calif) who had undergone screening pulmonary function studies in a mobile laboratory ( Breathmobile). A 3-percent sample of the population screened at the mobile laboratory was invited to undergo repeat studies in a reference or validation laboratory at the University of California, Los Angeles, in an effort to verify the results of field testing. Approximately one-third of the validation sample was randomly selected from the entire population studied at the mobile laboratory, and the remaining two-thirds had some abnormality on the basis of respiratory questionnaire responses only, nitrogen washout ( including CV), or spirometry. Seventy subjects were studied in the validation laboratory and underwent radionuclide lungimaging procedures on the same day. There were 35 male and 35 female subjects ranging in age from 16 to 78 years, with an average age of 50 years.

Pulmonary Function Testing Upon arrival at the validation laboratory at 9 :30 AM, subjects underwent a complete history and physical examination; a respiratory questionnaire incorporating questions from both the National Heart and Lung Institute and Medical Research Council of Great Britain;lO spirometric determinations of forced vital capacity ( FVC), forced expiratory volume in one second ( FEV 1 ) and forced expiratory flow rate over the middle half of the expiratory curve ( MMFR); SBo2 test for the distribution of ventilation (phase 3 of the nitrogen concentration curve ) ; and measurement of the CV fraction using a modification of Fowler's single-breath nitrogen test.ll At least five forced expiratory maneuvers were performed by each subject in the seated position using a rolling-piston dry-seal spirometer (Cardio-Pulmonary Instruments model 220) connected to a multichannel oscilloscopic recorder (Electronics for Medicine model DR-8). All volumes were electronically corrected to body temperature and pressure, saturated (BTPS). Calculations of FEV1 , FVC, and MMFR were made from the best breath, which was identified as the one yielding the highest FEV 1 provided the FVC was within 10 percent of the best FVC. The SBo2 and CV determinations were performed with the subject standing and breathing through a low-dead-space nine-way valve connected by one inspiratory port to a cylinder of 100 percent oxygen via a demand valve and through its expiratory port to an electronic spirometer ( Cardio-Pulmonary Instruments). The needle-valve assembly of a rapidly responding nitrogen analyzer (Cardio-Pulmonary Instruments model 410) was interposed between the mouthpiece and the nine-way valve. After exhaling to residual volume ( RV), the subject inspired 100 percent oxygen slowly to total lung capacity and then, without breath-holding, expired slowly down to RV over approximately ten seconds at a constant low rate not visibly exceeding 0.5 L/sec as monitored on an oscilloscope. Nitrogen concentration of expired gas and expired volume were simultaneously recorded oscilloscopically. The difference in nitrogen concentration (
CHEST, 68: 5, NOVEMBER, 1975

instances, no terminal deflection was observed on the expired nitrogen concentration tracing. In these cases, CV was assumed to be indeterminate. At least three determinations of
Lung-Imaging Procedures Following the completion of PFTs, subjects were escorted to the UCLA Nuclear Medicine Research Laboratory where all 70 subjects underwent radioaerosol lung imaging, 52 subjects underwent perfusion lung imaging, and 22 subjects had 133xenon single-breath and washout studies performed. All radionuclide procedures were performed with the patient in the sitting position. In those patients in whom all three procedures were performed, a typical examination included the follmving : (1) Ten to 15 millicuries of 13.1xenon gas were inhaled via a two-way valve from a 1-L anesthesia hag in a single deep breath from functional residual capacity ( FRC) followed by 15 to 20 seconds of breath-holding at 1.0 L above FRC. Gamma-camera images of the posterior lung were obtained during breath-holding and every 30 seconds thereafter during washout for two to five minutes or longer while the patient tidally breathed room air. The exhaled radioactive xenon was discharged into a vented hood. ( 2) Two millicuries of 99mtechnetium-labelled macroaggregated albumin were injected intravenously. Perfusion images of the lung were obtained in the anterior, posterior, and both lateral projections. A posterior view was obtained after 200,000 counts were accumulated, followed by the remaining three views, exposing each projection for the same number of counts. ( 3) Following the perfusion study with 140-kev 90"'technetium, the administration of the radioaerosol was begun using the higher-energy 390-kev 113"'indium-colloid as the test agent and a modified ultrasonic nebulizer ( Mistogen ultrasonic nebulizer, with a one-way demand valve replacing the motor-driven air blower). Fifteen to 25 millicuries of the acid namindium eluate from the tinindium generator were adjusted to pH 7.0 and converted to an insoluble colloid with phosphate buffer and to a volume of 10 ; ml with normal saline solution. This dose was added to the medication chamber of the nebulizer. Before inhaling the radioactive aerosol, the subject was given a three-minute practice session of inhaling nebulized normal saline solution during tidal volume breathing. Then under the same conditions, the subject inhaled nebulized radioactive colloid for five to ten minutes, the usual time required to convert the 10 ml of colloid to a polydispersed aerosol. Particle size was not measured by physical methods. Instead, it was estimated by measuring the initial bronchopulmonary deposition and lung retention after 24 hours. In several normal subjects, 24-hour retention values were measured and were found to exceed 60 percent of the initial deposition, suggesting that the aerodynamic-mass median diameter was less than 3.0J.L,l2-14 Before lung imaging was started, the subject was asked to rinse his mouth to remove radioactivity from his mouth and posterior pharynx to reduce the amount of early gastric deposition. Imaging was made in all four projections immediately after the aerosol administration. For each view, 200,000 counts were accumulated. The dose retained initially varied between 0.7 and 2.0 millicuries. The three imaging procedures were performed sequentially and were completed within 90 minutes or less. The wide differences in gamma-ray energy of the three radionuclides used ( 80, 140, and 390 kev) permit this multinuclide study

RADIOAEROSOL LUNG IMAGING IN COPD 635

OBSERVED FEV 1 FR 02

Sl GLE BREATH

4.397

12

5.256

167

0.67

ORMAL ORMAL

98.0

Po 2

OKER 0 SM IM PRESS IO : NORMAL

POSTER IOR

FIGURE 1. Normal perfusion and radioaerosollung images and PTs in a 57-year-old man. because the scintillation camera (Picker Dyna Camera model 2-C) was equipped with a gamma spectrometer. In 19 subjects, delayed aerosol lung images were obtained after one to two hours to help distinguish transiently abnormal aerosol lung images with excessive deposition in the major airways caused by particles larger than 5p. or by abnormal breathing patterns from similar abnormalities found in COPD which remain abnormal for two or more hours in most subjects.

Interpretation of Studies Spirometric indices were expressed as a percentage of predicted values using the regression equations of Morris et al. 1 ~ Values for FVC and FEV1 were considered abnormal if they were less than 75 percent of predicted values (mildly, 65 to 75 percent; moderately, 50 to 65 percent; and severely, less than 50 percent). Abnormal values for FEV 1 were interpreted as indicating COPD only when lung volumes detennined on the same subjects by the helium-dilution

PERFUSIO

technique showed a normal or elevated total lung capacity. Values for MMFR were interpreted as abnormal when they were less than 65 percent of predicted values (mildly, 45 65 percent; moderately, 25 to 45 percent; and severely, less than 25 percent). Values for ~N 2 exceeding 1.8 percent were considered abnormal.l6 The CV /VC was considered abnormal if it exceeded 133 percent of the mean predicted value of Buist and Ross.• Aerosol Lung Patterns. A typical normal aerosol lung image is shown in Figure 1, along with a normal perfusion scintiscan and the results of selected PFTs. The distribution of aerosol is uniform throughout the lungs and closely matches the corresponding perfusion images. Aerosol patterns were considered abnormal if the distribution was uneven with irregular "hot" and "cold" spots or if there was excessive deposition in the regions of the major airways.s The aerosol lung pattern was classified as mildly abnormal when there was slightly excessive deposition in the major airways or slightly uneven distribution throughout the lung parenchyma,

to

AEROSOL I HALA 10

s OBSERVED FEV 1 EFR Oz

SJ GLE BREATH

P0 2

% OF PREDICT D

2.484

87.0

1.330

8.5

1. 75

ORMAL

8 .0

SLIGHTLY

S KER- 2 CIGARS/DAY FOR 35 YEARS I PRESSIO : MILD AIRWAYS DISEASE FIGURE 2. Mildly abnormal lung perfusion and radioaerosol lung images and PFTs in a 64-yearold man.

636 RAMANNA ET AL

CHEST, 68: 5, NOVEMBER, 1975

PERFUSIO

AEROSOL I HALATIO

OBSERVED FEV 1

1.20

EFR Oz

Sl GLE BREATH

33.

0.801

9.7

3.17

ABtOR L ODERATELY

Po 2 6 .0 HEAVY S 0 ER

I PRESS IO : SEVERE AIR AYS DISEASE

RIGHT LATERAL

FrGURE 3. Mildly abnormal perfusion and moderately abnormal aerosol lung images in a 57-yearold man with moderately abnormal PFTs. or both . It was considered moderately abnormal if there was either excessive central deposition or distinctly uneven deposition in the smaller airways showing "hot" and "cold" spots involving 25 to 50 percent of the lung parenchyma. Combinations of these two abnormalities are frequently seen in COPD and indicate involvement of both large and small airways.17 The aerosol lung pattern was considered severely abnormal when there were obvious gross abnormalities of deposition in either the major or the minor airways, or both, together with absent or reduced deposition in more than half of the lung parenchyma. Examples of mildly, moderately, and severely abnormal lung patterns are shown in Figures 2 to 4. All the lung scintiscans in this study were interpreted by one of us ( G.V.T . ) without prior knowledge of the PFT results or chest x-ray film findings . Lung Pe rfusion Images. These images are indicators of pulmonary arterial blood-How distribution and can localize lobar, segmental, or subsegmental areas of i~chemia.18.1D The lung perfusion images were graded as normal, mild,

PERFUSIO

moderate, or severe according to the visually estimated percent of lung deprived of arterial blood How, namely, 10 to 25 percent as mild, 25 to 50 percent as moderate, and more than 50 percent as severe pulmonary arterial blood-How impairment.20 Xenon Lung Images. These images were examined for uneven distribution of ventilation during breath-holding and for localized air-trapping (regions becoming distinctly visible during washout) . Such abnormalities indicate the effects either of airway obstruction or of poorly ventilated regions of the lung, including bullae, or of both factors. The xenon lung images were similarly graded as normal or mildly, moderately, or severely abnormal according to the estimated reduction in volume of poorly or nonventilated lung, eg, mild as 10 to 25 percent, moderate as 25 to 50 percent, and severe as more than 50 percent of normal values. Chest Roentgenograms. Chest roentgenographic studies were performed in 56 of the 70 subjects. Films were interpreted by two of us ( L.R. and D.P.T . ) without knowledge of

AEROSOL I HALATIO

,,

OBSERVED EFR 0.855

L

ANTERIOR

II POSTERIOR

2.337

FEV 1 Oz

SINGLE BREATH

P02

1.50

77.6

% OF PREDICTED 75.3

28.3 fOR

L

SLIGHTLY

0 S OKI G PAST 10 YEARS I

H

POSTERIOR

PRESSIO :

ODERATE AIR AYS DISEASE

F rCURE 4. Gro ly bnom I perfusion and rad ioaero ol lung-image patterns and everely abnormal PFTs in a 58-year-old man.

CHEST, 68: 5, NOVEMBER, 1975

RADIOAEROSOL LUNG IMAGING IN COPD 637

the clinical, PFT, or lung-imaging findings and were read as abnormal if they showed evidenc-e of hyperinflation, decreased vascularity, increased bronchovascular markings, bullae, infiltrates, pleural abnormalities, or large solitary opacities.

Table I --Comparison of Reapiratory Symptom a, Poaitive Phyaical Findinga, Smoking Hiatory, Abnormal PFTa, and Abnormal Aeroaollmagea in 70 Subject&~ Percent

RESULTS

Aerosol lung patterns were compared to the results of selected PFTs. Twenty-three of 70 subjects had normal aerosol deposition patterns and normal results on PFTs. Fifteen subjects had abnormal aerosol patterns in the presence of completely normal results on PFTs. Among the 15 subjects having abnormal aerosol findings and normal results on PFTs, seven had excessive central deposition plus regional abnormalities, and eight showed abnormal central deposition only. In only one subject was the aerosol study normal in the presence of PFT abnormalities, which consisted of a mild reduction in MMFR and an abnormal CV. Of 31 subjects having both abnormal results on PFTs and abnormal aerosol lung patterns, 15 showed a definitely greater degree of abnormality in the aerosol images compared with PFT findings ( eg, PFTs mild and aerosol moderate or PFTs moderate and aerosol severe). Of the PFTs performed, the MMFR showed the best agreement with the aerosol findings. Perfusion images and chest roentgenograms were compared with aerosol studies and PFT results in subjects in whom perfusion lung images or chest xray films were obtained. Only 13 of the 52 subjects who underwent perfusion studies had abnormal perfusion images, whereas 24 and 35 had abnormal PFTs and aerosol patterns, respectively. However, only those subjects with moderate to severe abnormalities of pulmonary function or aerosol deposition had perfusion defects. Among the 56 subjects in whom chest films were made, 33 had abnormal aerosol deposition, 24 had abnormal PFTs, and 14 had abnormal x-ray film findings. Of the latter, only 11 had one or more of the changes consistent with COPD (increased bronchovascular markings, hyperinflation, or generalized hypovascularity), one had a left hilar mass, and two had localized scars confined to one segment or lobe. The results of 113"'indium-aerosol and 133xenon lung images in 22 subjects were compared. Six subjects had normal results on both, and 12 subjects had abnormal results on both aerosol and xenon lung imaging studies. One subject had normal aerosol and abnormal xenon lung images, while three persons had abnormal aerosol and normal xenon lung images. Thus, in all but those four individuals, there was agreement between the xenon and the aerosol findings with respect to normality or abnormality. Of those subjects showing abnormalities on both types of studies, the aerosol patterns were graded as

638 RAMANNA ET AL

No. of SympSuhjec ts toms Signs Smoking PFT's Aerosol Symptoms Signs Smoking PFT's Aerosol

40 21

36 33 46

+

76 75 70 65

37

+

65 76

45 39

76 61

50

+

57 71 69

+

70

67 86 81 97

+

*No. of subjects equals the total number of subjects with abnormal results for each factor. Percent values represent the number of subjects with abnormal results for factors listed at top of column as percent of number of subjects with abnormal results for factors listed at left side of table.

more abnormal than the corresponding xenon images in six subjects, whereas there was no subject in whom the xenon images were more abnormal than the aerosol patterns. Interrelationships among respiratory symptoms, physical findings, abnormal PFTs, abnormal aerosol images, and a history of cigarette smoking are presented in Table l. Abnormal aerosol patterns were found in 97 percent of subjects with any abnormality on PITs whereas PITs were abnormal in only 70 percent of the subjects with abnormal aerosol patterns. Moreover, the aerosol patterns were more frequently abnormal than PFTs in the presence of either abnormal symptoms, physical findings, or a positive smoking history. In view of the greater frequency of abnormal aerosol patterns than abnormal PFTs, the possibility of false-positive aerosol results was investigated by performing delayed aerosol imaging in 19 subjects. Of 15 subjects having abnormal aerosol patterns and normal PFTs, seven had delayed examinations. Of these seven, only one showed rapid removal of the centrally deposited aerosol, suggesting excessively large particle size ( > 5.0p.) as the cause of the falsepositive findings on the initial examination. Of 30 subjects having both aerosol and PFT abnormalities, 12 delayed studies were made. Of these, two had false-positive initial aerosol lung patterns which reverted to normal in the repeat examination made one to two hours later. Thus, false-positive findings were noted in a total of three ( 16 percent) of 19 subjects receiving delayed aerosol examinations. DISCUSSION

The findings of more frequent abnormalities on aerosol inhalation lung imaging compared with conventional tests of lung function, of more severe abnormalities of aerosol deposition than of pulmonary function when both types of tests were abnormal, and of closer agreement between certain correlates

CHEST, 68: 5, NOVEMBER, 1975

of obstructive airway disease ( eg, symptoms, physical findings, and smoking history) and abnormal aerosol deposition than between these same variables and abnormal PFTs suggest that radioaerosol lung imaging may be a more sensitive indicator of early COPD than tests of overall lung function, including MMFR, Fowler's SB02 test and CV fraction. Moreover, these results suggest that aerosol lung imaging is capable of detecting pulmonary abnormalities more readily than conventional chest x-ray films and perfusion lung imaging and with approximately the same frequency as single-breath radioactive xenon scintiscanning. However, these findings must be interpreted with some caution because of limited information regarding the pathologic significance of excessive aerosol deposition in the major airways. One of the incompletely solved problems with the administration of diagnostic radioaerosols is the size range of the nebulized droplets which determines the sites of their deposition in the airways. 12• 14 •22 The ultrasonic generator used in the present study produces polydispersed wet aerosols of the same size range when operated in a uniform manner. However, variations in breathing patterns, humidity, and temperature also affect the size distribution of the aerosol. An effort was made during this study to minimize these variables by performing all procedures and examinations under similar conditions. The same volume ( 10 ml) of solution was nebulized, and all subjects were instructed to breathe the aerosol at a normal rate and tidal volume. In addition, all subjects underwent a prior practice session using nebulized normal saline solution to reassure them of the ease and lack of irritation from breathing a wet aerosol. These standardizations and trial inhalation sessions reduce anxiety and abnormal breathing patterns, minimize temperature and humidity variations in the delivery system, and increase the reproducibility of the procedure. The delayed aerosol studies made after one to two hours in 19 cases have improved the interpretation of initial abnormal aerosol-deposition patterns by helping to distinguish falsely positive from pathologically significant abnormalities. In general, when a one- to two-hour delayed image shows essentially complete clearing of the abnormal deposition in the upper airways, it indicates that the cause of the excessive central airway deposition is most likely due either to particles larger than 5.0,u or to an abnormal breathing pattern, or to both factors . On the other hand, if only slight clearing occurs by this time or longer and the patterns continue to remain abnormal, the most likely cause is COPD. In three of the 19 subjects studied, the excessive central deposition of the radioaerosol

CHEST, 68: 5, NOVEMBER, 1975

noted on the initial examination was no longer evident on a delayed examination performed one to two hours later, suggesting that approximately 16 percent of the abnormal aerosol patterns might have represented false-positives. These findings may account for some, but not most, of the discrepancy between the findings on PFTs and aerosol lung imaging. The results of 133xenon ventilation examinations showed close correlation with the aerosol lung images with regard to identification of normal and abnormal patterns. However, the aerosol images were frequently graded as more abnormal than the xenon in subjects in whom both studies were abnormal. This discrepancy could be due to the performance of the radioaerosol imaging in four projections, whereas only posterior single-view radioactivexenon lung images were obtained. Also, aerosol and gas inhalation procedures are based on different principles and register the effects of functional and structural abnormalities in the images by different mechanisms. Xenon gas freely enters and leaves the airways and alveoli, and practically none is deposited or retained in either the major or minor airways. By contrast, aerosols of insoluble nonabsorbable aqueous colloids or inert solid particles are deposited in the normal respiratory tract by four main mechanisms: gravitational impaction, turbulence, sedimentation, and diffusion. 12 •13 Particles or droplets larger than 5,u are mainly deposited by impaction in the posterior pharynx or the nose when inhaled through the mouth or nose. Smaller 3,u-5,u particles are largely deposited in the trachea and major airways also by impaction, whereas most particles in the 1,u-3,u range remain airborne until they reach the distal nonciliated airways and alveoli where they are deposited by sedimentation and diffusion. They are retained in the lung parenchyma for weeks. 22 Those which are deposited on the mucous coat of the ciliated airways are removed much more rapidly (hours) by the mucociliary escalator mechanism. About 10 percent of the inhaled dose of 1,u-3,u particles is removed in the expired air. Particles smaller than 0.1,u behave much more like a gas, and only minute quantities are retained in the lung, while nearly all is exhaled. Excessive deposition of aerosol occurs in the trachea and major airways following the inhalation of 1,u-3,u particles with abnormal breathing patterns, such as in tachypnea, excessively slow breathing, and rapid deep breathing. These physiologic variations accentuate the normal deposition by gravitational impaction, turbulence, or sedimentation. Abnormal major-airway deposition is commonly encountered in patients with chronic bronchitis,

RADIOAEROSOL LUNG IMAGING IN COPD 639

bronchial asthma, and obstructive emphysema. In these disorders, there are abnormal breathing patterns plus pathologic changes, such as narrowing of the airways or increased mucous secretions, each of which can cause excessive deposition by the mechanisms previously mentioned. The results of preliminary studies in 70 selected volunteer subjects suggest that aerosol inhalation lung imaging may be a more sensitive screening procedure for detecting early obstructive airway disease than the other diagnostic procedures employed in the present study, except for xenon ventilation lung scintiscanning, the sensitivity of which was comparable to that of the radioaerosol procedure. The aerosol test appears to identify airway abnormalities in 15 of 70 subjects having normal findings on PFTs, including those considered to be sensitive indicators of early COPD. Delayed aerosol examinations in 19 subjects with normal and abnormal PFTs indicated that only about 16 percent of the initial abnormal central deposition patterns were falsely positive due to abnormal breathing patterns or particles larger than 5p. in the inhaled aerosol. However, many more delayed studies are needed to determine the true incidence of false-positive initial aerosol lung images. Excessive central radioaerosol deposition with or without associated regional abnormalities in the 15 subjects with completely normal PFTs suggests that early COPD may be associated with changes in the caliber or mucous lining, or both, of the large as well as the small airways. Moreover, these pathologic abnormalities may not be functionally significant in terms of reductions in spirometric flow rates or premature airway closure at times when tracheobronchial wall irregularities may increase the deposition of 1p.-3p. aerosols. Regional or unilateral abnormalities in seven of the 15 subjects with abnormal aerosol findings and normal PFT values can largely explain the apparently higher sensitivity of the radioaerosol procedure. Regional airway obstructive disease involving less than 25 percent of the lung seldom can be detected by standard PFTs which measure integrated, rather than regional, lung function. Reevaluation of these and other subjects during the next three to four years with respiratory questionnaires, conventional PFT, 133 xenon lung scintiscanning, and both immediate and delayed aerosol lung imaging should help determine the physiologic and pathologic significance of isolated aerosol lung-imaging abnormalities. ACKNOWLEDGMENTS : The authors are appreciative of the invaluable technical assistance of Dixie Kukes in performing the PFTs, of the help of Mrs. Mary Lee Griswold in preparing the illustrations and in making constructive suggestions in the development of the manuscript, and of the photographic assistance rendered by Hector Pimentel.

640 RAMANNA ET AL

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CHEST, 68: 5, NOVEMBER, 1975