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MEDICAL
BRITISH JOURNAL
LONDON SATURDAY OCTOBER 30 1948
STREPTOMYCIN TREATMENT OF PULMONARY TUBERCULOSIS
A MEDICAL RESEARCH COUNCIL INVESTIGATION
The following gives the short-term results of a controlled investigation into the effects of streptomycin on one
type of pulmonary tuberculosis. The inquiry was planned and directed by the Streptomycin in Tuber-
culosis Trials Committee, composed of the following members: Dr. Geoffrey Marshall (chairman), Professor
J. W. S. Blacklock, Professor C. Cameron, Professor N. B. Capon, Dr. R. Cruickshank, ProfessorJ. H. Gaddum,
Dr. F. R. G. Heaf, Professor A. Bradford Hill, Dr. L. E. Houghton, Dr. J. Clifford Hoyle, Professor
H. Raistrick, Dr. J. G. Scadding, Professor W. H. Tytler, Professor G. S. Wilson, and Dr. P. D'Arcy Hart
(secretary). The centres at which the work was carried out and the specialists in charge of patients and
pathological work were as follows:
Brompton Hospital, London.-Clinician: Dr. J. W. Bangour Hospital, Bangour, West Lothian.-Clinician:
Crofton, Streptomycin Registrar (working under the Dr. I. D. Ross; Pathologist: Dr. Isabella Purdie.
direction of the honorary staff of Brompton Hospital); Killingbeck Hospital and Sanatorium, Leeds.-Clini-
Pathologists: Dr. J. W. Clegg, Dr. D. A. Mitchison. cians: Dr. W. Santon Gilmour, Dr. A. M. Reevie;
Colindale Hospital (L.C.C.), London.-Clinicians: Dr. Pathologist: Professor J. W. McLeod.
J. V. Hurford, Dr. B. J. Douglas Smith, Dr. W. E. Snell; Northern Hospital (L.C.C.), Winchmore Hill, London.
Pathologists (Central Public Health Laboratory): Dr. -Clinicians: Dr. F. A. Nash, Dr. R. Shoulman; Patho-
G. B. Forbes, Dr. H. D. Holt. logists: Dr. J. M. Alston, Dr. A. Mohun.
Harefield Hospital (M.C.C.), Harefield, Middlesex.- Sully Hospital, Sully, Glam.-Clinicians: Dr. D. M. E.
Clinicians: Dr. R. H. Brent, Dr. L. E. Houghton; Thomas, Dr. L. R. West; Pathologist: Professor W. H.
Pathologist: Dr. E. Nassau. Tytler.
The clinicians of the centres met periodically as a working subcommittee under the chairmanship of
Dr. Geoffrey Marshall; so also did the pathologists under the chairmanship of Dr. R. Cruickshank.
Dr. Marc Daniels, of the Council's scientific staff, was responsible for the clinical co-ordination of the
trials, and he also prepared the report for the Committee, with assistance from Dr. D. A. Mitchison
on the analysis of laboratory results. For the purpose of final analysis the radiological findings were
assessed by a panel composed of Dr. L. G. Blair, Dr. Peter Kerley, and Dr. Geoffrey S. Todd.
Introduction ifbasedon adequatelycontrolled clinical trials(H4inshawand
When a special committee of the Medical Research Feldman, 1944). The onecontrolled trial of gold treatment
Council undertook in September, 1946, to plan clinical trials (and the only report of an adequately controlled trial in
of streptomycin in tuberculosis the main problem faced was tuberculosis we have been able to find in the literature)
that of investigating the effect of the drug in pulmonary reported negativetherapeutic results (Amberson, McMahon,
tuberculosis. This antibiotic had been discovered two years and Pinner,1931). In 1946nocontrolled trialofstreptomycin
previously by Waksman (Schatz, Bugie, and Waksman, in pulmonary tuberculosis had been undertaken in the
1944); in the intervening period its power of inhibiting U.S.A. The Committee of the Medical Research Council
tubercle bacilli in vitro, and the results of treatment in decided then that a part ofthe small supply ofstreptomycin
experimental tuberculous infection in guinea-pigs, had been allocated toitfor researchpurposeswould bebestemployed
reported; these results were strikingly better than those in a rigorously planned investigation with concurrent
with any previous chemotherapeutic agent in tuberculosis. controls.
Preliminary results of trials in clinical tuberculosis had The many difficulties of planning and conducting a trial
been published (Hinshaw and Feldman, 1945; Hinshaw, of this nature are important enough to warrant a full
Feldman, and Pfuetze, 1946; Keefer et al., 1946); the clini- description here of the methods of the investigation.
cal results in pulmonary tuberculosis were encouraging but
inconclusive. Plan and Conduct of the Trial
The natural course of pulmonary tuberculosis is in fact
Type of Case
so variable and unpredictable that evidence of improvement
or cure following the use of a new drug in a few cases A first prerequisite was thatall patients in thetrial should
cannot be accepted as proof of the effect of that drug. have a similar type of disease. To avoid having to make
The history of chemotherapeutic trials in tuberculosis is allowances for the effect of forms of therapy other than
filled with errors due to empirical evaluation of drugs bed-rest, the type of disease was to be one not suitable for
(Hart, 1946); the exaggerated claims made for gold treat: other forms of therapy. The estimated chances of spon-
ment, persisting over 15 years, provide a spectacular taneous regression must be small. On the other hand, the
example. It had become obvious that, in future, con- type of lesion should be such as to offer some prospect of
clusions regarding the clinical effect of a new chemothera- action by an effective chemotherapeutic agent; for this
peutic agent in tuberculosis could be considered valid only reason old-standing disease, and disease with thick-walled
4582
770 OCT. 30, 1948 STREPTOMYCIN TREATMENT OF PULMONARY TUBERCULOSIS MEDICLJOUNAL
cavities, should be excluded. Finally the age group must series were unknown to any of the investigators or to the
be reasonably limited, since the total number of patients co-ordinator and were contained in a set of sealed
in the trial could not be large. envelopes, each bearing on the outside only the name of
Such closely defined features were considered indispen- the hospital and a number. After acceptance of a patient
sable, for it was realized that no two patients have an by the panel, and before admission to the streptomycin
identical form of the disease, and it was desired to eliminate centre, the appropriate numbered envelope was opened at
as many of the obvious variations as possible. For these the central office the card inside told if the patient was to
several reasons the type of case to be investigated was be an S or a C case, and this information was then given
defincd as follows: acute progressive bilateral pulmonary to the medical officer of the centre. Patients were not told
tuberculosis of presumably recent origin, bacteriologically before admission that they were to get special treatment.
proved, unsuitable for collapse therapy, age group 15 to C patients did not know throughout their stay in hospital
25 (later extended to 30). that they were control patients in a special study; they
The selection of this type of disease constituted full justi- were in fact treated as they would have been in the past,
fication for having a parallel series of patients treated only the sole difference being that they had been admitted to the
by bed-rest, since up to the present this would be con- centre more rapidly than was normal. Usually they were
sidered the only suitable form of treatment for such cases. not in the same wards as S patients, but the same regime
Additional justification lay in the fact that all the strepto- was maintained
mycin available in the country was in any case being'used, It was important for the success of the trial that the
the rest of the supply being taken up for two rapidly fatal details of the control scheme should remain confidential.
torms of the disease, miliary and meningeal tuberculosis. It is a matter of great credit to the many doctors concerned
that this information was not made public throughout the
Recruitment and Admission of Cases 15 months of the trial, and the Committee is much indebted
Co-operation in the trial was obtained in the first place to them for their co-operation.
from Brompton Hospital (drawing on London County By definition, cases accepted.for the trial were unsuitable
Council cases), Colindale Hospital (London County for collapse therapy ; clinicians were therefore asked to
Council), and Harefield County Hospital (Middlesex adopt collapse therapy only if the course of the disease so
County Council). The L.C.C. and the M.C.C. gave full changed that some collapse measure became indispensable
co-operation, permitting recruitment of suitable cases from and urgent. In the S cases collapse therapy was in fact
the areas served by them, covering a population of nearly never applied during the four treatment months. It was
six million persons. Accordingly letters were sent, through given to five of the 52 C cases during that period.
the tuberculosis departments of these authorities, to tuber-
culosis officers and to medical superintendents of general Observation and Treatment Period
hospitals outlining the proposed trial and asking that par- Each patient was to remain in bed at the centre for at
ticulars and x-ray films of possibly suitable patients he least six months, and the results were to be assessed on the
sent to the co-ordinator of the trials for consideration. clinical status at the end of that period. In addition to
Visits were paid to the tuberculosis clinics and hospitals the usual hospital records, clinical observations were
to show by representative x-ray films thte type ofcase sought entered on standard record forms designed particularly
and to explain in detail the nature of the controlled trial. for this trial; these forms provided for details of history,
When cases were submitted the clinical particulars and criteria of acceptance, examination on admission, monthly
x-ray films were taken to the Committee's selection panel routine re-examinations with assessment of progress since
for consideration. When a patient had been accepted as last examination, observation of toxic reactions, tempera-
suitable, request was made through the local authority for ture and treatment records, and finally a pathological record
admission to one of the streptomycin centres; in spite of form. Instructions on required frequency of examinations
long waiting-lists thesepatients weregiven complete priority, were given.
and the majority were admitted within a week of approval. Clinicians and pathologists' meetings were held during
The first patients to be accepted were admitted to the t'he trials to discuss the work as it proceeded. The
centres in January, 1947. At first the impression was that co-ordinator visited centres and was constantly in touch
cases of the type defined are seen often. In fact, such with the clinicians concerned to discuss the progress of the
cases are not common. As it became evident after three trial and the problems arising. The working subcommittee
months that enough cases could not be found in the London of pathologists established the technical laboratory pro-
and Middlesex areas, other authorities were approached. cedures, discussed the findings at intervals, and arranged
The Welsh National Memorial Association, the Department for independent checking of sensitivity tests of tubercle
of Health for Scotland, and the Leeds Tuberculosis Service bacilli and streptomycin levels in the blood.
made available centres at Sully, Bangour, and Killingbeck,
and cases were recruited to those centres from the respec- Analysis of Results
tive areas. In addition, another centre was opened in the The general trend of results during the course of the
London area, at the Northern Hospital (L.C.C.). trial was followed through the monthly reports frqm the
By September, 1947, 109 patients had been accepted, and centres. The analysis of results up to six months after the
no more were admitted to this trial. Two patients had died patient's admission is presented here; it is based on infor-
within the preliminary observation week ; theseare excluded mation from the standard record forms completed for each
from the analysis. Of the remaining 107 patients 55 had patient and on the x-ray films which have been made avail-
been allocated to the streptomycin group and 52 to the able by the hospitals concerned.
control group. The films have been viewed by two radiologists and a
The Control Scheme clinician, each reading the films independently and not
Determination of whether a patient would be treated by knowing if the films were of C or S cases. One of the radio-
streptomycin and bed-rest (S case) or by bed-rest alone logists had been attached to a centre taking part in the
(C case) was made by reference to a statistical series based trial; the other two specialists had not been connected
on random sampling numbers drawn up for each sex at with the trial in any way. There was fair agreement among
each centre by Professor Bradford Hill ; the details of the the three; at a final session they met to review and discuss
OCT. 30, 1948 STREPTOMYCIN TREATMENT OF PULMONARY TUBERCULOSIS BSDITisH 771
films on which there had been a difference of interpretation, following exchange of correspondence with Dr. H. C.
and agreement was reached without difficulty on all films. Hinshaw, of the Mayo Clinic, to whom the Committee is
The results of radiological assessment presented in the main indebted for advice during the planning of the trial.
analyses are the agreed results, but the separate reports and
The original intention was to continue streptomycin treat-
their differences are discussed under the heading "Changes ment for six months. However, reports from observers in
in Radiological Picture." the U.S.A., and a growing impression in our own centres,
indicated that the maximum effect of streptomycin was
Condition on Admission reached within the first three or four months, and it was
Each patient was under observation at a centre for at therefore decided in July, 1947, to treat patients for four
least one week before streptomycin treatment or observa- months only, but to continue observation to the end of
tion proper for the trial started. Data in Table I reflect six months from admission as for C patients. (One patient
the condition on admission. was treatedwith streptomycinfor 6 months,2 for 51 months,
6for 5months, 5 for 4} months; the remainder, 41 patients,
TAXBLE I.-Coniditioni oni Adniiissionz were treated for 4 months.)
Patients in both groups were on bed-restduring the period
General G Max. Evening z = Sedimenta- z a of the trial, and were allowed only up to toilet where the
Condceio- Uo Temp. o o tion °Co
tion 0 0 inFirstWeek* 0 0 Rate 0 0 general condition allowed. As already indicated, although
patients admitted were considered unsuitable for collapse
Good 8 8 98-989° F. 3 4 0-10 0 0
(36-7-37-153C.) therapy, it was agreed that when the course of disease had
Fair . 17 20 (3799--29-9397-7950F.C.) 3 12 -120 3 2 so changed that collapse therapy was strongly indicated
Poor 30 24 100-10090F. 15 17 21-50 16 20 such treatment should be given. In 11 C patients collapse
(378-38-250C.)
101°F.(3833C.) 24 19 51- 36 29 measures(artificial pneumoperitoneumwith phrenicparalysis
Total 55 52 Total 55 52 ii Total 55 51t in 10cases, pneumothorax in one)were induced at some time
during the six months-three in the third month ofobserva-
*Temperaturebymouthinallbutsixcases. tExaminationnotdoneinonecase. tion, two in the fourth month, two in the fifth, and four in
the lastobservation month. In seven of the Ithe course of
Thirty patients (54%) in the S group and 24 (46%) in the the disease appears not to have been affected; in four there
C group were in poor general condition at the start of the was deterioration before and improvement afterinduction of
trial ; of these, 20 and 17 respectively were considered to artificial pneumoperitoneum. Collapse therapy was induced
be desperately ill. Twenty-four S patients (44%) and 19 in 11 S patients during the fifth or sixth month; in all but
C patients (36%) had during the preliminary observation two the course of the disease was apparently unaltered.
week maximum evening temperatures of 1010 F. (38.30 C.)
or over. In 36 S patients (65%) and 29 C patients (56%)
Results at End of Six Months
the sedimentation rate (Westergren, 200 mm. reading at one
Four of the 55 S patients (7%) and 14 of the 52 C
hour) was over 50.
patients (27%) died before the end of six months. The
These data reflect the fairly acute clinical condition of
difference between the two series is statistically significant;
most of the patients, though obviously the clinical picture
the probability of it occurring by chance is less than one in
was far from uniform in the 107 patients admitted to the
a hundred.
trial. The data show also that random distribution has
equalized the groups; if anything, there are more severe Assessment of condition at the end of the six-months
cases in the S group. There were 22 men and 33 women period should be based on a judicious combination of
in the S group, 21 men and 31 women in the C group. changes in the radiological picture, changes in general con-
dition, temperature, weight, sedimentation rate, and bacil-
lary content of the sputum. We have not attempted a
X-ray Classification
numerical evaluation of the relative importance of each
All cases conformed more or less to the type defined,
but within the possible limits of the definition there were of these, and changes in them will be reported in turn.
wide variations. All films showed opacities representing Appreciation of the clinical effects of the drug have not
been lacking in the many reports published within the past
extensive infiltration of apparently recent origin ; where
there was room for doubt the length of history was taken two years. So far as possible, the analysis in this report
will deal with the more readily measurable data only.
into consideration as evidence of the age of the lesions.
It was thought at first that gross cavitation should be The following preliminary analysis is based on changes
excluded, but this view was abandoned, as many otherwise in the radiological picture alone, this being in our opinion
suitable cases had large cavities. Thirty-two of the 55 the most important single factor to consider ; it will be
S cases and 30 of the 52 C cases showed large or multiple seen later that in the great majority of cases clinical and
radiological changes followed similar trends.
cavities in the film taken on admission (tomography was
not used as a routine) ; it must be stressed, however, that
TABLE II.-Assessment of Jiadiological Appearance at SixMonths as
from their radiological appearance these seemed to be of Compared with Appearance on Admission
recent development and that the lesions predominating in
the lungs were bronchopneumonic in type. RadiologicalAssessment StreptomycinGroup ControlGroup
In 19 S cases and in 19 C cases there was radiological Considerableimprovement 28 51% 8%
evidence of segmental atelectasis. Moderate or slight improvement 10 18% 13 25%
Nomaterialchange .. 2 4% 3 6%
Moderate or slight deterioration 5 9% 12 23%
Treatment Considerabledeterioration 6 11% 11%
Deaths . . 4 7% 14 27%
All S patients were given streptomycin* by the intra- 100% 100%/
muscular route. The dose was 2 g. per day, given in four Total 55 52
injections at six-hourly intervals. This dosage was adopted
The overall results given in Table II (extracted from
*The streptomycin used was in the form of the hydrochloride,
obtained from one American producer. For technical particulars of Table IX) show differences between the two series that
the product see article in Lancet, 1948, 1, 582. leave no room for doubt. The most outstanding difference
772 OCT. 30, 1948 STREPTOMYCIN TREATMENT OF.PULMONARY TUBERCULOSIS BRDIlRNAL
is inthe numbers who showed "considerable improvement" werein patients who had onadmission evening temperatures
in the radiological picture-i.e., those for whom at the end of 1010 F. (38.30 C.) or over. A second, more important,
of the six-months period there was a reasonable prospect point that emerges is that the superiority of results in the
of recovery. Twenty-eight of theS patients (51%) and only S group as a whole over the C group is almost entirely
four of the C patients (8%) were considerably improved accounted for bythemost febrile patients. Only seven (19%)
(the probability of such a difference occurring by chance of 36 C patients with a temperature of 1000 F. (37.80 C.)
is less than one in a million). or over were improved at the end of six months, compared
Results in men and women were similar, and need not with 26 (67%) of 39 S patients. Further analysis reveals
be tabulated here. There was a higher mortality among that eight of the 24 S patients with a temperature of 1010 or
males in both S and C groups; two of 22 male S patients over showed considerable improvement, and none of the
died and eight of 21 male C patients, compared with two of 19 C patients. In less febrile and in afebrile patients
33 female S patients and six of 31 female C patients, but the there is little difference in results between the two groups,
difference is not significant. though analysis shows that the number showing consider-
able improvement was greater in the S group.
Results Related to Condition on Admission
The next point to be considered is whether the prognosis Sedimentation Rate (E.S.R.)
was worse in those most acutely ill, and whether the dif- Relation of results to the E.S.R. on admission shows the
ference between the S and C groups applies to the less same trends. Of patients with an E.S.R. not higher than
or more acutely ill patients. 50, 13 (68%) of 19 S patients were improved, compared
with nine (41%) of 22 C patients. Eighteen (50%) of 36 S
Temperature patients with E.S.R. over 50 were improved, compared with
TABLE III.-Results at Six Months Related to Temperature on seven (24%) of 29 C patients.
Admission
Radiological Assessment on Admission
Max.Evening RadiologicalAssessmentat6Months
TOebmsepr.vadtuiroinngWFeierskt Improve- No Deteriora- DDeaathhs Tootaal TABLPrEesIeVn.c-eRaodrioAlbosgeinccael oAfssGersossmsentCavaittaStiixonMoonnthAsdmRieslsaitoend to
ment Change tion
(3968--7-9387--91°50F.C.) lfC 33 01 00 00 43 a 0I0 RadiologicalAssessmentat6 Months (A
(379-92--9379.9705F°.C.) fSC 97 21 23 01 1132 AXd-mRiasysioonn 00 Eluo siCdeoIrnma-pblreoveMSmoleidngehtrtaotre ChNaonge MSolidDgeehrttaeotrrieorasstididCeoeonrrna--blle
10(131070.F08.--1(303808.-239500CFC...))+ {lrCs~C 113235 0001 7296 0458 21114759 Casmclaauevrlsigtteiwipeilstoehr .-ss1I-3320I 111I-1--- -I- 78*I--I 22 46 ,~ 42 ,1-114
Othercases ASC 2232 173 35 0 61 42 03
IMt1ROVEMENT
+ NO CHANGE
KEY I X
MAXIMUM EVENING I~~~~~~~~~~~~~~~~~~~~~
I-W The data in Table IV show that in both S and C groups
TEMPERATURE DURING DETERIORATIO
FIRST WEE__ DEATH the results were better where there was no gross cavitation
on admission. In the S cases with no gross cavitation the
0 5 10 15 20 14 results were outstandingly good, with no deaths and 17 of
23 patients showing considerable improvement.
980-99-9 F
Clinical Changes During Period of Trial
C
General Condition
Assessment of changes in general condition is based onl
a combination of clinical facts, clinician's general impres-
sion, and patient's feeling of well- or ill-being. As such,
it is mentioned only briefly here. At four months after
100-0-100-9 F
admission the general condition had improved in 40 (73%)
C of the 55 S patients, compared with 26 (50%) of 52 C
patients: onlyseven (13%)Spatientswereworse,whereas 10
(19%) C patients had died and another 13 (25%) were
worse than on admission. At six months after admission
1010 F + S the difference between the two groups was less; in 33
(60%) S patients and in 24 (46%) C patients the general
condition was better thap on admission: 13 Spatients (24%)
were worse and four others (7%) had died; 12 C patients
, , ,. , ,I , ,I 1, (23%) were worse and 14 others (27%) had died.
0 5 10 15 2t 24
NUMBER OF PATIENTS Temperature
CHART I.-Results at six months (radiological assessment) related to Three S patients and four C patients were afebrile Onl
temperature on admission.
admission to the trial. Thethree Spatients remained afebrile
The results in Table III, represented graphically in throughout, with the exception of a short slight pyrexial
Chart I, show first what was to be expected-viz., in both episode in one case. Two of the four C patients remained
groups the most grave prognosis was in the patients most afebrile throughout; the other two had occasional low
febrile on admission ; indeed, in the S group the only deaths pyrexia, and one was still pyrexial at the end of the six
OCT. 30, 1948 BtrrISH
MEDICAL JOURNAL
MFDICAL RESEARCHI COUNCIL: STREPTOMYCIN TREATMENT OF PULMONARY TUBERCULOSIS
CASES DEMONSTRATING "CONSIDERABLE IMPROVEMENT"
690
I
FIG. I.-Case 69 (S). May 12, 1947. FIG. 2.-Case 69 (S). Nov. 17, 1947.
.1
.1
I,
906
900 ..3
FIG. 3.-Case 90(S). April 26, 1947. FIG.4.--Case90(S). Nov. 5, 1947.
OCr. 30, 1948 BRITISH
MEDICAL JOURNAL
MEDICAL RESEARCH COUNCIL: STREPTOMYCIN TREATMENT OF PULMONARY TUBERCULOSIS
CASES DEMONSTRATING "CONSIDERABLE IMPROVEMENT"
k
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390
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FIG. 5.-Case 39 (S). June 21, 1947. FIG. 6.-Case 39 (S). Oct. 20, 1947.
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FIG. 7.--Case 81 (C). Feb. 27, 1947. FIG. 8.-Case 81 (C). Aug. 27, 1947.
OCT. 30, 1948 BRITISH
OCTI3, 148MEDICAL JOURNAL
MEDICAL RESEARCH COUNCIL: STREPTOMYCIN TREATMENT OF PULMONARY TUBERCULOSIS
CASES DEMONSTRATING "MODERATE IMPROVEMENT"
_ s~9s
950
FiG. 9.-Case 95 (S). May 21, 1947. FIG. 10.-Case 95 (S). Nov. 21, 1947.
666
FIG. I1.-Case 66(C). April 11, 1947. Fio. 12.-Case 66 (C). Oct. 15, 1947.
OcT. 30, 1948 BRITISH
MEDICAL JOURNAL
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OcT. 30, 1948 STREPTOMYCIN TREATMENT OF PULMONARY TUBERCULOSIS MEDITALJOIL 773
months. Temperature changes in the febrilepatients at two These facts reveal, first, that many patients with a severe
months, four months, and six months after admission are form of tuberculosis gained weight on treatment by bed-
shown in Table V. rest alone; indeed, 12 at the end of six months had gained
a stone (6.35 kg.) or more in weight. Secondly, the weight
TABLE V.-Temperature Changes in Patients Febrile on Admission gains in the S group in the first four months were no
greater than in the C group, and therefore do not reflect
HighestEvening a _ whNoos.eoTfemPpaetireanttusre ShoNwoi.nogfTPeamtipe.ntFsall the important improvement observed in other respects; on
Temp.During was Normal atend of (including Fall to the other hand, there was more weight gain in the last two
Weekfollowing ; 0 Normal) at end of
Admission E months-i.e., after treatment had stopped. It is certain that
2Mos. 4Mos. 6Mos. 2Mos. 4Mos. 6Mos. some patients failed to gain weight, or gained little weight,
1010F. (3830C.) fS 24 1 5 6 15 14 11 during the course of streptomycin treatment, and this may
orover )C 19 0 2 3 7 6 8
be at least partly ascribed to the gastric disturbances, which
(39792--1308029500FC..) \rSC 2288 85 1150 1180 1120 1119 2142 were severe in a few cases and in others were mild but
sufficient to reduce appetite and retard weight gain.
*Temperature for one C case not available.
Menstruation
The difference between S and C series at any one point In 10 of 32 female S patients and in 12 of 31 female
of time is not statistically significant, but appears at every C patients menstruation was normal on admission and
stage-i.e., at every stage more S patients than C patients remained normal. In nine S patients and 12 C patients
show a temperature drop to normal or to a degree of amenorrhoea persisted throughout. In 11 S patients and
pyrexia lower than that on admission. A common effect seven C patients menstruation appeared atsome time during
of streptomycin not obvious in the above simplified observation and remained normal subsequently; in addi-
presentation of data is a rapid temperature drop in the tion two S patients had a temporary return ofmenstruation.
first weeks of therapy, followed sometimes by a rise to a
'level usually lower than the level on admission. Among Sedimentation Rate
the less acutely febrile patients (temperature 99,100.9' F.; TABLE VII.-Sedimentation Rate
37.2-38.85' C.) an increasing number of S cases show E.S.R. Group OnAdmission At2Months At4Months At6 Mlonths
falling temperature; at six months 18 of the 28 were
apyrexial and six others had temperatures lower than on 0-10 {S s 00 ~~~10 26 174
admission; 10 of 28 similar C cases were apyrexial and two
others had temperatures lower than on admission. 11-50 rs~c 2129 3110 2135 1187
groTuhpesr.e iIst tihsusimaporcotnasnitstteontnodtief,ferheonwceevebre,twteheant Sina2n0d oCf 51+ fS 2396 3274 2236 1154
47 febrile patients treated by bed-rest without streptomycin 5 0 0 4
the temperature was lower at the end of six months than DeaDthesth{C - 2 10 14
on admission; in 13 of the 20 it was within normal limits. Total* C~~c 5515. ~~ 5550 5500 5530
Forthetypeoflesions selected, theseresults serve to empha-
size both the value of prolonged bed-rest and the need of *Totals do not correspond in all columns, as results were not available in
controls in an investigation of this type. allcases.
In seven of the 13 C patients with normal temperature at Thedata in TableVII show two main differences between
the end of six months an artificial pneumoperitoneum had groups S and C. If one takes into account the patients
been induced at some time during the trial, but in every who died, in the C group the number of patients with a
case the temperature had come down to normal previous very high sedimentation rate (over 50) was never reduced;
to the induction of artificial pneumoperitoneum. The in theS group thenumber fell from 36 to 19 (including four
temperature fall in the C patients can be attributed to the deaths). Secondly, at six months in only four C patients
effect of bed-rest alone. had the E.S.R. fallen to within normal limits; in the S
group the corresponding number was 17.
Weight (Table VI)
In the first four months 20 S patients had gained weight Changes in Radiological Picture During Period of Trial
(5 lb.-2.27 kg.-or more), with a total weight gain between After the close of the trial the chest radiographs of all
them of 253 lb. (114.76 kg.), mean 12.6 lb. (5.71 kg.). The patients were viewed, and changes assessed, by the three
weight gains in the C group are very similar: 20 patients members of the radiological panel working separately.
gained weight,with a total gain of255 lb. (115.67 kg.), mean They were not told whether films were of patients from S
12.7 lb. (5.76 kg.). At the end of six months 24 S patients
or C series. Radiographs of each patient had been taken
had gained weight, with a total gain of 451 lb. (204.57 kg.), on admission and at monthly intervals subsequently. It
mean 18.8 lb. (8.53 kg.). Eighteen C patients had gained was decided to make as simple an assessment as possible,
weight, with a total gain of 313 lb. (141.97 kg.), mean reviewing progress at two-monthly intervals, each two-
17.4 lb. (7.89 kg.).
monthly film being compared with the film taken two
TABLE VI.-Weight Changes months previously and with the initial film. Thus the com-
parisons on which report was requested were: 0 with 2
4Months 6Months (initial film with film two months after admission), 2 with 4,
WeightChanges AfterAdmission AfterAdmission 0 with4, 4 with 6, and 0 with 6. Assessments were required
S S
C C to fall under one of the five headings "considerable
141lb.(6-35kg.)ormroregain 8 6 19 12 improvement," "moderate or slight improvement," "no
5-13lb.(227-5-89kg)gain 12 14 5 6
Lessthan 5lb (2-27 kg)gainorloss 15 910 12 change," "moderate or slight deterioration," "considerable
5lb.(2-27kg.)ormoreloss 13 7 5 11 deterioration." A report "no change" might signify no
Deaths . . 0 10 4 14
appreciable change in the radiological picture or improve-
Total. 48 46 51 47 ment in one part of the lung offset by deterioration in
Informationnotavailableforallcases; somepatientstooilltobeweighed. another.
774 OCT. 30, 1948 STREPTOMYCIN TREATMENT OF PULMONARY l'UBERCULOSIS BRITISH
MEDICALJOURNAL
So simple a classification invited difficulties, and these At a final session the three members of the radiological
were soon evident. How should atelectasis be classified ? panel met for discussion and review of films on which
Some films showed considerable clearing of infiltration con- there had been disagreement. After a short discussion it
currently with enlargement of cavities-radiologically they was agreed that changes in the prognosis for the patient
were both better and worse. The analysis in Table VIII should be taken as the base-line of assessment. In a com-
shows theseparate results ofreadings by the three assessors. parison of two radiographs of a patient the question should
Two most important readings have been chosen for this be, judging from these films alone, Has the outlook for the
analysis: 0 with4 (comparison of initial film with film four patient become better or worse? On this basis the films
months after admission) and 4 with 6. in question were reviewed, and agreement was reached on
TABLE VIII.-Comparison of Radiological Assessments by Three aalglreoefdtrheesmul.ts.ThTeheanoavleyrsailslwrheisuclhtsfuolnldoewrstihsebfaisveeddiofnfertehnet
Assessors
headings are given for each of the three assessments 0: 2,
RadiologicalAssessment 0: 4, and 0: 6 in Table IX and Chart II, and for each of
o 5 M Improvement Deterioration the three assessments 0: 2, 2: 4, 4: 6 in Table X and
Interval IntZrvol Con- Slight ChNanoge Slight Con- Charts III and IV.
_F-' Xsiderable or Mod. or Mod. siderable It is evident that at every stage there is between the two
X 18 24 4 5 4 groups a great difference in the course of the disease.
S 55 Y 27 17 3 4 4
Admission Z 27 15 1 6 6 At two months 76% of S patients showed radiological
t4othemnodnotfh - . X -- 0 11 1- 4 18 9 improvement, and in 14% the improvement was consider-
C 42 ZY 23 108 118 1150 98 able; only 6% of C patients were improved, and in none
was the improvement considerable. Of C patients 4% had
Endof4th S 51 XY 25 1178 1110 158 106 died and another 38% wereworse than on admission; 11%
emnodntohf6ttoh Z_ 3 12 11 19 6 of S patients were worse, and none had died.
month C 38 YX 02 191 1189 75 23 From the end of the second month to the end of the
Z 1 I10 11 14 2 fourth month the proportion of S patients who improved
(65%) was slightly lower than in the first two months and
It can be seen from Table VIII that there was some the corresponding proportion of C patients (18%) was
disagreement among the three members of the panel, but higher, but the difference between the two groups is still
the outstanding differences between results in S and C marked. Considering the overall change in the first four
groups remain unaffected. months, 78% of S patients were improved and only 21%
Where reports were identical they were adopted as the of C patients; in none of the latter and in 45% of S
final agreed report. Where the reports on a case by the patients the improvement was considerable. Of C patients
three members fell in two adjoining columns of the classi- 19% had died and another 42% were worse than on
fication (e.g., "considerable improvement" and "slight or admission; no S patients had died and only 14% had
moderate improvement") the majority of two was taken deteriorated.
as the final agreed report. In all other cases there was held The proportion of S patients who improved in the fifth
to bedisagreement. Thus in thecomparisons between radio- and sixth months was again lower than before (34% com-
graph on admission and radiograph at four months there pared with 65% in the third and fourth months and 76%
was agreement in 76 cases and disagreement in 21. In the in the first two months); this can be seen clearly in Charts
comparisons between radiographs at four months and at six III and IV. Of S patients 7% died in that period and
months there was agreement in 75 cases and disagreement another 31% deteriorated (the total 38% compares with
in 14. 20% in the preceding two months and 11% in the first two
TABLE IX.-Changes in the Radiological Pictuire
RadiologicalAssessment
Interval Group Total Improvement Deterioration Deaths
NoChange
Considerable SlightorMod. SlightorMod. Considerable
Admissiontoendof2nd:month |\CS, 5552 110000%%, 80 14% 343 662%%. 277 5123%% 145 2277%%. 61 121%%o 02 4%
Admission toendof4thmonth I\CC, 5552 9999%%. 250 45% 1181 3231%1%° 49 177%%., 144 277%%. | 48 157%%. 100 19%
Admissiontoendof6thmonth |C 52 100% 2 51% 13 21% 23 64% 12 239% 6 11% 14 7%o
TABLE X.-Changes in the Radiological Picture
RadiologicalAssessment
Interval Group Total Improvement NoChange Deterioration Deaths
Considerable SlightorMod. SlightorMod. Considerable
Admissiontoendof2ndmonth \CS 5552 110000%,%| 08 14% 343 626%%, 277 1523%%, 154 270%% 61 121%%. 0022 4%
End of 2nd month to end of fS 5 100% 6 11% 30 54% 8 15% 8 15% 3 5% 0
4thmonth QC 50 100%o 0 9 18% 13 26% 16 32% 4 8% 8 16%
End of 4t6hthmmoonntthhto end of rsC 455210909%%/ 3I 52%% 196 2291%% 1157 4217%%Y 190 2118%% 72 153%% 1 44 170%%