Corticosteroids in Chronic Bronchitis and Pulmonary Emphysema

CRITICAL REVIEW

Corticosteroids in Chronic Bronchitis and Pulmonary Emphysema* Steven A. Sahn, M.D., F.C.C.P. ••

Chronic bronchitis and emphyaema (chronic obstructive pulmonary disease [COPDD represent a major health problem in this country. Corticosteroids have provided an important advance in the management of bronchial asthma, but the role of these drop in the therapy for COPD has not been defined clearly. To gain further in· sight into this problem, an overview of the pharmacologlc properties and mechanisms of action of cortiC011teroids on the cellular systems of the lung and a critical analysis of the 17 studies evaluating the eflicacy of therapy with cor-

S ince

their introduction, corticosteroids have played a major role in improving the therapy for bronchial asthma, t.2 but their efficacy in chroniC bronchitis and emphysema (chronic obstructive pulmonary disease [COPD] ) remains a matter of controversy. If corticosteroids are beneficial in treating allergic obstructive disease of the airways ( bronchial asthma), could these drugs also be efficacious in treating the obstructive airway disease associated with cigarette smoking? PliABMAOOLOGIC PRoPERTIES AND MECHANISM OF ACTION

Steroid hormones, including corticosteroids, apparently share a common pattern of hormonal action, 8 as follows: ( 1) uptake by the target cell and binding to a specific cytoplasmic receptor protein; ( 2) transport of the steroid-receptor complex to the nucleus; ( 3) active binding of the complex to a specific receptor site on the genome; ( 4) transcription, with a resultant new species of RNA and specific messenger RNA molecules; ( 5) replication of messenger RNA to cytoplasmic ribosomes and synthesis of the new protein; and ( 6) a newly synthesized protein responsible for steroid-mediated re0From the Division of Pulmonary Sciences, Department of Medicine, University of Colorado Medical Center, Denver. ••Recipient of Young Pulmonary Investigator research grant 17237 from the National Heart and Lung Institute. Reprint requests: Dr. Sohn, 4200 EaBt Ninth, Denver 80262

CHEST, 73: 3, MARCH, 1978

ticosteroids in COPD were done. There are several theoretic reasons why corticosteroids might be useful in treating COPD; however the majority of studies have not demonstrated a positive effect, yet individual .-dents have attained marked improvement. An objectively monitored, finite trial of therapy with corticosteroids in the tmtient with COPD who has wonenina symptoms Is warranted, a& the benefit Is high in responsive individuals and the risk Is low in nonresponden.

sponse of the target cell of tissue. Thus, the efficacy of therapy with corticosteroids in asthma depends upon the action on the cellular systems in the lung. The target cells are bronchovascular smooth muscles, blood vessels, mucous glands, mast cells, connective tissue, and vagally controlled sensory motor nerves. Corticosteroids exert a facilitating effect on the adrenergic nervous system.4 Alpha-adrenergic stimulation enhances vasoconstriction, while Padrenergic stimulation facilitates relaxation of smooth muscle. 5 The {J-adrenergic receptors are linked closely to the adenyl cyclase in the cellular membrane, a substance which catalyzes the conversion of adenosinetriphosphatase to cyclic AMP. Thus, {J-adrenergic stimulation is associated with increased cellular levels of cyclic AMP. 8 Alphaadrenergic stimulation is associated with a lowering of levels of cyclic AMP in the tissue 7 and with the increased formation of cyclic GMP.8 Corticosteroids may augment the production of cyclic AMP in certain smooth muscles, while in others, production of cyclic GMP is favored. At present, there is active debate as to whether the cyclic nucleotides are the final mediators of the action of corticosteroids. In vivo,. corticosteroids induce a decrease in the activity of phosphodiesterase in various tissues. 9 Reducing cyclic AMP phosphodiesterase could be of clinical relevance by permitting increased accumulation of cyclic AMP.

CORTICOSTEROIDS IN CHRONIC BRONCHITIS AND EMPHYSEMA 389

The leukocytes of asthmatic patients have less of a response of their cyclic AMP to stimulation with catecholamines than do the leukocytes of normal subjects. 8 In asthmatic patients, Coffey et al 10 found that therapy with corticosteroids reduced the activity of adenosinetriphosphatase in the leukocytes, which tended to restore the catecholamineinduced increases in the levels of cyclic AMP. Conversion of norepinephrine to epinephrine in the adrenal medulla depends on the enzyme, phenylethanolamine-N-methyl transferase. Hydrocortisone has been shown to induce synthesis of this enzyme and, therefore, tends to increase the conversion of and to maintain concentrations of epinephrine in the adrenal medulla. 11 Corticosteroids also inhibit catechol-0-methyl transferase, a major enzyme that metabolizes ·catecholamines. 12 If these effects are operative in vivo, higher concentrations of catecholamines might be available at the membranes of effector cells. Asthma can be initiated by type 1 ( lgE-mediated) hypersensitivity, by mixed type 1 and type 3 ( IgE and immune complexes) hypersensitivity, and possibly by type 4 (cell-mediated) hypersensitivity. The effects of administration of corticosteroids on the production of IgE in man are poorly defined, 13 while therapy with high doses of methylprednisolone has been shown, over short periods, to reduce the metabolism of IgE, IgA, and IgM in man. 14 The possibility has been offered that corticosteroids may inhibit some of the chemical mediators of the anaphylactic response, by reducing the stores of the precursors of slow-reacting substance of anaphylaxis 111 and by affecting the metabolism of histamine. 18 Thus, some of the long-term benefits of therapy with corticosteroids may be related to their effect on stores of chemical mediators in the tissue. Corticosteroids have little inhibitory action on the biosynthesis of prostaglandins 17 but may alter the action of prostaglandins at sites in the tissue. Several effects of the prostaglandins are similar to those of corticosteroids. 18 Thus, a functional relationship between the two in the modulation of the tone of the airways yet may be uncovered. The addition of corticosteroids to the armamentarium of drugs for treating asthma has proved invaluable, yet the exact mechanisms of action of corticosteroids remain unknown. Patients with COPD who benefit from therapy with corticosteroids frequently have historic, physical, or laboratory findings similar to asthmatic patients; however, often these findings cannot be elicited, despite the presence of occult reversible obstruction of the airways. 390 STEVEN A SAHN

Morphologic Features in COPD

The most characteristic morphologic feature of chronic bronchitis is enlargement of the tracheobronchial mucous glands. 19 Other morphologic features include the presence of excess mucus within the airways, 20 narrowing of peripheral airways (presumably due to inflammation),20 and an increased frequency of emphysema.21 Goblet cell metaplasia and inflammation of both the central and peripheral airways are poorly documented. 19 Smooth muscle in the airways is increased in some bronchitic patients,22 most likely those with a prominent complaint of bronchospasm. A variety of lesions are found in the small airways of emphysematous lungs. Some are the lesions characteristic of chronic bronchitis ( intraluminal mucus and narrowing of peripheral airways), as bronchitis occurs more commonly in those with emphysema.21 Peripheral mucous plugging appears to be more marked in emphysematous than in nonemphysematous lungs, possibly related to poor mechanisms of clearance and not to hypersecretion of mucus, since the Reid index tends to be low. 20 With the observed abnormalities of the airways, not only in chronic bronchitis but also in emphysema, one can postulate the possible beneficial effects that therapy with corticosteroids might exert on these diseased airways. This effect could be due either to the anti-inflammatory properties or to the synergistic action on the smooth muscle of airways, or both. TRIAL

WITH

CORTIOOSTEROIDS

IN

COPD

Studies Showing a Positive Effect

A number of studies have shown a positive effect of therapy with corticosteroids in COPD (Table 1). In 1951, Lucas23 reported the findings in four patients with pulmonary emphysema who were treated with cortisone ( 100 to 200 mg) or ACTH ( 240 mg) daily. Studies of pulmonary function were performed just prior to and on the fourth and 28th days of treatment. A significant improvement in the maximum breathing capacity and the vital capacity ( VC) occurred in three of the four patients after administration of corticosteroids. In two patients, there was also significant improvement in the distribution of inspired air and the arterial oxygen tension ( Pa02) and a decrease in the arterial carbon dioxide tension ( PaC02). Both patients had a history of intermittent wheezing. The series was small and uncontrolled and consisted of patients with a prominent bronchospastic component. Bickerman and associates 24 described the effects CHEST, 73: 3, MARCH, 1978

Table I-Trial. of Therapy teilh Corticoderoid. S"-iq Poaili11e Raponae in Chronic BroncldlU and Emplayaema Group and Reference (Year)

No. of SubDisjects ease•

Cortico-

st.eroid

Duration Daily of Therapy, Improved Factors•• Dose, mg days

Control Control Group Period

DoubleBlind

Comments

4

E

Cortisone; ACTH

100-200 240

28

MBC; VC; clinical response

Small seriee; history of wheezing

Bickerman et aJIC (1955)

38

E

Prednisone

50-+20

60

VC; MBC;decreased VE; clinical response

Subjective improvement in 86 percent (43/50)

Franklin et aP'

29

E

Prednisone

4(}-+20

7-21

VC; FEV1; clinical response

28

CB

Prednisolone

30-+10

Fuleihan et al"' (1967)

10

CB

Betametbasone

4

Petty et aP8 {1970)

18

LucasU {1951)

(1958)

Clifton and StuartHarrislS

+

Steroids and bronchodilators combined had greatest effect

35-100 (17); FEV'·75 ; clinical response

Long-term improvement in severe disease

21

> 1 yr {11)

(1962)

E;CB Prednisone

*E, Emphysema; and CB, chronic bronchitia.

30-+7.5

30-150

VC; PaOt; venadmixturelike effect

4-mg dOll8 effective;

OUB

I-mg doae ineffective

VC; MVV; PaOt; SaOt; exercise tolerance

Asthmatic onset tends to predict response to steroids

**MBC, Maximum breathing capacity.

of therapy with prednisone in 50 patients with emphysema. Fifty milligrams of prednisone per day was administered for the first 72 hours, followed by 35 gm/ day for the remainder of the week, and then a daily dose of 20 mg. Treatment continued for 60 days. Fifty-eight percent ( 29/ 50) showed marked subjective improvement, with cessation of wheezing, relief of dyspnea, and increased tolerance of exercise. Fourteen patients ( 28 percent) obtained moderate benefit, and seven ( 14 percent) had little or no relief. Fifteen patients had measurements of the maximum breathing capacity and VC before and during therapy with prednisone. The mean increase in the VC was 32 percent and in the maximum breathing capacity was 21 percent. The mean resting minute ventilation (VE) before therapy was 11.3 L/min and dropped to 8.8 L/min during therapy. The study suffers from the lack of a control group and the failure to obtain data on pulmonary function in the entire population. Franklin et al 25 reported on the effect of therapy with bronchodilator drugs and corticosteroids in 58 patients with emphysema. One-half of the group received bronchodilator drugs and corticosteroids. Forty milligrams of prednisone was given daily for two to four days, followed by 10 mg daily for one to three weeks. In those treated with bronchodilator drugs alone, there was a mean increase of 10.2 percent in the VC and of 4.3 percent in the forced expiratory volume in one second ( FEV1) . Therapy with corticosteroids alone increased the mean VC by

CHEST, 73: 3, MARCH, 1978

15.6 percent and the FEV1 by 11.3 percent. Combined therapy with bronchodilator drugs and corticosteroids resulted in a mean increase of 29.2 percent in the VC and of 16.1 percent in the FEV1. Subjective improvement in many patients was often out of proportion to the change in VC or FEV 1. The control group was not well matched, but the data suggest a positive effect of therapy with corticosteroids, especially when combined and bronchodilator drugs. Clifton and Stuart-Harris28 evaluated the effect of therapy with corticosteroids in 28 patients with chronic bronchitis who had symptoms severe enough to prevent regular attendance at work. All were treated with prednisolone ( 30 mg daily), and then therapy was tapered to 5 to 15 mg/day. The shortest period of therapy was five weeks, and the longest was five years. Ten of the 28 patients showed no subjective improvement after treatment, and three had a doubtful clinical response, while the other 15 had a varying degree of improvement (decrease in breathlessness and wheezing). In the majority the improvement became evident a few days after corticosteroids were given; however, there was a minority in whom improvement became apparent only after two to three weeks. In 23 patients the mean forced expiratory volume during the first 0.75 second of the forced vital capacify ( FEVo. 111) was 0.82 L before treatment and rose to 1.12 L ( 36 percent increase) one week after therapy ( P < 0.01). This improvement was maintained for up to

CORTICOSTEROIDS IN CHRONIC BRONCHITIS AND EMPHYSEMA 391

six months. This study showed a decrease in ventilatory obstruction after therapy with corticosteroids in two-thirds of the severely impaired bronchitis patients who were unable to work regularly, but the study was uncontrolled and not double-blind. Fuleihan et al27 studied the effect of therapy with betamethasone in ten patients with chronic bronchitis. Patients were treated with 4 mg of betamethasone daily for three weeks, and then therapy was tapered by 0.5 mg/week to a daily maintenance dose of 1 mg. This dosage was continued for an additional three weeks. After the initial three weeks of treatment, the mean increase in VC was 0.57 L ( P < 0.05). When the daily dosage of betamethasone was decreased to 1 mg/day, the VC was not significantly different from values before treatment. Therapy with betamethasone in dosages of either 4 or 1 mg/ day produced no significant change in FEV1. The higher dosage of betamethasone was associated with a mean increase in Pa~ of 11.3 mm Hg ( P < 0.05) and a decrease of 9.2 percent in the venous admixture ( P < 0.01). Despite the fact that the low dosage of betamethasone was not associated with statistically significant changes in the VC, Pa~, and venous admixture, improvement was maintained; and the lack of statistical significance may have been due to the small number of subjects studied. Petty et al 28 reported the findings in 18 of 182 patients from a COPD rehabilitation clinic (mean FEV1, 0.97 L) who showed an improvement of 30 percent or greater in the maximal voluntary ventilation ( MVV) and other measurements of air How after six months. These patients had been screened previously for evidence .of reversibility, and all had an improvement of less than 30 percent in the FEV1 after inhalation of a bronchodilator drug. The study was not designed to make critical inquiry into the merits of therapy with corticosteroids in patients with COPD but was intended to identify factors in those who showed physiologic improvement. A trial of therapy with corticosteroids was given only to individuals with intractable symptoms (cough and dyspnea) that persisted despite aggressive efforts at bronchial hygiene and bronchodilator therapy. Retrospectively, it was noted that ten of the 18 patients had been treated with corticosteroids at an initial dose of 30 mg of prednisone per day, with subsequent maintenance doses of 5 to 10 mg daily. In a similar group of 21 contemporary patients not demonstrating an increase of 30 percent in the MVV after six months, it was found that only three had received corticosteroids. The 18 improved patients and a history of more attacks of wheezing and a shorter duration of symptoms. and a greater per392 STEVEN A. SAHN

centage had received corticosteroids ( P < 0.05). These 18 patients also showed a significant increase in the VC, Pa02, arterial oxygen saturation (Sa~), and tolerance to walking ( P < 0.05). This study suggests that a history of asthmatic onset of disease and frequent bouts of wheezing predicts responsiveness to therapy with steroids. It is also conceivable that Petty et al 28 did not accurately diagnose those with occult asthma. Studies Showing a Negative Effect Various other studies have shown a negative effect of therapy with corticosteroids in COPD (Table 2). In 1954, Kennedy29 reported on the effects of a regimen of cortisone ( 100 mg/ day for 14 days) on the FEVus, both before and after inhalation of epinephrine in 12 patients with chronic pulmonary disease. Even though eight of the 12 patients reported subjective improvement, no mean change in the FEVo.75 was observed. The effect of inhalation of epinephrine was not enhanced by therapy with corticosteroids. The nine patients with pneumoconiosis in this study make its interpretation difficult. Felix-Davies and Westlake80 performed a controlled trial to evaluate the effectiveness of therapy with ACTH ( corticotrophin) in relieving bronchial obstruction in patients admitted to the hospital with acute exacerbations of chronic bronchitis. Twentyfour patients were alternately placed in a group receiving ACTH or a control group and were treated for ten days. In addition to treatment with antibiotics and all usual measures of therapy, the group receiving steroids received 60 units of ACTH gel daily. Felix-Davies and Westlake80 found no beneficial effects in the clinical response, the results of physiologic testing, or mortality. It is conceivable that a larger dose of circulating adrenocorticoids is required to show an effect and was not provided by adrenal stimulation. Moyes and Kershaw11 conducted a four-month double-blind controlled trial of therapy with prednisolone ( 15 mg/ day) in 90 patients with chronic bronchitis. Twenty-nine patients were randomly allocated to the group receiving corticosteroids and tetracycline, 29 to the group receiving aminophylline and tetracycline, and 32 to the group receiving placebo and aminophylline. Moyes and Kershaw11 evaluted the effect of therapy on dyspnea and bronchospasm by history and physical ex-amination. They concluded that ·therapy with prednisolone ( 15 mg/ day) did not offer any benefit over that derived from tetracycline and aminophylline. This otherwise well-designed study suffers from the sole use of assessment of subjective factors.

CHEST, 73: 3, MARCH, 1978

Table 2-Triab of Therapy with Cordemteroia Siaowi,.. a Ne•adtJe E#eel in Claronie Bronelaitb and Empla:r•ema Group and Reference (Year)

No. of Sub-

Dis-

ject.s

-·

Kennedy" (1954)

12

Felix-Davies and Weatlake111 (1956) Moyes and Kershaw11 (1957)

Corticost.eroid

Duration Daily of Therapy, Improved Dose, mg days Factors••

Control Group

100

14

FEVo.11

24

CB

ACTH

60 units

10

Clinical response; MVV; mortality

+

90

CB

Prednisolone

15

120

Clinical response

+

42

Clinical response; FEV1; ditfusing capacity; VE

CB; E Prednisone

Lorriman• (1959)

7

loo-+20

Ogilvie and Newell11 (1960)

60

CB

Methylpredniaolone

12

Cullen and Reidt" (1960)

14

E

Prednisone

60-->30

7

Beerel et al• (1963)

10

E

Prednisone

60-->30

14

120

"Sick days"

DoubleBlind

ACTH may not have provided adequate st.eroid levels

+

Well-designed, but only subjective 8811e881118nt 2 patients showed appreciable increaae in FEV1

+

+

Absence from work is multifaceted variable 8/ 14 with symptomatic improvement; poor design

Clinical response

+

FEV1

Comments 9 patients with pneumoconiosis

CB; E; Cortisone

p

Control Period

+

2/10 with large increues in FEV1;

single-blind; placebo Freedman• (1963)

26

Morgan and Ruache"I (1964)

7

Pecora et al• (1964)

7E

Klein et aP (1969)

18

CB; E Prednisolone

60-->15

28

FEV1; response to bronchodilators; clinical response

+

CB; E Betamethaaone

3.&-+1.2

28

Clinical response; FEV1;MMEF; FRC;Raw

+

7

Spirometric data; lung volumes; arterial blood gas levels

+

All emphysema; short duration of therapy

14

Clinical response; FEV1

+

6/18 with both subjective and objective improvement

Methyl40 predniaolone (intravenous) CB; E Prednisone

40

4/26 with increase in FEV1 >20 percent

+

Small number of patients; well designed

*CB, Chronic bronchitis; E, emphysema; and P, pneumoconiosis. **MMEF, Muimal midexpiratory Sow; and FRC, functional residual capacity.

Lorriman32 reported on the response of seven patients with COPD to initial doses of prednisone of 30 to 100 mg daily, with tapering to 20 mg/ day or less over six weeks. There was no clinical improvement or significant difference in the mean FEV1, diffusing capacity, or VE after therapy with corticosteroids. The series was small and the mean changes nonsignificant, but two of the seven patients showed an appreciable improvement in FEV1. Ogilvie and Newell83 studied 60 men with a diagnosis of asthmatic bronchitis who were treated with a combined regimen of antibiotics and either methylprednisolone ( 12 mg daily) or placebo during four months in the winter. Twenty-nine patients CHEST, 73: 3, MARCH, 1978

were in the group receiving corticosteroids, and 31 were in the group receiving placebo. The sole criterion of improvement was the number of "sick days," compared with two preceding winters. Fourteen men ( 12 in the group receiving placebo) clain)ed deterioration and had their regimen of treatment changed. The mean number of days absent from work was 14 days for the group receiving corticosteroids and 21 days for the group receiving placebo (not significant). Compared to the two previous winters, neither the group receiving placebo nor the one receiving corticosteroids showed a significant difference in the number of days absent from work. Absence from work encompasses many

CORTICOSTEROIDS IN CHRONIC BRONCHITIS AND EMPHYSEMA 393

variables which may have masked an effect of a drug. Cullen and Reidt34 examined the effect of therapy with prednisone (60 mg daily, tapered to 30 mg daily over a one-week period) in 14 patients with emphysema who had attained maximal improvement while in the hospital. Following a week of therapy with prednisone, eight of the 14 patients noted symptomatic improvement; however, no significant individual or mean change in the results of tests of pulmonary function, including studies of air flow and gas exchange, was noted. This study demonstrates the difficulty in evaluating therapeutic methods in an uncontrolled nonblind fashion. In a double-blind controlled study, Beerel and associates35 evaluated the effect of therapy with prednisone in ten patients with severe emphysema. Beerel et al 311 found that therapy with prednisone (60 mg on the first day, 45 mg on the second day, and 30 mg/ day for 12 days) did not result in a statistically significant increase in the mean FEV1; however, two of the ten patients behaved differently and demonstrated large increases in the FEV1. These two patients had long-standing disease that began with asthmatic symptoms and did not exhibit the characteristic downhill course observed in the other eight. Freedman88 studied the effect of therapy with corticosteroids in 26 patients with chronic bronchitis and emphysema. They received prednisolone ( 60 mg for three days, 45 mg for four days, and 15 mg for 21 days). Four patients showed an increase of greater than 20 percent in .the FEV1 at the end of the study; however, no significant mean increase was noted in the FEV1, either before or after inhaled isoproterenol following corticosteroid therapy. Most of the group had an improved appetite, increased energy, and general well-being after therapy. Morgan and Rusche37 studied seven patients with COPD in a double-blind controlled manner. After a four-week baseline period, subjects were given either a placebo or 3.6 mg of betamethasone for three days and then 1.2 mg of betamethasone daily for the remainder of the four weeks. After six weeks, subjects received the alternate medication for an additional four weeks. There was no significant change in FEV1 and maximum midexpiratory flow, functional residual capacity ( FRC), or airway resistance (Raw) at FRC after four weeks of therapy with corticosteroids. Several of the subjects noted an improvement in appetite and a sense of well-being following treatment with corticosteroids. This welldesigned trial suffers from the small population under study. Pecora et al 38 studied the effects of intravenous 394 STEVEN A. SAHM

therapy with methylprednisone ( 40 mg/ day for one week) in seven patients with emphysema. Baseline tests of pulmonary function and arterial blood gas analyses were obtained after one week of conventional therapy and then were repeated after one week of therapy with corticosteroids. No significant change was observed in spirometric data, lung volumes, or arterial blood gas levels. In a controlled study, Klein and associates2 evaluated 18 patients with "idiopathic" obstructive pulmonary disease. These patients had chronic bronchitis by history and variable degress of emphysema clinically. After baseline studies of pulmonary function, the patients received a seven-day course of therapy with ephedrine and inhaled isoproterenol. Tests of pulmonary function were repeated at the end of this time, and then therapy with 40 mg of prednisone daily was given for an additional two weeks. .Spirometric studies were repeated at the seventh and 14th days. The mean improvement in FEV1after14 days of therapy with prednisone was not significant; however, six of the 18 subjects showed objective improvement. All six responders were subjectively improved after therapy with prednisone, four of five had elevated eosinophilic counts (vs three of nine who did not respond), and three of· six demonstrated a wheal-and-flare cutaneous reaction to some inhalant allergens (vs three of 11 who did not respond). DISCUSSION

Published reports on the effect of therapy with corticosteroids in COPD are conflicting, with some reports showing benefit and others showing lack of efficacy. The majority of the studies were uncontrolled and were not double-blind. Many depended on subjective impressions alone or on simple spirometric measurements, such as the forced expiratory volume. Since the beneficial effect of therapy with corticosteroids in asthma is well-documented, it is imperative to eliminate this group from the population with COPD when evaluating response. This requires careful questioning to exclude patients with a history of atopy and positive wheal-and-flare cutaneous reactions, eosinophilia in the blood or sputum, and a response of greater than 30 percent to bronchodilator drugs. After accurate selection of patients has been established, studies must be performed in a controlled manner. An uncontrolled study evaluating the effect of the drug on obstruction of airways is likely to be unreliable due to the following: ( 1) between-day fluctuation in respiratory mechanics and lung volumes; ( 2) diurnal variability; ( 3) deCHEST, 73: 3, MARCH, 1978

pendence on the effort of the patient (the possibility that therapy with corticosteroids, by increasing the general well-being, tend to increase the cooperation and maximal effort of patients); and ( 4) the possibility that any new form of therapy, whether effective or ineffective, will produce subjective improvement in a substantial proportion of patients. The majority of studies of corticosteroids in COPD have not been double-blind or controlled; and the results, therefore, must be interpreted with caution. It is noteworthy that of the six studies purporting to show a positive effect of therapy with corticosteroids, five were uncontrolled, and the one controlled study was not double-blind. The 11 communications reporting a negative effect, as a group, had better designs for their studies. Only three studies were uncontrolled, while the remaining eight had either a control group or a control period, and two were double-blind. Thus, the available data suggest that therapy with corticosteroids are not objectively helpful in most patients with COPD; however, clinical experience provides numerous examples of responsiveness to corticosteroids. The explanation is either that some patients with COPD are responsive to therapy with corticosteroids or that clinicians fail to diagnose asthma. In either instance, the patient has benefitted whether he was a COPD responder or an occult asthmatic subject. At present, a rational approach to the symptomatic patients with COPD is to attempt to achieve maximum reversibility of the obstruction of the airways, ie: ( 1) initial therapy should be with a preparation of theophylline (in order to achieve levels in the serum of 10 to 20 p.g/ml, with a sympathomimetic amine (either inhaled or oral), and with systematic bronchial hygiene; ( 2) when this "routine" therapy has not produced stabilization or improvement, in certain patients a trial of therapy with corticosteroids may be warranted; ( 3) patients most likely to respond to therapy with corticosteroids will be those with an atopic history and positive wheal and Hare skin reactions, those whose onset of disease was with wheezing, those who have wheezing as a predominant symptom, those with eosinophilia of sputum or blood, and those who show a marked improvement following inhalation of bronchodilator drugs; ( 4) prednisone is administered in a dose of 25 to 30 mg daily for two to four weeks, and if objective improvement is documented, the dosage is tapered to the lowest alternate-day dose that will maintain the level of improvement; and ( 5) objective improvement can be assessed by monitoring simple tests, such as spirometric analysis with and without therapy with bronchodilator drugs, lung volumes, and arterial blood gas levels. Some patients CHEST, 73: 3, MARCH, 1978

state that they feel better without significant changes in spirometric data or gas transfer. It is conceivable that more sophisticated studies, such as the Raw, dynamic compliance, and maximum expiratory How-volume curves would corroborate the clinical response. The complications of therapy with corticosteroids relate more closely to dosage than to duration of therapy. The initial dosage used in patients with COPD is moderately low and is given for a short time. If a trial of therapy with corticosteroids is conducted in a controlled objective manner, the benefit-to-risk ratio should be high. As with any therapeutic method in medicine, the decision for a trial of therapy with corticosteroids should be made on an individual basis, with the data from the literature clearly in mind.

1 Hume KM, Jones ER: Bronchodi1ators and corticosteroids in asthma. Lancet 2:1319-1322, 1960 2 Klein RC, Salvaggio JE, Kundur VG: The response of patients with "idiopathic" obstructive pulmonary disease and "allergic" obstructive bronchitis to prednisone. Ann Intern Med 71:711-718, 1969 3 O'Malley BW: Mechauism of action of steroid hormones. N Engl J Med 284:370-377, 1971 4 Brodie BB, Davis JI, Hynie S, et al: Interrelationships of catecholamines with other endocrine systems. Pharmacol Rev 18:273-289, 1966 5 Townley RG, Reeb R, Fitzgibbons T, et al: The effects of corticosteroids on the tt-adrenergic receptors in bronchial smooth muscle. J Allergy 45:118, 1970 6 Longsdon PJ, Middleton E Jr, Coffey RG: Stimulation of leukocyte adenyl cyclase by hydrocortisone and isopr~ terenol in asthmatic and non-asthmatic subjects. J Allergy Clin Immunol 50:45-56, 1972 7 Turtle JR, Kipnia OM: An adrenergic receptor mechanism for the control of cyclic 3'. 5'-adenosine monophosphate synthesis in tissues. Biochem Biophys Res Commun 28:797-802, 1967 8 Schultz G, Hardman JG: Regulation of cyclic CMP levels in the ductus deferens of the rat. Adv Cyclic Nucleotide Res 5:339-351, 1975 9 Senft G, Schultz G, Munske K, et al: Effect of glucocorticoids and insulin on 3',5'-AMP phosphodiesterase activity in adrenalectomi7.ed rats. Diabetologia 4:330-335, 1968 10 Coffey RG, Hadden JW, Middleton E Jr: Increased adenosine triphosphatase in leukocytes of asthmatic children. J Clin Invest 54:138-146, 1974 11 Wurtman RG, Aselrod J: Control of enzymatic synthesis of adrenalin in the adrenal medulla by adrenal corticol steroids. J Bio Chem 241:2301-2305, 1966 12 Kalsner S: Mechanism of hydrocortisone potentiation of responses to epinephrine and norephinephrine in rabbit aorta. Cir Res 24:383-395, 1969 13 Kumar L, Newcomb RW, lshizaka K, et al: lgE levels in sera of children with asthma. Pediatrics 47:848-856, 1971 14 Butler WT, Rossen RD: Effects of corticosteroids on immunity in man: 1. Deceased serum IgG concentration caused by 3 or 5 days of high doses of methylpredn~ lone. J Clin Invest 52:2629-5640, 1973

CORTICOSTEROIDS IN CHRONIC BRONCHms AND EMPHYSEMA 395

15 Goadby P, Smith WG: Observations on the anti-anaphylactic activity of hydrocortisone and related steroids. J Pharm Pharmacol 16:108-114, 1964 16 Kovacs EM: Changes in tissue histamine content of guinea pigs following treabnent with cortisone and metyrapone. Br J Pharmacol 24:574-578, 1965 17 F1ower R, Gryglewski R, Herbaczynska-Cedra K: Effects of anti-inflammatory drugs on prostaglandin biosynthesis. Nature 238:104-106, 1972 18 Middleton E Jr: Mechanism of action of corticosteroids. In Stein M ( ed): New Directions in Asthma. Park Ridge, Ill, American College of Chest Physicians, 1975, pp 433446

19 Reid L: Measurement of bronchial mucous gland layer: A diagnostic yardstick in chronic bronchitis. Thorax 15: 132141, 1960 20 Matsuba K, Thurlbeck WM: Disease of the small airways in chronic bronchitis. Am Rev Respir Dis 107 :552558, 1973 21 Thurlbeck WM, Angus GE: The relationship between emphysema and chronic bronchitis as assessed morphologically. Am Rev Respir Dis 87:815-819, 1963 22 Hossain S, Heard BE: Hyperplasia of bronchial muscle in chronic bronchitis. J Pathol 101:171-184, 1970 23 Lucas DS: Some effects of adrenocorticotrophic hormone and cortisone on pulmonary function of patients with obstructive emphysema. Am Rev Tuberc 64:279-294, 1951 24 Dickerman HA, Beck GJ, Barach AL: The use of prednisone ( Meticorten) in respiratory disease: 2. Pulmonary emphysema and pulmonary fibrosis. J Chronic Dis 2:247259, 1955 25 Franklin W, Michelson AL, Lowell FC, et al: Bronchodilators and corticosteroids in the treabnent of obstructive pulmonary emphy~ema. N Engl J Med £58:774-778, 1958 26 Clifton M, Stuart-Harris CH: Steroid therapy in chronic bronchitis. Lancet 1:1311-1313, 1962

396 STEVEN A. SAHN

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