Acute pulmonary tuberculosis in East Africans: A controlled trial of isoniazid in combination with streptomycin or PAS

.Ju,~e z956

151

ORIGINAL

ARTICLES

Acute Pulmonary Tuberculosis in East Africans" A Controlled Trial of Isoniazid in Combination with Streptomycin or PAS By P. W. H U T T O N , Y. K. L U T A L O , and A. W. W I L L I A M S Mulago Hospital and the Departnunt of Medicine, Makerere College, Kampala, Uganda ISABEL M. T O N K I N Medical Laboratories, Kampala

and WALLACE F O X Tuberculcsi~ Research Unit, Medical Research Coun:il, London Tuberculosis is no new disease in tropical Africa, but the means for its spread in the interior of the continent have increased enormously, and are still increasing ; and it may well become the most important of the infectious diseases. In East Africa a primitive agricultural community has become subject to many of the stresses of modern development, including the introduction of varying degrees of industrialization and urbanization, and of a monetary economy. There has been no tradition of urban life, and towns of any size are an innovation. With rapidly changing social and economic conditions on the one hand, and ignorance and often poverty and poor nutrition on the other, the medical services face the growing problem of tuberculosis with limited resources in money and man-power. Pulmonary tuberculosis as seen in hospital practice in Uganda is usually acute and progressive and few cases of this kind responded satisfactorily to rest and collapse measures. Although by z952 chemotherapy was known to be of some benefit for the earlier and less extensive lesions, no controlled trial of any of the drugs reported on here had been undertaken. Such a trial was considered to be important for several reasons. First, there was a pressing need to work out effective drug regimes for the common forms of the disease, since it could not be assumed that .the response in East Africans would be the same as in Europeans; indeed the available evidence suggested that the course of untreated pulmonary tuberculosis was much less favourable (Haynes, I952; Haynes and Henderson, z952 ). Secondly,' it was important to know how far, if at all, in a poor country chemotherapy could obviate the need for the costly organization which has been built up in Europe to deal with the disease. In particular, because the facilities for collapse therapy and major surgery are still very limited in East Afric.a, it was necessary to test the effectiveness of chemotherapy uninfluenced by the effects of collapse therapy or resection. Thirdly, the treatment of hyperacute pulmonary tuberculosis, which is a very common and grave form of the disease, needed special study.

I52

TUBERCLE

June

I95G

P l a n and C o n d u c t of the T r i a l T h e methods o f selecting cases, allocating treatments a n d recording p r e t r e a t m e n t a n d progress d a t a have followed the p a t t e r n o f the M e d i c a l Research Council ( M R C ) trials in Britain. Moreover, the treatments studied were two o f the s t a n d a r d regimes in those trials. T h e r e have, however, been certain departures f r o m and additions to the M R C p r o c e d u r e and these a r e described in the a p p r o p r i a t e sections. SELECTION OF PATIENTS

All 65 patients included in the trial were indigenous Africans from Uganda or neighbouring East African territories. They were selected from the out-paticnts at ~{ulago Hospital, the main general hospital for Africans in Uganda, or they wcrc referred from district or mission hospitals. A paticnt considered eligible by either physician (P. ~V. H. or A. "~V.~V.) was seen by them jointly before being accepted into the trial. Those accepted received treatment as in-patients in ~[ulago Hospital. The shortage of beds, as a rule, necessitates the restriction of admission to the more treatable cases, but this restriction was waived in se|ecting patients for the trial. The criteria for acceptance were those of tile clinical categories IA and IB of the iMRC isoniazid trials (~ledical Research Council, I95% 1953a), that is, tile case was newly diagnosed and untreated, aged 15 or over, with acute rapidly progressive bilateral pulmonary tuberculosis, belie~'ed to be of recent origin and associated with a positive" sputum, the organisms being sensitive to the drugs used. Patients so ill as to be unlikely to survive more than a few weeks were not accepted. Some patients had received a few tablets or 'injections', t h e nature of which was not established. After admission, treatment, either with streptomycin plus isoniazid (33 SH patients) or with p-aminosalicylic acid (PAS) plus isoniazid (32 PH patients) was. allocated by reference to a prearranged list based on random sampling numbers. This was provided by the MRC's Tuberculosis Research Unit (T.R.U.), London,. and held confidentially by a medical secretary at Mulago Hospital. NUMBER OF PATIENTS

The admission of patients to the trial for the twenty-four-week period began~ in March 1953, and ended in February 1955 by which time 67 patients had been: allocated treatment. Two patients who absconded in the first twelve weeks (I SH, x PH) were excluded from the trial leaving 65 patients for the analysis; of these: 33 were in the SH group and 32 in the PH group. In the second twelve weeks, 4 other patients absconded; at eighteen weeks (PH), at twenty weeks (SH), and at twenty-one weeks (I SH, i PH). These patients are excluded from the clinical. analysis at twenty-four weeks which is therefore Based on 31 SH and 3 ° P H patients. Patients are included in the bacteriological anal)sis for as long as they remained without interruption on a chemotherapeutic regime. INVESTIGATION BEFORE TREATMENT

All the patients were investigated for the xveekpreceding the start of treatment; in addition to a physical examination, observations were made on the wcight, daily evening temperature, exTthrocytesedimentation rate (ESR XVcstcrgrcn), the volume, character and bacterial content of the spdtum, the haemoglobin (Sah]i), and on the presence of any extra-pulmonary tuberculosis or other disease. A fullplate chest radiograph was also taken. OBSERVATIONS DURING TREATMENT

Regular observations, including a note of any toxic manifestations, were made during the course of the trial; they.were recorded at four-weekly intcrva]s for the first twelve weeks after the start of chemotherapy and again at twenty-four weeks. At the end of the trial an indcpendcnt radiographic assessment was arrangcdlin

June 1956

TUBERCULOSIS IN AFRICANS

153

London by the T.R.U.; this assessment was made by Drs L. G. Blair, A. F. FosterCarter and G. Simon, who knew neither the treatment of any individual patient nor even the country of origin of the films. TREATMENT

For the first tweh'e weeks

The two treatment regimes studied were: S H : streptomycin I g. daily in one intra-muscular injection, plus isoniazid 2oo rag. daily in two equal doses by mouth; PH : PAS (sodium salt) 2o g. daily, in four equal doses by mouth, plus isonlazid 2oo rag. daily in two equal doses by mouth. For the second twelve weeks The original intention was to limit the period of prescribed chemotherapy to twelve weeks, tile subsequent treatment to be selected in the light of progress. When the satisfactory response of the early cases was observed, it was decided to study the effects of more prolonged chemotherapy without collapse measures and to extend the period of uninterrupted chemotherapy, whenever this was still possible, to twenty-four \reeks, using the same drug combination but allowing some flexibility of dosage and rhythm. The S H Series.- Of the SH patients who survived and completed twenty-four weeks' observation, the majority (24 of 29) received chemotherapy throughout the second twelve weeks. For 23 the dosage was streptomycin i g. plus isoniazid 2oo rag., administered together ever)' other day;'the other patient had intermittent streptomycin and daily isoniazid. 4 patients received the combination only during the last four weeks, and one received no chemotherapy in the second twelve weeks. The patient who died in the eighteenth week continued the chemotherapy in reduced dosage until his death. The P H Series. - Of the 27 PH patients who survived and completed twenty-four weeks' observation, all but one received chemotherapy in the second twelve weeks; 22 had both drugs daily for the whole period, 2 for eight weeks, and the remaining 2 for four weeks. The dosage of both drugs was unaltered except that 3 patients received a smaller dosage of PAS. Collapse Therapy Only 2 patients had collapse therapy during the twenty-four-week period. One patient (SH) had a pneumoperitoneum induced in the twenty-first week, and a phrenlc nerve crush a week later; another patient (PH) had an artificial pneumothorax induced in the twenty-fourth week. C o n d i t i o n of Patients Before T r e a t m e n t COMPARABILITY OF TItE GROUPS

Thc agc (cstimatcd) and sex distributions wcrc similar in thc two scrics, x8 o f t h c 33 SH paticnts and 2o o f t h c 32 PH paticnts bcing undcr 30, and thc majority of both series (26 SH and 23 PH) bcing male. Table I shows thc condition of thc paticnts bcforc thc start of trcatmcnt as rcflcctcd by their general condition (asscssment by thc clinician in chargc), temperature, ESR (Westergrcn), haemoglobin (Sahli), thc volumc of thc sputum and its bactcrial content and thc indcpcndent asscssmcnt of thc cxtcnt of cavitation and o f t h c numbcr of lung zoncs involved. It can bc sccn that the two scrics wcrc similar in most of thc factors listcd, but that morc of thc S H patients had cxtcnsivc (3-plus) cavitation and morc had a heavily positivc sputum. This disadvantage to the SH series must bc bornc in mind in comparing the responsc to trcatmcnt of thc two scries.

I54

June I956

TUBERCLE

]~XTENT OF CAVITATION AND BACTERIAL C O N T E N T OF SPUTUM

T a b l e I I relates t h e e x t e n t o f c a v i t a t i o n o n a d m i s s i o n to t h e t r i a l to t h e bacterial content of the sputum on admission. Extensive cavitation and heavily i n f e c t e d s p u t u m a r e a s s o c i a t e d to s o m e e x t e n t , s i n c e 14 o f 30 p a t i e n t s w i t h t h r e e - p l u s c a v i t a t i o n h a d a s p u t u m g r a d e d as + + + o r + + o n d i r e c t e x a m i n a t i o n , c o m p a r e d w i t h 2 o f 14 p a t i e n t s w i t h o n e - p l u s o r n o c a v i t a t i o n . N e v c r t h e lcss, it c a n n o t b e c o n c l u d e d t h a t e a c h o f these t a c t o r s m e r e l y reflects t h e o t h e r . LARYNGITIS AND EXTRA-PULMONARY TUBERCULOSIS

R o u t i n e l a r y n g o s c o p y was n o t p e r f o r m e d , b u t p a i n o r a l t e r a t i o n o f voice was recorded in 9 SH patients and 5 PH patients. Evidence of extra-pulmonary TABLE I . - CONDITION ON ADMISSION

.~ ";',

T o t a l Fatients

. . . .

.~. "~,

~

~' ~

~,

~'~

(SH)

(PH)

(SH)

(PH)

33

32

33

32

3 8 22

4 Io 18

General condition

Average evening temperature in pre-treatment week (°F. ) Afebrile . . . . U n d e r 99 . . . . 99-99"9 .. .'" Ioo or m o r e . . . .

. . . .

51 or more

""

Haemoglobin (Sah'li) g. per cent . . . . . . . . . . . .

Sputum volume (mi. i Less t h a n 5 ° 5o-99 Ioo-149 I5o or more

. . . .

4 9 18 2

5 12 8 7

. . . .

. . . .

I

2

32

3°

9

I

5 9

9 7

Scanty . . . . 9 Direct e x a m i n a t i o n negative; c o n c e n t r a t i o n positive I Direct e x a m i n a t i o n and concentration -negative; culture positive . . . . o

II

.... ....

.

.

.

.

I

3

Extent of cavitationf 2 lO I2

.. . . . .

Direct e x a m i n a t i o n positive +++ . . . .

++ +

ESR (mm./r hr.) (Westergr:n 200 mm.)

14 or more 12-13- 9 IO-II-9 9"9 or less

. . . .

Bacteriological examination

Good . . . . . . Fair . . . . . . Poor . . . . . .

21--50

T o t a l patients

3 13 8 8

9 2 17 6 8

5 I6 3 8

Nil islight)" x-plus 2 - p l u s (moderate) 3 - p l u s (extensive)

Number of lung zones involvedt 3 or 4 . . . . . . 5 . . . . . . 6 . . . . . .

...

I 4 Io 18

2* 7* xI I2"

1 1o 22

5* 6* 21"

""

* Including I assessment by the clinician in charge. The radiograph was subsequently lost. ~Assessment on a single full-plate chest radiograph taken before start of treatment.

jTune I956 TABLE I f . -

TUBERCULOSIS IN AFRICANS

I55

RELATION OF CAVITATION ON ADMISSION TO THE BACTERIAL CONTENT OF TIIE SPUTUM* ON ADMISSION

Bacterial content of sputum Direct examination positive Extent of Total cavitation patients + + + Nil or i-plus 14 (slight) 2-plus 2I (moderate) 3-plus 3° (extensive)

Direct negative; Direct negath'e; concentration concentration negative; Scanty positive culture pos#ive

++

+

o

2

3

6

2

I

4

4

5

7

o

I

6

8

8

7

o

I

*For definitions of the grades of positive sputum

see

text.

tuberculosis was confined to epididymo-orchitis in one patient (SH), cervical adenitis in 3 patients (i SH, 2 PH) and synovitis of the wrist in I patient (PH). One patient (PH) had healed tuberculosis of the spine. P r e s e n c e of Other D i s e a s e s

Other diseases proved to be less important than cxpcctcd. The commonest abnormality was anacmia, 37 of the 65 patients having a haemoglobin below 12-o g. per cent, and 17 of them below Io-o g. per cent, in the pre-trcatment wcck (Table I). There were single cases of relapsing fever, asymptomatic S. mansoni infection, bacillary dysentery and duodenal ulcer, and 2 patients (i SH, i PH) had diabetes mellitus. A palpable spleen was present in 17 patients'. Splenomegaly not related to malaria, bilharzia or leishmaniasis is a wellrecognized but unexplained finding at Mulago Hospital; its relationship, if any, to liver disease has not been determined. A firm, non-tender liver was palpated in 6 patients. Neither treatment series had a preponderance of patients with these other diseases. Overt malaria did not occur. Results

TOXICITY Toxicity was not a problem with any of the three drugs used. No difficulty was encountered in administering PAS, in spite of the large dosage in relation to body weight" (the mean weight on admission to the trial of the 32 PH patient s was IO5~7 lb). Treatment was interrupted in only one patient (PH) and this was for five days due to vomiting following an attack ofhcute bacillary dysentery. Two other PH paticnts experienced paraesthesiae during the first few wccks of treatment, accompanicd in one by weakness of the muscles of the hands, which recovered without interruption of therapy. One SH patient h a d art urticarial rash in the third month; 2 had limb pains in the first fcw xCeeks. DEATHS

Five of the 65 patients died during the twenty-four weeks of the trial, 2 Sift patients in the fifth and eighteenth weeks and 3 PI-I patients in the third, fifth a n d twelfth weeks. All the deaths Were due to pulmonary tuberculosis, with

I56

June I956

TUBERCLE

TABLE III. -

PROGRESS

IN G E N E R A L

CONDITION

AND

]VEIGIIT

SH

Period of observation J2-24 u'eek~ o-24 wed's PH SII PH SH PH

24 8 o o

I9 9 I o

4 2o 4 ~

5 17 5 o

26 3 o o

26 I o o

I

3

I

0

2

3

33

32

3°

27

31

3°

I9 6 7 o

5 17 3 4

o 8 20 I

5 Io Io 2

22 6 x o

17 9 o I

32 i4. 7

29 9.i

29 4.8

27 7-I

29 2o-i

27 16.6

o - t 2 weeks

General condition Improvement : Considerable Moderate No change Deterioration Death Total

IVeight* (lb.) Gain 14 or more ,, 7-i3 ,, less than 7 or no change Loss Total weighed Mean gain in weight (lb.)

*One SH and 3 PH patients who died in the first twelve weeks have been excluded ; the SH patient who died in the second twelve weeks appears in the analysis at twelve weeks.

autopsy confirmation. The disease had pursued a steadily deteriorating course in all except the S H patient who survived eighteen weeks. At twelve weeks this patient showed 'conSiderable' clinical improvement and 'slight' radiographic improvement, but subsequently deteriorated and developed right heart failure shortly before death. T h e P H patient who died in the fifth week had diabetes. FINDINGS General Condition Change in the general condition (Table III) was assessed by the physician in charge. Improvement was usually considerable by twelve weeks, and continued, but more slowly, in the second twelve weeks. All the survivors at twenty-four weeks in both series showed imp{ovement. Weight The S H series gained more weight in tile first twelve weeks (Table III), the mean weight gain being I4- 7 lb. compared with 9.I lb. for the P H series, the difference being statistically significant. In the second twelve weeks the P H series gained weight more rapidly and partially redressed the early disadvantage. Over the twenty-four-week period the mean gains were 2o.x lb. for the S H series and I6.6 lb. for the P H series. TemperatUre A patient was considered to be initially afebrile if the evening temperature was below 99 ° F. (37.2 ° C.) on every day of the week of preliminary investigation. 22 of e8 S H survivors febrile in the pre-treatment week were afebrile at twelve weeks, compared with I8 of 24 febrile P H patients. At twenty-four CLINICAL

oTune i956

TUBERCULOSIS IN AFRICANS

157

weeks the figures were 19 o f 25 S H patients a n d 15 o f 22 P H patients. O n l y r patient (SH) h a d a n averag e evening t e m p e r a t u r e o f m o r e t h a n 99 ° F. at twelve weeks, a n d n o p a t i e n t h a d a pyrexia o f this level at twenty-four wecks. T h e two series fared similarly and the results have not been tabulated.

Erythrocyte Sedimentalion Rate T a b l e I V sets out the distribution o f the E S R s at the start o f the trial, at twelve and at t w e n t y - f o u r weeks. I n b o t h series there was a shift in the distribution to lower levels at twelve weeks a n d again at twenty-four weeks. T h e r e was little difference i n the progress o f the two series a n d at twenty-four weeks I6 o f 2 9 S H patients a n d I i o f 27 P H patients h a d an E S R ofless t h a n 2I m m . ; at the start o f t r e a t m e n t no patient h a d a n E S R as low as this. Haemoglobin Whereas only 2 o f 32 S H a n d 3 o f 29 Pt-I patients h a d a h a e m o g l o b i n o f 14 or m o r e g. per cent at the start o f t r e a t m e n t ( T a b l e IV), the n u m b e r s increased to I3 in each series at twelve weeks. By twenty-four weeks most patients in b o t h series h a d a n o r m a l h a e m o g l o b i n level. Character and Volume o f the Sputum T h e c h a r a c t e r o f the s p u t u m was classified on inspection as purulent, m u c o - p u r u l e n t a n d n o n - p u r u l e n t . O f the patients w h o survived twelve weeks t h e m a j o r i t y , 30 o f 32 S H patients a n d 26 o f 29 P H patients, h a d p u r u l e n t TABLE I V . -

CHANGES IN THE SEDIMENTATION RATE~ HAEMOGLOBIN AND SPUTUM

VoLUME:j AT TWELVE AND AT TWENTY-FOUR WEEKS

Pre-treatment SH PH Total*

,Sedimentation rate (ram.) o-Io I x-2o

2I-5O 51 plus Haemoglobin (g. per cent) 14 or more 12-I3. 9 ,o-II. 9 9"9 or less Sputum volume (ml.) None Less than 5 ° 5o-99 Ioo--~49 I5O or more Mean volume

32

29

At ze weeks SH PH 32

At 24 weeks SH PH

29

29

27

o

o

I

2

Io

7

o

o

3

4

6

4

I 31

2 27

14 14

7 16

5 8

Io 6

2 Io 12 8

3 Ii 8 7

x3 13 5 I

I3 13 3 o

22 6 x o

17 7 3 o

o I x7 6 8 112

o 5 I4 3 7 Io 5

I 17 x3 I o 46

7 I5 6 I o 33

9 I8 I I o 26

II 14 2 o o x9

* xStt and 3 P H patients who died in the first twelve weeks have been excluded; the S H patient who died at eighteen weeks appears in the analysis at twelve weeks.

B

I58

ffune I956

TUBERCLE

sputum at the start of treatment. By twelve weeks 8 SH and 7 PH patients still had purulent sputum. At twenty-four weeks only 3 patients, all in the SH series, had purulent sputum. The sputum volume in the pre-treatment week and in the twelfth and twenty-fourth weeks was carefully measured by one observer. The mean daily volume on admission (Table IV) was 112 ml. for the 32 SH patients and IO5 ml. for the 29 PH patients. By twelve weeks the average volume had decreased to 46 ml. in the SH series and 33 ml. in the PH series, and a further reduction to an average of 26 ml. for the SH series and 19 ml. for the PH series had occurred by twenty-four weeks. 9 of 29 SH patients and I I of 27 PH patients had no sputum at twenty-four weeks. Again the progress of the two series is similar. RADIOGRAPHIC FINDINGS

The radiological pancl initially undcrtook the radiographic assessments for the first twelve weeks (Table V). Those for the twenty-four-week period were undertaken at subsequent sessions (Table VI). The twenty-four-week assessment relates to a longer period of treatment and was made when more radiographic information was available, the same three-point scale of improvement being used both for the twelve and the twenty-four-week assessment. The improve mcnts in the twelve-week assessment (Table V) and those apportioned to the first twelve weeks in the twenty-four-week assessment (Table VI) are, therefore, not necessarily identical. By twelve weeks the majority of patients in both series, 93 per cent of 33 SH patients and 75 per cent of 32 PH patients, showed radiographic improvement (Table V). There were 8 SH patients with considerable improvement compared with 3 in the P H series. There was i death and no deteriorations in the SH series, and 3 deaths and I deterioration in the PH series. The SH series fared rather better than the PH series. In the twenty-four-week period (Table VI) all the survivors in both series showed radiographic improvement, and there was little to choose between the two treatments, although io of 31 SH patients had considerable radiographic improv6ment compared with 5 of 3 ° PH patients. In both series progress was similar, but there was less radiographic improvement in the second than in the first twelve weeks. TABLE V. - CHANGES IN RADIOGRAPHIC APPEARANCES IN THE FIRST TWELVE ~VEEKS

Total hnprovement Treatment patients No Slight series assessed Considerable Moderate Slight Change Deterioration SH PH

33 (99%) 32 (1OO%)

8

(24%) 3* (9%)

14

(42%)

Deaths

9

I

o

i

(27%)

(3%)

(0%)

(3%)

13"

8

4

i

3

(4I%)

(25%)

(I3%)

(3%)

(9%)

*For x patient the radiographic assessment is that recorded by the clinician in charge. The x-rays were subsequently lost.

dTune 1956, TABLE VI.

TUBERCULOSIS IN' AFRIOANS - CHANGES

159

IN RADIOGRAPHIC APPEARANCES IN TIIE T~VENTY-FOUR-WEEK

PERIOD

Total Patients Improvement Assessedfor No Slight the period Considerable Moderate Slight change Deterioration

Deaths

Change o-~4 weeks SH PH

31 (99%) 3° (zoo%)

io (32%) 5* 07%)

17. (55%) I9" (63%)

2 (6%) 2 (7%)

o (o%) z (3%)

o (o%) o (o%)

2 (6%) 3 (IO%)

Change o--ze weeks SH PH

(ioo%)

31

(io%)

3

(35%) (52%) (0%)

II

I6

o

(0%)

o

(3%)

I

30 (lOO%)

2" (7%)

7* (23%)

I5 (50%)

2 (7%)

i (3%)

3 (io%)

30 (99%) 27 (IoI%)

o (0%). o (0%)

7 (23%) 5 09%)

2i (70%) 2I~ (78%)

i (3%) I (4%)

o (0%) O (0%)

i (3%) O (0%)

Change z2-e 4 weeks SH PH

*For I patient the radiographic assessmentis that recorded by the clinician in charge. The x-rays were subsequently lost. tFor 2 patients the radiographic assessmentswere those recorded by the clinician in charge. The x-rays were subsequently lost. BACTERIOLOGICAL FINDINGS

Bacterial Content of the Sputum Sputum collected during the pre-treatment week, and subsequently at fourweekly intervals, was examined by microscopy, both of direct smears and of concentrated specimens, and also by culture. (Where there was no sputum, gastric lavage specimens were obtained.) T h e sputum was homogenized with 5 per c e n t caustic potash and cultures were set up on L6wenstein-Jensen slopes. Cultures were reported as negative if no growth had occurred after eight weeks' incubation. G u i n e a - p i g inoculation was sometimes performed in addition to culture. T h e bacterial content on the direct smear examination was graded, mainly by one obse/ver (I. hi. T.), using a I / I n oil immersion lens and a X 8 eye-piece, according to the following scale: q---}-+ each field very crowded with bacilli; +-b each field crowded with bacilli; q-- i or more bacilli or groups of bacilli per field; scanty i bacillus or group of bacilli in a m a x i m u m of I O fields. T h e concentrated specimens were graded either as -}- or as scanty. T a b l e V I I sets o u t the d a t a on the presence o f t u b e r c l e bacilli for the t w o series before t r e a t m e n t a n d at four-weekly intervals u p to t w e n t y - f o u r weeks. I n this t a b l e a test a p p e a r s u n d e r its m o s t positive element, so t h a t a test

160

TUBERCLE

oTune 1956

reported as + on direct examination and q- on concentration is recorded as -1- on direct examination. Results are included in the table only as long as the patient remained without interruption on a chemotherapeutic regime. An increasing number of patients in both series had tests negative both on direct examination and on culture and by twenty-four weeks only 2 of 24 S H patients and I of 22 P H patients had a positive sputum. T h e findings at four, eight, twelve and sixteen weeks suggest, at first sight, that the P H regime was more effective in reducing the bacterial content of the sputum than the S H regime. However, before treatment started, the S H patients had on average a higher bacterial content of the sputum, for 9 had a -k + - k result on direct examination compared with only I in the P H series. The findings for the twenty-four-week period in this sub-group of 9 patients are given in brackets in Table VII. All 4 SH patients with a q- -b result on direct examination at four weeks came from this sub-group of 9 patients with a heavily positive sputum, as did all 4 q- q- results at eight weeks and the only q- q- result at twelve weeks. At sixteen weeks, 4 of the 6 direct positive results were from this sub-group as was I of the 2 remaining direct positive results at twenty weeks. At twenty-four weeks there were only 2 S H patients who were still positive bacteriologically, and both were in this sub-group. Thus the persistence of a positive sputum in these patients was related to the high bacterial content of the sputum at the start of treatment, and it cannot be concluded that the P H treatment was the more effective in converting the sputum to negativity.

Sensilivity Tests All strains isolated from specimens collected before the start of treatment, and subsequently at four-weekly intervals were tested for isoniazid sensitivity; those from SH patients were also tested for streptomycin sensitivity and those from PH patients for PAS sensitivity. Results have been tabulated for each patient, only for as long as the patient remained without interruption on a chemotherapeutic regime. For the streptomycin and PAS sensitivity tests the M R C Dubos liquid medium techniques were used (Medical Research Council, i953b ). In the early stages of the trial, isoniazid sensitivity tests were also performed in Dubos liquid medium, but later tests were carried out on L6wenstein-Jensen slopes by the M R C technique (Medical Research Council, i953b ). In order to confirm that the techniques had been standardized, 19 cultures were flown to England and sensitivity tests to the drugs prescribed were undertaken in the M R C .Reference Laboratory by Dr D. A. Mitchison. In every strain tested the findings of the Uganda Laboratory were confirmed. All the strains obtained before the start of treatment were sensitive to each of the drugs in the prescribed combination.

Isoniazid Sensitivity-

The results of the isoniazid-sensitivity tests are set out in Table VIII. All the strains tested throughout the twenty-four-week period in both treatment series were sensitive to isoniazid, whether tested by the M R C solid medium technique or in Liquid Dubos medium.

Streptomycin Sensitivity-Streptomycin-sensitivity

tests were performed on cultures from 29 patients at four weeks, from 26 at eight weeks, from 17 at twelve weeks, from 6 at sixteen weeks, and from 3 at twenty weeks. All the cultures were sensitive. There were no positive cultures for sensitivity tests at twentyfour weeks.

23

SH PH

Sift PH

SH

PH

i2

I6

20

24

26

SH PH

8

o

o

o o

o o

o o

o o

o o

9 I

o

o

o o

o 0

I (I) o

o

i (i)

o I

o 0

6 (3) o

4 (2) 3

i o (3) 4

4 (4)~ I (I) 4 (4) o

9 7

5 9

o

o

2 (,) 2

6 (4) I

4 (r) 3

6 5

5 II

9 tI

I

x (1)

i o

o 0

o I 0)

I 4

4 I

o o

o

o

3 (1) 2

2 r2

3 (I) 6

7 5 (i)

4 (i) 8

I I

o

o

o I (x)

o I

7 (2) Io

7 (3) 9

3 3

o 3

+

21 (1)

22 (5)

17

20(5)

16 (4) 20 ( I )

IO (I) 7

3 4

i I

o o

Negative

Direct neg.; concentration neg.; culture and/orguinea-pig inoculation

*A test was regarded as incomplete and was ignored unless a culture or guinea-plg inoculation result was available, ~'Even if culture-negative or guinea-pig inoculation negative. ~.The results given in brackets (included in the previous figure) are those for the patients with a + + + direct examination pre-treatment (o-weeks). One paUent does not appear after twelve weeks as chemotherapy was then stopped ; another died at eighteen weeks.

24

22

SH

PH

24 24

31 27

32 3°

3I 29

SH PH

4

33 32

SH PH

o

Scanty

+

Scanty

++

+

Direct negative; concentrationt

Direct positivet

PRESENCE OF TUBERCLE BACILLI AT SINGLE EXAMINATIONS I~V~ADE AT FOUR-'~VEEKLY INTERVALS

Weeks after Total start of Treatment patients chemotherapy series examined* + + +

TABLE V I I . -

24 24 26 23

SH PH

SH PH

SH PH

SH PH

I2

16

20

24

24 22

~3 22

18 22

14 9

3 6

3 2

Culture-negative (no sensitivity test possible)

o o

o o

o o

o I

I 4

I ~

Culturepositive but no sensitivity test available

o o

3 z

6 2

I7 I7

28 2o

27 ~5

Total results available

o o

2 i

4 2

IO 14

x4 I2

IX I3

Sensitive by MRC* solid medium tedmique

o o

z o

2 o

7 3

14 8

I6 I~

Sensitive in liquid Dubos medium

o o

3 I.

6 2

x7 I7

28 2o

27 25

Total~ sensitive

Patients culture-positive with sensitivity test

RESULTS OF ISONIAZID-SENSITIVITY TESTS

*Medical Research Council (x953b). "i'None were resistant in either series throughout the twenty-four weeks. The discrepancies between the numbers of negative'cultures-in this table and Table VII are due to tile results that were positive on direct examination or concentration, but negative on culture.

24 22

3I 27

32 3°

SH PH

8

3z 29

SH PH

Treatment series

4

Weeks after start of dtemotherapy

Total patients with culture examined

TABLE V I I I . -

Lrt

l,a

June I956

TUBERCULOSISIN AFRICANS

x63

PAS Sensitlvi~-PAS-sensitivity tests were performed on cultures from 23 patients at four weeks, I8 ateight weeks, 13 at twelve weeks, I at sixteen weeks, and I at twenty weeks. All the cultures were sensitive. Discussion

In the present trial acute extensive bilateral disease, the severest and one of the most common types of pulmonary tuberculosis encountered in hospital practice in Uganda, has been studied. The trial has shown the effectiveness of combinations of streptomycin plus isoniazid and of PAS plus isoniazid o~¢er a period of twenty-four weeks in African patients on bed-rest in hospital. This has been demonstrated by improvement in the clinical, radiographic and bacteriological features. The results were" in striking contrast to previous experience with similar disease treated by rest in bed only (Haynes and Henderson, I952 ) . There was" little difference in the therapeutic response to the two regimes. Radiographically at twelve weeks the SH series had a slight advantage and this finding is in conformity with the slight superiority of the streptomycin regime reported in trials in Great Britain (Medical Research Council, I953c, I955), particularly as the patients in the present trial in the SH series were initially more ill, having on average more extensive cavitation and a more heavily positive sputum on admission. Both combinations prevented the emergence of drug-resistant organisms throughout the twenty-four weeks. There were no troublesome toxic effects from any of the drugs in the dosage used, and althot/gh the patients were slightly built, those receiving 20 g..of sodium PAS daily tolerated this dosage well. It is noteworthy that the combination of PAS with isoniazid has emerged as a satisfactory regime for the severest form of pulmonary disease. U n d e r the present conditions in East Africa "this oral combination has obvious advantages over a combination that necessitates regular injections. The ESR and temperature are less useful criteria for the assessment of progress in East African patients than they were in the M R C trials in Britain. On the other hand, certain additional observations not included in those trials, namely, the haemoglobin, the character and volume of the sputum, and the detailed grading of its bacterial content, have all proved useful assessments. The ESR is a rather unsatisfactory assessment since very higlf rates are common in general hospital practice in Africa (Courdurier a n d Bfygoo, I947; McGregor and Deegan, i954) , related in part to anaemia and other conditions, and in part to differences in the serum proteins; in the present series 24 of 65 patients had an initial ESR above Ioo mm. The level of the ESR provides r/o direct comparison with findings in Great Britain. Quite high fever in Africans with pulmonary tuberculosis may subside rapidly, even within a few days, on bed-rest without chemotherapy. Resolution ofpyrexia is thus not a reliable indication of an early response to drug treatment, and bed-patients may be apyrexial yet be more acutely ill than those seen in European practice. Haemoglobin estimations, one of the additional assessments, showed that anaemia was very common on admission and, altfiough only two of the patients were given iron, there was a steady improvement in haemoglobin levels in both series during the course of the trial, this being clearly apparent in the first twelve weeks. T h e nature o f the 'anaemia was not investigated in detail, but

i64

TUBERCLE

June I956

it was not considered that malaria, hookworm infestation, nutritional iron deficiency or deficiencies of specific haemopoietic factors were responsible. Since a degree of malnutrition is common in East Africans, particularly in respect of proteins, it is possible that the larger and better balanced hospital diet was in part responsible for the increasing haemoglobin levels. However, the rapidity with which the haemoglobin rose with improvement in the general condition is in favour of the anaemia being associated with tuberculous toxaemia. Particular attention was paid to the volume, character and bacterial content of the sputum, which when considered together may be regarded as an index of infectivity. Whereas at the start of the trial most of the patients were producing large quantities of heavily infectious purulent sputum, at twelve weeks the sputum volume in both series wag reduced to less than a half, and by twentyfour weeks to less than a quarter. Moreover, 2o patients had no sputum at all at the end of the trial. Since only 3 patients still had a positive sputum at twenty-four weeks the immediate potentiality of this group of patients as a source of infection had been greatly reduced. The changes in the naked-eye appearance and the daily volume of the sputum paralleled the bacteriological and radiographic changes and provided valuable information. Both these observations can conveniently be made in rural hospitals where visits to a radiographic department may be difficult to arrange and where facilities for sputum culture may not be available. Grading the sputum according to the degree of positivity showed that there was a sub-group of patients in the streptomycin series with a heavily positive sputum at the start of the trial who took longer to become sputum-negative than the rest. Moreover, the bacterial content of their sputum did not simply reflect the extent of initial cavitation. It therefore seems probable that patients with a heavily positive sputum at the start of treatment should be given longer and more intensive chemotherapy than those with smaller numbers of bacteria in their sputum. It is necessary in future, in trials of this kind, to study the pre-treatment bacterial content of the sputum, not only from the point of view of comparing the groups on admission to the trial but in order to interpret the response to treatment (Fox and Sutherland, I955). In conclusion, the two combinations studied in this trial have proved very effective for up to twenty-four weeks in patients on bed-rest in hospital and are capable of modifying radically the course" of severe acute disease in East Africans. It remains to be seen, however, whether, when patients return home, the initial improvement will be maintained or whether recrudescence will be frequent or rapid. It is only after much longer observation that the contribution that chemotherapy has made in the group of patients in this trial can be fully assessed. A follow-up study is at present in progress to investigate survival, quiescence, and relapse. It is also of interest to know how the response of East Africans to chemotherapy compares with that of Europeans with similar disease. This is being investigated and will be the subject of a further report. Summary Sixty-five East Africans with acute bilateral pulmonary tuberculosis, bacteriologically positive, were treated either with streptomycin x g. plus isoniazid 200 mg. daily (33 SH patients) or with PAS sodium 20 g. plus isoniazid 200 mg. daily (32 PH patients) for a period of twelve weeks, the

ff//ne i 9 5 6

TUBERCULOSIS IN AFRICANS

I~ 5

treatments being allocated at random. The majority of patients in each treatment series continued on the same combination for a second twelve weeks, though in the S H series the dosage of both drugs was reduced. At the start of the trial there were more very ill patients in the S H than in the P H series. No troublesome toxic effects from any of the drugs were encountered. Nearly all the patients in both series improved clinically and bacteriologically. Thus at the end of twenty-four weeks, 93 per cent of the SH patients and 87 per cent of the P H patients showed radiographic improvement, and only 3 patients (2 SH, I PH) still had a positive sputum. At the end of twelve weeks the S H combination was slightly superior to the P H combination in respect of weight gain and radiographic changes; at the end of twenty-four weeks, the differences between the two regimes were smaller. In the whole twenty-four-week period 2 S H and 3 P H patients died. The SH combination took longer to diminish the bacterial content of the sputum than the P H combination, but this was associated with larger numbers of bacteria in the sputum of some of the patients in the S H series at the start of the trial. No drug resistance was encountered in either series. Changes in the character of the sputum, and reduction in its daily volume, proved to be simple and valuable indices of progress. Anaemia was present in many ofthe patients before treatment. This improved at the same time as the tuberculosis, without specific treatment. It is concluded that b o t h combinations are effective, and that the PASisoniazid combination is a powerful and valuable form of oral chemotherapy in East Africans. We should like to record the interest and encouragement shown by the late Dr Marc Daniels in the initiation of this trial We are indebted to Dr D. A. Mitchison for checking the sensitivity of the cultures and to Dr A. A. M. Wilson who undertook the bacteriological examinations during the temporary absence of one of us. We are grateful to the Director of Medical Services, Uganda, for facilities, and to Dr A. A. Alderdice, Medical Superintendent of Mulago Hospital, Dr A. B. Raper, Senior Pathologist, and to Dr A. G. M. Davies and his radiographers for their help and co-operation. We are grateful to Dr Ian Sutherland for his statistical advice. Mr Samuel ~Vamala performed the haemoglobin estimations and sedimentation rates. Most of the drugs used in this trial were given by Messrs Smith and Nephew Ltd., ~Velwyn Garden City, and Messrs E. R. Squibb and Sons of Liverpool. References Courdurler, J., and Brygoo, E. (I947) M/d. trop., 7, 254. Fox, W., and Sutherland, I. (x955) Thorax, 10, 85. Haynes, W. S. (1952) E. Aft. rned. ft., 29, 339. Haynes, W. S., and Henderson, R. R. (1952) E. Aft. reed. 3., 29, 357McGregor, I. A., and Deegan, T. (x954) Ann. trop. rned. Parasit., 48, No. 2, 2~o. Medical Research Council (1952) Brit. meal. ft., 2, 735Medical Research Council (1953a) Brit. rned. ft., 1, 52I. Medical Research Council (1953b) Lancet, 2, 2x 3. Medical Research Council (t953¢) Brit. reed. o7., 2, xoo5. Medical Research Council (1955) Brit. med. J., 1, 435-