A trial of corticotrophin and prednisone with chemotherapy in pulmonary tuberculosis

Tubercle, Lond., (1961), 42, 391

ORIGINAL

ARTICLES

A TRIAL OF CORTICOTROPHIN AND PREDNISONE WITH CHEMOTHERAPY IN PULMONARY TUBERCULOSIS A

REPORT FROM THE RESEARCH COMMITTEE OF THE BRITISH TUBERCULOSIS ASSOCIATION

*

SUMMARY

Three hundred and forty-six patients with acute pulmonary tuberculosis were allocated at random to treatment with chemotherapy alone (streptomycin 1 g., sodium PAS l6g. and isoniazid 300 mg. daily - the Control series, 119 patients), or the same chemotherapy with three months corticotrophin 30 i.u. daily (the AC.T.H. series, III patients) or the same chemotherapy with three months prednisone 30 mg. daily (the Prednisone series, 116 patients). The chemotherapy was prescribed for six months and the patients were treated in bed in hospital during this time; chemotherapy was continued without hormones in all three series, and observations were made for a further six months. For patients allocated to the A.C.T.H. series, the purified preparation 'Cortrophin ZN' was at first used; subsequently a cruder preparation 'Cortrophin Z' (not now available) was prescribed. The efficacies of the two products were similar, but 'CortrophinZ' produced considerably more side-effects than 'Cortrophin ZN'. It is possible that the dosage of the corticotrophin used was too low in some patients, but it would be necessary to adjust the dosage for each patient's adreno-corticol activity in order to avoid undesirable side-effects. In the A.C.T.H. and Prednisone series there was rapid improvement in clinical condition in the first three months, as observed by the clinician and as shown by the increase in weight, and falls in the erythrocyte sedimentation rate and average temperature; the improvement was maintained after stopping the hormones. The progress of the Control patients was slower but by twelve months the improvement was similar to that of the two hormone series. The A.C.T.H. and Prednisone series had significantlyless residual radiographic shadowing at three months, and the Prednisone series at six and twelve months, than the Control series. Transient radiographic deterioration between three and four months was observed in 47 patients (5 Control, 12 A.C.T.H. and 30 Prednisone). Clinical 'rebound' phenomena occurred in 6 A.C.T.H. and 34 Prednisone patients. There was little difference between the three series in terms of cavitation changes and sputum conversion at any time. Almost all the patients in the three series had negative cultures at six months, and all but 1 Control patient at nine and 1 at twelve months. Severe hypersensitive reactions to streptomycin, PAS or isoniazid, streptomycin toxicity or PAS intolerance, which necessitated a change of the chemotherapy, occurred in 31

* The following took

part in the investigation; Corticosteroids with Chemotherapy Sub-committee: Dr. L. E. Houghton (Chairman), Dr. P. E. BaJdry (Secretary), Drs. R. 1. Bayliss, J. V. Hurford, S. W. A. Kuper, A. Lehane, G. P. Maher-Loughnan, E. Nassau, J. G. Scadding, W. E. Snell and Ian Sutherland, and Miss B. J. Kinsley. The investigation was co-ordinated by Dr. Lehane from Harefield Hospital, Middlesex.; the report was prepared by Dr. Lehane and Miss Kinsley (of the Statistical Research Unit of the Medical Research Council). The report should be referred to as; British Tuberculosis Association (1961), Tubercle, Lond., 42, 413. Reprints may be obtained from the Hon. Secretary of the Research Committee, British Tuberculosis Association, 59 Portland Place, London, W.1. B

392

TUBERCLE

patients (16 Control, 7 AC.T.R. and 9 Prednisone); in 13 of these (8 Control, 3 A.C.T.H. and 2 Prednisone) the reactions occurred during the first three months. A further 7 patients (5 Control and 2 A.C.T.H.) had prednisone added to their chemotherapy because of lack of progress. In 22 patients (15 AC.T.H. and 7 Prednisone) side-effects caused the hormone therapy to be changed or stopped before the end of the prescribed three months. Of these, 6 AC.T.H. patients (given 'Cortrophin Z') developed psychotic manifestations but all recovered on stopping the hormone. A further 18 patients (9 A.C.T.H. and 9 Prednisone) had transient reactions but only a brief interruption of the hormone. It is concluded that prednisone has a place, with chemotherapy, in the treatment of selected cases of acute, extensive pulmonary tuberculosis, but that corticotrophin, in the dosage used in the present trial, was less effective.

This investigation was co-ordinated for the Research Committee by Dr. A. Lehane, who, with Miss B. J. Kinsley, prepared the report. Early reports of the use of cortisone in experimental tuberculosis in animals showed deleterious effects (Hart and Rees, 1950); in man the use of cortisone, without additional anti-tuberculous chemotherapy, resulted in the spread or reactivation of disease (Freeman and others, 1950; Des Autels and others, 1956). However, a combination of corticotrophin, or cortisone, with antituberculous chemotherapy has been reported as being of therapeutic benefit, particularly in critically ill patients (Houghton, 1951, 1954; Favez, 1954; Even and SOl'S, 1954). There were two early controlled studies of the use of these hormones. In Lisbon, Alemquer (1955) gave cortisone (a total of 2100 mg. in fifteen days) with chemotherapy to patients dying of tuberculosis. He found that the immediate mortality was significantly lower and the clinical improvement in the survivors was both greater and more rapid in the patients treated with cortisone, than in those given chemotherapy alone. In 1956, the Tuberculosis Society of Scotland (1957) studied the use of prednisolone, in a daily dosage of 20 mg. for three months with chemotherapy. They found that clinical improvement was more rapid in those treated with prednisolone than in the series given chemotherapy alone, especially among the more acutely ill patients, and that radiographic improvement was significantly more rapid in the six-month observation period in tills group. All the patients receiving prednisolone improved, although temporary radiographic deterioration was observed in a sixth of the patients on stopping the prednisolone; no serious side-effects were recorded. Because of these encouraging results, the British Tuberculosis Association, with support from the Medical Research Council, undertook an investigation, in 1957, to assess the value in pulmonary tuberculosis of corticotrophin and of prednisone, each with chemotherapy. The results of this study are presented here. Organisation and Conduct of the Trial Chest physicians from 140 hospitals and chest clinics throughout England and Wales co-operated in the study. Three similar series of patients were treated concurrently in bed in hospital for six months, and either in hospital or as out-patients for a further six months, one series with chemotherapy alone (the 'Control' series), another with chemotherapy and three months of corticotrophin (the 'A.C.T.H.' series) and the third with chemotherapy and three months of prednisone (the 'Prednisone' series). The first patient was submitted on September 27th, 1957 and the last on July 27th, 1959.

STEROIDS IN PULMONARY TUBERCULOSIS

393

Selection of Patients All patients in the trial were: (a) aged between 15 and 60 years inclusive, (b) with acute pulmonary tuberculosis, newly diagnosed and believed to be of recent origin, (c) with or without serious constitutional symptoms, (d) with more than one lung zone involved, (e) previously untreated, (or treated for not more than three weeks) and (f) with tubercle bacilli in the sputum. Patients with extensive pulmonary tuberculosis who had received chemotherapy for six months or more without satisfactory results were at first accepted; as only 5 such patients were submitted in the first twelve months this category was discontinued, and these patients are not further considered. The following patients were ineligible: those with empyema or spontaneous pneumothorax; with gross active tuberculosis outside the thorax or with evidence of other bacterial infection; with diabetes; with cardiovascular disease, including considerable hypertension; with a history of radiographically confirmed peptic ulcer; with Addison's disease; with a history of mental disorder; and pregnant women. Before admission to the trial, the chest radiographs together with a brief medical history of each patient were examined for their suitability for the trial by at least two of the following: Dr. L. E. Houghton, Dr. G. P. Maher-Loughnan, Dr. D. R. McPherson and Dr. W. E. Snell. After acceptance, the treatment for each patient was allocated by reference to pre-arranged lists based on random sampling numbers, and held confidentially by a medical secretary at the co-ordinating centre. Number ofpatients Four hundred and eight patients were accepted for the trial; 133 were allocated to the Control series, 138 to the A.C.T.H. and 137 to the Prednisone series. In all, 62 patients were excluded from the analysis. Twenty-five of them were excluded before chemotherapy was started (6 Control, 11 A.C.T.H. and 8 Prednisone): 5 died from their tuberculosis (3 Control, 1 A.C.T.H. and 1 Prednisone); 3 were discovered to have had previous chemotherapy for more than three weeks (l Control and 2 A.C.T.H.); 1 Control patient had renal tuberculosis and 1 was pregnant; 8 AC.T.H. patients had disease other than pulmonary tuberculosis (l miliary tuberculosis, 1 spontaneous pneumothorax, 3 duodenal ulcers, 1 subarachnoid haemorrhage, 1 hiatus hernia and 1 history of mental instability); of the remaining 7 Prednisone patients excluded, 1 had cancer of the lung in addition to tuberculosis, 1 had unexplained occult blood in the stools, 1 had hypertension, 2 discharged themselves and 2 were admitted to a hospital not participating in the trial. Thirty-seven patients were excluded after the start of chemotherapy (8 Control, 16 AC.T.H. and 13 Prednisone): 13 failed to provide a positive sputum before the start of chemotherapy (3 Control, 5 ACT.R. and 5 Prednisone); 11 had cultures resistant initially to streptomycin, PAS or isoniazid (4 Control, 4 AC.T.H. and 3 Prednisone); 4 were not treated according to allocation (3 A.C.T.H. and 1 Prednisone) and 9 discharged themselves within the firstthree months (1 Control, 4 A.C.T.H. and 4 Prednisone). After these 62 exclusions there remained 346 patients for analysis (119 Control, 111 ACT.H. and 116 Prednisone); this included 21 patients who had received chemotherapy previously, but for less than three weeks. Investigations before the start of treatment All patients were investigated in hospital before the start of chemotherapy and hormone therapy. The investigations consisted of a full-size postero-anterior chest radiograph with tomographs, a

394

TUllERCLE

physical examination, recording weight, daily evening temperature for one week, volume and bacterial content of sputum, ESR (Westergren), blood pressure, urine examination for sugar and Mantoux tuberculin test (with either 1 or 10 TV). Observations during treatment Regular observations, with special emphasis on signs and symptoms of drug toxicity or hormone side-effects, were made during the course of the trial; for this, the blood pressure was taken and urine examinations for sugar were made weekly. Other examinations, as before the start of treatment, were made at monthly intervals during the first six months and thereafter at nine and twelve months. Tomographs were taken again only at six months. Collapse therapy or surgery was not undertaken until a patient had received chemotherapy for at least six months. Chemotherapy and hormone therapy The patients in all three series received streptomycin 1 g. daily in a single dose, sodium PAS 16 g. daily in three or four divided doses, and isoniazid 300 mg. daily in two equal doses, for the first six months. (During the first three months of the trial, between September and November 1957, no PAS was given; only a very few patients did not receive PAS subsequently.) For the first three months the patients in the A.C.T.H. series received in addition to the chemotherapy: A.C.T.H. 60 i.u. for 4 days } A.C.T.H. 40 i.u. for 4 days daily in two equal doses. A.C.T.H. 30 i.u, for 10 weeks A.C.T.H. 20 i.u. for 7 days A.C.T.H. 10 i.u. for 7 days

}

daily as a single dose.

For the first three months the patients in the Prednisone series received in addition to the chemotherapy: given in five equal doses during Prednisone 50 mg. for 4 days Prednisone 37· 5 mg. for 4 days the day i.e. four hourly Prednisone 30 mg. for 10 weeks excluding the night dose.

}

A.C.T.H. 20 i.u. daily as a single dose for 7 days plus daily reduction of prednisone to 20, 15, 10, 5 and 0 mg. A.C.T.H. 10 i.u. daily as a single dose for 7 days. Patients in the two hormone series also received potassium chloride 3 g. daily with food throughout the course of the hormone treatment. During the second six months, chemotherapy (without hormones) was continued for all patients, according to the choice of each hospital or clinic. The majority (approximately 90 %) received a combination of PAS and isoniazid during this period; approximately 10 % of these also continued the streptomycin for a further three months. The remaining patients received streptomycin with either PAS or isoniazid; a very few had cycloserine or viomycin in addition. Departure from prescribed hormone therapy Because it was recognised that hormones may cause severe side-effects, the circumstances in which the treatment might be altered, or the hormones stopped completely, were defined in the protocol of the trial as follows: considerable rise in blood pressure, enlargement of the heart, glycosuria with abnormal glucose tolerance curves, mental instability, peptic ulcer or hypersensitivity to the hormones. The A.C.T.H. preparation used in the trial For patients allocated to the A.C.T.H. series, it was arranged that a single batch of the purified preparation, known as A.C.T.H. 'Cortrophin ZN,' should be used. The trial had been in progress for about nine months when doubts arose about the potency of this purified product, because side-

395

STEROIDS TN PULMONARY TUBERCULOSIS TABLE

I.-AGE

AND SEX DISTRIBUTION OF THE PATIENTS (AFTER EXCLUSION) .~_._

-

..

-_.

__

.~,

Treatment series Age (years)

Control

A.C.T.H.-ZN &Z

Male

Female

Total

15 -24 25 -34 35 -44 45-54 55 or more

19 19 14 16 15

15 12 2 6 1

All ages

83

36

---

Prednisone

Male

Female

Tatal

Male

Female

Total

34 31 16 22 16

21 11 18 9 4

20 16 8 4 0

41 27 26 13 4

18 14 17 19

19 10 10

5

0

37 24 27 23 5

119

63

48

III

73

43

116

4-

effects encountered from previous use with another preparation of A.CT.H. had not been observed. As a result, urinary 17-ketosteroid and 17-hydroxycorticosteroid estimations were made on a group of subjects not in the trial; these showed that the purified preparation, 'Cortrophin ZN,' produced a smaller increase in adreno-corticol activity, as judged by urinary corticoid excretion, than the earlier cruder preparation, known as A.C.T.H. 'Cortrophin Z' and no longer generally available. It was, therefore, decided to prescribe A.C.T.H. 'Cortrophin Z,' in the same dosage, for patients subsequently admitted to the trial, and allocated to the A.C.T.H. series. Analyses of the progress of the three series admitted to the trial, when A.CT.H. 'Cortrophin ZN' or 'Cortrophin Z' were used, were made separately. In comparison with the progress of the Control and Prednisone patients admitted concurrently, that of the A.C.T.H. patients was similar, whether given 'Cortrophin ZN' or' Z', except for side-effects; for ease of presentation, therefore, the results have been amalgamated. However, a short comparison between the patients admitted when 'Cortrophin ZN' and 'Z' were in use is made in a separate section below.

Condition of Patients Before Treatment The distribution of the patients in the three series by age and sex is shown in Table I. There were more males than females in all three series. The A.C.T.H. series had fewer patients aged 45 years or more than either of the other two series, namely 17 (15 'Yo) compared with 38 (32 'Yo) Control and 28 (24 'Yo) Prednisone patients. The extent of tuberculous lesions and of cavitation were estimated from a single chest radiograph with tomographs by an independent assessor (H.E.S.), who was unaware of the treatment allocated to each patient. The assessor adopted the following criteria in making the assessments, allowing for density of lesions in those cases without apparent cavity, even if all the lung zones were affected. For mottling: (all patients had more than one lung zone involved)

Extent of lesions

I No. of lung

Estimated total cavity volume

zones involved

Moderate

2-4 5

up to 50 cern. without cavity

Extensive

2-4 5 6

more than 50 ccm., up to 150 cern. up to 50 cern. without cavity

Very Extensive

2-4

more than 150 cern. more than 50 cern. with any cavity

5 6

396

TUBERCLE

For cavitation: Extent of cavitation

Estimated total cavity volume

up to 50 cern. more than 50 cern., up to 150 cern. more than 150 cern.

Slight Moderate Extensive

The clinical condition, bacteriological and radiographic state of the patients before the start of treatment is summarised in Table II. The three series were reasonably similar in all respects. As judged radiographically, 63 (53 %) Control, 55 (50 %) A.C.T.H. and 60 (52 %) Prednisone patients had very extensive lesions initially; 38 (32 %) Control, 29 (26 %) A.C.T.H. and 32 (28 %) Prednisone patients had extensive cavitation (that is, more than 150 ccm, in total volume). Few patients in each series had an ESR of 101 mm. or more but 51 (43%) Control, 51 (46%) A.C.T.H. and 53 (46%) Prednisone patients had an ESR of 51 mm. or more.

Patients Not Completing Treatment DEATHS

In the Control series 1 death occurred at three months from aplastic anaemia attributed to streptomycin, toxicity. There was 1 death in the A.C.T.H. series (given 'Cortrophin Z') at one month due to pulmonary tuberculosis. Of the 2 "deaths in the Prednisone series, 1 occurred at three TABLE n.-CONDITION ON ADMISSION -..

-

~.-----.---.-.~.~

Treatment series

Control

A.C.T.H.

Prednisone

Total patients

119

111

116

Clinical condition

Good Fair Poor

19 52 40

14 74 31

28 58 30

I

Treatment series

Control

I

Total patients

119

ESR (mm. in 1 hr. Westergren 200mm.)

Moderate Extensive Very extensive Not available

* Assessment

---

A.C.T.H. PrednlsotIe JlI

116

1 -10 11 -20 21 - 50 51 -100 101 or more

8 15 45 47 4

11

6 14 42 45 8 1

6 43 44 7 0

0

Sputum volume I

23

30 25 63 1

33

55 0

1

26 30 60 0

Cavitation"

Nil Slight Moderate Extensive Not available

_

.. , .._ .. ....,,-

I

Not available Radiographic extent of lesions"

_._--

..

2 49 29 38 1

I

5 38 39 29 0

5 56 35

Nil Scanty Moderate Copious Not assessed

21

2

Culture examination 0

40 44 32 0

Negative'[

Positive Not available'[

I

11 39 36 23 2

[ I

j

5 113 I

t

9 102

I

I ---

0

1

I

I I

I I

i

13 46 37 19 1

4 111

\

1

,I

--".~-

on a single full-size chest radiograph and tornographs taken before the start of treatment.

t Positive on direct examination.

STEROIDS IN PULMONARY TUBERCULOSIS

397

and a half months from pulmonary tuberculosis and bronchiectasis (three weeks after stopping hormones) and 1 at eleven months from a cerebral thrombosis. CHANGES OF CHEMOTHERAPY AND HORMONE THERAPY

Chemotherapy or hormone therapy was changed or stopped in the twelve-month period in 60 patients (20 Control, 24 AC.T.H. and 16 Prednisone). Their progress has been included in the tables for as long as they continued with the prescribed chemotherapy and hormone therapy. In 22 of these patients (15 A.C.T.H. and 7 Prednisone), the changes were made because of side-effects caused by the hormones in the first three months; the details of these changes, as well as all other reactions to the hormones, are given in a separate section later (page 406). In the remaining 38 patients (20 Control, 9 A.C.T.R. and 9 Prednisone), the changes were made because of reactions to streptomycin, PAS or isoniazid, or because oflack of progress, and were as follows: (a) Due to hypersensitivity Sixteen patients changed chemotherapy because of hypersensitive reactions (9 Control, 2 AC.T.H.-both given 'Cortrophin ZN'-and 5 Prednisone). In the Control series, during the first six months, 3 patients developed reactions to streptomycin, all at three months (2 were also intolerant to PAS-l developed a duodenal ulcer in addition); 2 became hypersensitive to PAS (1 at two weeks and 1 at three weeks), 2 to both streptomycin and PAS at three months (1 had hepatitis) and 1 to all three drugs at one month. One A.C.T.H. patient developed hypersensitive reactions to both streptomycin and PAS at one month and 1 to all three drugs at six weeks. In the Prednisone series 2 patients became hypersensitive to streptomycin (1 at one month and 1 at three months) and 2 to both streptomycin and PAS (1 at one month and 1 at three months). In all but 1 case the drug to which a patient was hypersensitive was stopped; in this patient (Control) the dose of streptomycin was reduced. At six months, 2 patients (I Control and 1 Prednisone) became hypersensitive to streptomycin (the latter also to PAS); hormones were given during desensitisation, prednisone to the Control uatient for two and a half months and A.C.T.H. to the Prednisone patient for one month. (b) Due to streptomycin toxicity Twelve patients changed chemotherapy because of dizziness caused by the streptomycin: 5 Control patients between one and four weeks and 1 other at four months, 4 A.C.T.H. (all given 'Cortrophin Z') and 2 Prednisone patients all at three months. (c) Due to PAS intolerance Three patients changed chemotherapy because of gastro-intestinal intolerance of PAS, 1 A.C.T.H. patient (given 'Cortrophin Z') at two months and 2 Prednisone patients at three months. In addition to the above reactions, which necessitated a change of chemotherapy, other minor hypersensitive or toxic reactions to streptomycin, PAS or isoniazid occurred in the first six months in a number of patients who nevertheless continued, with only temporary departures from, the prescribed chemotherapy. The progress of these patients has been included in the tables. (d) Due to lack of progress Seven patients were considered by their clinician not to have made satisfactory progress and prednisone was added to their chemotherapy: in 2 Control patients at two months and in 3 more at six months, and in 2 A.C.T.H. patients (given 'Cortrophin ZN') both at six months. In 2 of the Control patients the clinician considered them still to have 'active' disease at twelve months; the other five patients made satisfactory progress. After the prescribed three-month period, no patient in the Prednisone series had any additional hormones because of lack of progress. Diseases Other Than Tuberculosis Fourteen patients (6 Control, 3 AC.T.R. and 5 Prednisone) developed diseases other than tuberculosis during the course of the trial; in the Control series, 1 patient developed herpes zoster at one

398

TUBERCLE TABLE IlL-SURGERY AND COLLAPSE THERAPY DURING THE SECOND SIX MONTHS

Treatment series Type of operations undertaken

Pneumonectomy Lobectomy Segmental resection Thoracoplasty Pneumoperitoneum Artificial pneumothorax Total

Control

A.C.T.H.

Prednisone

0

0

1 6 4 I 3 0

13

15

13

1 8

2 1 I

5 3 1 3 1

month, 2 (including 1 who was hypersensitive to streptomycin and intolerant to PAS-described above) developed duodenal ulcers at two months, I developed mild diabetes at two months, I had an epileptic fit at three months, and I anaemia at five months. In the A.c.T.H. series, I patient developed diabetes at two months, 1 had acute cholecystitis at four months and I pernicious anaemia at eight months; in the Prednisone series, I patient developed a superficial thrombophlebitis at one month, I a urinary infection at two months, I a spontaneous pneumothorax at three months, I a duodenal ulcer at six months and 1 had an acute paranoid schizophrenic episode at nine months. The progress of all these patients (except of the I Control who developed reactions to streptomycin and PAS) has been included in all the assessments. Further Treatment SURGERY AND COLLAPSE THERAPY (Table III) No collapse therapy or surgery was undertaken unless a patient had received chemotherapy for at least six months. The numbers of patients who received the additional forms of treatment were very similar in the three series: 13 Control, 15 A.C.T.H. (11 of whom had received 'Cortrophin ZN' and 4 'Cortrophin Z') and 13 Prednisone patients. The type of treatment is summarised in Table JI1 and the progress of these patients has been included in all assessments. Because of the risk of adrenal insufficiency during and after surgical intervention in patients who have had hormone therapy (Salassa and others, 1953; Slaney & Brooke, 1957; Bayliss, 1958), all participating physicians were notified of these publications. They were advised to give hormone cover to any patient in the A.C.T.H. or Prednisone series in whom surgery was undertaken; the regimen suggested was that used by Slaney & Brooke (1957). Of the 21 patients in the two hormone series, in whom surgery was undertaken, 16 (9 A.CT.H. and 7 Prednisone) received additional hormone therapy during the pre- and post-operative period; it was not given in the remaining 5 patients and no complications were reported. RESULTS Progress During Treatment CLINICAL PROGRESS (Table IV) The clinician in charge of the patient assessed the clinical progress made during the first six months in terms of considerable, moderate or slight improvement, no change or deterioration. Throughout each period for which the assessments were made the Prednisone series showed the greatest improvement, and the Control series the least. In the first month 15 (13 %) Control patients made considerable clinical improvement compared with 28 (28 %) A.C.T.H. and 50 (43 %) Prednisone patients. During this period 2 Control patients had slightly deteriorated; there was no other deterioration in the six-month period. In the first three

399

STEROIDS IN PULMONARY TUBERCULOSIS TABLE IV.-CLINICAL PROGRESS IN THE SIX-MONTH PERIOD (AS ASSESSED BY THE CLINICIAN IN CHARGE OF THE PATIENT)

Improvement Period of observation

Treatment series

Total patients

No change

Considerable No. %

Moderate

Slight

Slight

deterioratlon

0-1 month

Control A.C.T.H. Prednisone

114 99 116

15 28 50

/3 28 43

83 68 63

2 0 0

12 3 3

2 0 0

0- 3 months

Control A.C.T,H. Prednisone

107 92 108

39 50 64

36 54 59

63 41 43

0 0 0

5 I 1

0 0 0

0- 6 months

Control A.C.T.H. Prednisone

95 86

49 53 71

52 62 72

44 32 27

1 0 0

1 I 0

0 0 0

98

months, the period of hormone therapy for the two series concerned, the corresponding figures for patients showing considerable improvement were 39 (36 %), 50 (54 %) and 64 (59 %). The Prednisone series also maintained the greatest progress by six months; thus 49 (52 %) Control, 53 (62 %) A.C.T.H. and 71 (72%) Prednisone patients showed considerable improvement. (Fig. 1) closely similar in all three series, between 90% and 95 % having a sedimentation rate of 11 mm. or more. The figure shows a steady improvement CHANGES IN ERYTHROCYTE SEDIMENTATION RATES The initial ESR (Westergren) estimations were

100

80

CONTROL

~ \.

~

~

'-

0

~ 60 0ex: vj

\\\

.\

." \

\

\.

\

\\

........../

\ .~.CT,H, ...,...... ,/ \ '-'-'./

./::>~

"

''"'\ .

\ "'\

-s 40 § v .Ec

e-

~

o,

\\

\ ........

:'....

\

-----._--.

....... ,

....

\\ .

\PREDNISq~E

"

o

"

..............

\

20

'" :::--

.

\

l.U

" , ,..

2

---.--.

""--.....""-..

-.

.

3

4

5

-'-'-"--'--

,- - - - - --

q

Months after start of treatment

Fig.l Changes in erythrocyte sedimentation rates in the twelve-month period. (The estimates at 3 months 101' the tll'O hormone series are /101 reliable-see text)

12

400

TUBERCLE

in the Control series throughout the twelve-month period. In the two hormone series, however, there was a well-marked reduction of the ESR in the first month; 49 (49 %) A.C.T.H. and 21 (18 %) Prednisone patients had a sedimentation rate of 11 mm. or more, as compared with 89 (78 %) Control patients. At the end of three months, when the hormones were stopped, there was a slight rise from the one-month level in the A.C.T.H. series, 51 (55 %) having a level of 11 mm. or more, but the Prednisone series showed a more marked increase from one month, to 52 (50 %); the Control series still had the greatest proportion 74 (70 %) with a level of 11 mm. or more. (The estimations at three months were not made at exactly the same time for all the patients in the two hormone series; some were made a few days before and some after stopping the hormones. The estimations at this time for the two hormone series are therefore not entirely reliable.) By six months the proportion with II mm. or more were similar in all three series, namely 41 (44 %) Control, 33 (38 %) A.C.T.H. and 33 (35 %) Prednisone patients. At twelve months the corresponding proportions were 20 (30%) Control, 14 (25%) A.C.T.H. and 14 (20%) Prednisone patients; the last series had thus made the greatest improvement by this time. 100

~E 80

o

u...

:>

cr cr

0' 60 f! .2

\ '\,.

~ II)

0..

E

\'

.2!

1J., 40

~ II)

\~\ .ACT.H.

>

o -£

\

II)

E ~

...../.....

\\--.•.... .. .

.~

20

'

\

s:

:/

./:...

\_--

:

-,

.

~ ~

PREDNisONE

a

2

3

4

5

Monrhs after starr of treotrnenr

Fig. 2 Changes in average evening temperature in the first six months. (The estimates at 3 months for the two hormone series are not reliable-see text)

(Fig. 2) The evening temperature was taken for one week prior to each assessment during the first six months. The initial average temperatures were similar in all three series, between 65 % and 69 % having an average of 990 F. or more. At one month all the series showed an improvement, but the Prednisone series had the most reduction in temperature; 52 (46 %) Control, 23 (23 %) A.C.T.H. and 17 (15 %) Prednisone patients had an average of 99° F. or more. At three months, the Control and A.C.T.H. series continued to improve, 24 (23 %) and 12 (13 %) having an average of 990 F. or CHANGES IN AVERAGE EVENING TEMPERATURE

401

STEROIDS IN PULMONARY TUBERCULOSIS TABLE Y.-RESULTS OF (MANTOUX) TUBERCULIN TESTS DURING THE FIRST SIX MONTHS.

At 3 months

At 1 month

Pre-treatment

At 6 months

- - - - - - -- --P--C-- - - -C- -C-ACTH P ACTH P ACTH C ACTH P - - - - -- - - - - - - - - - - - - - - - - 106 70 79 Total patients tested 115 109 113 83 95 81 91 98 77 - - - - - -- - - - - - - - - - - - - - - to 1 T.U. Mantoux tuberculin lest

Diameter of

induration (mm.)

0-4 5 or more

72

26 52

27 55

16 59

32 31

32 43

20 49

21 35

35 31

10 44

11 37

11 40

to 10 T.U. 0-4 5 or more

6 20

9 22

9 22

0 23

12

18

5 20

5 18

2

13

4 22

16

8

20

9 19

17

9

more. However, the Prednisone series showed a well-marked rise in temperature at the end of three months, when the hormone was stopped and 36 (34 %) then had an average of 99° F. or more. (As for the estimations of ESR, the temperatures at three months for the two hormone series are not entirely reliable.) At six months, however, only 10 % Control, 8 % A.C.T.H. and 7 % Prednisone had an average of 99° F. or more. RESULTS OF (MANTOUX) TUBERCULIN TESTS (Table V) Mantoux tuberculin tests, with either I or 10 TU, were performed in the first six months to discover whether any change in tuberculin sensitivity occurred in patients who received the hormones. The results of the tuberculin tests are given only for those patients who received the same strength of tuberculin on each occasion the tests were made. The proportion in each series negative to lor 10 T.U. (that is, who had reactions with a diameter of induration less than 5 mm.) are as follows:

Months after start of treatment

Percentage negative to I TV

C

0 1 3 6

15

16 21 13

to 10 TV P

C

24

24

39

30 38

5 0

ACTH

26 16

14

4 6

ACTH

8

P

8

14 6

18

3

1l

17

Before the start of treatment 15 % of the Control, 24 %of the A.C.T.H. and 24 %of the Prednisone series were negative to 1 T.V. and 5 %,8 % and 8 %respectively to 10 T.U. There was little change of tu berculin sensitivity in the Control series during the six months; in contrast, there was considerable reduction in sensitivity at one month in the two hormone series, and a substantial proportion of patients initially positive became tuberculin negative. At three months, the AC.T.H. series had proportions negative similar to those initially, but the Prednisone series continued to show the reduction in sensitivity. By six months, however, the proportions negative in all three series were again similar to those initially. CHANGES IN WEIGHT (Fig. 3) The figure shows that throughout the twelve-month period, the Control patients made a steady average gain in weight; in contrast the two hormone series showed a rapid increase in the first three months. while receiving the hormones, and the gain was maintained afterwards. By the end of

TUBERCLE

402

twelve months, however, the Control and Prednisone series had gained a similar amount, the A.C.T.H. series very slightly more. At one month, the Control series had gained an average of 6 lb. compared with 12 lb. in the A.C.T.H. and 9 lb. in the Prednisone series. At three months, the average gains were ll lb.. 21 lb. and 26 lb. respectively; the differences between the former and each of the two latter values are significant at the 0·1 %level. At six months, the average gains were 17 lb., 24 lb. and 24 lb. respecti vely; the differences between the former and each of the two latter values are also significant at the 0·1 % level. By twelve months , the average gains were 21 lb. , 23 lb. and 21 lb. respectively; there are no statistically significant differences between these values . 30

r ... _ I

/

20

/

/

r

,9

/,

...___.>-.-.-

-------

PREDNISONE/

--' ./

»>:

---'

. --. - .~

. . . ..:.-::::-,.-._ .....

ACTH· . .. .

--- ..............

-.

./

.l

c:

g.

/1 . I (I . /

z

C7'

'Qj

~

I

10

.

I

I

II

'j

II

1/

.1

fI

o

2

3

4

5 b Months after start of treatment

q

12

Fig. 3 We ight gains in the twelve-month period.

CHANGES IN GENERAL RADIOGRAPHIC ApPEARANCES (Table VI) The chest radiographs were examined either by three independent assessors (K. E. J ., D. R . M. and H. E. S.) or by two (D. R. M. and H . E. S.); all were unaware of the treatment allocated to each patient. Each assessor separately recorded the radiographic shadowing remaining at each time as a percentage of the original shadowing (that is, the extent of the shadowing before the start of treatment). The percentages were averaged, but when there was considerable disagreement between the assessors, the radiographs were reviewed by them together and an agreed assessment made . As with the other assessments of progress, the Control patients showed a steady clearing of radiographic shadowing in the twelve-month period, whereas the A.CT.H. and Prednisone series made considerable and rapid progress in the first three months while receiving hormones. and had still made the greater progress than the Control series at six and twelve months. At one month, all the Control patients had three-fifths (60 %) or more of the original shadowing left compared with 93 % of the A. CT. H. and 90 % of the Prednisone series; the corresponding

403

STEROIDS IN PULMONARY TUBERCULOSIS TABLE VI.-RESIDUAL RADIOGRAPHIC SHADOWING IN THE TWELVE-MONTH PERIOD (FROM INDEPENDENT ASSESSMENTS)

Time after start 0/ treatment

Treatment series

I month

Control

3 months

6 months

12 months

Total patients assessed III 96

Number a/patients with proportion oj original radiographic shadowing remaining Less than 80% or more 60-79% 40-59% 20-39% 20% 86 39 27

25 50 76

0 6 11

0

1 1

0 0 0

105 91 108

18

5 3

56 35 29

29 42 54

2 8 22

0 1 0

A.C.T.H. Prednisone

94 87 97

3 0 3

16 14 8

39 30 26

31 37 49

5 6 11

Control

88

A.C.T.H. Prednisone

78

0 0

0

7 6 4

36 28 23

43 44

94

2 0 2

A.C.T.H. Prednisone

115

Control A.C.T.R Prednisone Control

65

proportions at three months were 70 %, 44 ~{, and 30~;'; respectively, the differences between the former and each of the two latter values being significant at the 0·1 % level. One of the assessors (H. E. S.) reported on radiographic deterioration between three and four months (not shown in the Table); such deterioration occurred in 5 Control, 12 A.C.T.H. and 30 Prednisone patients. In all these cases, however, the deterioration was only of a temporary nature. At six months, 38 %of the Control series had less than two-fifths (40 %) of original shadowing left compared with 49 %of the A. C. T. H. series and 62 % of the Prednisone series; the difference between the first and last value is significant at the l/~ level. At twelve months the proportions with less than one-fifth (20%) of original shadowing left were 49 %, 56 %, and 69 %respectively; the differences between the latter and each of the two former values are significant at the 1 %level. (This last assessment is considered to be the most reliable of all the radiographic assessments; if little or no shadowing was seen on the radiograph taken at twelve months, it could be stated with considerable accuracy that, compared with the radiograph taken before the start of treatment, less than one-fifth (20 %) of original shadowing remained. The assessments at other months, because there was less clearance of shadowing, could not be expected to have similar accuracy; nevertheless, this applied for the patients in all three series and the proportions given above do indicate real differences between the series.) The same assessments of residual radiographic shadowing at six and twelve months are shown in Table VII, according to the extent of the initial lesions. In each category of the extent of the initial lesions, the Control series made the least progress, in terms of residual shadowing, at six and twelve months, and the Prednisone series the most progress. In all three series, a greater proportion of the initial shadowing had cleared by twelve months in patients with moderate lesions initially than in those with extensive or very extensive lesions initially. (Table Vlll) There was little difference between the series in the presence of cavitation at three and six months in those who had had cavitation initially; those with cavitation were 89 (86 %) Control, 72 (83 %) A.C.T.H. and 90 (83 %) Prednisone patients at three months and 51 %,55 %and 51 %respectively at six months. At twelve months, however, the A.C.T.H. series had made the greatest improvement, only 13 (18 %) still having cavitation, compared with 21 (24 %) of the Control and 22 (23 %) of the Prednisone series; but the differences are not significant. Considering the presence of cavitation according to its extent (no assessment was made of its CHANGES IN CAVITATION

404

TUBERCLE TABLE

VI I.-RESIDUAL

RADIOGRAPHIC SHADOWING AT SIX AND TWELVE MONTHS, ACCORDING TO THE EXTENT OF LESIONS ON ADMISSION

Time after start of treatment Radiographic extent of lesions on admission"

At 6 months Treatment series I

Percentage with i less than i No. of flfo-fi/ths (4D%) patients of original assessed shadowing !

No. of patients assessed

Extensive

Very extensive

Control A.C.T.H. Prednisone

23 18 22

52 67

Control A.C.T.H. Prednisone

20 24 27

55 54

Control A.C.T.H. Prednisone

51 45 48

40

Control A.C.T.H.

94 87 97

I Total

I Prednisone I

*

Percentage with less than one-fifth (20 %) of original shadowing

I

,

Moderate

At 12 months

,

- -i - - - - - - - - - - - -

I I

68

59 61 87

I----zoI

I

23

i

37 45

, ::

70

25 54

55

---

57

I---:~

54 64

!

i

1--88-'--49--

38 49

,

22 18 23

78 94

62

56

69

Assessment on a single full-size chest radiograph and tornographs taken before the start of treatment.

TABLE VIII.-CAVITATlON CHANGES IN THE TWELVE-MONTH PERIOD, ACCORDING TO THE EXTENT OF CAVITATION ON ADMISSION ~

Extent of cavitation

. Treatment series

011

admission"

Slight

Moderate

Extensive

Total with cavitation initially

* Assessment on

Time after start

At 6 months

At 3 months With om cavita-

With cavita-

tion

tion

13 10

44 31 36

28 20 24

Total

Wltl!out cavitation

Control A.C.T.H. Prednisone

16

31 21 20

Control A.C.T.H. Prednisone

1 5 2

25 27 39

26 32 41

10 16 22

Control A.C.T.H. Prednisone

0 0 0

33 24 31

33 24 31

7 1 2

Control A.C.T.H. Prednisone

14 15 18

89 72

90

103 87 108

45 37 48

With I covita-

I

11

9 7

I

12 16 15

I

i

i

24 21 27

I I I

At 12 months Without cavitation

cavita-

39 29 31

35 24 29

3 2 2

38 26 31

22 32 37

17 26 31

5 3 3

22 29 34

13

13 8 17

26 19 29

21** 13** 22**

86 74 94

Total

tion

I,

47

46 49

--"-

0/ treatment

---- ---31 22 29 92 83 97

---11

12 65t

6U 72§

With

Total

tion

a single full-size chest radiograph and tomographs taken before the start of treatment. Cavitation did not subsequently develop in the 2 Control and 5 A.C.T.H. patients who did not have cavitation initially. t Including 9 who had surgery and therefore no cavitation at 12 months. :j: Including 8 who had surgery and therefore no cavitation at 12 months. § Including 7 who had surgery and therefore no cavitation at 12 months. ** Including 1 who had persistence of cavitation after surgery.

405

STEROIDS IN PULMONARY TUBERCULOSIS TABLE IX.-RESULTS OF DIRECT AND CULTURE EXAMINATIONS OF BACTERIOLOGICAL SPECIMENS

Direct examination Months after start of treatment

0

Treatment series

Total patients examined

Culture examination

Negative or no sputum No.

%*

Total patients examined

III

Positive

Control A.C.T.H. Prednisone

118 111 116

94 90 100

24 21 16

20 19 /4

1

Control A.C.T.H. Prednisone

to7 97 113

48 34 47

59 63 66

3

Control A.C.T.H. Prednisone

106 91 105

28 .17 19

Control A.C.T.H. Prednisone

94 87 97

Control A.C.T.H. Prednisone

74 67 80

Control A.C.T.H. Prednisone

40 40 45

6

9

12

* of total

No.

5t

%*

115

113 102 111

9t 4t

8 3

55 65 58

109 100 109

78 64 73

31 36 36

28 36 33

78 74 86

74 81 82

104 89 104

27 19 24

70 80

77

74 79 77

5 2 6

89 85 91

95 98 94

95 87 95

4 I 2

91 86 93

96 99 98

0 0

I

73 67 80

99 100 100

74 67 80

0 0 0

74 67 80

100

0 0 0

40 40 45

100 100 100

40 40 45

1 0 0

39 40 45

98 100 100

patients examined.

118

Negative Positive 4

lOa

100

t positive on direct examination.

type) before the start of treatment, there was a close relation in all three series between the initial extent and subsequent progress; the patients with no or slight cavitation initially had a greater proportion without cavitation throughout the twelve-month period, and those with extensive cavitation initially showed lower proportions. (Table IX) Specimens of sputum were examined at monthly intervals according to the customary technique of the local laboratory. In general, two specimens were taken; if there was no sputum, laryngeal swabs or gastric lavages were undertaken. The results of the direct smear and culture examinations were reported as either positive or negative. If either (or both) of two specimens was positive, this is regarded as positive in the Table. Some patients were not examined at twelve months as they were no longer in hospital. At three and six months the results of the direct smear and culture examinations were very similar in all three series. Thus, at three months, negative cultures were obtained in 74 %of the Control, 79 % of the A.C.T.H. and 77 %of the Prednisone series, at six months 96 %, 99 %and 98 %respectively. At nine months, I Control patient had an isolated specimen which was positive on direct smear examination (but negative on culture) and at twelve months another Control patient had an isolated specimen which was positive on culture; all other specimens obtained from the three series at nine and twelve months were negative. Sensitivity Tests Sensitivity tests to streptomycin, PAS and isoniazid were carried out, where possible, by the local laboratories, according to their own standard techniques; in all but three of the positive cultures tested at any time after the start of treatment, the cultures were sensitive to the three drugs. Two Control patients had cultures resistant to streptomycin at three months; the prescribed chernoRESULTS OF BACTERIOLOGICAL EXAMINATIONS

406

TUBERCLE

therapy, including this drug, was continued until six months and later cultures were negative. One A.C.T.H. patient had cultures resistant to isoniazid and PAS at six months; the culture at nine months was negative. REACTIONS TO THE HORMONES It will be recalled that in 22 patients (15 A.C.T.H. and 7 Prednisone) the hormone therapy was changed or stopped before the end of the prescribed three months because of side-effects caused by the hormones. Their progress was included in the tables only for as long as they continued with the prescribed hormone therapy. A further 18 patients (9 AC.T.H. and 9 Prednisone) had transient reactions but only a brief interruption of the hormone; 'mooning' of the face was reported in II AC.T.H. and 30 Prednisone patients. In addition, 'rebound' phenomena on stopping the hormone occurred in 6 A.C.T.H. and 34 Prednisone patients. The progress of these patients has been included in the tables throughout the twelve-month period. The details of all the reactions are as follows: AC.T.H. SERIES (72 PATIENTS GIVEN 'CORTROPHIN ZN') (a) Corticotrophin stopped (2 patients, 3 %) Two patients developed hypertension, I (female, aged 31 years) at twelve days with a blood pressure of 180/115, and the other (male, aged 20 years) at two months with a blood pressure of 160/110. The former also developed epileptiform fits at the same time, but the clinician thought this may have been caused by starting the hormone during the puerperium; her pregnancy was uneventful. (b) Corticotrophin continued 'Mooning' of the face was reported in 7 patients; this did not interfere with the hormone therapy. No other complications were reported.

A.CT.H. SERIES (39 PATIENTS GIVEN 'CORTROPHIN Z') (a) Corticotrophin stopped or reduced (13 patients, 33 %) (i) Six patients developed psychotic manifestations within the first month of receiving the hormone (1 of these also had hypokalaemia and I female, aged 33 years was hypertensive with a blood pressure of 160/100); all made immediate recoveries on stopping the hormone with the exception of I who recovered after treatment in a mental hospital for two months. (ii) Three further patients developed hypokalaemia between three and six weeks despite an increase in dosage of potassium chloride; I of these also had glycosuria and I gross oedema, tachycardia and a fall in blood pressure (the latter died of extensive pulmonary tuberculosis after eight months). Two further patients developed glycosuria between one and four weeks, both with a raised blood sugar level and I also with pitting oedema. One patient developed gross oedema at three weeks; a satisfactory diuresis was obtained but the A.C.T.H. was not resumed. One patient developed a hypersensitive reaction to the A.C.T.H. after six days. (b) Corticotrophin continued (9 patients) Four patients (2 males and 2 females, aged under 54 years) had a raised blood pressure ranging from 165/120 to 145/90 and also glycosuria at one month; 2 of these patients stopped the hormone a few days before the end of the prescribed three months. Two more patients (I male and I female) had a raised blood pressure, I at one month and I at two months. In all these patients the blood pressure reverted to normal. In addition, 2 patients had transient glycosuria, and I had slight oedema. 'Mooning' of the face was reported in 4 patients. (c) 'Rebound' phenomena (6 patients) Six patients developed slight clinical 'rebound' phenomena on stopping the hormone, with evidence of fever, nausea, anorexia and depression.

PREDNISONE SERIES (116 PATIENTS) (a) Prednisone stopped, reduced or changed (7 patients, 6 %) Four patients (1 male and 3 females, aged 50 years or less) developed hypertension within one

STEROIDS IN PULMONARY TUBERCULOSIS

407

month, the blood pressure ranging from 145/105 to 190/120. Of these, 1 also exhibited a 'rebound' phenomenon on stopping the prednisone, and 3 had glycosuria and raised blood sugar (1 also with gross oedema). Two patients had glycosuria at two months (1 also with hyperglycaemia). One further patient developed a severe 'rebound' phenomenon on stopping the prednisone after the prescribed three months and the A.C.T. H. was therefore continued for two more months. (b) Prednisone continued (9 patients) Two patients (l male, aged 39 and 1 female, aged 22) became hypertensive just before three months with a blood pressure of 160/100. Five patients had glycosuria at two months, in 3 transient only and in 2 with raised blood sugar. Two patients developed personality changes at two and half months; 1 of these also had an appendix abscess and a psychiatrist considered that this may have been the sole cause of the mental upset. 'Mooning' of the face was reported in 30 patients. (c) 'Rebound' phenomena (34 patients) Clinical 'rebound' phenomena occurred in 34 patients with evidence of some or all of the following: general malaise, rise in temperature and ESR, headaches, nausea, anorexia and rash. COMPARISON OF THE A.CT.H. 'CORTROPHIN ZN' AND 'CORTROPHIN Z' PREPARATIONS It will be recalled that patients allocated to the AC.T.H. series received at first 'Cortrophin ZN'. The trial had been in progress for about nine months when doubts arose as to its efficacy, as the rapid improvement in erythrocyte sedimentation rate and side-effects experienced from previous use of AC.T.H. had not been observed. Patients subsequently admitted to the trial and allocated to the ACT.H. series were given 'Cortrophin Z'. The results when 'Cortrophin ZN' and 'Z' were in use were amalgamated, as the progress of the patients given the two A.C.T.H. preparations appeared to be similar, despite the differences in side-effects just described. A summary of these results is given in Table X. Considering the residual radiographic shadowing, the percentage of patients in the AC.T.H. series (whether given 'Cortrophin ZN' or 'Z') with stated proportions of original shadowing remaining was at each time between the percentages of the Control and the Prednisone series, although the levels in the two periods of the trial differed. The percentage with negative cultures and the average weight gain of the A.C.T.H. patients (whether given 'Cortrophin ZN' or 'Z') resembled those in the Prednisone series. Thus, there appeared to be no difference in the therapeutic effects of the two ACT.H. products in the dosage used. However, 2 patients (3 %) given 'Cortrophin ZN' developed hypertension and the hormone was stopped whereas the hormone was stopped or reduced in 13 patients (33 %) given 'Cortrophin Z' because of side-effects, 6 being psychotic manifestations. Wide variations in individual responsiveness to AC.T.H. give rise to a wide range of endogenous adrenal hormone secretion. The proportion of patients having a small response, with a slight increase in adreno-corticol activity but some therapeutic benefit, was not balanced by the proportion having a high response to A.CT.H. with greater adrenal stimulation, obtaining little additional therapeutic benefit; but with a higher incidence of undesirable side-effects. For these reasons, the ACT.H. dosage for each patient would have to be adjusted according to his responsiveness as judged, for example, by the level of urinary corticoid excretion. It seems that the 'Cortrophin Z', although it provided greater adrenal stimulation in a larger proportion of patients than the 'Cortrophin ZN', in that there were more side-effects, did not produce additional therapeutic benefit, in the dosage used. Discussion In the treatment of pulmonary tuberculosis today the use of streptomycin, PAS and isoniazid in combination provide, in the great majority of patients, an effective means of recovery from the disease. In the present trial, with at least six months in bed in hospital and chemotherapy for twelve months, excellent progress was made by the Control series; almost all the patients had negative c

~

o00

TABLE x.-COMPARISON

OF

THE PROGRESS

OF

PATIENTS ADMlTfED CONCURRENTLY WHEN A.C.T.H. 'CORTROPlllN ZN' AND

I

When A.C.T.H. "Cortrophin ZN' in use Residual radiographic shadowing Months after start 0/ treatment

1

3

6

12

Treatment series Total assessed Control A.C.T.H. Prednisone

67

56 74

100

three-fifths (6O%) or more

Control A.C.T.H. Prednisone

65 56 70

three-fifths (60YJ or more

Control A.C.T.H. Prednisone

61 56 64

Less than two-fifths (40%)

Control A.C.T.H. Prednisone

56 50 62

Less than one-fifth

(20%)

93

86 74 52

34 38 50

61 50 [ I

60

71

WERE IN USE.

When A.G.T.H. "Cortrophin Z' in use Residual radiographic shadowing

Percentage Average negative weight Percentage on gain culture (lb.) 0/ patients examination

Proportion 0/ original shadowing remaining

'z'

27 34

30 75 85

79 97

98 98 92

100

100

6 11 9

Percentage negative

Proportion

of original

Total assessed

shadowing remaining

44

three-fifths (60%) or more

40

41

Percentage on of culture patients examination

100

92

95

11 20 25

40 35 38

three-fifths (60%) or more

62

16

24

33 31

39

23

33

Less than two-fifths (40%) !

20 25 20

32 28 32

i ,

30 40 39 72

Average weight gain (lb.) >o.,j

6 14 9 11

31

69

23

26

74

26

94

18

48 64

100 97

24

22 20 24

Less than one-fifth

45

100

50

100

(20%)

66

I

100

26

c:: til ttl

?:l

o

rttl

STEROIDS IN PULMONARY TUBERCULOSIS

409

cultures at six months and all except 1 at nine and 1 at twelve months. In assessing the value of a drug as a possible adjunct, there is therefore limited scope for further improvement on the ultimate progress that can be achieved with chemotherapy already known to be effective. Nevertheless, this investigation has shown that the introduction of hormones with chemotherapy led to a more rapid improvement at the beginning of treatment which lessened the damage to lung tissue. In the present trial, comparing one series given chemotherapy alone with another given chemotherapy and corticotrophin, 30 i.u, daily for ten weeks, and a third given chemotherapy and prednisone, 30 mg. daily for ten weeks, the patients receiving the hormones showed the greater improvement in many respects, the Prednisone series, however, making the most progress. Throughout the trial, the progress of the A.C.T.H. patients was less than that of the Prednisone series; this may have been due to the maintenance dosage of 30i.u. corticotrophin daily inducing in some patients a blood level of corticosteroids lower than that achieved by the maintenance dose of 30 mg. prednisone. Radiographic changes

Considering the changes in general radiographic appearances, the A.C.T.H. and Prednisone series showed a significantly greater clearing of radiographic shadowing by three months than the Control series. At twelve months, however, the AC.T.H. series had made only slightly more progress than the Control series, but the Prednisone series had significantlyless residual radiographic shadowing than either of them. The Tuberculosis Society of Scotland (1957), whoseinvestigation was reported in detail by Horne (1960), using prednisolone 20 mg. daily for three months, and Weinstein and Koler (1959), using prednisolone 10 mg. daily for two months, both with chemotherapy, also showed significant differences in the early months oftreatment. Angel and others (1959; 1961), using corticotrophin gel 40 i.u. for three weeks and 30 i.u. for six weeks with chemotherapy, and Johnson and others (1960), using methyl prednisolone 16 mg. daily for ten weeks with chemotherapy, reported similar results. In all these studies, however, there was little or no difference between the hormone and control series in radiographic clearing at six months. In the present trial there was little difference at any time between the three seriesin cavity closure; no assessment was made of the type of the initial or residual cavitation. Bell, Brown & Horn (1960), using prednisolone 20 mg. daily for eight weeks with chemotherapy in Ashanti patients, also showed no greater improvement in cavitation in the patients given prednisolone than in the control series; Johnson and others (1960) reported a similar result. Clinical progress

The return to normal well-being, as indicated by the improvement in clinical condition and increase in weight, was more rapid in the hormone than in the Control series. Throughout the sixmonth period for which the assessment of clinical progress was made, the Prednisone series showed the greatest improvement. A rapid increase in weight was made in the first three months in the patients receiving hormones; the gain was maintained after stopping the hormones and was therefore not due to fluid retention. A similar result was reported by Horne (1960), Angel and others (1960) and also by Browning (1961), who used prednisolone 20mg. daily for nine weekswith chemotherapy. The rate of sputum conversion was similar in the three series of the present investigation and almost all the cultures were negative by six months. The use of hormones with the three standard drugs did not delay sputum conversion. The rapid improvement in the clinical condition of patients given hormones has been ascribed to the anti-inflammatory action of the hormones and to a reduction in sensitivity to tuberculin (Smith, 1959). In the present study, the two hormone series showed a well-marked reduction in sensitivity at one month; this was not maintained in the A.C.T.H. series, but continued in the Prednisone

410

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series for the three months of hormone therapy. By six months, however, the proportions tuberculin negative to I or 10 T. U. in all three series were again similar to those initially. It is of interest that not all the patients were tuberculin positive initially to the doses given. Johnson and others (1960) and Salomon & Angel (1961) also showed a reduction in tuberculin sensitivity in patients given hormones in addition to the chemotherapy. The rapid improvement in erythrocyte sedimentation rates and temperature was also shown in the Prednisone series. In the A.C .T .H. series, however, less response to the corticotrophin was made ; th is may have been due to the maintenance dosage of 30 i.u. daily used not producing sufficient adreno-corticol activity in some patients; Angel and others (1961) using 60 i.u. of A.C.T.H. gel daily for the first four days, showed considerable reduction in temperature immediately after the start of the hormone therapy. Reactions to the chemotherapy It is now generally recognised that hormone therapy in sufficient dosage suppresses hypersensitive reactions to streptomycin, PAS and isoniazid (Houghton 1954). Johnson and others (1960) observed hypersensitive reactions to PAS in 24 % of patients immediately following the stopping of methylpredn isolone. Nevertheless, in the present trial, during the first three months while on the hormones, 4 patients developed severe reactions which necessitated a change of the prescribed chemotherapy : of these, I (A.C.T.H.) became hypersensitive to streptomycin and PAS at one month and I other to all three drugs at six weeks; 1 (Prednisone) became hypersensitive to streptomycin and I other to streptomycin and PAS both at on e month. For these patients, the dosage used (of either the corticotrophin or the prednisone) was not sufficient to suppress these reactions. Three Control patients developed severe hypersensitive reactions and changed chemotherapy in the first three months, 2 became hypersensitive to PAS at two and six weeks and 1 to all three drugs at one month. In addition to the hypersensitive reactions in the first three months during hormone therapy, I A.C.T.H. patient developed gastro-intestinal intolerance of the PAS at two months while receiving the corticotrophin , which also necessitated a change of the prescribed chemotherapy. Five Control patients developed dizziness from the streptomycin between one and four weeks and changed chemotherapy. Thus the hormone therapy, in the dosage used, did not entirely suppress either hypersensitive reactions to the three drugs or intolerance to PAS; however, there were no toxic reactions to streptomycin in the hormone series. After the first three months, when hormone therapy was no longer given. 18 patients (7 Control, 4 A.C.T.H. and 7 Prednisone) changed or stopped chemotherapy because of severe hypersensitive or toxic reactions. In 16 of these , the reactions occurred at three months and in 2 at six months; 4 of them (1 Control, also hypersensitive to streptomycin, and 2 Prednisone) became intol erant to PAS at three months. In addition, other minor hypersensitive or toxic reactions occurred in the first six months in a number of patients who nevertheless continued, with only temporary departures from, the prescribed chemotherapy. Reactions to the hormone therapy The interruption of adequate chemotherapy for some time, because of severe reactions, may delay a patient's recovery. This is therefore potentially mo re serious than stopping a hormone because of side-effects. for the patient still has the full benefit of chemotherapy. Although the use of hormones in addition to chemotherapy has been shown to hasten recovery, thei r side-effects must be taken into account when assessing its total value. It was recogni sed that , because of the wide variation in individual response to hormones, the standard maintenance dose for all patients in the two hormone series might have caused severe reactions in some of them. However, the side-effects subsided in all but 1 patient immediately on reduction of or stopping the hormone, and (except for 1 patient who died of pulmonary tuberculosis after eight months) could not be said to have interfered with the patients' ultimate recovery.

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In 22 patients (15 A.C.T.H. and 7 Prednisone), the hormone therapy was changed or stopped before the end of the prescribed three months. Because of the wide variations in individual responsiveness to AC.T.H., the corticotrophin (particularly the 'Z' preparation) probably induced a high steroid level in some patients, which may have been responsible for the higher incidence of sideeffects observed in the AC.T.H. than in the Prednisone series. Of those with reactions to the hormone therapy, although patients with a history of mental disorder were excluded from the trial, 6 A.C.T.H. patients (given 'Cortrophin Z', which is not now available) developed psychotic manifestations within the first month. However, all 6 patients made uneventful recoveries, except for 1 who recovered after treatment in a mental hospital for two months. Angel and others (1961) reported 3 patients given ACT.H. gel who had transient mental disturbance and d'Esopo (1961) on 1, given prednisone 30 mg. daily and AC.T.H. 40 i.u. on alternate days for three months, with psychosis. It must, however, be recognised that isoniazid can also produce psychotic manifestations (Hunter, 1952; Vysniauskas & Brueckner, 1954; Hare, 1958). In addition, it has been known for patients to develop peptic ulceration when given hormone therapy with PAS (Bollett, Black & Bunim, 1955; Dordick and others 1957; Wells, 1957). In the present trial, 3 patients developed duodenal ulcers, 2 (Control) at two months and 1 (Prednisone) at six months. Clinical 'rebound' phenomena occurred in 6 (15 %) A.CT.H. (given 'Cortrophin Z') and 34(30 %) Prednisone patients on stopping the hormone, but the symptoms lasted only for a few days. In I further Prednisone patient, the 'rebound' was so severe that the A.C.T.H. given on stopping the prednisone was continued for two months. The lower incidence of this phenomenon in the AC.T.H. than in the Prednisone series suggests that it is probably due to pituitary-adrenal unresponsiveness in the former series and to adrenal suppression in the latter. Johnson and others (1960) reported clinical 'rebound' phenomena in 38 % of the hormone series. In the present investigation, 42 patients (12 - 11 %- A.CT.H. and 30 - 26% - Prednisone) had radiographic deterioration between three and four months; 5 (4 %) Control also showed radiographic deterioration in this period. Horne (1960) has described transitory radiographic deterioration on stopping prednisolone-radiographic 'rebound' phenomenon-as presumably due to a recrudescence of inflammatory response which had been suppressed by the hormone; one-sixth of the patients given prednisolone showed such deterioration between the third and fourth months. Johnson and others (1960) observed temporary radiographic deterioration in 41 % and d'Esopo (1961) in 90% of patients on stopping hormones. Conclusions It is evident, from the results of the trial, that prednisone has a place in the treatment of selected

cases of acute, extensive pulmonary tuberculous disease. Especially for patients in poor clinical condition, the immediate rapid response to the prednisone, as shown by weight gain, falls in ESR and temperature, is of great advantage. The Prednisone series also had significantly less residual radiographic shadowing than the Control series both at six and twelve months. Although the ACT.H. series also showed an immediate rapid response to the corticotrophin, but less marked than in the Prednisone series, there were no significant differences from the Control patients in the progress made by twelve months. It is possible that the dosage of corticotrophin used in the present trial may have been too low for some patients, but in order to avoid undesirable side-effects, it would be necessary to adjust the dosage according to the individual adreno-corticol activity. The British Tuberculosis Association Research Committee is grateful to the many people who helped in this investigation and thanks especially the Medical Research Council for financial support, the very large number of hospital and chest clinic physicians for their co-operation, Organon Laboratories Ltd. for the supply of A.C.T.H. 'Cortrophin ZN' and 'Cortrophin Z' at a reduced cost, Roussel Laboratories Ltd. for the free supply of prednisone, Dr. K. E. Jefferson, Dr. D. R. McPherson and Dr. Harley E. Stevens for the independent assessments of chest radiographs, Dr. H. J. Wilkinson for the urinary 17-ketosteroid and 17-hydroxycorticosteroid estimations and Miss M. Bundy for her unstinting secretarial assistance.

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REFERENCES ALEMQUER, M. DE (1955). Act. tuberc. scand., 31, 356. ANGEL, J. H., CHU, L. S., LYONS, H. A., & SALOMON, H. (1959). Trans. 18th Can/. Chemo, Tubere., p, 191, Veterans Administration, Washington. ANGEL, J. H., CHU, L. S., & LYONS, H. A. (1961). Arch. intern. Med., 108, 353. BAYLISS, R. 1. S. (1958). Brit. med. J., ii, 935. BELL, W. J., BROWN, P. P., & HORN, D. W. (1960). Tubercle, Land., 41, 341. BOLLETT, A. J., BLACK, R., & BUNIM, J. J. (1955). J. Amer. med. Ass., 158,459. BROWNING, R. (1961). Paper given at the 20th Conference on Chemotherapy of Tuberculosis, Veterans Administration, U.S.A. To be published. DES AUTELS, E. J., ZVETINA, J. R., BERG, G. S., FF.RSHING, J., & FREEMAN, S. (1956). Dis. Chest, 30, 486. D'Esroso, N. (1961). Paper given at the 20th Conference on Chemotherapy of Tuberculosis, Veterans Administration, U.S.A. To be published. DORDICK, J. R., FELDER, S. L., POLANSKY, S., & GEFFEN, A. (1957). N.Y. J. Med., 57, 204. EVEN, R., & SORS, C. (1954). Sem. Hop. Paris, 30, 2852. FAVEZ, G. (1954). Med. Hyg., Geneve, 12, 1. FREEMAN, S., FERSHING, J., WANG, C. C, & SMITH, L. C. (1950). hoc. First A.C.T.H. Conf., p 509, Blakiston Co. Philadelphia. HARE, E. H. (1958). Tubercle, Lond., 39, 90. HART, P. D'A., & REES, R. J. W. (1950). Lancet, ii, 391. HORNE, N. W. (1960). Brit. med. J., il, 1751. HOUGHTON, L. E. (1951). Brit. med. J., ii, 609. HOUGHTON, L. E. (1954). Lancet, i, 595. HUNTER, R. A. (1952). Lancet, ii, 960. JOHNSON, J. R., TAYLOR, B. C., JENNE, J. W., MORRISEY, J. F., LOEB, G. L., & MACDONALD, F. M. (1960). Trans. 19th Conf. Chemo. Tuberc., p, 129, Veterans Administration, Washington. SALASSA, R. M., BENNETT, W. A, KEATING, F. R., & SPRAGUE, R. G. (1953). J. Amer. Med. Ass., 152, 1509. SALOMON, H., & ANGEL, J. H. (1961). Amer. rev. Resp, ins; 83, 235. SLANEY, G., & BROOKE, B. N. (1957). Lancet, i, 1167. SMITH, D. T. (1959). Trans. 18th Con}: Chemo. Tuberc., p. 196, Veterans Administration, Washington. TUBERCULOSlS SOCIETY OF SCOTLAND (1957). Brit. med. J., ii, 1131. VYSNIAUSKAS, c., & BRUECKNER, H. H. (1954). Amer. rev. Tuberc., 69, 759. WEINSTEIN, H. J., & KOLER, J. J. (1959). New Engl. J. Med., 260,412. WELLS, R. (1957). Brit. med. J., ii, 1113.