Original Article
A Comparison of Bronchodilator Therapy with or without Inhaled Corticosteroid Therapy for Obstructive Airways Disease
N Engl J Med 1992; 327:1413-1419November 12, 1992
- Abstract
- Abstract
Background.
The morbidity from obstructive airways disease (asthma and chronic obstructive pulmonary disease) is considerable, and the mortality rate is rising in several countries. It has been hypothesized that long-term improvement in prognosis might result from vigorous bronchodilator or antiinflammatory therapy.
Methods.
In a multicenter trial we compared three inhalation regimens in which a β2-agonist (terbutaline, 2000 μg daily) was combined with a corticosteroid (beclomethasone, 800 μg daily), an anticholinergic bronchodilator (ipratropium bromide, 160 μg daily), or placebo. Patients with airways hyperresponsiveness and obstruction who were 18 to 60 years old were followed for 2 1/2 years.
Results.
Of the 274 patients enrolled, 56 percent had allergies. The mean forced expiratory volume in one second (FEV1) was 64 percent of the predicted value. The mean PC20 (the concentration of inhaled histamine causing a 20 percent decrease in FEV1, a measure of hyperresponsiveness) was 0.26 mg per milliliter. Withdrawal from the study, due mainly to pulmonary symptoms, was less frequent in the corticosteroid group (12 of 91 patients) than in the anticholinergic-drug group (45 of 92 patients) or the placebo group (44 of 91 patients; P<0.001). The mean FEV1 (±SE) increased by 10.3±1.3 percent of the predicted value in the corticosteroid group within three months and remained stable thereafter, whereas it did not change in the other two groups (P<0.001). The PC20 increased by 2.0 doubling concentrations in the corticosteroid group but did not change in the other groups (P<0.001). In the corticosteroid group, patients who did not smoke, who had allergies, or who were less than 40 years old benefited more from their treatment than did those who smoked, did not have allergies, or were over 40, but all subgroups of the corticosteroid group had improvement as compared with the anticholinergic-drug or placebo group.
Conclusions.
The addition of an inhaled corticosteroid — but not an inhaled anticholinergic agent — to maintenance treatment with a β2-agonist (terbutaline) substantially reduced morbidity, hyperresponsiveness, and airways obstruction in patients with a spectrum of obstructive airways disease. (N Engl J Med 1992;327:1413–9.)
Media in This Article
Figure 1
Cumulative Percentage of Patients Withdrawn, According to Treatment Group.Figure 2
Mean (±SE) FEV1 before Bronchodilation in Patients Followed for at Least 21 Months.Article Activity
- Article
ASTHMA, a disorder characterized by attacks of dyspnea or wheezing and variable airways obstruction, may cause severe morbidity.1 The mortality from asthma is rising in several countries.2 3 4 Chronic obstructive pulmonary disease (COPD) causes progressive loss of lung function, which also leads to increased morbidity and mortality.5 Improvement in the prognosis of these diseases should be a major goal of therapy. In asthma, the prognosis is related primarily to the levels of airways obstruction and hyperresponsiveness.6 , 7 In COPD, the prognosis is related primarily to age and the initial level of airways obstruction,8 and secondarily to smoking, airways hyperresponsiveness, and perhaps reversibility of obstruction.9 10 11 Hence, asthma and COPD share the presence of obstruction and hyperresponsiveness as risk factors.1 Corticosteroids, β2-agonists, and anticholinergic agents are all currently used to relieve the symptoms of asthma and COPD.
Inhaled corticosteroids have a well-established short-term beneficial effect on airways hyperresponsiveness and obstruction in asthma,12 , 13 probably due to their antiinflammatory properties.14 Recently, two studies have also demonstrated beneficial long-term effects of inhaled corticosteroid monotherapy in mild asthma.15 , 16 Long-term retrospective studies (14 to 20 years) have suggested a beneficial effect of maintenance doses of oral steroids on the level of obstruction in COPD.17 , 18 Short-term studies of inhaled corticosteroids for COPD have shown conflicting results with respect to changes in airways obstruction and hyperresponsiveness.19 20 21
β2-Agonists provide symptomatic relief by producing bronchodilation rapidly but with a relatively short duration of action. Hyperresponsiveness may increase slightly and transiently during treatment with β2-agonists.12 , 13 Anticholinergic drugs have a somewhat slower onset and longer duration of action than β2-agonists. They appear to be almost as effective as β2-agonists in asthma,22 , 23 whereas they may be more potent in COPD24; they seem to have no effect on airways hyperresponsiveness.25
The present study was designed to investigate the long-term effects of pharmacologic treatment in patients with obstructive airways disease who were selected according to objective criteria for lung function. We tested the hypothesis that long-term treatment directed at both bronchodilation and airways hyperresponsiveness may be superior to treatment directed at vigorous bronchodilation (β2-agonist plus an anticholinergic agent), which may in turn be superior to treatment with a single agent (β2-agonist alone).
Methods
Patients 18 to 60 years old with obstructive airways disease and no other major illnesses26 were selected from six university pulmonary outpatient clinics if they met the following two criteria. (1) The forced expiratory volume in one second (FEV1) was between 4.5 and 1.64 residual standard deviations below the predicted value (men, 0.84 liter; women, 0.62 liter) and was above 1.2 liters, or the ratio of the FEV1 to the inspiratory vital capacity was less than 1.64 residual standard deviations below the predicted value (men, 11.7 percent; women, 10.7 percent) provided that total lung capacity was more than 1.64 residual standard deviations below the predicted value (men, 1.15 liters; women, 0.98 liter). The rationale for using residual standard deviations and the predicted values have been described elsewhere.27 , 28 (2) The concentration of histamine causing a 20 percent decrease in the FEV1 (the PC20) was ≤8 mg per milliliter. Patients with conditions or medication requirements likely to interfere with the purpose of the study were excluded.26 Further details of the study methods have been reported previously.26
The use of inhaled corticosteroids was tapered and discontinued completely four weeks before the patients made a prerandomization visit. Other maintenance medication was withheld for at least six weeks (ketotifen or antihistamines), four weeks (cromolyn sodium), or 48 hours (theophylline) before the start of the study. Maintenance treatment with oral steroids was not allowed. At base line, skin reactivity to 12 common aeroallergens was measured intradermally; patients were categorized as allergic if a wheal developed on the test with the house-dust mite or a minimum of two other skin tests that was at least equal to the wheal on the histamine skin test. Randomization was performed by telephoning an independent center that used a computerized minimization method29 with stratification according to sex, age, previous use of inhaled corticosteroids, FEV1, PC20, reversibility of obstruction, allergy, smoking habits, and study center.26
The patients were randomly assigned to one of three double-blind regimens, with a planned follow-up of three years. All the patients received the following agents from identical metered-dose inhalers: a β2-agonist (terbutaline, 250 μg per puff; two puffs four times a day) combined with a corticosteroid (beclomethasone, 100 μg per puff; two puffs four times a day), an anticholinergic bronchodilator (ipratropium bromide, 20 μg per puff; two puffs four times a day), or placebo (two puffs four times a day). They were instructed to rinse their mouths after taking the study medication. Compliance was assessed by weighing the inhaler canisters. Additional bronchodilator medication consisted of albuterol (salbutamol) on demand, inhaled as a dry powder (400 μg). No other concomitant pulmonary medication was allowed except during exacerbations,26 for which a 12-day course of oral prednisolone was administered. The primary criterion for withdrawal of a patient by his or her physician was a requirement for more than two courses of prednisolone over a three-month period or for more than four courses in a year. Patient-initiated withdrawal was classified as being caused by unacceptable increases in pulmonary symptoms, adverse effects, unrelated problems (to be specified), or refusal to participate further.
Follow-up visits were to be made every three months; the FEV1 was measured at every visit, and the reversibility of airways obstruction and the PC20 were determined at alternate visits. Measurements were made only during clinically stable periods, and not within four weeks after the termination of a course of prednisolone. All pulmonary medications were discontinued eight hours before each test.
FEV1 was measured with calibrated water-sealed spirometers according to standardized guidelines.27 At least three reproducible values (i.e., with less than 5 percent difference among the recordings) were obtained; the highest value was used in the analyses. To test whether obstruction was reversible, FEV1 was measured before and 20 minutes after four single inhalations of 250 μg of terbutaline administered through a 750-ml spacer device (Nebuhaler). Subsequently, FEV1 was measured 40 minutes after four single inhalations of 20 μg of ipratropium.
Histamine provocation tests were performed with a two-minute tidal-breathing method.26 , 30 For purposes of analysis, a PC20 value of 0.015 was assigned to each patient already responding to saline or to the lowest concentration of histamine (0.03 mg per milliliter). During follow-up, if the FEV1 did not decrease by 20 percent when the highest concentration of histamine was applied (32 mg per milliliter), a PC20 value of 64 was assigned.26
Using data from a standardized medical history, we identified different pulmonary syndromes, adhering to the criteria of the American Thoracic Society.1 Patients who reported attacks of breathlessness and wheezing (asthmatic attacks) without chronic cough or sputum production (i.e., for more than three months per year) were identified as having asthma. Current or former smokers without a history of asthmatic attacks who reported either chronic cough with or without sputum production or dyspnea when walking quietly on level ground, or both, were identified as having COPD. Patients with both asthmatic attacks or recurrent wheezing and chronic cough and sputum production were identified as having asthmatic bronchitis. Patients with insufficient data to establish a diagnosis from the medical history were considered to have an undefined diagnosis.26
All data were collected, checked, and analyzed at a central data-management center. An independent Data Monitoring Committee performed interim analyses every six months.
All calculations of PC20 were performed with the base-2 logarithm (log2), since this reflects doubling concentrations. Values are expressed as means ±SE, and P values are two-tailed. Differences in withdrawal rates were analyzed with the log-rank test, differences in proportions with z-tests, and differences in FEV1 and log2 PC20 between treatment groups with t-tests.31 Individual regression lines of the FEV1 (before bronchodilator therapy) on time were calculated for all patients with at least four measurements of FEV1 (one year of follow-up); the first measurement used was that obtained after three months of treatment, since the FEV1 increased in a nonlinear (i.e., stepwise) fashion during the first three months in the corticosteroid group. Differences in slopes were analyzed with the Mann—Whitney U-test because distribution was not normal.31 Subgroup analyses were performed with interaction tests. Because the number of patients withdrawn increased during the study, the subgroup analyses included data obtained after six months of follow-up, to retain sufficient numbers for meaningful comparisons.
The study protocol was approved by the medical ethics committees of all participating centers; all the patients gave written informed consent.
Results
Between October 1987 and January 1989, 274 patients were enrolled in the study. Their characteristics at randomization are shown in Table 1Table 1
Base-Line Characteristics of the Patients, According to Treatment Group.. The characteristics of the three treatment groups were comparable at base line except that the corticosteroid group was slightly less hyperresponsive (as reflected by a higher PC20).In June 1990, the Data Monitoring Committee recommended termination of the study because of predefined, significant differences in the withdrawal rate, FEV1, and PC20 between patients given maintenance β2-agonist treatment plus corticosteroid and those given a β2-agonist plus an anticholinergic agent or a β2-agonist plus placebo.
Withdrawals
The withdrawal rate in the corticosteroid group (12 patients) differed significantly (P<0.001) from the rate in both the anticholinergic-drug group (45 patients) and the placebo group (44 patients) (Fig. 1Figure 1
Cumulative Percentage of Patients Withdrawn, According to Treatment Group.). The reasons for withdrawal are shown in Table 2Table 2
Reasons for Withdrawal, According to Treatment Group.*. The number of episodes of exacerbation per patient-year (adjusted for variable follow-up) was 0.72±0.13 in the placebo group, as compared with 0.25±0.05 in the corticosteroid group (P<0.001) and 0.76±0.12 in the anticholinergic-drug group (P = 0.81). Three patients withdrew because of adverse effects: hoarseness in one patient taking corticosteroid, tremor in another taking corticosteroid, and a sore throat after each inhalation in one patient taking placebo. Eight other patients were withdrawn for reasons unrelated to their illness (pregnancy, lung cancer, acquired immunodeficiency syndrome, emigration, psychosis, severe trauma, interstitial pulmonary fibrosis, and sarcoidosis). No patients died during the study. More women were withdrawn than men (45 percent [44 of 98] vs. 32 percent [57 of 176], P = 0.04). There was no significant difference between the patients withdrawn and those remaining in their ages, smoking habits, allergies, and prior use of inhaled corticosteroids. Base-line lung function tended to be worse in the patients who were withdrawn: the mean FEV1 before bronchodilation (as a percentage of the predicted value) was 60.8±1.4 percent in the patients who were withdrawn and 65.4±1.2 percent in those who completed the study (P = 0.02); the geometric mean PC20 was 0.19 and 0.31 mg per milliliter, respectively (P = 0.009). All 173 patients who were not withdrawn were able to be followed for at least 21 months before termination of the study, and 129 were followed for the maximum of 30 months.The rate of compliance with the prescribed dosage of medication was 85.1±3.3 percent in the placebo group, 92.9±3.0 percent in the anticholinergic-drug group, and 79.9±2.8 percent in the corticosteroid group.
Airways Obstruction
After 3 months, the mean increase in the FEV1 before bronchodilation was 10.3±1.3 percentage points in the corticosteroid group, as compared with a decrease of 1.0±1.2 percentage point in the placebo group; the mean difference of 11.3 percent (P<0.001) was maintained throughout the 2 1/2 years of follow-up.* There was no significant difference between the placebo and anticholinergic groups at any time during follow-up.* After three months the mean FEV1 after terbutaline bronchodilation decreased by 1.2±1.1 percentage points in the placebo group, increased by 7.5±1.1 percentage points in the corticosteroid group (P<0.001), and decreased by 0.6±1.2 percentage point in the anticholinergic group (P = 0.7). These differences remained the same throughout follow-up. Figure 2Figure 2
Mean (±SE) FEV1 before Bronchodilation in Patients Followed for at Least 21 Months. shows the changes in the FEV1 in all patients followed for at least 21 months.The median slopes of FEV1 from three months onward were -64 ml per year (n = 60 patients) in the placebo group, -19 ml per year (n = 61) in the anticholinergic group, and -33 ml per year (n = 86) in the corticosteroid group. These slopes did not differ significantly from each other.
Airways Hyperresponsiveness
The PC20 increased by 1.27±0.21 doubling concentrations in the corticosteroid group during the first six months, as compared with 0.15±0.23 in the placebo group (P<0.001). The difference between the anticholinergic and placebo groups (0.28 doubling concentration) was not significant (P = 0.33).* Figure 3Figure 3
Geometric Mean (±SE) PC20 (in Response to Histamine) in Patients Followed for at Least 24 Months. shows the changes in PC20 in the patients followed for at least 24 months: although most of the improvement in the corticosteroid group occurred during the first 6 months, the PC20 increased by an additional 0.42±0.28 doubling concentration in the next 6 months (P = 0.04); thereafter, the rate of improvement appeared to plateau.* A PC20 of more than 8 mg per milliliter after 24 months of treatment, which is considered normal,30 was observed in 6 of 77 patients (8 percent) in the corticosteroid group, as compared with 2 of 44 (5 percent) in the placebo group, and none of 48 in the anticholinergic-drug group.Subgroup Analyses
In all subgroups, patients receiving corticosteroid had larger increases in both FEV1 and PC20 than those receiving placebo (Table 3Table 3
Difference between Corticosteroid and Placebo Groups in Mean Change in FEV1 and PC20, According to Subgroup.*). In several subgroups, we found evidence of an interaction between the treatment and the subgroup factor. For instance, patients 40 years old or younger had a greater change in FEV1 after six months (an increase of 13.9 more percentage points with corticosteroid than with placebo) than patients more than 40 years old (only 5.8 percentage points better with corticosteroid; P value for interaction, 0.04). Similarly, improvement in FEV1 with corticosteroid as compared with placebo was more marked in patients who did not smoke, who had allergies, or who were more hyperresponsive (Table 3). There was evidence of an interaction between diagnosis group and improvement in both FEV1 (P = 0.04) and PC20 (P = 0.03): improvement was more marked in the subgroup with symptom-based asthma than in the subgroups with other types of diagnoses (Table 3).When improvements in FEV1 and PC20 in the corticosteroid group were compared with those in the placebo group, the changes were similar in men and in women, as well as in patients who had previously used inhaled corticosteroids and those who had not.
There were no significant interaction effects between the anticholinergic and placebo treatments in the different subgroups.
Adverse Effects
No major adverse effects were observed. Minor adverse effects consisted of hoarseness, a sore throat, and tremor and could be easily reversed by attaching a spacer device to the inhaler or discontinuing the inhaled drugs for two weeks.
Discussion
Our study shows that the addition of an inhaled corticosteroid to maintenance treatment with a β2-agonist (terbutaline) in hyperresponsive patients with obstructive airways disease leads to a significant reduction of respiratory symptoms, exacerbation rates, airways obstruction, and hyperresponsiveness. Most clinical trials in patients with airways obstruction have studied polarized groups comprising either young, nonsmoking patients with allergies who have highly reversible airways obstruction (asthma) or older, currently smoking patients without allergies who have largely irreversible obstruction (COPD). This approach is useful in rigorous trials, but it does not necessarily reflect routine clinical practice, in which patients frequently have overlapping characteristics between these extremes and are not easily categorized as having either asthma or COPD.32 , 33 In the current study, patients were selected on the basis of objective functional criteria, resulting in a study population with great differences in airways obstruction, airways hyperresponsiveness, and age. The unique feature of this study is that it compared blinded treatment regimens for a prolonged period, thus reflecting the clinical practice of prescribing long-term use of drugs in obstructive airways disease. The study design allowed us to analyze the effects of both treatment time and patients' characteristics on the response.
Withdrawal rates were substantially worse among the patients given bronchodilators alone than among those given bronchodilators combined with inhaled corticosteroids. The majority of withdrawals from the study were due to pulmonary complications, either an increase in the frequency of exacerbations or an increase in symptoms. Because of the high withdrawal rates, the effects of treatment on FEV1 and PC20, especially at later time points, were subject to considerable selection bias. Since the withdrawals occurred largely in the two treatment groups not receiving inhaled corticosteroids, and since the patients who were withdrawn had lower values for FEV1 and PC20 than the patients who remained, the observed treatment benefits are likely to reflect conservative estimates.
The decreases in airways obstruction in the corticosteroid group occurred mainly in the first three months of treatment, remaining constant afterward. By contrast, PC20 improved for at least a year during treatment with corticosteroids before reaching a plateau. The lack of further improvement was not due to the achievement of normal levels of FEV1 and PC20. The failure to achieve normal levels in the majority of patients is compatible with the finding of ongoing inflammation in asthma even after 10 years of treatment with inhaled corticosteroids.34 It remains to be established whether earlier institution, longer duration, or higher dosages of antiinflammatory treatment may more completely reverse airways inflammation in obstructive airways disease.
Subgroup analyses were performed to determine whether treatment benefits were more pronounced in specific types of patients. Since there is no agreement about how to distinguish asthma from COPD precisely,32 , 35 we selected (and stratified) patients according to age and the objective criteria of FEV1 and PC20 and subsequently analyzed the factors thought to be important to disease classification and outcome. The largest improvements in FEV1 were found in younger patients, nonsmoking patients, patients with allergies, and patients with greater hyperresponsiveness. Improvement in PC20 with corticosteroid was also more pronounced in younger patients with less airways obstruction and more easily reversible impairment. As expected, the treatment benefits of inhaled corticosteroids were greater in patients with a symptom-based diagnosis of asthma than in those with COPD. Nevertheless, treatment effects, though not always significant, were observed in all subgroups, including the patients with a symptom-based diagnosis of COPD. Earlier short-term studies found no clear benefits of inhaled corticosteroids in patients with COPD.19 20 21 This difference in results may be due to selection factors, since patients were selected only if they were hyperresponsive and under 60 years of age. However, since more than two thirds of patients with early COPD have increased airways responsiveness to methacholine,36 this is unlikely to be the only explanation. Alternatively, because treatment effects are time-dependent and dose-dependent,17 , 37 , 38 it may be hypothesized that longer treatment with higher dosages of inhaled corticosteroids may result in significant improvements in disease control even in patients with more "classic" COPD. Indeed, in a recently completed two-year study in patients without allergies who had COPD, the FEV1 increased during treatment with inhaled corticosteroids, but not the PC20.39 The daily dose of inhaled corticosteroids chosen for our study (800 μg) is well below the range of doses (1000 to 1500 μg) thought to produce systemic effects or adrenal suppression.14 , 40
Although it has been suggested that bronchodilator treatment itself may improve the course and prognosis of obstructive airways disease,6 , 8 , 17 and that β2-agonists and anticholinergic agents may work synergistically,41 , 42 the second part of our study hypothesis —namely, that bronchodilator therapy including both an anticholinergic agent and a β2-agonist would compare favorably with less vigorous bronchodilator therapy — was not substantiated. The lack of difference was not due to the fact that maximal bronchodilation was achieved with a β2-agonist alone, since testing for reversibility at base line and follow-up revealed additional effects of the anticholinergic drug given after the β2-agonist.
Recently, it has been suggested that maintenance treatment with inhaled bronchodilators alone may lead to increased mortality4 and to worsening of symptoms or lung function, as compared with treatment as needed.43 , 44 Because our study had no placebo group in which bronchodilators were given only on demand, our results do not allow direct comparison with these studies. However, the decline in lung function in our patients receiving daily bronchodilator treatment was not significantly greater than the decline expected because of aging, but the calculated declines may be underestimates because of selective withdrawal. Future studies should address the question of whether in addition to maintenance therapy with inhaled corticosteroids, use of inhaled bronchodilators daily or on demand is indicated.
The results of this study show improvements not only in the control of clinical disease and lung function with the addition of an inhaled corticosteroid to a β2-agonist, but also in airways hyperresponsiveness, which reflects the underlying inflammatory mechanism in obstructive airways disease.
Supported by a government grant from the Netherlands Health Research Promotion Program (Stimuleringsprogramma Gezondheids Onderzoek).
*Other members of the Dutch Chronic Non-Specific Lung Disease Study Group are listed in the Appendix.
We are indebted to Astra Pharmaceuticals, Boehringer—Ingelheim, and Glaxo for supplying the study medication and inhalers.
Source Information
From the Department of Pulmonology, University Hospital Groningen, Groningen, the Netherlands (H.A.M.K., P.L.P.B., D.S.P., H.J.S.); the Department of Epidemiology and Population Sciences, Medical Statistics Unit, London School of Hygiene and Tropical Medicine, London (M.D.H., N.J.R.); the Department of Pulmonary and Critical Care Medicine, University of Maryland School of Medicine, Baltimore (E.R.B.); the Department of Pulmonology, University Hospital St. Radboud, Nijmegen, the Netherlands (P.N.R.D.); the Department of Pulmonology, University Hospital Leiden, Leiden, the Netherlands (P.M.J.); the Department of Pulmonology, University Hospital Utrecht, Utrecht, the Netherlands (H.J.J.M.); the Department of Pulmonology, University Hospital Dijkzigt, Rotterdam, the Netherlands (S.E.O.); and the Department of Pulmonology, Academic Medical Centre, Amsterdam (D.F.M.E.S.). Address reprint requests to Dr. Postma at the Department of Pulmonary Medicine, University Hospital Groningen, Oostersingel 59, 9713 EZ Groningen, the Netherlands. A copy of the study protocol is also available on request.
Appendix
In addition to the authors, the following investigators and institutions are members of the Dutch Chronic Non-Specific Lung Disease Study Group: Departments of Pulmonology: Academic Medical Centre, Amsterdam (E.M. Pouw, C.M. Roos, and H.M. Jansen); University Hospital Groningen (A. de Gooyer, Th.W. van der Mark, and G.H. Koëter); University Hospital Leiden (P.J. Sterk, A.M.J. Wever, and J.H. Dijkman); University Hospital St. Radboud, Nijmegen (H. Folgering and C.L.A. van Herwaarden); University Hospital Dijkzigt, Rotterdam (J.M. Bogaard and C. Hilvering); and University Hospital Utrecht (S.J. Gans, B. v.d. Bruggen, and J. Kreukniet). Departments of Pediatric Pulmonology: Sophia Children's Hospital, Rotterdam (E.E.M. van Essen-Zandvliet and K.F. Kerrebijn); Juliana Children's Hospital, the Hague (E.J. Duiverman, J.M. Kouwenberg, and J.E. Prinsen); and University Hospital Groningen (H.J. Waalkens, J. Gerritsen, and K. Knol). Department of Allergology: University Hospital Groningen (J.G.R. de Monchy). Department of General Practice: University of Leiden (A.A. Kaptein and F.W. Dekker). Department of Physiology: University of Leiden (P.J.F.M. Merkus and Ph.H. Quanjer). Scientific counsel: Department of Epidemiology and Population Sciences, Medical Statistics Unit, London School of Hygiene and Tropical Medicine, London (S.J. Pocock), and Department of Medicine, Johns Hopkins University School of Medicine, Baltimore (D.A. Meyers).
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