Mucociliary Clearance in Adult Asthma'?
THOMAS G. O'RIORDAN, JEFFREY ZWANG, and GERALD C. SMALDONE
Introduction
Impaired mucociliary clearance (MC) has long been suspected of playing a significant role in asthma (1). However, it was not related to clinicalseverityof asthma until a recent study by Messina and coworkers (2). In serial studies of hospitalized patients, they demonstrated severe impairment of MC during acute exacerbations, which improved in tandem with the patients' clinical state. In stable patients, previous studies have demonstrated impairment of MC relative to normal volunteers. However, the relevance of these often subtle derangements to clinical asthma remains unclear. Bateman and coworkers (3) and Pavia and colleagues (4) found that MC is impaired in asthmatics with mild, stable disease and in asthmatics in remission, respectively, relative to normal volunteers. However, both groups used collimated counters and 24-h retentfon images to standardize for differences in initial deposition pattern. Recently published data suggest that methods of determining MC that are based on direct measurement of the initial deposition pattern may be more accurate because of central airway retention after 24 h (5, 6). Agnew and coworkers(7) demonstrated impaired MC in asthmatic patients when compared with normal volunteers, but they did not relate the MC abnormalities to severity of obstruction. The interpretation oftheir data is complicated by the fact that half the patients coughed frequently during the study (average, 39 bouts) and expectorated large quantities of sputum. Foster and coworkers (8) found that MC was severely impaired in the central airways of asthmatics, but their study was confined to patients with severe, chronic airway obstruction. Mossberg and colleagues (9) found no differences in MC between asthmatics and normal subjects, but their study did not allow for differences in the initial deposition of aerosol and is therefore difficult to interpret. Mezey and coworkers (10) demonstrated decreased baseline tracheal mucus velocity (TMV) in ragweed-sensitive asthmatics, which 598
SUMMARY Severe Impairment of mucoclllary clearance (MC) In hospitalized asthmatics has recently been demonstrated in peripheral and central airways. MC was also shown to Improve with clinical recovery and hospital discharge (2). In the present study, we measure MC In chronic, stable asthma In subjects with a wide range of obstruction to see If MCwas related to the severity of chronic disease. Weseparated the subjects Into those with severeobstruction with expiratory flow limitation during tidal breathing (FL subjects) and those without tidal flow limitation (NFL subjects) to see if the presence of chronic flow limitation was associated with regional MC abnormalities. Seventeen asthmatic patients were studied. Mucoclllary clearance was assessed using Inhaled radloaerosol and serial measurements of the retention of radioactivity over 2 h. By controlling breathing pattern, the Initial pattern of deposition In the lungs was matched, with all subjects having a predominance of particles In the central airways. This pattern was normalized for regional lung volume using a xenon equilibrium scan and expressed as a specific central to peripheral (sC/P) ratio. The percentage retention of deposited radioactivity at 120min ranged from 19 to 83% (mean, 52%). FL subjects had a mean retention at 120min of 66% (range, 55 to 83%). The NFL subjects had a mean retention at 120 min of 33% (range, 19 to 51%). Throughout the z-h study period, retention by the FL group was significantly greater than that of the NFL group with separation of 95% confidence Intervals. At the beginning of the study, the sC/P of both the NFL and the FL groups were similar (FL mean ± SEM = 1.97 ± 0.14; NFL = 1.72 ± 0.10, P = NS, Mann-Whitney test). Analysis of regional MC, using serial sC/P ratios, revealed that after 2 h the mean sC/P (± SEM) of the FL subjects was unchanged (2.33 ± 0.33, P = NS, Wilcoxon's signed rank test), Indicating persistent retention of particles In central airways. In contrast, mean (± SEM) sC/P ratio for the NFL patients decreased significantly (1.10 ± 0.07, P = 0.014, Wilcoxon's signed rank test), Indicating that these patients emptied central airways. We conclude that measurement of MC In chronic asthma reveals a broad range of abnormality. Categorizing patients Into those with and those without tidal flow limitation effectively separated the patients on the basis of their rate of MC. Relative to previously published studies of MC In normal volunteers at this center using Identical techniques and similar deposition patterns, the NFL patients had faster than normal rates of MC. In the FL patients, MC was slower than normal with prolonged retention of particles In central airways. AM REV RESPIR DIS 1992: 148:598-803
became further impaired after acute bronchospasm had been induced by inhalation of specific antigen. However, TMV may not necessarily be representative of MC in distal airways. Therefore, we note that acute hospitalization is associated with severeMC impairment, but the relationship between MC impairment and the severity of asthma has not yet been characterized in outpatients with clinically apparent disease. To address this issue, we measured MC in a group of asthmatics with chronic stable disease who demonstrated a wide range of airway obstruction. The finding of abnormal 24-hour retention of inhaled particles in the central airways of patients with tidal flow limitation (5), and the demonstration of marked impairment of MC in the central airways of patients with severe airwayobstruction (8), prompted us to analyze regional clearance and to subclassi-
fy our patients by the presenceor absence of chronic flow limitation, i.e., flowlimited (FL) and non-flow-limited (NFL) patients, respectively. Methods Seventeen patients, who had asthma as defined by American Thoracic Society criteria
(Received in original form August ~ 1991 and in revised form April 17, 1992) 1 From the Department of Medicine, Division of Pulmonary/Critical Care, State University of New York, Stony Brook, New York. 2 Supported byGrantAI-16337 from the National. Institutes of Health. 3 Correspondence and requests for reprints should be addressed to Gerald C. Smaldone, M.D., Ph.D., Associate Professor of Medicine, Division of Pulmonary/Critical Care Medicine, Health Sciences Center T-17 Room 040, State University of New York, Stony Brook, NY 11794-8172.
599
REGIONAL MUCOCILIARY CLEARANCE IN ADULT ASTHMA
16L
L;,
S
L
4
L
2
L 2
16L
L;,
S
L 4
L
L
2
2
tO~
(j7
Fig. 1. Flow volume curves of individual patients. Non-flow-limited (NFL) (upper rows). Patients 1 to 7. Flow-limited (FL) (ICNlfJr rows). Patients 8 to 17.
(11), wererecruited. Informed written consent was obtained from all patients, and the study protocol was approved by the hospital ethics committee. Clinical history was obtained, and physical examination was carried out immediately prior to each study. All patients were well known to the Pulmonary Division at Stony Brook. They had not had acute exacerbations of their disease for at least 1 month and were in their usual state of health on the study days. Patients wereadvised to take their usual medications on the morning ofthe study day, but they were asked to refrain from the use of inhaled bronchodilators for at least 2 h prior to the study. Spirometry was per-
formed with a rolling-seal spirometer (PulmoLab; SRL Systems, Houston, TX), and values for FVC and FEV1 were obtained. The patients were subclassified by the presence of tidal flow limitation into FL and NFL patients. Tidal expiratory flow limitation means that during tidal breathing, flowlimiting segments (FLS) form at discrete points in the airways, so that incremental increases in pleural pressure are no longer associated with increases in expiratory flow. The presence of tidal flow limitation was assessed by observingthe relationship between the tidal flow-volume loop and the maximal expiratory flow-volume (MEFV) curve (12). The in-
dividual flow-volume curves of all patients are shown in figure 1. The tidal loop for the FL patients overlapped their MEFV curves, and the expiratory part of their tidal loop was similar in shape to the forced loop, indicating that during quiet breathing FLS are forming in their airways. The NFL patients were classified as such because their tidal loops were below their MEFV curves and the tidal loops were of normal configuration. On the study day, after spirometry, the subject was seated with a posteriorly positioned gamma camera (Picker-Dyna Camera; Picker, Northford, CT). Immediately prior to aerosol deposition, an equilibrium 133Xe ventilation scan was performed in order to obtain an estimate of lung volume with lung images at FRC obtained via computer (Nova 3; Data General, Anaheim, CAl. Then the camera was set to 99tnTc, and aerosol deposition was performed. The aerosol was generated by condensation of bis-(2-ethylhexyl)-sebacate on nuclei of 99rnTc-Iabeled human serum albumin. This produced a monodisperse aerosol with a mass mean aerodynamic diameter of 2.0 urn and a geometric standard deviation of 1.1 (13).The aerosol was inhaled at inspiratory flow rates ranging from 0.6 to 3.0 Lis. By having the less obstructed patients inhale more rapidly than the severelyobstructed patients, it was possible to match the initial deposition pattern in patients with different airway caliber. Exhalation was tidal for all patients. After aerosol deposition, retention of radioactivity was measured at I-min intervals for 2 h. Data Analysis With the computer, regions of interest were drawn over the 133Xe equilibrium scan; a region over the entirety of both lungs called the whole lung zone, and another region centered overthe large central airwaysconstituting 330J0 of the area of both lungs, which we called the central zone. The area remaining after the central zone was deducted from the whole lung zone was called the peripheral zone. Regions of interest involving the right lung alone were used in those patients in whom there was significant stomach radiation. Using the 133Xe regions of interest, the ratio between the central (C) and peripheral (P) lung counts (sC/P) was calculated in a manner that normalized for differences in relative lung thickness by dividing the C/P 99tnTc counts by the C/P 133Xe counts. This ratio defined the specific C/P ratio (sC/P) (5). Using the resulting sC/P values, a ratio of 1.0reflectsdeposition proportional to regional volume. Because the central region outlines both central airways and the lung parenchyma surrounding them, an sC/P ratio of unity reflects predominantly alveolar deposition. Increasing sC/P ratios greater than unity indicate increasing deposition in the proximal airways. Clearance patterns werecalculated by using the whole lung 133Xe regions to define initial lung activity. Background radiation was deducted, and the counts from each image
600
O'RIORDAN, ZWANG, AND SMALDONE
TABLE 1 CLINICAL AND SPIROMETRIC DETAILS, DEPOSITION PATIERNS (sC/P), AND RETENTION FOR THE INDIVIDUAL PATIENTS Subject No.
FL No No No No No No No Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
Age (yr) 31 26 31 42 38 22 59 31 65 72 60 62 47 62 50 62 39
Sex
sC/P
FEV1 %
M F F F F F M M M F F M F F F M F
1.38 1.84 2.03 2.02 1.61 1.36 1.77 1.50 1.99 1.84 1.70 2.22 2.04 2.12 1.56 1.67 3.03
99.0 100.0 72.0 83.0 91.0 102.0 100.0 107.0 59.7 68.2 57.9 50.0 53.9 68.0 67.0 82.0 63.0
FEV 1 (%FVC)
R30
R60
R90
82.6 77.8 76.0 82.3 62.8 87.1 78 64.7 47.9 72.2 47.4 52.1 55.5 30.3 67.0 73.2 77.0
63 51 55 76 68 48 39 83 87 72 86 90 73 82 81 94 78
38 50 32 56 55 29 32 79 82 74 82 76 68 78 73 93 71
25 46 22 50 47 27 30 74 75 59 81 59 69 66 82 55
79 55
19 46 20 43 51
71 55 83 55 65
35.6 4.7
1.72 0.10
92.4 4.2
78.1 2.9
57 5
42 4
35 5
33 6
Mean FL ± SE
55.1 4.1
1.97 0.14
67.7 5.2
60.3 5.1
83 2
77 2
69 3
66 4
47 3.8 < 0.01
1.86 0.10 NS
77.9 4.6 0.01
67.7 3.8 < 0.01
THOMAS G. O'RIORDAN, JEFFREY ZWANG, and GERALD C. SMALDONE
Introduction
Impaired mucociliary clearance (MC) has long been suspected of playing a significant role in asthma (1). However, it was not related to clinicalseverityof asthma until a recent study by Messina and coworkers (2). In serial studies of hospitalized patients, they demonstrated severe impairment of MC during acute exacerbations, which improved in tandem with the patients' clinical state. In stable patients, previous studies have demonstrated impairment of MC relative to normal volunteers. However, the relevance of these often subtle derangements to clinical asthma remains unclear. Bateman and coworkers (3) and Pavia and colleagues (4) found that MC is impaired in asthmatics with mild, stable disease and in asthmatics in remission, respectively, relative to normal volunteers. However, both groups used collimated counters and 24-h retentfon images to standardize for differences in initial deposition pattern. Recently published data suggest that methods of determining MC that are based on direct measurement of the initial deposition pattern may be more accurate because of central airway retention after 24 h (5, 6). Agnew and coworkers(7) demonstrated impaired MC in asthmatic patients when compared with normal volunteers, but they did not relate the MC abnormalities to severity of obstruction. The interpretation oftheir data is complicated by the fact that half the patients coughed frequently during the study (average, 39 bouts) and expectorated large quantities of sputum. Foster and coworkers (8) found that MC was severely impaired in the central airways of asthmatics, but their study was confined to patients with severe, chronic airway obstruction. Mossberg and colleagues (9) found no differences in MC between asthmatics and normal subjects, but their study did not allow for differences in the initial deposition of aerosol and is therefore difficult to interpret. Mezey and coworkers (10) demonstrated decreased baseline tracheal mucus velocity (TMV) in ragweed-sensitive asthmatics, which 598
SUMMARY Severe Impairment of mucoclllary clearance (MC) In hospitalized asthmatics has recently been demonstrated in peripheral and central airways. MC was also shown to Improve with clinical recovery and hospital discharge (2). In the present study, we measure MC In chronic, stable asthma In subjects with a wide range of obstruction to see If MCwas related to the severity of chronic disease. Weseparated the subjects Into those with severeobstruction with expiratory flow limitation during tidal breathing (FL subjects) and those without tidal flow limitation (NFL subjects) to see if the presence of chronic flow limitation was associated with regional MC abnormalities. Seventeen asthmatic patients were studied. Mucoclllary clearance was assessed using Inhaled radloaerosol and serial measurements of the retention of radioactivity over 2 h. By controlling breathing pattern, the Initial pattern of deposition In the lungs was matched, with all subjects having a predominance of particles In the central airways. This pattern was normalized for regional lung volume using a xenon equilibrium scan and expressed as a specific central to peripheral (sC/P) ratio. The percentage retention of deposited radioactivity at 120min ranged from 19 to 83% (mean, 52%). FL subjects had a mean retention at 120min of 66% (range, 55 to 83%). The NFL subjects had a mean retention at 120 min of 33% (range, 19 to 51%). Throughout the z-h study period, retention by the FL group was significantly greater than that of the NFL group with separation of 95% confidence Intervals. At the beginning of the study, the sC/P of both the NFL and the FL groups were similar (FL mean ± SEM = 1.97 ± 0.14; NFL = 1.72 ± 0.10, P = NS, Mann-Whitney test). Analysis of regional MC, using serial sC/P ratios, revealed that after 2 h the mean sC/P (± SEM) of the FL subjects was unchanged (2.33 ± 0.33, P = NS, Wilcoxon's signed rank test), Indicating persistent retention of particles In central airways. In contrast, mean (± SEM) sC/P ratio for the NFL patients decreased significantly (1.10 ± 0.07, P = 0.014, Wilcoxon's signed rank test), Indicating that these patients emptied central airways. We conclude that measurement of MC In chronic asthma reveals a broad range of abnormality. Categorizing patients Into those with and those without tidal flow limitation effectively separated the patients on the basis of their rate of MC. Relative to previously published studies of MC In normal volunteers at this center using Identical techniques and similar deposition patterns, the NFL patients had faster than normal rates of MC. In the FL patients, MC was slower than normal with prolonged retention of particles In central airways. AM REV RESPIR DIS 1992: 148:598-803
became further impaired after acute bronchospasm had been induced by inhalation of specific antigen. However, TMV may not necessarily be representative of MC in distal airways. Therefore, we note that acute hospitalization is associated with severeMC impairment, but the relationship between MC impairment and the severity of asthma has not yet been characterized in outpatients with clinically apparent disease. To address this issue, we measured MC in a group of asthmatics with chronic stable disease who demonstrated a wide range of airway obstruction. The finding of abnormal 24-hour retention of inhaled particles in the central airways of patients with tidal flow limitation (5), and the demonstration of marked impairment of MC in the central airways of patients with severe airwayobstruction (8), prompted us to analyze regional clearance and to subclassi-
fy our patients by the presenceor absence of chronic flow limitation, i.e., flowlimited (FL) and non-flow-limited (NFL) patients, respectively. Methods Seventeen patients, who had asthma as defined by American Thoracic Society criteria
(Received in original form August ~ 1991 and in revised form April 17, 1992) 1 From the Department of Medicine, Division of Pulmonary/Critical Care, State University of New York, Stony Brook, New York. 2 Supported byGrantAI-16337 from the National. Institutes of Health. 3 Correspondence and requests for reprints should be addressed to Gerald C. Smaldone, M.D., Ph.D., Associate Professor of Medicine, Division of Pulmonary/Critical Care Medicine, Health Sciences Center T-17 Room 040, State University of New York, Stony Brook, NY 11794-8172.
599
REGIONAL MUCOCILIARY CLEARANCE IN ADULT ASTHMA
16L
L;,
S
L
4
L
2
L 2
16L
L;,
S
L 4
L
L
2
2
tO~
(j7
Fig. 1. Flow volume curves of individual patients. Non-flow-limited (NFL) (upper rows). Patients 1 to 7. Flow-limited (FL) (ICNlfJr rows). Patients 8 to 17.
(11), wererecruited. Informed written consent was obtained from all patients, and the study protocol was approved by the hospital ethics committee. Clinical history was obtained, and physical examination was carried out immediately prior to each study. All patients were well known to the Pulmonary Division at Stony Brook. They had not had acute exacerbations of their disease for at least 1 month and were in their usual state of health on the study days. Patients wereadvised to take their usual medications on the morning ofthe study day, but they were asked to refrain from the use of inhaled bronchodilators for at least 2 h prior to the study. Spirometry was per-
formed with a rolling-seal spirometer (PulmoLab; SRL Systems, Houston, TX), and values for FVC and FEV1 were obtained. The patients were subclassified by the presence of tidal flow limitation into FL and NFL patients. Tidal expiratory flow limitation means that during tidal breathing, flowlimiting segments (FLS) form at discrete points in the airways, so that incremental increases in pleural pressure are no longer associated with increases in expiratory flow. The presence of tidal flow limitation was assessed by observingthe relationship between the tidal flow-volume loop and the maximal expiratory flow-volume (MEFV) curve (12). The in-
dividual flow-volume curves of all patients are shown in figure 1. The tidal loop for the FL patients overlapped their MEFV curves, and the expiratory part of their tidal loop was similar in shape to the forced loop, indicating that during quiet breathing FLS are forming in their airways. The NFL patients were classified as such because their tidal loops were below their MEFV curves and the tidal loops were of normal configuration. On the study day, after spirometry, the subject was seated with a posteriorly positioned gamma camera (Picker-Dyna Camera; Picker, Northford, CT). Immediately prior to aerosol deposition, an equilibrium 133Xe ventilation scan was performed in order to obtain an estimate of lung volume with lung images at FRC obtained via computer (Nova 3; Data General, Anaheim, CAl. Then the camera was set to 99tnTc, and aerosol deposition was performed. The aerosol was generated by condensation of bis-(2-ethylhexyl)-sebacate on nuclei of 99rnTc-Iabeled human serum albumin. This produced a monodisperse aerosol with a mass mean aerodynamic diameter of 2.0 urn and a geometric standard deviation of 1.1 (13).The aerosol was inhaled at inspiratory flow rates ranging from 0.6 to 3.0 Lis. By having the less obstructed patients inhale more rapidly than the severelyobstructed patients, it was possible to match the initial deposition pattern in patients with different airway caliber. Exhalation was tidal for all patients. After aerosol deposition, retention of radioactivity was measured at I-min intervals for 2 h. Data Analysis With the computer, regions of interest were drawn over the 133Xe equilibrium scan; a region over the entirety of both lungs called the whole lung zone, and another region centered overthe large central airwaysconstituting 330J0 of the area of both lungs, which we called the central zone. The area remaining after the central zone was deducted from the whole lung zone was called the peripheral zone. Regions of interest involving the right lung alone were used in those patients in whom there was significant stomach radiation. Using the 133Xe regions of interest, the ratio between the central (C) and peripheral (P) lung counts (sC/P) was calculated in a manner that normalized for differences in relative lung thickness by dividing the C/P 99tnTc counts by the C/P 133Xe counts. This ratio defined the specific C/P ratio (sC/P) (5). Using the resulting sC/P values, a ratio of 1.0reflectsdeposition proportional to regional volume. Because the central region outlines both central airways and the lung parenchyma surrounding them, an sC/P ratio of unity reflects predominantly alveolar deposition. Increasing sC/P ratios greater than unity indicate increasing deposition in the proximal airways. Clearance patterns werecalculated by using the whole lung 133Xe regions to define initial lung activity. Background radiation was deducted, and the counts from each image
600
O'RIORDAN, ZWANG, AND SMALDONE
TABLE 1 CLINICAL AND SPIROMETRIC DETAILS, DEPOSITION PATIERNS (sC/P), AND RETENTION FOR THE INDIVIDUAL PATIENTS Subject No.
FL No No No No No No No Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
Age (yr) 31 26 31 42 38 22 59 31 65 72 60 62 47 62 50 62 39
Sex
sC/P
FEV1 %
M F F F F F M M M F F M F F F M F
1.38 1.84 2.03 2.02 1.61 1.36 1.77 1.50 1.99 1.84 1.70 2.22 2.04 2.12 1.56 1.67 3.03
99.0 100.0 72.0 83.0 91.0 102.0 100.0 107.0 59.7 68.2 57.9 50.0 53.9 68.0 67.0 82.0 63.0
FEV 1 (%FVC)
R30
R60
R90
82.6 77.8 76.0 82.3 62.8 87.1 78 64.7 47.9 72.2 47.4 52.1 55.5 30.3 67.0 73.2 77.0
63 51 55 76 68 48 39 83 87 72 86 90 73 82 81 94 78
38 50 32 56 55 29 32 79 82 74 82 76 68 78 73 93 71
25 46 22 50 47 27 30 74 75 59 81 59 69 66 82 55
79 55
19 46 20 43 51
71 55 83 55 65
35.6 4.7
1.72 0.10
92.4 4.2
78.1 2.9
57 5
42 4
35 5
33 6
Mean FL ± SE
55.1 4.1
1.97 0.14
67.7 5.2
60.3 5.1
83 2
77 2
69 3
66 4
47 3.8 < 0.01
1.86 0.10 NS
77.9 4.6 0.01
67.7 3.8 < 0.01
