Changes in Mucociliary Clearance during Acute Exacerbations of Asthma 1 - 3
MATTHEW
s.
MESSINA, THOMAS G. O'RIORDAN, and GERALD C. SMALDONE
Introduction
For the majority of patients, asthma is characterized by mild airways obstruction that is adequately controlled by intermittent, inhaled bronchodilators (1). A minority, however, have severe exacerbations, which require systemicglucocorticosteroid therapy and are potentially fatal even in an acute hospital setting (2). Bronchial smooth musclecontraction has been shown to have an important role in asthma. It has been studied extensively because it is well quantified by spirometry, and it usually responds to pharmacologic intervention. However, in isolation it cannot explain the clinical features of a severe exacerbation (3, 4). Mucociliary clearance (MC) (5, 6) and mucosal edema (3) are believed to have important roles, but in clinically apparent disease they have not been as extensively studied. Evidence from autopsies performed on patients dying suddenly of asthma (2, 7) and studies performed on mild or stable asthmatic subjects have suggested that MC may be impaired in these patients (8-11), but indices of secretory function have not been related to clinical exacerbations. If, as suspected, mucociliary abnormalities are related to death, and in less severe cases to prolonged obstruction, it should be possible to demonstrate significant impairment of MC during acute exacerbations of asthma that improves in tandem with the patient's clinical condition. To test this hypothesis we measured MC in acutely ill hospitalized asthmatic patients using radiolabeled particle inhalation and repeated the measurements after the patients had been discharged from the hospital in clinically stable condition. Methods Five subjects who satisfied the American Thoracic Society criteria (12)for asthma were studied. The study protocol had been approved by the hospital ethics committee. Informed written consent was obtained from every subject. MC was first assessed on the second day (two patients) or third day (three patients) af-
SUMMARY Previous studies have suggested that mucoclllary clearance (MC) Is Impaired In asthmatic subjects. If so, Impaired clearance may be an Important factor In acute exacerbation. We proposed that If MC playa a significant role In acute Illness, MCshould be Impaired during the exacerbation but Improve after recovery. Totest this hypothesis, five asthmatic patients with attacks requiring hospitalization underwent meatlurement of MC using radlolabeled aerosol and a gamma camera. They were studied on the second or third day after admission with repeat measurements after die. charge. Spirometry was performed before all studies. After an equilibrium xenon scan C33Xe), which defined lung borders and measured regional volume, radlolabeled 88l1ne particles containing technetium-labeled (88mTc) sulfur colloid were deposited and used to label airway mucus. Deposition patterns were matched by regulating particle distribution and breathing pattern. MC was then measured as percentage retention of radioactivity at 1G-mlnIntervals for 2 h. When hospitalized, 96.0 ± 2.06% (SEM) of the Initial radioactivity was retained In the lung after 2 h, Indicating little clearance of mucus from the lung. In fact, no significant changes were detected when activity at 120min was compared with measurements at 10 min (99.2 ± 0.22%, NS). After discharge clearance was markedly enhanced. That Is, retention of lung activity was significantly lower at all time Intervals from 10 min onward, with only 70.9 ± 3.86% retained at 120 min (p = 0.008). During an asthmatic attack warr.ntlng hospital admission, MC Is significantly Impaired, with marked Improvement following recovery. Although a causal relationship remains to be established between mucoclllary Impairment and the clinical features of an acute exacerbation of asthma, the association demonstrated In this paper suggests that MC assessment may yet provide a further obJective means of a..... Ing the severity of a patient's asthma and the response to therapy. AM REV RESPIR DIS 1991; 143:993-997
ter admission to the University Hospital, State University of New York at Stony Brook. The studies were repeated 2 to 10 wk after discharge. All patients had been admitted to the pulmonary or allergy services by physicians who were independent of the investigators. All clinical decisions, including those regarding admission and discharge, were made without reference to the study. On admission all patients complained of dyspnea at rest and increased cough. Marked wheezing was heard on examination, and they had signs of respiratory distress as evidenced by tachypnea and use of accessory muscles of respiration. When assessed on the second or third postadmission day before the radioisotope study, the patients were beginning to improve clinically as evidenced by reduced respiratory distress at rest and a reduction in respiratory rate. All patients received intravenous aminophylline (0.7 mg/kg/h), intravenous methylprednisone (60mg four times a day), nebulized J}-agonists, and oxygen at inspired fractions between 24 and 35070. After discharge full medical therapy was continued in every case, including J}-agonistinhaler, oral theophylline, and oral corticosteroids, which were tapered on an individual basis but continued through the repeat study. Recovery was evidenced by resolution of dyspnea and by an improvement in
exercise tolerance and marked dimunition in cough and wheeze. The patients were discharged when stabilized at their usual clinical and spirometric baselines on oral medications. Patients did not receive inhaled J}-agonistsduring the actual measurement of MC. During the study period (2 h) patients were asked not to cough, and all were able to comply with this request. ..Clinical history was obtained and physical .examination carried out immediately before each study. Spirometry was then performed with a dry seal spirometer (Pulmo-Labs; SRL Systems, Houston, TX) and values for forced vital capacity (PVC) and forced expiratory vol-
(Receivedin originalform September 20, 1990and in revised form December 7, 1990) 1 From the Department of Medicine, Division of Pulmonary and Critical Care, State University of New York, Stony Brook, New York. 2 Supported by Grant No. AI 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 and Critical Care Medicine, Health Sciences Center T-17, Room 040, State University of New York, Stony Brook, NY 11794-8172.
993
MESSINA, O'RIORDAN, AND SMALDONE
994
ing them, an se/P ratio of unity reflects predominantly alveolar deposition. Increasing sC/P ratios greater than unity reflect increasing deposition in the proximal airways. The determination of the sC/P ratio allowed quantification of the initial deposition patterns and comparison between patients. Clearance patterns werecalculated by using the whole lung xenon regions to define initial lung activity. Background radiation was subtracted and the counts from each image decay corrected to the time of deposition (t = zero). MC was calculated as the percentage of retention at 10-min intervals over 120min. These studies (spirometry, xenon equilibrium, deposition, and MC) were repeated on all patients 12 to 72 days after discharge. To duplicate the sC/P ratios achieved in the hospital, the breathing pattern used for the repeat studies was controlled. Subjects were asked to breathe rapidly and shallowly at a lung volume close to total lung capacity. Further, it was also necessary to use a larger particle size to duplicate the central deposition pattern of the initial study. [99mTc]Sulfur colloid particles of diameter 3.2 J.1m (Og = 2.0) were generated using a different compressed air nebulizer (Mini-nebs; Inspiron, Bannockburn, IL) at flow rate of 3 L/min. Every individual's inpatient and outpatient clearance curves were compared using paired analysis (Student's t test).
ume in one second (FEV 1) obtained. Imaging of lung radioactivity was performed with the subject seated using a posteriorly positioned gamma camera (Picker-Dyna Camera, Northford, CT). Immediately before aerosol deposition a xenon (133Xe) ventilation scan was performed to obtain an estimate of lung volume. An aqueous aerosol containing 5 mCi technetium (99mTc)-labeled sulfur colloid was then inhaled using a compressed air nebulizer (Scintivents; Sinaco, Palo Alto, CA) driven by a flow of air at 11 L/min until at least 5,000 cpm was recorded. Particle distribution was assessed by cascade impactor. The mass median aerodynamic diameter (MMAD) was 0.74 J.1m and the geometric distribution (Og) was 1.64 (13). Immediately following deposition MC was measured by recording serial gamma camera images at l-min intervals via computer (Data General Nova'" II, Anaheim, CA). Images were acquired for 120 min. We analyzed data in the following manner: With the computer, regions of interest were drawn over the xenon equilibrium scan: a region over the entire right lung called the whole lung zone, and another region centered over the large central airways comprising 330/0 of the right lung area, 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. The left lung was not analyzed because of radioactivity in the stomach. Using the xenon regions of interest, the ratio between the central (C) and peripheral (P) lung counts (C/P) was calculated in a manner that normalized for differences in relative lung thickness by dividing the C/P 99mTc counts by the C/P 133Xe counts. This ratio defined the specific C/P ratio (sC/P) (14, 15). Using the resulting sC/P values, a ratio of 1.0 reflects equal deposition in all regions. Because the central region outlines both central airways and the lung parenchyma surround-
Results
Clinical details, pulmonary function, and deposition data are listed in table 1. The five patients had a median age of 26 yr (range 20 to 75 yr). There werethree males and two females; they had asthma for a median period of 20 yr (range 12 to 60 yr); all were nonsmokers except for one patient who had stopped smoking 25 yr previously after 29 pack -years but had
asthma since age 20. No patients gave a history suggestive of antecedent febrile illness or upper respiratory tract infection. The mean FEV 1 and FVC (expressed as a percentage of predicted values ± standard error of the mean, SEM) for the inpatients were 42.4 ± 7.63 and 62.2 ± 8.250/0, respectively. After discharge the mean FEV 1 improved to 70.2 ± 10.4070, but this change was statistically insignificant by paired analysis because improvement did not occur in all patients. The FVC, however, was more uniformly increased to 95.6 ± 4.85070, p = 0.019.The FEV 1 % FVC ratio was slightly improved (53.8 ± 4.38 versus 63.3 ± 8.57070), but these changes were not significant. By paired analysis mean ± SEM sC/P ratios for the inpatient and outpatient studies were not significantly different (2.11 ± 0.24 versus 1.85 ± 0.14, respectively). Whole-lung retention curves for the inpatient and outpatient studies are shown in figure 1. The percentage retention of radioactive aerosol is plotted against time at 10-min intervals for 120 min. The amount of radioactivity at the start of the test (t = zero) is designated 100%. When the patients were hospitalized, the percentage retention at 120min was 96.8 ± 2.060/0, indicating that almost none of the isotope left the lung in 2 h. In fact, when compared with the 10-min point (99.2 ± 0.220/0), there was no statistically significant change in retention over the entire 2-h observation period. After discharge the same patients had significantly increased clearance of mucus as evidenced by the reduced lung
TABLE 1 CLINICAL, SPIROMETRIC AND DEPOSITION DATA
Subject
2
Sex
Age
Years with Asthma
F
24
20
M
3
F
4
M
5
M
20 69 26 75
12 60 20 55
Days After Admission
3 19
44 82
54 102
54.4 66
3 12
27 105
58 95
38.8 91.8
109
3.06 1.78
2 36
34 58
46 79
62.1 61.0
143
1.84 2.40
3 72
71 57
94 94
63.0 59.7
96
1.78 1.68
3 33
36 49
59 108
50.7 38.0
98
2.10 1.76
FEV,
FVC
(% predicted)
(% predicted)
FEV,% FVC
Specific OLeo (%)
sC/P*
98.0
1.79 1.62
Mean (hospitalized) ± SEM
42.4 7.63
62.2 8.25
53.8 4.38
2.11 0.24
Mean (postdischarge) ± SEM P
70.2 10.4
95.6 4.85 0.019
63.3 8.57
1.85 0.14
• Regional radioaerosol deposited per unit lung volume.
NS
NS
NS
995
MUCOCILIARY CLEARANCE IN ACUTE ASTHMA
MC plays a significant role in severeasthmatic exacerbations. To date some of the strongest evidence in favor of this hypothesis comes from autopsy studies performed on patients dying in status asthmaticus. In a recent British study of hospital deaths from acute asthma virtually all autopsies revealed bronchial obstruction with mucus and hyperinflated lungs, which did not deflate on opening the thoracic cavity (2). Similar findings have been published over the past 50 yr (7). Previous studies have shown that MC is impaired in stable asthmatic subjects compared to normal volunteers (8-10), but those investigators did not relate MC impairment to changes in the patient's clinical state over time. Others (11) found that tracheal mucous velocityin ragweedsensitive asthma is reduced relative to age-matched normal volunteers and further reduced after acute bronchoprovocation. However, tracheal mucous velocity may not reflect clearance from more distal airways, and changes induced by acute bronchoprovocation may not necessarily be the same as those found during a clinical exacerbation lasting many hours or even days. A link had, therefore, not been established between the autopsy findings and the laboratory demonstration of MC impairment. We know from autopsy and clinical data that
.009.011 .031 .005 .001 .001 .001 .005.009.009.007 .007 100
o
I 90
80
Fig. 1. Retention of radioactivity versus time: patients in the hospital (open symbols); after discharge (closed symbols). Error bars indicate standard errors of the mean. Numerical values are p values.
c
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70
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c CD
Gi a:
60
50
40
+-......,....~-....--r--....-,.....-....,......-r----.-~--r---,---.
o
20
40
60
80
Time
Discussion
retention at each point of observation (differences weresignificant from 10min; p values listed in figure 1). At 2 h their retention averaged 70.9 ± 3.86010 retention, p = 0.008. Retention data for individual subjects are shown in figure 2. Each patient's MC improved without exception, with less retention of radioisotope noted from 10 min onward. The percentage changes in FEV 1, FVC, and FEV 1010 FVC for individual patients were correlated against two representative indicators of MC, the percentage retention at 30 and 60 min (R30 and R60, respectively), but none of these relationships were significant.
Patient
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100
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90
l
80
c
70
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This is the first published study to demonstrate that patients with exacerbations of asthma of sufficient severity to warrant hospitalization have severe impairment of MC. When the studies were repeated after discharge, remarkable improvement in MC function was demonstrated. Not only did the mean MC rates of the outpatients significantly exceedthe mean rates achieved when they were in hospital, but, in the case of each individual subject, the outpatient MC rate was greater at every time interval after 10min of observation. These findings are supportive of the suggestion that impaired
II
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80
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40
40
20
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80
(min)
100
120
60
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100
•••
40
20
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(min)
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a::
0
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60
120
#4
IJ
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60
Time
Patient
II
#3
. .. ..
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(min)
100
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#2
Patient
#1 II
120
100
(min)
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20
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60 Time
Fig. 2. Retention curves of individual subjects: patients in the hospital (open symbols); after discharge (closed symbols).
100 80 (min)
120
80
(min)
100
120
996
bronchial smooth muscle contraction, mucosal edema, and the accumulation of secretions are all involved in the pathogenesis of acute asthma, but to date we do not have objective means of evaluating the relative importance of these factors during exacerbations. The demonstration of an association between MC abnormalities and clinical exacerbations of asthma does not necessarily prove cause and effect but suggests that MC assessment may yet provide a further objective means of assessing the severity of a patient's asthma on serial occasions. In this study we detected significant, reversible changes in mucociliary function that appeared able to discriminate more clearly between inpatients and outpatients than spirometry. Because of the small size of the study this finding needs to be interpreted with caution until confirmed by further studies. Nevertheless, the limitations of spirometry in the acute setting are well recognized. In three groups of patients with acute asthma graded in terms of clinical severity, Rebuck and Read (16) found considerable overlap in FEV 1 (070 of predicted). Woolcock and. Read (17) demonstrated that clinical recovery was not always reflected in improvement in FEV 1, and TurnerWarwick (18)described clinically improving asthmatic patients whose FEV 1% FVC ratio decreased with recovery. In addition, studies have found that spirometric abnormalities can resolve more quickly than abnormalities in ventilationperfusion mismatch and that prednisone is capable of improving POl without a concomitant improvement in FEV 1 (19). The lack of a close correlation between spirometric and MC improvements in this study suggest that these two modalities may be measuring different but clinically relevant aspects of the asthmatic state. It has long been suspected that disorders of secretory function may play an important role in acute exacerbations of asthma, and many theories concerning possible mechanisms of action have been proposed. MC impairment may be a reflection of airways inflammation that is sufficiently severe to cause disruption of the integrity of the mucociliary system (20). The demonstration of substantial destruction of ciliated epithelium in bronchoscopic biopsies of inflamed asthmatic airways supports the suggestion that inflammation may disrupt mucociliary mechanisms. However, it is also possible that increased bronchial inflammation and decreased MC may interact and be mutually exacerbating. Bronchi-
MESSINA, O'RIORDAN, AND SMALDONE
al inflammation may disrupt MC mechanisms and cause the retention of inflammatory secretions resulting in the prolongation of bronchial inflammation, leading to further disruption of MC (3). In other words, impaired MC may be both a complication of bronchial inflammation and an aggravation of bronchial inflammation. If MC impairment is found to be an indicator of severe bronchial inflammation, it may be possible to utilize MC assessment in future studies to measure the effectiveness of antiinflammatory therapy in acute asthmatic exacerbations. Measurements of MC are cumbersome and time consuming and are not suitable in their present format for routine patient care or even for large multicenter clinical studies. However, small clinical trials designed to assess the efficacy of new antiinflammatory agents in acute exacerbations of asthma could incorporate studies of MC to add an extra dimension to a drug profile. These studies may also have a role in evaluating the use of glucocorticosteroids in asthma. Despite almost three decades of widespread clinical usage and multiple-drug trials, the optimum dosage schedule for an acute exacerbation of asthma has yet to be established (21).That all the patients in this study were on parenteral glucocorticosteroids at the time 0 f their inpatient studies and were on tapering oral steroids at the time of their convalescent studies suggests that although there does not appear to be an immediately detectable MC response to steroids, the recovery of MC function may be due to the resolution of airway inflammation effected by the steroids. The suggestion of a delayed improvement in MC in response to glucocorticosteroid therapy is further supported by the work of Agnew and associates (22), who previously demonstrated a small increase in MC in stable asthmatic subjects after 4 wk of oral prednisone. A number of practical difficulties arise in performing these studies in acutely ill patients. To meaningfully compare MC on serial occasions it is necessary to ensure similar initial deposition patterns. The more central the deposition pattern, the more rapidly the deposited particles clear as a result of the shorter distances from bronchi to pharynx (15). As hospitalized patients are treated, changes in breathing pattern and airway geometry will likely result in differences ininitial patterns of deposition of the radio- . labeled particles and complicate the as-
sessment of changes in MC. Because it was impractical to control the breathing patterns of the patients in the hospital, we adjusted the breathing patterns and aerosol MMAD used for the outpatient study to ensure matched deposition patterns. The use of two different sizes of aerosol was also required to match distribution patterns between the two groups. Larger particles are deposited in more proximal airways and were therefore administered to the outpatients, who had less airways obstruction than the hospitalized group. Data from this laboratory suggest that particle diameter, aside from its effect on deposition pattern does not affect MC (15). The mean values for both inpatient and outpatient groups describe deposition patterns that include a significant number of particles in central airways (14, 15). Therapy cannot ethically be withheld to perform studies. I3-Agonists and theophylline have been shown to transiently improve MC rates (5). However, this cannot explain why the inpatients achieved slower MC despite receiving more intensive therapy than after discharge. A number of studies have suggested that the administration of high concentrations of oxygen can have deleterious effects on MC; however, it is unlikely that the relatively low concentrations of oxygen given to our patients could be responsible for the profound changes observed in MC (5, 23). Exact matching of sC/P ratios for both inpatient and outpatient studies was attempted but not achieved in every case. However, the discrepancies were small. Significant differences in mean sC/P ratio were not detected by paired t test, and, despite a greater sC/P ratio in the inpatient studies of four subjects, MC was reduced in all patients when they were hospitalized. Because viral illnesses are common precipitants of acute exacerbations of asthma, the possibility of a viral etiology for the impairment in MC, although unlikely, cannot be fully discounted. There is convincing evidence that influenza A can cause severe but reversible MC dysfunction (24-26). However, a role for the more commonly occurring viruses has yet to be demonstrated (26). None of the subjects in this study gave a history of an antecedent febrile or upper respiratory illness. . Asthma is characterized by variable bronchial obstruction when assessed clinically and by spirometry. This study, in which each subject served as his or her
997
MUCOCILIARY CLEARANCE IN ACUTE ASTHMA
own control, demonstrates that MC varies with the patient's clinical state. A causal relationship has yet to be proven, but MC assessment may provide a further objective means of assessing the severity of a patient's asthma and the response to therapy. Acknowledgment The authors thank Mr. Robert Perry for his technical assistance in performing the deposition and clearance measurements and Ms. Pamela Prudenti for typing the manuscript.
References 1. Snider GS. Staging therapy to the severity of asthma in bronchial asthma: mechanisms and therapeutics. In: Weiss EB, Segal MS, Stein M, eds. Bronchial asthma. Boston: Little Brown, 1985; 577-89. 2. MacDonald JB, MacDonald ET, Seaton Williams DA. Asthma deaths in Cardiff 1963-74: 53 deaths in hospital. Br Med J 1976; 2:2721-3. 3. Barnes PJ. New concepts in the pathogenesis of bronchial hyper-responsiveness and asthma. J Allergy Clin Immunol 1989; 83:1013-26. 4. Reed CEoThe emergency visit and management of asthma. Ann Intern Med 1990; 112:801-2. 5. Wanner A. Clinical aspects of mucociliary transport. Am Rev Respir Dis 1977; 116:73-125. 6. Editorial. Pulmonary mucociliary clearance. Lancet 1982; 1:203-4. 7. Benatar SR. Fatal asthma. N Engl J Med 1986; 314:423-8.
8. Foster WM, Langenbach EG, Bergofsky EH. Lung mucociliary function in man: interdependence of bronchial and tracheal mucus transport velocities with lung clearance in bronchial asthma and healthy subjects. Ann Occup Hyg 1982; 26(1):227-44. 9. Bateman JRM, Pavia 0, Sheahan NF, Agnew JE, Clarke SW. Impaired mucociliary clearance in patients with mild stable asthma. Thorax 1983; 38:463-7. 10. Pavia 0, Bateman JRM, Sheahan NF, Agnew JE, Clarke SW. Tracheobronchial mucociliary clearance in asthma: impairment during remission, Thorax 1985; 40:171-5. 11. Mezey RJ, Cohn MA, Fernandez RJ, et al. Mucociliary transport in patients with antigeninduced bronchospasm. Am Rev Respir Dis 1978; 118:677-84. 12. American Thoracic Society Committee on Diagnostic Standards. Definitions and classification of chronic bronchitis, asthma, and pulmonary emphysema. Am Rev Respir Dis 1962; 85:762. 13. Smaldone GC, Perry RJ, Deutsch DG. Characteristics of nebulizers used in the treatment of AIDS-related Pneumocystis carinii pneumonia. J Aerosol Med 1988; 1:113-26. 14. Smaldone GC, Perry RJ, Bennett WD, Messina MS, Zwang J, Ilowite J. Interpretation of "24 hour lung retention" in studies of mucociliary clearance. J Aerosol Med 1988; 1:11-20. 15. Ilowite JS, Smaldone GC, Perry RJ, Bennett WD, Foster WM. Relationship between tracheobronchial particle clearance rates and sites of initial deposition in man. Arch Environ Health 1989; 44:267-73. 16. Rebuck AS, Read J. Assessment and management of severe asthma. Am J Med 1971;51:788-98.
17. Woolcock AJ, Read J. Improvement in bronchial asthma not reflected in forced expiratory volume. Lancet 1965; 2:1323-5. 18. Turner-Warwick M. On observing patterns of airflow obstruction in chronic asthma. Br J Dis Chest 1977; 71:73-86. 19. FIenley DC, Warren PM. Gas exchange and acid-base balance in bronchial asthma. In: Weiss EB, Segal MS, Stein M, eds. Bronchial asthma. Boston: Little, Brown, 1985; 577-89. 20. Djukanovic R, Roche WR, Wilson J, et al. Mucosal inflammation in asthma. Am Rev Respir Dis 1990; 142:434-57. 21. Collins J, McAllister WAC, Morley J. Corticosteroids: mechanisms and dosage schedules. In: Weiss EB, Segal MS, Stein M, eds. Bronchial asthma. Boston: Little, Brown, 1985; 675-97. 22. Agnew JE, Bateman JRM, Pavia 0, Clarke SW. Peripheral airways mucous clearance in stable asthma is improved by oral glucocorticosteroid therapy. Bull Eur Physiopathol Respir 1984;20:295-301. 23. Sackner MA, Hirsch JA, Epstein S, Rywlin AM. Effect of oxygen in graded concentrated concentrations upon tracheal mucus velocity: a study in anaesthetized dogs. Chest 1976; 69:164-7. 24. Camner P, Jarstrand C, Philipson K. Tracheobronchial clearance in patients with influenza. Am Rev Respir Dis 1973; 108:131-5. 25. Levandowski R, Gerrity T, Garrard C. Modifications of lung clearance mechanisms by acute influenza A infection. J Lab Clin Med 1985; 106:428-32. 26. Gerrard C, Levandowski R, Gerrity T, Yeates 0, Klein E. The acute effects of acute respiratory viral infection upon tracheal mucus transport. Arch Environ Health 1985; 40:322-5.
MATTHEW
s.
MESSINA, THOMAS G. O'RIORDAN, and GERALD C. SMALDONE
Introduction
For the majority of patients, asthma is characterized by mild airways obstruction that is adequately controlled by intermittent, inhaled bronchodilators (1). A minority, however, have severe exacerbations, which require systemicglucocorticosteroid therapy and are potentially fatal even in an acute hospital setting (2). Bronchial smooth musclecontraction has been shown to have an important role in asthma. It has been studied extensively because it is well quantified by spirometry, and it usually responds to pharmacologic intervention. However, in isolation it cannot explain the clinical features of a severe exacerbation (3, 4). Mucociliary clearance (MC) (5, 6) and mucosal edema (3) are believed to have important roles, but in clinically apparent disease they have not been as extensively studied. Evidence from autopsies performed on patients dying suddenly of asthma (2, 7) and studies performed on mild or stable asthmatic subjects have suggested that MC may be impaired in these patients (8-11), but indices of secretory function have not been related to clinical exacerbations. If, as suspected, mucociliary abnormalities are related to death, and in less severe cases to prolonged obstruction, it should be possible to demonstrate significant impairment of MC during acute exacerbations of asthma that improves in tandem with the patient's clinical condition. To test this hypothesis we measured MC in acutely ill hospitalized asthmatic patients using radiolabeled particle inhalation and repeated the measurements after the patients had been discharged from the hospital in clinically stable condition. Methods Five subjects who satisfied the American Thoracic Society criteria (12)for asthma were studied. The study protocol had been approved by the hospital ethics committee. Informed written consent was obtained from every subject. MC was first assessed on the second day (two patients) or third day (three patients) af-
SUMMARY Previous studies have suggested that mucoclllary clearance (MC) Is Impaired In asthmatic subjects. If so, Impaired clearance may be an Important factor In acute exacerbation. We proposed that If MC playa a significant role In acute Illness, MCshould be Impaired during the exacerbation but Improve after recovery. Totest this hypothesis, five asthmatic patients with attacks requiring hospitalization underwent meatlurement of MC using radlolabeled aerosol and a gamma camera. They were studied on the second or third day after admission with repeat measurements after die. charge. Spirometry was performed before all studies. After an equilibrium xenon scan C33Xe), which defined lung borders and measured regional volume, radlolabeled 88l1ne particles containing technetium-labeled (88mTc) sulfur colloid were deposited and used to label airway mucus. Deposition patterns were matched by regulating particle distribution and breathing pattern. MC was then measured as percentage retention of radioactivity at 1G-mlnIntervals for 2 h. When hospitalized, 96.0 ± 2.06% (SEM) of the Initial radioactivity was retained In the lung after 2 h, Indicating little clearance of mucus from the lung. In fact, no significant changes were detected when activity at 120min was compared with measurements at 10 min (99.2 ± 0.22%, NS). After discharge clearance was markedly enhanced. That Is, retention of lung activity was significantly lower at all time Intervals from 10 min onward, with only 70.9 ± 3.86% retained at 120 min (p = 0.008). During an asthmatic attack warr.ntlng hospital admission, MC Is significantly Impaired, with marked Improvement following recovery. Although a causal relationship remains to be established between mucoclllary Impairment and the clinical features of an acute exacerbation of asthma, the association demonstrated In this paper suggests that MC assessment may yet provide a further obJective means of a..... Ing the severity of a patient's asthma and the response to therapy. AM REV RESPIR DIS 1991; 143:993-997
ter admission to the University Hospital, State University of New York at Stony Brook. The studies were repeated 2 to 10 wk after discharge. All patients had been admitted to the pulmonary or allergy services by physicians who were independent of the investigators. All clinical decisions, including those regarding admission and discharge, were made without reference to the study. On admission all patients complained of dyspnea at rest and increased cough. Marked wheezing was heard on examination, and they had signs of respiratory distress as evidenced by tachypnea and use of accessory muscles of respiration. When assessed on the second or third postadmission day before the radioisotope study, the patients were beginning to improve clinically as evidenced by reduced respiratory distress at rest and a reduction in respiratory rate. All patients received intravenous aminophylline (0.7 mg/kg/h), intravenous methylprednisone (60mg four times a day), nebulized J}-agonists, and oxygen at inspired fractions between 24 and 35070. After discharge full medical therapy was continued in every case, including J}-agonistinhaler, oral theophylline, and oral corticosteroids, which were tapered on an individual basis but continued through the repeat study. Recovery was evidenced by resolution of dyspnea and by an improvement in
exercise tolerance and marked dimunition in cough and wheeze. The patients were discharged when stabilized at their usual clinical and spirometric baselines on oral medications. Patients did not receive inhaled J}-agonistsduring the actual measurement of MC. During the study period (2 h) patients were asked not to cough, and all were able to comply with this request. ..Clinical history was obtained and physical .examination carried out immediately before each study. Spirometry was then performed with a dry seal spirometer (Pulmo-Labs; SRL Systems, Houston, TX) and values for forced vital capacity (PVC) and forced expiratory vol-
(Receivedin originalform September 20, 1990and in revised form December 7, 1990) 1 From the Department of Medicine, Division of Pulmonary and Critical Care, State University of New York, Stony Brook, New York. 2 Supported by Grant No. AI 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 and Critical Care Medicine, Health Sciences Center T-17, Room 040, State University of New York, Stony Brook, NY 11794-8172.
993
MESSINA, O'RIORDAN, AND SMALDONE
994
ing them, an se/P ratio of unity reflects predominantly alveolar deposition. Increasing sC/P ratios greater than unity reflect increasing deposition in the proximal airways. The determination of the sC/P ratio allowed quantification of the initial deposition patterns and comparison between patients. Clearance patterns werecalculated by using the whole lung xenon regions to define initial lung activity. Background radiation was subtracted and the counts from each image decay corrected to the time of deposition (t = zero). MC was calculated as the percentage of retention at 10-min intervals over 120min. These studies (spirometry, xenon equilibrium, deposition, and MC) were repeated on all patients 12 to 72 days after discharge. To duplicate the sC/P ratios achieved in the hospital, the breathing pattern used for the repeat studies was controlled. Subjects were asked to breathe rapidly and shallowly at a lung volume close to total lung capacity. Further, it was also necessary to use a larger particle size to duplicate the central deposition pattern of the initial study. [99mTc]Sulfur colloid particles of diameter 3.2 J.1m (Og = 2.0) were generated using a different compressed air nebulizer (Mini-nebs; Inspiron, Bannockburn, IL) at flow rate of 3 L/min. Every individual's inpatient and outpatient clearance curves were compared using paired analysis (Student's t test).
ume in one second (FEV 1) obtained. Imaging of lung radioactivity was performed with the subject seated using a posteriorly positioned gamma camera (Picker-Dyna Camera, Northford, CT). Immediately before aerosol deposition a xenon (133Xe) ventilation scan was performed to obtain an estimate of lung volume. An aqueous aerosol containing 5 mCi technetium (99mTc)-labeled sulfur colloid was then inhaled using a compressed air nebulizer (Scintivents; Sinaco, Palo Alto, CA) driven by a flow of air at 11 L/min until at least 5,000 cpm was recorded. Particle distribution was assessed by cascade impactor. The mass median aerodynamic diameter (MMAD) was 0.74 J.1m and the geometric distribution (Og) was 1.64 (13). Immediately following deposition MC was measured by recording serial gamma camera images at l-min intervals via computer (Data General Nova'" II, Anaheim, CA). Images were acquired for 120 min. We analyzed data in the following manner: With the computer, regions of interest were drawn over the xenon equilibrium scan: a region over the entire right lung called the whole lung zone, and another region centered over the large central airways comprising 330/0 of the right lung area, 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. The left lung was not analyzed because of radioactivity in the stomach. Using the xenon regions of interest, the ratio between the central (C) and peripheral (P) lung counts (C/P) was calculated in a manner that normalized for differences in relative lung thickness by dividing the C/P 99mTc counts by the C/P 133Xe counts. This ratio defined the specific C/P ratio (sC/P) (14, 15). Using the resulting sC/P values, a ratio of 1.0 reflects equal deposition in all regions. Because the central region outlines both central airways and the lung parenchyma surround-
Results
Clinical details, pulmonary function, and deposition data are listed in table 1. The five patients had a median age of 26 yr (range 20 to 75 yr). There werethree males and two females; they had asthma for a median period of 20 yr (range 12 to 60 yr); all were nonsmokers except for one patient who had stopped smoking 25 yr previously after 29 pack -years but had
asthma since age 20. No patients gave a history suggestive of antecedent febrile illness or upper respiratory tract infection. The mean FEV 1 and FVC (expressed as a percentage of predicted values ± standard error of the mean, SEM) for the inpatients were 42.4 ± 7.63 and 62.2 ± 8.250/0, respectively. After discharge the mean FEV 1 improved to 70.2 ± 10.4070, but this change was statistically insignificant by paired analysis because improvement did not occur in all patients. The FVC, however, was more uniformly increased to 95.6 ± 4.85070, p = 0.019.The FEV 1 % FVC ratio was slightly improved (53.8 ± 4.38 versus 63.3 ± 8.57070), but these changes were not significant. By paired analysis mean ± SEM sC/P ratios for the inpatient and outpatient studies were not significantly different (2.11 ± 0.24 versus 1.85 ± 0.14, respectively). Whole-lung retention curves for the inpatient and outpatient studies are shown in figure 1. The percentage retention of radioactive aerosol is plotted against time at 10-min intervals for 120 min. The amount of radioactivity at the start of the test (t = zero) is designated 100%. When the patients were hospitalized, the percentage retention at 120min was 96.8 ± 2.060/0, indicating that almost none of the isotope left the lung in 2 h. In fact, when compared with the 10-min point (99.2 ± 0.220/0), there was no statistically significant change in retention over the entire 2-h observation period. After discharge the same patients had significantly increased clearance of mucus as evidenced by the reduced lung
TABLE 1 CLINICAL, SPIROMETRIC AND DEPOSITION DATA
Subject
2
Sex
Age
Years with Asthma
F
24
20
M
3
F
4
M
5
M
20 69 26 75
12 60 20 55
Days After Admission
3 19
44 82
54 102
54.4 66
3 12
27 105
58 95
38.8 91.8
109
3.06 1.78
2 36
34 58
46 79
62.1 61.0
143
1.84 2.40
3 72
71 57
94 94
63.0 59.7
96
1.78 1.68
3 33
36 49
59 108
50.7 38.0
98
2.10 1.76
FEV,
FVC
(% predicted)
(% predicted)
FEV,% FVC
Specific OLeo (%)
sC/P*
98.0
1.79 1.62
Mean (hospitalized) ± SEM
42.4 7.63
62.2 8.25
53.8 4.38
2.11 0.24
Mean (postdischarge) ± SEM P
70.2 10.4
95.6 4.85 0.019
63.3 8.57
1.85 0.14
• Regional radioaerosol deposited per unit lung volume.
NS
NS
NS
995
MUCOCILIARY CLEARANCE IN ACUTE ASTHMA
MC plays a significant role in severeasthmatic exacerbations. To date some of the strongest evidence in favor of this hypothesis comes from autopsy studies performed on patients dying in status asthmaticus. In a recent British study of hospital deaths from acute asthma virtually all autopsies revealed bronchial obstruction with mucus and hyperinflated lungs, which did not deflate on opening the thoracic cavity (2). Similar findings have been published over the past 50 yr (7). Previous studies have shown that MC is impaired in stable asthmatic subjects compared to normal volunteers (8-10), but those investigators did not relate MC impairment to changes in the patient's clinical state over time. Others (11) found that tracheal mucous velocityin ragweedsensitive asthma is reduced relative to age-matched normal volunteers and further reduced after acute bronchoprovocation. However, tracheal mucous velocity may not reflect clearance from more distal airways, and changes induced by acute bronchoprovocation may not necessarily be the same as those found during a clinical exacerbation lasting many hours or even days. A link had, therefore, not been established between the autopsy findings and the laboratory demonstration of MC impairment. We know from autopsy and clinical data that
.009.011 .031 .005 .001 .001 .001 .005.009.009.007 .007 100
o
I 90
80
Fig. 1. Retention of radioactivity versus time: patients in the hospital (open symbols); after discharge (closed symbols). Error bars indicate standard errors of the mean. Numerical values are p values.
c
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70
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60
50
40
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o
20
40
60
80
Time
Discussion
retention at each point of observation (differences weresignificant from 10min; p values listed in figure 1). At 2 h their retention averaged 70.9 ± 3.86010 retention, p = 0.008. Retention data for individual subjects are shown in figure 2. Each patient's MC improved without exception, with less retention of radioisotope noted from 10 min onward. The percentage changes in FEV 1, FVC, and FEV 1010 FVC for individual patients were correlated against two representative indicators of MC, the percentage retention at 30 and 60 min (R30 and R60, respectively), but none of these relationships were significant.
Patient
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90
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80
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This is the first published study to demonstrate that patients with exacerbations of asthma of sufficient severity to warrant hospitalization have severe impairment of MC. When the studies were repeated after discharge, remarkable improvement in MC function was demonstrated. Not only did the mean MC rates of the outpatients significantly exceedthe mean rates achieved when they were in hospital, but, in the case of each individual subject, the outpatient MC rate was greater at every time interval after 10min of observation. These findings are supportive of the suggestion that impaired
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40
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80
100
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20
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40
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80
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II II
II
IJ
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a::
40
40
20
40
60
Time
80
(min)
100
120
60
Time
100
•••
40
20
0
(min)
Patient
a::
0
•••
60
120
#4
IJ
• ~
60
Time
Patient
II
#3
. .. ..
..
III
..
••••
40
120
(min)
100
80
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II
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20
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60
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a: 50
II
• ••
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c
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Patient
#2
Patient
#1 II
120
100
(min)
0
20
40
60 Time
Fig. 2. Retention curves of individual subjects: patients in the hospital (open symbols); after discharge (closed symbols).
100 80 (min)
120
80
(min)
100
120
996
bronchial smooth muscle contraction, mucosal edema, and the accumulation of secretions are all involved in the pathogenesis of acute asthma, but to date we do not have objective means of evaluating the relative importance of these factors during exacerbations. The demonstration of an association between MC abnormalities and clinical exacerbations of asthma does not necessarily prove cause and effect but suggests that MC assessment may yet provide a further objective means of assessing the severity of a patient's asthma on serial occasions. In this study we detected significant, reversible changes in mucociliary function that appeared able to discriminate more clearly between inpatients and outpatients than spirometry. Because of the small size of the study this finding needs to be interpreted with caution until confirmed by further studies. Nevertheless, the limitations of spirometry in the acute setting are well recognized. In three groups of patients with acute asthma graded in terms of clinical severity, Rebuck and Read (16) found considerable overlap in FEV 1 (070 of predicted). Woolcock and. Read (17) demonstrated that clinical recovery was not always reflected in improvement in FEV 1, and TurnerWarwick (18)described clinically improving asthmatic patients whose FEV 1% FVC ratio decreased with recovery. In addition, studies have found that spirometric abnormalities can resolve more quickly than abnormalities in ventilationperfusion mismatch and that prednisone is capable of improving POl without a concomitant improvement in FEV 1 (19). The lack of a close correlation between spirometric and MC improvements in this study suggest that these two modalities may be measuring different but clinically relevant aspects of the asthmatic state. It has long been suspected that disorders of secretory function may play an important role in acute exacerbations of asthma, and many theories concerning possible mechanisms of action have been proposed. MC impairment may be a reflection of airways inflammation that is sufficiently severe to cause disruption of the integrity of the mucociliary system (20). The demonstration of substantial destruction of ciliated epithelium in bronchoscopic biopsies of inflamed asthmatic airways supports the suggestion that inflammation may disrupt mucociliary mechanisms. However, it is also possible that increased bronchial inflammation and decreased MC may interact and be mutually exacerbating. Bronchi-
MESSINA, O'RIORDAN, AND SMALDONE
al inflammation may disrupt MC mechanisms and cause the retention of inflammatory secretions resulting in the prolongation of bronchial inflammation, leading to further disruption of MC (3). In other words, impaired MC may be both a complication of bronchial inflammation and an aggravation of bronchial inflammation. If MC impairment is found to be an indicator of severe bronchial inflammation, it may be possible to utilize MC assessment in future studies to measure the effectiveness of antiinflammatory therapy in acute asthmatic exacerbations. Measurements of MC are cumbersome and time consuming and are not suitable in their present format for routine patient care or even for large multicenter clinical studies. However, small clinical trials designed to assess the efficacy of new antiinflammatory agents in acute exacerbations of asthma could incorporate studies of MC to add an extra dimension to a drug profile. These studies may also have a role in evaluating the use of glucocorticosteroids in asthma. Despite almost three decades of widespread clinical usage and multiple-drug trials, the optimum dosage schedule for an acute exacerbation of asthma has yet to be established (21).That all the patients in this study were on parenteral glucocorticosteroids at the time 0 f their inpatient studies and were on tapering oral steroids at the time of their convalescent studies suggests that although there does not appear to be an immediately detectable MC response to steroids, the recovery of MC function may be due to the resolution of airway inflammation effected by the steroids. The suggestion of a delayed improvement in MC in response to glucocorticosteroid therapy is further supported by the work of Agnew and associates (22), who previously demonstrated a small increase in MC in stable asthmatic subjects after 4 wk of oral prednisone. A number of practical difficulties arise in performing these studies in acutely ill patients. To meaningfully compare MC on serial occasions it is necessary to ensure similar initial deposition patterns. The more central the deposition pattern, the more rapidly the deposited particles clear as a result of the shorter distances from bronchi to pharynx (15). As hospitalized patients are treated, changes in breathing pattern and airway geometry will likely result in differences ininitial patterns of deposition of the radio- . labeled particles and complicate the as-
sessment of changes in MC. Because it was impractical to control the breathing patterns of the patients in the hospital, we adjusted the breathing patterns and aerosol MMAD used for the outpatient study to ensure matched deposition patterns. The use of two different sizes of aerosol was also required to match distribution patterns between the two groups. Larger particles are deposited in more proximal airways and were therefore administered to the outpatients, who had less airways obstruction than the hospitalized group. Data from this laboratory suggest that particle diameter, aside from its effect on deposition pattern does not affect MC (15). The mean values for both inpatient and outpatient groups describe deposition patterns that include a significant number of particles in central airways (14, 15). Therapy cannot ethically be withheld to perform studies. I3-Agonists and theophylline have been shown to transiently improve MC rates (5). However, this cannot explain why the inpatients achieved slower MC despite receiving more intensive therapy than after discharge. A number of studies have suggested that the administration of high concentrations of oxygen can have deleterious effects on MC; however, it is unlikely that the relatively low concentrations of oxygen given to our patients could be responsible for the profound changes observed in MC (5, 23). Exact matching of sC/P ratios for both inpatient and outpatient studies was attempted but not achieved in every case. However, the discrepancies were small. Significant differences in mean sC/P ratio were not detected by paired t test, and, despite a greater sC/P ratio in the inpatient studies of four subjects, MC was reduced in all patients when they were hospitalized. Because viral illnesses are common precipitants of acute exacerbations of asthma, the possibility of a viral etiology for the impairment in MC, although unlikely, cannot be fully discounted. There is convincing evidence that influenza A can cause severe but reversible MC dysfunction (24-26). However, a role for the more commonly occurring viruses has yet to be demonstrated (26). None of the subjects in this study gave a history of an antecedent febrile or upper respiratory illness. . Asthma is characterized by variable bronchial obstruction when assessed clinically and by spirometry. This study, in which each subject served as his or her
997
MUCOCILIARY CLEARANCE IN ACUTE ASTHMA
own control, demonstrates that MC varies with the patient's clinical state. A causal relationship has yet to be proven, but MC assessment may provide a further objective means of assessing the severity of a patient's asthma and the response to therapy. Acknowledgment The authors thank Mr. Robert Perry for his technical assistance in performing the deposition and clearance measurements and Ms. Pamela Prudenti for typing the manuscript.
References 1. Snider GS. Staging therapy to the severity of asthma in bronchial asthma: mechanisms and therapeutics. In: Weiss EB, Segal MS, Stein M, eds. Bronchial asthma. Boston: Little Brown, 1985; 577-89. 2. MacDonald JB, MacDonald ET, Seaton Williams DA. Asthma deaths in Cardiff 1963-74: 53 deaths in hospital. Br Med J 1976; 2:2721-3. 3. Barnes PJ. New concepts in the pathogenesis of bronchial hyper-responsiveness and asthma. J Allergy Clin Immunol 1989; 83:1013-26. 4. Reed CEoThe emergency visit and management of asthma. Ann Intern Med 1990; 112:801-2. 5. Wanner A. Clinical aspects of mucociliary transport. Am Rev Respir Dis 1977; 116:73-125. 6. Editorial. Pulmonary mucociliary clearance. Lancet 1982; 1:203-4. 7. Benatar SR. Fatal asthma. N Engl J Med 1986; 314:423-8.
8. Foster WM, Langenbach EG, Bergofsky EH. Lung mucociliary function in man: interdependence of bronchial and tracheal mucus transport velocities with lung clearance in bronchial asthma and healthy subjects. Ann Occup Hyg 1982; 26(1):227-44. 9. Bateman JRM, Pavia 0, Sheahan NF, Agnew JE, Clarke SW. Impaired mucociliary clearance in patients with mild stable asthma. Thorax 1983; 38:463-7. 10. Pavia 0, Bateman JRM, Sheahan NF, Agnew JE, Clarke SW. Tracheobronchial mucociliary clearance in asthma: impairment during remission, Thorax 1985; 40:171-5. 11. Mezey RJ, Cohn MA, Fernandez RJ, et al. Mucociliary transport in patients with antigeninduced bronchospasm. Am Rev Respir Dis 1978; 118:677-84. 12. American Thoracic Society Committee on Diagnostic Standards. Definitions and classification of chronic bronchitis, asthma, and pulmonary emphysema. Am Rev Respir Dis 1962; 85:762. 13. Smaldone GC, Perry RJ, Deutsch DG. Characteristics of nebulizers used in the treatment of AIDS-related Pneumocystis carinii pneumonia. J Aerosol Med 1988; 1:113-26. 14. Smaldone GC, Perry RJ, Bennett WD, Messina MS, Zwang J, Ilowite J. Interpretation of "24 hour lung retention" in studies of mucociliary clearance. J Aerosol Med 1988; 1:11-20. 15. Ilowite JS, Smaldone GC, Perry RJ, Bennett WD, Foster WM. Relationship between tracheobronchial particle clearance rates and sites of initial deposition in man. Arch Environ Health 1989; 44:267-73. 16. Rebuck AS, Read J. Assessment and management of severe asthma. Am J Med 1971;51:788-98.
17. Woolcock AJ, Read J. Improvement in bronchial asthma not reflected in forced expiratory volume. Lancet 1965; 2:1323-5. 18. Turner-Warwick M. On observing patterns of airflow obstruction in chronic asthma. Br J Dis Chest 1977; 71:73-86. 19. FIenley DC, Warren PM. Gas exchange and acid-base balance in bronchial asthma. In: Weiss EB, Segal MS, Stein M, eds. Bronchial asthma. Boston: Little, Brown, 1985; 577-89. 20. Djukanovic R, Roche WR, Wilson J, et al. Mucosal inflammation in asthma. Am Rev Respir Dis 1990; 142:434-57. 21. Collins J, McAllister WAC, Morley J. Corticosteroids: mechanisms and dosage schedules. In: Weiss EB, Segal MS, Stein M, eds. Bronchial asthma. Boston: Little, Brown, 1985; 675-97. 22. Agnew JE, Bateman JRM, Pavia 0, Clarke SW. Peripheral airways mucous clearance in stable asthma is improved by oral glucocorticosteroid therapy. Bull Eur Physiopathol Respir 1984;20:295-301. 23. Sackner MA, Hirsch JA, Epstein S, Rywlin AM. Effect of oxygen in graded concentrated concentrations upon tracheal mucus velocity: a study in anaesthetized dogs. Chest 1976; 69:164-7. 24. Camner P, Jarstrand C, Philipson K. Tracheobronchial clearance in patients with influenza. Am Rev Respir Dis 1973; 108:131-5. 25. Levandowski R, Gerrity T, Garrard C. Modifications of lung clearance mechanisms by acute influenza A infection. J Lab Clin Med 1985; 106:428-32. 26. Gerrard C, Levandowski R, Gerrity T, Yeates 0, Klein E. The acute effects of acute respiratory viral infection upon tracheal mucus transport. Arch Environ Health 1985; 40:322-5.
