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The use of prednisolone in chronic bronchitis
Brit. 07. Dis. Chest (x963) 57, 133.
THE USE OF PREDNISOLONE IN CHRONIC BRONCHITIS J. V. HVRFORD, G. M. LITTL~ AND H. W. G. LOUDON* King George V Hospital for Diseases of the Chest, Godalming, Surrey
SOME years ago the authors began to use adrenal corticosteroids or corticotrophin occasionally in cases of chronic bronchitis and emphysema in an attempt to relieve bronchospasm which had responded insufficiently to other measures. Though apparent successes were achieved it was felt that perhaps these might be due to steroids being responsible for a sense of increased wellbeing, providing an impetus to undertake greater activity, and that in any case it was important not to continue the use of a potentially dangerous group of drugs without more objective evidence of their Value. To try to obtain this, a small controlled trial with prednisolone was devised. Literature on the use o f " steroids " in chronic bronchitis and emphysema is scanty and conclusions reached not unanimous. Oswald (I957) mentions the use of prednisolone in short courses or even (for " advanced bronchitics who do not respond to other treatment ") for many weeks, more effective where there are fluctuations in degree ofbronchospasm and where there is eosinophifia. Bickerman and Barach (1954) observed remissions in cases of pulmonary emphysema treated with ACTH, cortisone or hydrocortisone, but this series included patients with bronchial asthma and might leave a doubt with regard to the exact differentiation. In a trial with prednisolone, Bickerman, Beck and Barach (1955) studied 5 ° patients with pulmonary emphysema and fibrosis and found " moderate to excellent improvement with relief of dyspnoea and increased exercise tolerance " in 86 per cent. They thought that the change in function probably resulted from reduction in mucosal cedema, inflammatory or allergic, in addition to relief of bronchospasm. Cullen and Reidt (I96O) gave prednisolone to 14 cases of chronic pulmonary emphysema and found that half alleged subjective improvement, unsupported by significant change in lung function tests. Warren and Cameron (x957) also used prednisolone for 41 emphysematous patients with some good effects, but despite reported change in function tests in a few, absence of detail makes the report unconvincing. Moyes and Kershaw (1957) undertook a blind, controlled trial in 86 cases of chronic bronchitics, primarily to assess the value of out-patient treatment with long-term tetracycline but included two groups----one on tetracycline+ prednisolone (15 rag. daily) and another on tetracycline +aminophyline (0. 3 g. daily). The results in these two latter groups were very similar. More recently, Clifton and Stuart-Harris (1962) treated 28 bronchitic patients with corticosteroids (30 rag. prednisolone daily at first, later reduced). * Now at Croydon Chest Clinic.
(Receivedfor publication February 22, 1963)
I34
HURFORD,
LITTLE AND L O U D O N
The F.E.V 0.75 second increased by 20 per cent, or more within a week in two-thirds of the patients and the authors concluded that prednisolone " produced a definite effect upon the ventilatory obstruction which affects about two-thirds of patients with chronic bronchitis ".
METHODS
The study comprised thirty-nine patients suffering from chronic bronchitis of which the accepted definition was " a chronic infection of the bronchi and bronchioles having cough, sputum and breathlessness as its outstanding symptoms " (Oswald 1957). No case involving a suspicion of bronchial asthma was included. Thirty-five patients were over 5 ° years of age and cough had been present for 5 to 40 years*. None suffered from clear-cut bronchiectasis. The schedule of the trial excluded any with a condition on which steroids might have a deleterious effect. Double-blind technique was used, group allocation being made by the hospital pharmacist and the composition of the "prednisolone " given each patient remaining unknown to all in contact with him till the whole trial was completed. Nineteen patients were given prednisolone and twenty d u m m y tablets of similar appearance and taste. In the event, the two groups may have differed in degree of bronchitis or some other factor. Sixteen of the treatment group had an M.B.C. of4o litres a minute or less, compared to 14 of the control group. On admission to hospital, all patients had 4 to 5 days without specific treatment, then a week or more of chemotherapy, usually tetracycline, often an isoprenaline spray and sometimes aminophyUine. The antibiotic used was always continued for the week of the trial and, in addition, the aminophylline and isoprenaline spray if they had been given previously. Tests were done on admission (when response to a i-IOO isoprenaline spray was also estimated) and just before and after the trial. Of all patients, the period before the trial varies from 8-23 days (av. 13½). The trial proper lasted one week, during which each patient had 6 tablets daily (30 mg. in the case ofprednisolone) followed b y " tailing off" over afew days, unless it was decided to give prednisolone for a period (the actual substance given in the trial remaining unknown.)
INVESTIGATIONS
I. Clinical assessment. Exercise on the fiat with subjective and objective assessment o/respiratory distress. Blood eosinophilia before the trial. Average daily amount of sputum from admission. 2. Respiratory function tests. Maximum breathing capacity (M.B.C.) and one-second forced expiratory volume (F.E.V.1). * With the exception of case 39.
THE USE OF PREDNISOLONE IN CHRONIC BRONCHITIS
x35
RESULTS
One observer (H.W.G.L.) carried out the clinical assessment on all patients. As might perhaps have been expected, the standards were too inexact. Some patients claimed to be subjectively better, out of the majority who did not improve on ventilatory tests. Objective clinical assessment produced 12 who were thought to be improved, usually in respect of wheezing and ausculatory signs; of these 2 in fact had improved ventilatory tests. The amount and 'nature of sputum did not as a rule change during the week. However, of the 4 cases whose vendlatory tests improved on prednisolone, 3 did have a slight reduction in sputum (2 cases ½ oz. to trace, i case 1½ oz. to i oz.). Eosinophilia was not consistent with the results. In 4 padents apparently responding to steroids, eosinophils just before the trial were 5, i, 2 and 12 per cent. respectively. O f those not responding, 2 h a d high eosinophils (14, 9 per cent.). The effects on M.B.C. and F.E.V. I are shown in the accompanying table. O f 2o patients given d u m m y tablets only one (case I i) had more than a slight increase in M.B.C. (7 i.) and this was not accompanied by any increase in F.E.V. v O f the 19 who received prednisolone, 4 (cases 34, 36, 38, and 39) showed a significant increase in both M.B.C. and F.E.V. I and none in one test only. (A "significant increase" was arbitrarily defined as one of more than 7 L in M.B.C. or 15o c.c. in F.E.V.1. ) One on predrdsolone (case 23) showed a significant decrease in F.E.V.~ only, 2 on d u m m y tablets (cases 5 and 17) a decrease in both tests, and a further one on d u m m y tablets (case 16) a decrease in F.E.V. I only. • In both groups a n u m b e r of patients responded on admission in one or, usually, both tests to the bronchodilator, but as it happened the 4 cases who reacted to prednisolone responded to a rather slight degree. The following is a brief note on each of the 4 patients who in the trea~ed •group responded to prednisolone.
Case 34. Age 35. Cough and dyspnoea since pneumonia 13 years ago. 1 t o I OZ. mucopurulent sputum. Marked bronchospasm. Apical bullous emphysema. Bronchial diverticula in bronchogram. Max. eosinophilia (of 5 examinations): 5 per cent. (58o per c.mm.). Bronchospasm marked. H a d to continue prednisolone after discharge to keep well. Case 36. Age 58. Cough and sputum I2 years. History of pneumonitis. I to i½ oz. muco-purutent sputum. Max. eosinophilia (2 examinations): I per cent. (129 per c.mm.). Case 38. Age 51. Cough and sputum 20 years. Profuse muco-purulent s p u t u m . Sinusitis. Max. eosinophilia (4 examinations): 3 per cent. (327 per c.mm.). Deteriorated when trim prednisolone stopped and improved again when steroids re-started, an experience repeated over next 2 years. Case 39. Age 34. Sore throat followed by persistent cough and sputum for 7 months. T r . - - I oz. muco-purulent or purulent sputum. Sinus opacity (? allergic). No response to spray. Max. eosinophilia (2 examinations): i'2 per cent. (126o per c.mm.). Remained well on continued prednisolone, but after nearly two years d u m m y tablets seemed to be as beneficial.
136
HURFORD, L I T T L E A N D
LOI/DON
TABLE I
F.E.V.1 ces.
Sex B~r~ trial
Eosinophilia
M.B.C. Litres min.
After Differtrial enee
Initial Increase with bronchodilator
~efore ial
Aft~ tria
Differ-[ ence
I
i
~itia ¢rea. oith rnch ~lato
CONTROLS
48 59 41 56 57 67 52 63 62 54 52 55 62 55 7I 62 62 54 58 56
M M M M M M M M M M M M M M M M F M M M
TR~-AT~.D 2I 53 22 61 23 55 24 65 25 47 26 51 27 55 28 53 29 59 30 59 31 57 32 54 33 57 34 36 35 60 36 58 37 64 38 52 39 34
M M M M M M M M M M M M M M M M M M F
1 2
3 4 5 6 7
8 9
io 11
12 13 14 15 16 . 17 18 I9 20
1,7oo 900 60o 62o 52o 8oo 95 ° 850[
--12o --50
320 13o 380 120 o 3° I6O 7° o
+ 100
0
820 650 1,o7o 950 95 ° 650 620
--5 ° --80 I,IOO [ + IOO 820 0 700 + 5 ° 850 - - 2 2 0 650 - - 4 0 0 900 --5 ° 580 - - 7 ° 55 ° --7 °
5° 1oo 230 200 50 360 I3o 60 o Ioo
8oo I,O00
I,OOO
1,65o 760 580 550 880 750 1,000
970 1,2OO
1,150
65o
75o 1,35o 75 °
1,4oo
830 1,000
940 75o 1,200
75o 850 67o
1,3oo 820 620 1,050
700 900 650 800 1,050 520 1,O80
+ + + +
5° 14o 20 7°
--360 + 5°
--5°
800 650 75 °
0
0
o --290
4oo 70
0
200
--IOO I 300 o I5O 75 ° 820 - - 3 ° o ioo 75 ° --80 1,3o0 o I 250 800 --2o 5° 700 + 80 230 i,ooo - - 5 ° ] i8o 650 [ - - 5 o I5O i,o6o + 16o o 650 o 250 i,i5o +35 ° 280 I,IO0
I,O00
--5 °
1,38o 1,85o
+86o + 77 °
0
7° o
79 34 28 28 33 32 40 52 51 29
58
8o 39 27 3° 21 35 40 48 51 32
65
46 57 35 22 36 35
42 60 35 26 36 29
39
43
29 28
35 37 3o 27 5° 25 36 34 68 38 28 48 32 4° 32 38 37 19 35
28 27
32 37 26 26 5° 27 34 38 65 36 32
48 3I 49 33 45 38 68 83
+ i ' +5 I --1
! +2 +;2 ] o 1--o4 , ] +3 ] +3 [ o + 4
[ o ] --6
I
[ [
I8
o
5
2.0
Io 6 o 7 1i 5
6.0 0. 5 5"o 6.0 0"5 3"5
o
3.0
0
0
2
2"0
7 6 5 3 3 6
0"5 4"5 o'5 o'5 I'O o'5
i
3
2'0
o
0"5 1.o
8
-1
] --3 [ o [ --4 --i : 0 I +2 --2 +4 --3 --2 +4 O
+9 +i +7 +i + 49
+48
0
I'O
8 o 2 9 6 o
9.0 2"5 3"5 2"5 2"5
4
I'O
9 4 lO 8 8
o'5 o 3"0 14"o 2"5
--
5.0
11 5
3"0 1.o
2
2"0
5
2.0
0
I2"O
T H E USE OF PREDNISOLONE IN CHRONIC BRONCHITIS
PREDNISOLONE
I37
SUBSEQUENT TO THE TRIAL
The trial proper consisted of the week on real or d u m m y tablets, but two groups from those who participated in the trial who had prednisolone subsequent to this are of interest. The first is that of I I patients who following treatment with d u m m y tablets had a course of steroids. Two showed significant increases in ventilatory tests as follows: Case 6 (on dummy) F . E . V . I + 5 o c.c.M.B.C.+31. (after 13 days prednisolone) F . E . V . l + 8 3 o c . c . M . B . C . + 3 o 1. F.E.V. 1+ 2 o c . c . M . B . C . - t 1. Case 3 (on dummy) (after 31 days prednisolone) F.E.V. 1 + 9 5 ° c.c.M.B.C. + 3 ° 1. The second group, also i i patients, had prednisolone in the trial without increase in M.B.C. or F.E.V.1, but were continued on the drug beyond the period. Four showed increases as follows: Case Case Case Case
32 24 22 25
(30 (25 (18 (13
days days days days
prednisolone) prednisolone) prednisolone) prednisolone)
F.E.V.I+4oo F.E.V.l+45o F.E.V.I+IOO F.E.V.I+I5O
c.c.M.B.C. +21 1. c . c . M . B . C . + 2 2 1. c . c . M . B . C . + 7 1. c . c . M . B . C . + 8 1.
The existence of this group might indicate that a response to steroids is not always a rapid one. This point was examined in 9 patients (not in this investigation) who responded to prednisolone and had ventilatory tests carried out daily. Six gave significant increase in 2 days, 2 in 7 days, i in 8 days. The maximum response was more delayed (i 7, 12, IO, 8, io, i6 days) in some cases.
Discussion Out of a limited number of chronic bronchitic patients (i 9) given adequate doses of prednisolone for the period of one week, 4 showed an improvement in both ventilatory tests (M.B.C., F.E.V.1) , compared to one out of a control group of 20 who improved on the M.B.C. alone. Only the 4 patients in the treated group fulfilled the arbitrary standard of an increase of 15o c.c.F.E.V. 1 or more plus 7 1. M.B.C. or more, 2 (and perhaps a third) quite definitely. I f we subtract these 4 from the total of treated cases, those who remain appear neither to benefit nor suffer from having had prednisolone. To take the F.E.V. 1 alone, the average for the controls was --37 c.c. and for the treated cases (minus the 4 who showed definite improvement) it was --39 c.c. It would appear, therefore, that in this series 80 per cent. of chronic bronchitics do not respond to a week on prednisolone at a dose of 30 mg. a day. It is difficult to avoid the suspicion that the 20 per cent. (4 patients) who did respond were characterized by something different which would explain their heterogeneity. In the series described by Clifton and Stuart-Harris (I 962), of 23 patients 15 showed increase in the the F.E.V. 0.75 of between 20 and 136 per cent., a week after the start. It is hard to see why our results are so much less favourable than those of Clifton and Stuart Harris. Their patients were all classed as chronic bronchitics
x38
HURFORD, LITTLE AND LOUDON
and " patients with typical spasmodic asthma were excluded." All those in the present series, both treated and controls, had had symptoms of cough and sputum for some time and none was considered a case of spasmodic asthma. O f the 4 who showed improvement, only one (case 39) might perhaps be regarded as doubtful. She was one of the only 2 patients out of both series below the age of4o, had had a very short history compared to all the others (where it is to be measured in years) and had had an eosinophilia. T h a t clinically she had been regarded as a bronchitic with a marked infective element emphasizes the difficulty of making a distinction between chronic bronchitis and bronchitis with asthma. The fact that some patients in the treated group responded to steroids after longer periods than one week is interesting, but though the drug was continued in only I I out of 15 " treated " cases who did not respond in the shorter period, the indication is that the results still are less favourable that those achieved by Clifton and Stuart-Harris. I f there are occasional cases of chronic bronchitis in which endobronchial changes and bronchospasm will be relieved by prednisolone, they are probaly much fewer than would appear if this drug is used without close control with ventilatory tests. There is no doubt that it can temporarily bring a general feeling of well-being which will lead some patients with chronic bronchitis to feel better able to carry on despite virtually unchanged exercise tolerance. But this is certainly not sufficient excuse for continuing the use of steroids. Needless to say, prednisolone ranks as a potentially dangerous drug. In the majority of bronchitics it can be expected to have little action. However, in the occasional case it may have a dramatic effect and it should be tried on intractable cases. It should only be continued if the venfilatory tests give objective evidence of a satisfactory improvement and of course always under antibiotic cover. Finally, it should be remembered that corticosteroids are a steed from which once mounted it is sometimes difficult to descend.
Summary A controlled trial of the effect of prednisolone on chronic bronchitis was carried out on 39 patients, using a double-blind technique. The period of administration of prednisolone or d u m m y tablets was one week and results were assessed mainly using two test of ventilatory function (M.B.C. and F.E.V.a). O f 19 patients in the treatment group, 4 were thought t o show a true response to the drug with increase in M.B.C. of 7 litres or more and an F.E.V. 1 of more than i5o c.c. One patient in the control group gave an increase of 7 1. in M.B.C. only. Outside the trial proper it was found that 2 of i i patients who had been on d u m m y tablets, responded when put on prednisolone, and 4 of I I patients who had not responded to one week of the drug subsequently improved after more prolonged therapy. It is suggested that a small proportion of patients with chronic bronchitis
T H E USE OF P R E D N I S O L O N E IN C H R O N I C BRONCHITIS
I39
a n d e m p h y s e m a w h o have n o t reacted to m o r e conservative t r e a t m e n t will show a response to prednisolone. We wish to thank Miss E. Wenban-Smith and Mr. T. Bennett for technical assistance. REFERENCES BICr~aMAN, H. A., and BARACH,A. L. (x954): 3. Allergy, 25, 4, 3 x2. BICm~aMAN,H. A., BSCK, G. J., and BATCH, A. L. (I955) : ~7. chr. D/s., 2, 3, 247. CUFTON, M., and STUnT-HARRIS,C. H. (x962): Lancet, x, 13x x. CULL~, J. H., and REmT, W. V. (I96o): Amer. resp. D/s., 82, 4, 5°8. MoYss, E. N., and KERSHAW,R. A. (I957): Lancet, ii, I I87. OSWALD,N. G. (1957): Recent Trends in Chronic Bronchitis, 175. WAaR~, J. M., and C~ERON, L. M. (1957): Geriatrics, x2, xx, 653.
THE USE OF PREDNISOLONE IN CHRONIC BRONCHITIS J. V. HVRFORD, G. M. LITTL~ AND H. W. G. LOUDON* King George V Hospital for Diseases of the Chest, Godalming, Surrey
SOME years ago the authors began to use adrenal corticosteroids or corticotrophin occasionally in cases of chronic bronchitis and emphysema in an attempt to relieve bronchospasm which had responded insufficiently to other measures. Though apparent successes were achieved it was felt that perhaps these might be due to steroids being responsible for a sense of increased wellbeing, providing an impetus to undertake greater activity, and that in any case it was important not to continue the use of a potentially dangerous group of drugs without more objective evidence of their Value. To try to obtain this, a small controlled trial with prednisolone was devised. Literature on the use o f " steroids " in chronic bronchitis and emphysema is scanty and conclusions reached not unanimous. Oswald (I957) mentions the use of prednisolone in short courses or even (for " advanced bronchitics who do not respond to other treatment ") for many weeks, more effective where there are fluctuations in degree ofbronchospasm and where there is eosinophifia. Bickerman and Barach (1954) observed remissions in cases of pulmonary emphysema treated with ACTH, cortisone or hydrocortisone, but this series included patients with bronchial asthma and might leave a doubt with regard to the exact differentiation. In a trial with prednisolone, Bickerman, Beck and Barach (1955) studied 5 ° patients with pulmonary emphysema and fibrosis and found " moderate to excellent improvement with relief of dyspnoea and increased exercise tolerance " in 86 per cent. They thought that the change in function probably resulted from reduction in mucosal cedema, inflammatory or allergic, in addition to relief of bronchospasm. Cullen and Reidt (I96O) gave prednisolone to 14 cases of chronic pulmonary emphysema and found that half alleged subjective improvement, unsupported by significant change in lung function tests. Warren and Cameron (x957) also used prednisolone for 41 emphysematous patients with some good effects, but despite reported change in function tests in a few, absence of detail makes the report unconvincing. Moyes and Kershaw (1957) undertook a blind, controlled trial in 86 cases of chronic bronchitics, primarily to assess the value of out-patient treatment with long-term tetracycline but included two groups----one on tetracycline+ prednisolone (15 rag. daily) and another on tetracycline +aminophyline (0. 3 g. daily). The results in these two latter groups were very similar. More recently, Clifton and Stuart-Harris (1962) treated 28 bronchitic patients with corticosteroids (30 rag. prednisolone daily at first, later reduced). * Now at Croydon Chest Clinic.
(Receivedfor publication February 22, 1963)
I34
HURFORD,
LITTLE AND L O U D O N
The F.E.V 0.75 second increased by 20 per cent, or more within a week in two-thirds of the patients and the authors concluded that prednisolone " produced a definite effect upon the ventilatory obstruction which affects about two-thirds of patients with chronic bronchitis ".
METHODS
The study comprised thirty-nine patients suffering from chronic bronchitis of which the accepted definition was " a chronic infection of the bronchi and bronchioles having cough, sputum and breathlessness as its outstanding symptoms " (Oswald 1957). No case involving a suspicion of bronchial asthma was included. Thirty-five patients were over 5 ° years of age and cough had been present for 5 to 40 years*. None suffered from clear-cut bronchiectasis. The schedule of the trial excluded any with a condition on which steroids might have a deleterious effect. Double-blind technique was used, group allocation being made by the hospital pharmacist and the composition of the "prednisolone " given each patient remaining unknown to all in contact with him till the whole trial was completed. Nineteen patients were given prednisolone and twenty d u m m y tablets of similar appearance and taste. In the event, the two groups may have differed in degree of bronchitis or some other factor. Sixteen of the treatment group had an M.B.C. of4o litres a minute or less, compared to 14 of the control group. On admission to hospital, all patients had 4 to 5 days without specific treatment, then a week or more of chemotherapy, usually tetracycline, often an isoprenaline spray and sometimes aminophyUine. The antibiotic used was always continued for the week of the trial and, in addition, the aminophylline and isoprenaline spray if they had been given previously. Tests were done on admission (when response to a i-IOO isoprenaline spray was also estimated) and just before and after the trial. Of all patients, the period before the trial varies from 8-23 days (av. 13½). The trial proper lasted one week, during which each patient had 6 tablets daily (30 mg. in the case ofprednisolone) followed b y " tailing off" over afew days, unless it was decided to give prednisolone for a period (the actual substance given in the trial remaining unknown.)
INVESTIGATIONS
I. Clinical assessment. Exercise on the fiat with subjective and objective assessment o/respiratory distress. Blood eosinophilia before the trial. Average daily amount of sputum from admission. 2. Respiratory function tests. Maximum breathing capacity (M.B.C.) and one-second forced expiratory volume (F.E.V.1). * With the exception of case 39.
THE USE OF PREDNISOLONE IN CHRONIC BRONCHITIS
x35
RESULTS
One observer (H.W.G.L.) carried out the clinical assessment on all patients. As might perhaps have been expected, the standards were too inexact. Some patients claimed to be subjectively better, out of the majority who did not improve on ventilatory tests. Objective clinical assessment produced 12 who were thought to be improved, usually in respect of wheezing and ausculatory signs; of these 2 in fact had improved ventilatory tests. The amount and 'nature of sputum did not as a rule change during the week. However, of the 4 cases whose vendlatory tests improved on prednisolone, 3 did have a slight reduction in sputum (2 cases ½ oz. to trace, i case 1½ oz. to i oz.). Eosinophilia was not consistent with the results. In 4 padents apparently responding to steroids, eosinophils just before the trial were 5, i, 2 and 12 per cent. respectively. O f those not responding, 2 h a d high eosinophils (14, 9 per cent.). The effects on M.B.C. and F.E.V. I are shown in the accompanying table. O f 2o patients given d u m m y tablets only one (case I i) had more than a slight increase in M.B.C. (7 i.) and this was not accompanied by any increase in F.E.V. v O f the 19 who received prednisolone, 4 (cases 34, 36, 38, and 39) showed a significant increase in both M.B.C. and F.E.V. I and none in one test only. (A "significant increase" was arbitrarily defined as one of more than 7 L in M.B.C. or 15o c.c. in F.E.V.1. ) One on predrdsolone (case 23) showed a significant decrease in F.E.V.~ only, 2 on d u m m y tablets (cases 5 and 17) a decrease in both tests, and a further one on d u m m y tablets (case 16) a decrease in F.E.V. I only. • In both groups a n u m b e r of patients responded on admission in one or, usually, both tests to the bronchodilator, but as it happened the 4 cases who reacted to prednisolone responded to a rather slight degree. The following is a brief note on each of the 4 patients who in the trea~ed •group responded to prednisolone.
Case 34. Age 35. Cough and dyspnoea since pneumonia 13 years ago. 1 t o I OZ. mucopurulent sputum. Marked bronchospasm. Apical bullous emphysema. Bronchial diverticula in bronchogram. Max. eosinophilia (of 5 examinations): 5 per cent. (58o per c.mm.). Bronchospasm marked. H a d to continue prednisolone after discharge to keep well. Case 36. Age 58. Cough and sputum I2 years. History of pneumonitis. I to i½ oz. muco-purutent sputum. Max. eosinophilia (2 examinations): I per cent. (129 per c.mm.). Case 38. Age 51. Cough and sputum 20 years. Profuse muco-purulent s p u t u m . Sinusitis. Max. eosinophilia (4 examinations): 3 per cent. (327 per c.mm.). Deteriorated when trim prednisolone stopped and improved again when steroids re-started, an experience repeated over next 2 years. Case 39. Age 34. Sore throat followed by persistent cough and sputum for 7 months. T r . - - I oz. muco-purulent or purulent sputum. Sinus opacity (? allergic). No response to spray. Max. eosinophilia (2 examinations): i'2 per cent. (126o per c.mm.). Remained well on continued prednisolone, but after nearly two years d u m m y tablets seemed to be as beneficial.
136
HURFORD, L I T T L E A N D
LOI/DON
TABLE I
F.E.V.1 ces.
Sex B~r~ trial
Eosinophilia
M.B.C. Litres min.
After Differtrial enee
Initial Increase with bronchodilator
~efore ial
Aft~ tria
Differ-[ ence
I
i
~itia ¢rea. oith rnch ~lato
CONTROLS
48 59 41 56 57 67 52 63 62 54 52 55 62 55 7I 62 62 54 58 56
M M M M M M M M M M M M M M M M F M M M
TR~-AT~.D 2I 53 22 61 23 55 24 65 25 47 26 51 27 55 28 53 29 59 30 59 31 57 32 54 33 57 34 36 35 60 36 58 37 64 38 52 39 34
M M M M M M M M M M M M M M M M M M F
1 2
3 4 5 6 7
8 9
io 11
12 13 14 15 16 . 17 18 I9 20
1,7oo 900 60o 62o 52o 8oo 95 ° 850[
--12o --50
320 13o 380 120 o 3° I6O 7° o
+ 100
0
820 650 1,o7o 950 95 ° 650 620
--5 ° --80 I,IOO [ + IOO 820 0 700 + 5 ° 850 - - 2 2 0 650 - - 4 0 0 900 --5 ° 580 - - 7 ° 55 ° --7 °
5° 1oo 230 200 50 360 I3o 60 o Ioo
8oo I,O00
I,OOO
1,65o 760 580 550 880 750 1,000
970 1,2OO
1,150
65o
75o 1,35o 75 °
1,4oo
830 1,000
940 75o 1,200
75o 850 67o
1,3oo 820 620 1,050
700 900 650 800 1,050 520 1,O80
+ + + +
5° 14o 20 7°
--360 + 5°
--5°
800 650 75 °
0
0
o --290
4oo 70
0
200
--IOO I 300 o I5O 75 ° 820 - - 3 ° o ioo 75 ° --80 1,3o0 o I 250 800 --2o 5° 700 + 80 230 i,ooo - - 5 ° ] i8o 650 [ - - 5 o I5O i,o6o + 16o o 650 o 250 i,i5o +35 ° 280 I,IO0
I,O00
--5 °
1,38o 1,85o
+86o + 77 °
0
7° o
79 34 28 28 33 32 40 52 51 29
58
8o 39 27 3° 21 35 40 48 51 32
65
46 57 35 22 36 35
42 60 35 26 36 29
39
43
29 28
35 37 3o 27 5° 25 36 34 68 38 28 48 32 4° 32 38 37 19 35
28 27
32 37 26 26 5° 27 34 38 65 36 32
48 3I 49 33 45 38 68 83
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T H E USE OF PREDNISOLONE IN CHRONIC BRONCHITIS
PREDNISOLONE
I37
SUBSEQUENT TO THE TRIAL
The trial proper consisted of the week on real or d u m m y tablets, but two groups from those who participated in the trial who had prednisolone subsequent to this are of interest. The first is that of I I patients who following treatment with d u m m y tablets had a course of steroids. Two showed significant increases in ventilatory tests as follows: Case 6 (on dummy) F . E . V . I + 5 o c.c.M.B.C.+31. (after 13 days prednisolone) F . E . V . l + 8 3 o c . c . M . B . C . + 3 o 1. F.E.V. 1+ 2 o c . c . M . B . C . - t 1. Case 3 (on dummy) (after 31 days prednisolone) F.E.V. 1 + 9 5 ° c.c.M.B.C. + 3 ° 1. The second group, also i i patients, had prednisolone in the trial without increase in M.B.C. or F.E.V.1, but were continued on the drug beyond the period. Four showed increases as follows: Case Case Case Case
32 24 22 25
(30 (25 (18 (13
days days days days
prednisolone) prednisolone) prednisolone) prednisolone)
F.E.V.I+4oo F.E.V.l+45o F.E.V.I+IOO F.E.V.I+I5O
c.c.M.B.C. +21 1. c . c . M . B . C . + 2 2 1. c . c . M . B . C . + 7 1. c . c . M . B . C . + 8 1.
The existence of this group might indicate that a response to steroids is not always a rapid one. This point was examined in 9 patients (not in this investigation) who responded to prednisolone and had ventilatory tests carried out daily. Six gave significant increase in 2 days, 2 in 7 days, i in 8 days. The maximum response was more delayed (i 7, 12, IO, 8, io, i6 days) in some cases.
Discussion Out of a limited number of chronic bronchitic patients (i 9) given adequate doses of prednisolone for the period of one week, 4 showed an improvement in both ventilatory tests (M.B.C., F.E.V.1) , compared to one out of a control group of 20 who improved on the M.B.C. alone. Only the 4 patients in the treated group fulfilled the arbitrary standard of an increase of 15o c.c.F.E.V. 1 or more plus 7 1. M.B.C. or more, 2 (and perhaps a third) quite definitely. I f we subtract these 4 from the total of treated cases, those who remain appear neither to benefit nor suffer from having had prednisolone. To take the F.E.V. 1 alone, the average for the controls was --37 c.c. and for the treated cases (minus the 4 who showed definite improvement) it was --39 c.c. It would appear, therefore, that in this series 80 per cent. of chronic bronchitics do not respond to a week on prednisolone at a dose of 30 mg. a day. It is difficult to avoid the suspicion that the 20 per cent. (4 patients) who did respond were characterized by something different which would explain their heterogeneity. In the series described by Clifton and Stuart-Harris (I 962), of 23 patients 15 showed increase in the the F.E.V. 0.75 of between 20 and 136 per cent., a week after the start. It is hard to see why our results are so much less favourable than those of Clifton and Stuart Harris. Their patients were all classed as chronic bronchitics
x38
HURFORD, LITTLE AND LOUDON
and " patients with typical spasmodic asthma were excluded." All those in the present series, both treated and controls, had had symptoms of cough and sputum for some time and none was considered a case of spasmodic asthma. O f the 4 who showed improvement, only one (case 39) might perhaps be regarded as doubtful. She was one of the only 2 patients out of both series below the age of4o, had had a very short history compared to all the others (where it is to be measured in years) and had had an eosinophilia. T h a t clinically she had been regarded as a bronchitic with a marked infective element emphasizes the difficulty of making a distinction between chronic bronchitis and bronchitis with asthma. The fact that some patients in the treated group responded to steroids after longer periods than one week is interesting, but though the drug was continued in only I I out of 15 " treated " cases who did not respond in the shorter period, the indication is that the results still are less favourable that those achieved by Clifton and Stuart-Harris. I f there are occasional cases of chronic bronchitis in which endobronchial changes and bronchospasm will be relieved by prednisolone, they are probaly much fewer than would appear if this drug is used without close control with ventilatory tests. There is no doubt that it can temporarily bring a general feeling of well-being which will lead some patients with chronic bronchitis to feel better able to carry on despite virtually unchanged exercise tolerance. But this is certainly not sufficient excuse for continuing the use of steroids. Needless to say, prednisolone ranks as a potentially dangerous drug. In the majority of bronchitics it can be expected to have little action. However, in the occasional case it may have a dramatic effect and it should be tried on intractable cases. It should only be continued if the venfilatory tests give objective evidence of a satisfactory improvement and of course always under antibiotic cover. Finally, it should be remembered that corticosteroids are a steed from which once mounted it is sometimes difficult to descend.
Summary A controlled trial of the effect of prednisolone on chronic bronchitis was carried out on 39 patients, using a double-blind technique. The period of administration of prednisolone or d u m m y tablets was one week and results were assessed mainly using two test of ventilatory function (M.B.C. and F.E.V.a). O f 19 patients in the treatment group, 4 were thought t o show a true response to the drug with increase in M.B.C. of 7 litres or more and an F.E.V. 1 of more than i5o c.c. One patient in the control group gave an increase of 7 1. in M.B.C. only. Outside the trial proper it was found that 2 of i i patients who had been on d u m m y tablets, responded when put on prednisolone, and 4 of I I patients who had not responded to one week of the drug subsequently improved after more prolonged therapy. It is suggested that a small proportion of patients with chronic bronchitis
T H E USE OF P R E D N I S O L O N E IN C H R O N I C BRONCHITIS
I39
a n d e m p h y s e m a w h o have n o t reacted to m o r e conservative t r e a t m e n t will show a response to prednisolone. We wish to thank Miss E. Wenban-Smith and Mr. T. Bennett for technical assistance. REFERENCES BICr~aMAN, H. A., and BARACH,A. L. (x954): 3. Allergy, 25, 4, 3 x2. BICm~aMAN,H. A., BSCK, G. J., and BATCH, A. L. (I955) : ~7. chr. D/s., 2, 3, 247. CUFTON, M., and STUnT-HARRIS,C. H. (x962): Lancet, x, 13x x. CULL~, J. H., and REmT, W. V. (I96o): Amer. resp. D/s., 82, 4, 5°8. MoYss, E. N., and KERSHAW,R. A. (I957): Lancet, ii, I I87. OSWALD,N. G. (1957): Recent Trends in Chronic Bronchitis, 175. WAaR~, J. M., and C~ERON, L. M. (1957): Geriatrics, x2, xx, 653.