WO RLD HEALTH ORGANIZATION
ORGANISATION lv\ONDIALE DE LA SANTE WHO/TB/Techn. Information/lo-/ 22 April 1963 ORIGINAL: ENGLISH
REPORT ON TUBERCULOSIS CHEMOTHERAPY PILOT PROJECT (TUNISIA 9) by ,J. Nyboe, A. R. Farah and O. W. Christ ensen J:ntroduction became evident that this drug was a very effective therapeutic. Shortly after INH was first used in the treatment of pulmonary tuberculosis, it As it was also cheap
and relatively non-toxic, the question was soon raised whether a means had at last It was in order to investigate various aspects of this possibility that so-called b0en found of influencing favourably the course of tuberculosis in the community.
the governments of a number of countries - one of them Tunisia.
ntuberculosis pilot projects" were started by WHO in co-operation with UNICEF and A detailed plan of operations, outlining the purposes and procedures of the
Tunisian project, was worked out and signed by the interested parties - the Government of Tunisia, UNICEF, and WHO - in June and July 1957.
consultation with the WHO 'I'uberculosis Research Office. (1)
prepared by the national director of the project and the WHO field staff, in questions were taken up for investigation in this project: hospitalization; (2)
On the basis of this plan, a protocol with detailed working instructions was From the outset two
whether the therapeutic effect of INH is the same with and without to what extent INH could be used as a prophylactic. It
p:..�oved impossible to keep most patients in hospital for more than a few weeks. the rest of this report.
TI,e study of the first of these questions soon had to be given up because it
is thus mainly the second question - the prophylactic use of INH - that is dealt with in
WHO/TB/Techn.Information/10 page 2 Study population The project was carried out among the population of Djebel Lahmar, a suburb 2 of Tuni~ City~ The inhabited area of Djebel Lnhmar is about 3 km and its population is about 25 000 persons. of the Tunisian population~
The inhabitants bBlong to the poorest section The dwellings are practically all one-storey, The rooms are generally
the bread earners usually being unskilled labourers who
find only occasional employment.
brick or mud houses consisting of a central courtyard surrounded by a varying number of rooms (3-6) of which one household occupies one or two.
badly lighted and ventilated, and sanitary installations leave much to be desired. The local administrative executive is the sheikh, who commands a certain amount of authority over t~e
population.
The national political party
~·represented
by
various committees which·are.in close contact with the population.and assist very actively in the implementation and realization of social and health programmes. The inhabitants of Djebel Lahmar are extremely health-conscious and will seek medical advice and demand treatment even for minor ailments, in one of the two local out-patient clinics or in hospitals in Tunis. the disease. Tuberculosis is well known to this population and there does net seem to be any particular sccial stigma attached to
In principle, everyone living in Djebel Lahmar was to participate in the investigation on the prophylactic use of INH, unless he belonged to one of the following categories: (1) (2) persons under two years of age; persons who had been .BCG-vaccinated by the project (i.e., a random
sample of the "tuberculin-negatives"); (3)
persons who were already being given antituberculosis treatment by.·
private physicians or in hospitals or clinics;
( 4)
persons who, at the ini-tial examination made by the project, were
found to excrete acid-fast rods.
WHO/TB/Techn.Information/10 page 3 The latter two groups had to continue or commence treatment for tuberculosis and therefore had to be excluded from the study on the prophylactic use of INH. Methods and procedures Before the start of th6 field operations, a circular letter was sent by the Ministry cf Health to all ch0st physicians, hospitals, and dispensaries in Tunis City and surroundings, requesting them to send all tuberculosis patients in their charge living in Djebel Larunar to a centre established by the project. in the area. Registration As registers of the Djebel Larunar population did not exist, and as complete control of participation in the project was desirable, the field operations started by registering the population. This was accomplished by having one person visiting all houses in the area, assigning a serial number to each house, and painting this number at the entrance. In order to be able to find a particular house easilY later The purpose
was to make the project staff sol8ly responsible fer all antituberculosis activities
on; a two-year-old map of the area was brought up to date and the house numbers were entered on this map. Each house was then visited by a registration team who filled in an individual card for each member of the household, present or absent. All persons were invited
to participate in an examination for tuberculosis and were given a slip of paper on which was noted the place, date, and hour of examination. The initial examination This comprised tuberculin testing, chest X-ray examination, and, when indicated, a bacteriological examination. Tuberculin test. The test was given to all persons aged one month or more. ~ose
An intradermal (Mantoux) test was applied with a '
corresponding to about three The tuberculin
units of the internatiGnal standard of human PPD tuberculin.
products and dilutions were prepared by the Statens Seruminstitut, Copenhagen.
"
.,
-·
'
\
\
WHO/TB/Techn.Information/10 page 4
In the beginning, the test consisted of 0.1 microgram of PPD from the batch RT 19~20-21, in 0.1 ml of ordinary buffer diluent. However, as from 1 January 1959,
the test was carried out with 0.02 microgram of the batch RT 23 in 0.1 ml of diluent containing 0.05 per cent. of Tween 80. The test was given very superficially in the middle dorsal aspect of the left forearm, and was read after three or four days by measuring the transverse diameter of the induration. In a random sample of those tested, the left shouldt:r was inspected for BCG lesions. This was done with a view to studying whetht:r possible previous BCG
vaccination had influenced th8 pattern of tuberculin sensitivity in the popuHrtioh; X-ray examination. A ch~st
X-ray examination was made cf all persons aged yearr~
six years or more (from 1 Jcmuary 1959, four
or more).
It consisted in the
taking of two 70-mm photoflucrograms with the X-ray tube and camera lifted 4 cm between the two exposures. Each set of photofluo~ograms was read independently by indice~ting
two medical officers, who noted the presGnC8 of shadows pleural pathology.
pulmonary or
They also tried to classify the pathology causing the shadow~
i.e., infiltrate with or without cavity, fibrctic lesion, calcification, enlarged isolated hilus gland with atelectasis, pleurisy, and pleurisy sequelae. Originally it was intended that, when at l0ast one reader considered that a photuf1uorogram contained a shadow indicating pulmonary or pleural pathology, the person in question would be considered and treated as having such pathology. 11
However,
after all the films had been read in this way, both readers felt that this procedure would lead to considerable over-reading 11 probably due to the element of competition They therefore decided that one of them should
which is inherent in this method.
cri tic ally review all the films for which shadoi'rs had been recorded and make a decis3.on as to '-Jhether a shadow was present or not, and which type of pathology had caused the shadow. following. Bacteriological examination. Eligible fer this examination was any person in It is the result uf this latter reading which is given in the
whose photofluorograms a shadcw indicating pathology 0ther than calcification was found. The examination consisted in collecting one sputum specimen, which was
examined by direct microscopy, and one laryngeal swab, which was examined by culture.
WHO/TB/Techn.Information/10 page 5 The sputum was obtained by asking the examinee to cough vigorously and to spit into a small box what was present in the mouth after coughing. microscopically. A smear was prepared
from the specimen, stained according to the Ziehl-Ncels.;;n method, and examined With a magnification of 800, each field of focus along two only if 100 acid-
horizontal and two vertical lines on the slide was inspected;
fast bacilli had been seen was the examination discontinued earlier. For obtaining the laryngeal swab the examinee was asked to attend in the morning without having eaten or drunk. Care was taken to pass the swab into the larynx; if the irritation thus made did not cause the examinee to cough, he was asked to do se. In the laboratory, the svmbs were treated with five per cent. oxalic acid for Each swab was then inoculated on to two test tubes containing The test-tubes were 0
25 minutes.
Lowenstein-Jensen medium prepared without potato flour.
incubated at 37 C and inspected at the end of one, three, six, and eight weeks. During the initial examination, persons aged six years or more were weighed so that the daily dose of INH (or placebo) could be determined. Furthermore, a portrait photograph (24 x 36 mm) was taken of persons aged six months er more. Together with the person, his individual number - a five A print of the digit number which was noted on all records, phote,fluograms, and bacteriological specimens - was photographed in the lower part of the picture. photo was given to the person to keep. check the identity of those examined. BCG vaccination A certain number of persons living in Djebel Lahmar were BCG vaccinated and excluded from the investigation on the prophylactic use of INH: one month were vaccinated without previous tuberculin testing; So as to ensure that th~se
When he reported later for examination,
he was usually able to show his photograph - a procedure which helped greatly to
All children under over this age, a
sample of tuberculin-negative persons (reacting with an induration of 9 mm or less) were vaccinated. included in the investigation did not constitute a special group, the selection for BCG vaccination was made by means of random numbers.
WHO/TB/Techn.Information/10 page 6
The vaccination was pcrfcrmed by injecting 0.1 ml cf vaccine intradermally in the deltoid region of the left shoulder. The vaccine, which contained 3/4 mg
of bacilli (moist weight) per ml, was prepared by the Statens Seruminstitut, Copenhagen. Tablet distribution In order to study the prc:,blems involved in th8 prophylactic use of INH, the population was divided intc two halves of which cne was given INH and the other not. However, so as to avoid psychulogical and oth3r cr.jmplications caused by giving tablets only to some perscns, tablets were in fact distributed to everyone, but only half of them contained INH. The ~;ther
half were placebo tablets, i.e., tablets that looked The INH and
and tasted the same as the INH tablets but did net contain the drug.
the placebo tablets were bought from the same firm and packed in the same type of tin. The labels on the tins did not state whether the contents were INH or placebo instead they showed a code number between one and 64. Half of these
tablets;
numbers sto.od for INH and the other half. for placebo, but the code was not known to the project staff. observations: These precautions v1ere introduced in order to avoid bias in
as nobody knew whether a certain person had been given INH or placebo,
there was no risk that the staff - consciously or subconsciously - were influenced by knowing this point when making their observations on tuberculin testing or X-ray and bacteriological examinations. For a precise evaluation of the effect of using INH prophylactically, it was desirable that the population group given INH and that given placebo should be as similar as possible at the outset of the study. For this purpose, the whole area
of Djebel Lahmar was divided into 153 blocks of houses, each block containing approximately the same number of persons. All persons (with the exception of those
mentioned on page 2) living in 76 blocks were given INH tablets whereas those living in the remaining 77 blocks v{ere given placebo. The decision regarding the blocks
in which INH was to be distributed was made by means of random numbers. One consequence of giving only one type of tablet to persons living within a block was that someone who moved from an vice versa, had his treatment changed. 11
INH block" to a !!placebo block", or.
However, the number of such movements was
not large, and the persons in question have been omitted from the latter part of the analysis.
WHO/TB/Techn.Information/10 page 7
Each INH tablet contained lOO mg of INH.
The number of tablets (INH or placebo) less than 30 kg: four tablets.
to be taken every day depended on the body weight, as follows: two tablets; between 30 and 39 kg: three tablets;
40 kg and over:
Thus for the great majority of persons, the daily INH dose was in the range of 5-10 mg per kg of body weight. According to the plan, tablets were to be
distributed for one year, but this goal was not reached for a large proportion of persons because they moved away from Djebel Lahmar. In a few instances it was not
reached because the person died during the treatment period or because he refused to receive the tablets. The tablets were distributed in the home evsry three weeks; all distributions
were noted on a ntreatment card" established for each person, by recording the date, the code number, and the number of tablets given. Much effort was spent on ensuring that the tablets were taken regularly. Each
person was visited by a senior assistant health visitor before he or she received the first supply of tablets. The health visitor explained that the risk of being
contaminated with tuberculosis and becoming ill was high in the area and that the tablets therefore should be taken daily in order to obtain protection. The personnel
distributing the tablets in the homes was instructed to stress the importance of taking the tablets regularly. An explanatory booklet was distributed to all households at
the beginning of the treatment period, and mass meetings were held which third of the population attended. Follow-up and final examinations
an
estimated
All persons participating in the study were to undergo certain control examinations, the thoroughness of which depended on the findings at the initial examination. If the initial photofluorograms showed shadows indicating pulmonary or pleural pathology other than calcifications, the:: p-..;rson in qu-:;sti._.,n six months. ~,ras
to be examined every
Each time, a·radiological examination and- regardless uf the result
of this - a bacteriological examination were made.
WHO/TB/Techn.Information/10 page 8
If only calcification had been seen on the initial photofluorograms, the person was to be examined radiologically every 12 months. And, if any of these periodic X-ray examinations indicated the presence of pulmonary pathology other than calcifications, a bacteriological examination was to be made, If, on the other hand, pulmonary '..>r pleural pathology had not been seen on the initial photofluorograms, or the person had not been radiologically examined initially, he or she was not examined periodically but had a final examination made at the end of the project. A tuberculin test was to be given to all persons who were initially A test was given also to
"tuberculin-negatives" and had net been BCG-vaccinated, a random sample of the ~CG-vaccinated
and of persons initially tuberculin-rositive.
Each person who had reachvd the age of four years at th0 time of the final examination was also to be examined radiologically and, if the new set of photofluorograms indicated the presence Gf pulmonary or pleural pathology other than calcifications, he or she vms t::ligible for a bacteriological examination. The methods of tuberculin testing and bacteriological examination were the same as those applied during the initial examination, whereas the X-ray examination was somewhat different. The photofluorograms taken during the final examination were first read by one reader and, if abnormal shadows were seen, a comparison was made with the initial photofluorograms. If this comparison showed that the shadow vms present (but not
previously recorded) in the initial photofluorograms, the person was not registered as having developed a lesion. The photofluorograms taken at the periodic
examinations were always compared with the initial photofluorograms and the result was recorded as improved, identical, or wors8, Execution of work The daily work was directed from a fixed centre located in a residential area of Tunis only a few kilometres from Djebel Lahmar. This centre contained offices,
a photofluorographic section, a room for taking sputum and laryngeal swab specimens, dark rooms, stores, etc. The inhabitants of Djebel Lahmar could come to the
centre for medical consultations, and all periodic examinations were made there.
WHO/TB/Techn.Information/10 page 9 On the other exam~nation~ hand~
the bulk of the field
operations~
viz.the initial and the final This centre, which normally was
were carried out in a mobile
~entre.
set up in a tent, v:as supplied with a mobile photofluorogrE'.phic unit including a generator. The bacteriological examinations carried out in the project were handled by a small laboratory unit established for this.purpose on the premises of the Pasteur Institute of Tunis. The personnel attached to the project consisted of two medical officers, one statistician, two laboratory teclmiciann, three Mcntoux/BCG technicians, three X-ray manipulators, four health visitors, two record keepers, one secretary, one administrator~
and two drivers.
These included the international staff seconded by
WHO, namely one medical officer, one statistician, one laboratory technician, and one nurse (the latter responsible mainly for tuberculin testing and BCG vaccination). The field work started in March 1958 and the initial examination was practically completed by August 1959. The final examination of the population began in
,
September 1960 and lasted for about six months. Results of the initial examination The results of the initial examination have been tabulated in detail in Appendix Tables 1-8. 11
'
i
: I
In some of these tables, the data are broken down
I
in~o
INH blocks" and nPlacebo blocks".
This way of presentation has been used in
i
order to save space, and reference to the breakdowns will not be made until the following section (Comparison of study groups). At t.endanc e. During registration, a total of 24 505 persons were found to be Excepting 109 babies under one month of age, all were 94.5 per cent.
living in Djebel Lahmar.
eligible for the tuberculin test, and 23 276 (95.4 per cent.) had this test given and read. Attendanc.e at the X-ray examination was nearly the same: The result of the X-ray examination indicated a bacteriological examination for 1039 persons, 1005 of whom (96.7 per cent.)were actually examined (see Appendix Table 1).
VJH0/113/'I\:::clm. Infvrmatic•n/lO page 10
Although great efforts WGr<" made to encourage as many as possible of the inhabitants of Djebel Lahmar to quite as high as desired. p~rticipate
in the examination, attendance was not
HowcvGr, <m analysis according tc age and sex shows Thus the data on tuberculin
much variation in the completeness of attendance.
testing, which are given as an illustration (Appendix Table 2), show a very high attendance among females (98 per cent.), but among males only 93 per cent. Furthermore, it is seen that attendance is particularly poor among men aged from 15 to
39 years, but relatively guod amcng boys and older men (except the very old). Tuberculin testing. The distributi'--n according tc sizo of reaction.s tG the
low-dose tuberculin test among males and females in various age-groups is shown in Appendix Table 3. The pGrcentage distribution of the reactions according to size .• The reactions
for all age-groups and th8 tw, sexes cc_,mbined, is seen in Fig. 1. are c-learly of two kinds: tubercle bacilli, and small of such infection. 11
large reacticns which presumably indicate infection with (,~.r
zero) reactions which presumably indicate the absence
There are vnly a few intermediate reactions (in the range
6-ll mm), and it would appear that, if a dividing line, separating "positive" from negative 11 reactions, is fixed between nine and 10 mm, the pre;purticn of "positive"
reactions will provide a geed estimate of the proportion uf infected persons. In this connoxion, it is of scme interest tc examine the results uf inspecting in a sample of persons - the shoulder fer lesions louking as if they might have been
caused by BCG vaccination.
A mass BCG vaccination campaign was carried out in Tunisia
in the period 1949-1951 and scJmc vaccinations havo been perfurmed since then.
Therefore it was important tc investigate whether previous BCG vaccinations have appreciably changed the tuberculin sensitivity pattern in this population. In
fact, the analysis of the data for persons with BCG (;r dr_ubtful lesions indicates that the error caused by BCG vaccination in the estimates of the prevalence of tuberculous infection is less than five per cent. in all age-grcups. Estimates by ago and sex of the pn:::valence of tuberculous infection, based on 10 mm of induration as the lc·wer limit fur positive reactions, are shown in Fig. 2.
The percentage increases very rapidly with age, indicating that the risk of infection has been - and probably still is - very high in this population. Up to 10-12 years but after that
of age, the percentages for males and females wc;re at tho same level;
age the percentage fur malos was high0r, indicating that adult males have been exposed more heavily to infection with tubercle bacilli than adult femaleB.
Fig. 1 Distribution by size of reactions to the MX ITU or 5 TU test
30.---------------------------------~
.. c Gl
Gl Cl Gl
20
r::
~
ll..
10
0
8 12 16 20 24 Diameter of induration (mm)
28 WHO 3208
Fig. 2
Estimated prevalence of tuberculous infection by age and sex
100.-----------------------------------~
80
Males
.. Cl
G,)
60
u
c c G,)
a. 40
G,)
20
5
10 Age (years)
15
20 WltO 1209
WHO/TB/Techn.Infcrmation/10 page 11 X-ray examination. The results of the X-ray examination are tabulated in The frequency of persons whose
Appendix Tables 5-7, and summarized in Table 1.
photofluorograms showed shadows suspect for tuberculosis is generally higher among males than among females, and it increases with age. TABLE l. PREVALENCE IN PER CENT. OF PERSONS WITH X-RAY SHADOWS INDICATING PULMONARY OR PlEURAL PATHOLOGY (EXCLUDING SHADOWS IN PERSONS WITH A TUBERCULIN REACTION OF LESS THAN 10 mm) Age in years Males Apparently Apparently healed active lesions lesions 1.9 4.9 5.4 8.4 7·9 8.8 i
Females Apparently Apparently active healed lesions lesions 2.3 4.3 4.0 5.9 6.1 8.2 2.2 1.8 2.8 3.5 7.2 9.2
5-9 10-19 20-29 30-39 4C>-49 50 and more
2.1 2.5 5.2 6.0 9.3 13.1
l
In an attempt to evaluate what proportion ".f the X-ray shadows seen was in fact due to tuberculosis, the data were correlated with those obtained in tuberculin testing (Appendix Table 6). In persons under 20 years cf age, the proportion with
shadows is low among "tuberculin-negatives" and at least 10 times less than among "tuberculin-positives". This indicates that in these age-groups a high proportion Above tl').e
(at least 80 per cent.) ;f the shadows seen arc, 0f tubGrculous origin. increases with age.
age of 20 years, the frequency of X-ray shadows among the "tuberculin-negatives" This observation is probably best explained by.the hypothesis
that an increasing proportion of the lung shadows seen among elder persons is of non-tuberculous origin.
\IJHO/TB/rechn .In:furmation/10 page 12
TABLE 2. 0~"
ESTilVl'\TE' ?REVALENCE Il\T PER CENT. PERSONS EXCHEI'ING /,CL<·'!Sl' BACILLI
Ago in yE>-'.rs 5-9 10-19 20-29 30-39 40-49 50 and 0ver All ages
r.1ale s 0 .~) 0.4 1.4 1.2
F'en12lGS 0.1 0.2 0.7 0.9 0.6 0.9 0.5
Both sexes 0.1 0.) 1.0 l.l 1.0 1.1 0.7
1.3 1.2 0.9
Bacteriological examination. given in Appon~ix Table tubercle bacilli is
8etails o? the bacteriolqgical ex&minations are
8.
In Table 2, thG estimated prevalence accc,rcling to age and :~ex.
er
persons excreting
s~1own
The computation of th2se estimates
is bascc1 on several assumptions - one of them bt.:ing that tubercle bo.c:illi :J.rG not excreted by persons with a normal cJ1est X-ray. Another o.ssumption is that persons
founcl eligible for bc.cteriulogic::J.l E:xc.mination, but n,Jt e;xQminccl, woul( yield the same proportion of positive results as those examined bacteriologically. instead of simpl;Jr putting the number to the numbe:;r examinee\ by X-ray, 2c
Therefore
,Jf
be,cte;ri.;logically positive persons in relation
c:orr.::;ction factor has been appliecl, which i,s the;
number eligible for bact2riclogicnl cx:ctmincction di vi,4ec by th0 number cc::.:tucclly examinee:. T!1c ovc::r-i::.ll prevc:.lt:n:;e .::": persons uxcre:ting tubercle: bacilli is The percentage in,;rc;CLS(:;S with agG up to t11.c o.gc-group 20-29 Y'-'CLrs, it is ne::trly twice c,s high 2-mong mo.les as
0.7 per C8nt.
whcreaftc::r it rGmo.ins 0.lmost ·::onstCLnt; among females. In summary, the rcsul ts
f th.2 ini ti&l GXo.mination inc!icette tl:mt therE.: W'lS a
high prevalencl' of tub'-'rsulous infuction :-cnr: morbic:Iity among the population living ~n
the study area.
WHO/TB/Techn.Information/10 page 13 Comparison of study groups As mentioned, before it was desirable that the group of persons given INH tablets and that given placebo tablets (the control group) should be similar at the outset of the study. In the present section, the two groups will be compared
..
with regard to the findings at the initial examination and with regard to the persons excluded from the study. It will be seen from Appendix Table 9 that the sex and age distribution of persons living in the INH blocks and in the placebo blocks was very similar. placebo blocks contained about 500 more persons than the INH blocks, but the percentage distributions by age and sex were practically alike. Attendance at the initial examination was slightly higher in the placebo blocks than in the INH blocks (see Appendix Tables 1 and 2). testing were also somewhat different (Appendix Table 4). The results of tuberculin In the age-groups The
2-5 years, the estimated prevalence of tuberculous infection was higher in the INH blocks than in the placebo blocks, indicating that the risk of infection had been somewhat higher among persons in the INH blocks in recent years. in the age-groups of 1 year and less than 1 year; began. The data from X-ray examination show that the prevalence of persons with lung shadows was very nearly the same in the INH blocks as in the placE'!bo blocks (Table 3). TABlE 3. PREVALENCE IN PER CENT. OF PERSONS WITH LUNG SHADOWS, IN INH BLOCKS AND PLACEBO BLOCKS Age in years 5-9 10-19 20-39 40-59 60 and over All ages INH blocks 5.2 7.2 10.2 18.2 22.9 10.6 Placebo blocks 4.9 7·2 10.5 17.3 26.1 10.5 On
the other
hand, there is no significant difference between the prevalence in the two groups it is therefore not established that the risk of infection was different in the two groups at the time when the study
WGI/TB/Techn.Information/10 page 14 Information about persons excluded from the INl-J: study is presented in Appe-ndix Table 10. There were, of course, some persons who should have been excluded from
the study for more than one re; as on, e. i?;., children below the age of two years who had been BCG-vaccinated and persons who had already begun antituberculosis treatment and were found to excrete tubercle bacilli. Such persons are only mentioned once In addition to the categories
in the table, namely under the reason appearing first.
of excluded persons mentioned previously, a further category has been excluded from the analysis, viz. persons who did not begin to receive tablets until l January 1960 or later. The reason for this exclusion was that there was not sufficient time for
such persons to receive the prescribed amount of tablets bvfore the end of the observation period. Because of non-attendance and exclusions, only 15 910 persons participated in the INH study, i.e., 64.9 per cent. of the total registered population. This
percentage is n<.:arly the same in the INH blocks and the placebo blocks, i.e., 64.7 per cent. and 65.1 per cent. respectively. differences in the reasons for exclusion. There are, how0ver, some
For example, the number of BCG-
vaccinated persons is somewhat higher in the placebo blocks than in the INH blocks also when the numbers are related to the numbers of "tuberculin-negatives", viz. 34.2 per cent. in the placebo blocks as against 31.4 per cent. in the INH blocks. The reason for this difference is unknown. As a few persons moved from an INH block to a placebo block (55) or vice versa (27) before the treatment Has started, the numbers of persons tabulated as "eligible for study" under "INH blocks" e..nd "placebo blocks" do not correspond exactly to the numbers in the two study groups (INH group ru1d control group) referred to in the folloHing. respectively. Completeness of tablet distribution Appendix Table ll shov.rs tha number of persons Hho received a supply of tablets corresponding to the period specifL;d in th'-' first column. Nearly 10 per cent. The numbers of p~rsons
in the latter groups an.: 7741 and 8169
received only tablets for half a year and another seven per cent. r8Ceived only tablets for 20 more weeks, so that there were 83 per cent. who received a number of tablets corresponding to . 45 weeks or more (which way bo considered a satisfactory amount). The reason for drscontinuing distribution was in the large majority of
WHO/TB/Techn.Information/10 page 15 cases that the person moved out of the area. In a few cases, the reason was
refusal or death and, in still a few other cases, the reason for not giving the "standard" tablets was that the person T.'las switched to specific anti tuberculosis treatment. The completeness of the tablet distribution is not significantly different in the INH group and the control group. Although a large proportion of the study population received the prescribed amount of tablets, they did not receive them within the prescribed period of time. This is illustrated in Table 4, which shows the period of tablet distribution for persons given the full 9mount of tablets (the amount corresponding to 50-54 weeks). If the tablets had been distributed according to schedule, all should have received their tablets in 12 months or less (as tablets were distributed for three weeks at a time). In fact, only half of the persons received the tablets within 12 months The reason for the delay in and for nearly a quarter it took 15 months or more.
distribution was that many persons were not found at home when the team came to deliver the tablets; a second visit, whj_ch was always made on the day following There are only slight
the unsuccessful distribution, was sometimes also a failure.
differences between the INH group and the control group with regard to the time it took to distribute this number of tablets. TABLE 4. TIME TAKEN TO DISTRIBUTE TABLETS TO PERSONS WHO RECEIVED A SUPPLY FOR 50-54 WEEKS Difference between month I of last and month of first distribution* 10 11 12 13 14 15-17 18-20 'l1otal
Percentage of persons INH group Placebo group
0.1 12.2 38.4
0.1 11.3 36.8 17.4 9.7 15.2 6.0 3.5 100.0
0.1 13.0 40.0 16.5 9.1 14.5 4.5 2.3 100.0
17 .o 9.3 14.9 5.2 2.9 100.0
.
21 and over Total
* This difference is based on calendar months without regard to the dates of the month:;;.
WEO/'l'B/TE.oclm. In:formation/10 page 16
Information on this point was obtained by collecting and analysing urine from a sample of the persons given INH tablets. In ord0r to obtain reliable results,
it was considered necessary to coll<Jct the urine during surprise vLsi ts to homes. As all persons in the study were instructed to tako their tablets during the evening mGo.l (this being the staple; meal and the time. of the day when all members of the family arc usually together) and as the urin0 test Has hc.:ld to remain positive only for about six to 0ight hours after intake of the tablets, during the night. as desirable. th~
visit had to be made
It iE> thcrd'urc understandable that th-.: data are not as extensive
Of the 243 porsons re.ndomly selected for e;xamination, 61 v'lePe not found A urine specimen
at home at the time of the: visit, and nine r0fuscd to co-operate. was obtained from the remaining 173 persons.
The urino was analysed by a m0thod d'-'v0loped by Hoffmann-La Rochc;, Basle, Switzerland, using test pn:opar""ttions mad0 by that firm. The ovcr-.~.11
r:;;;ults
VLJ:'c:
19 per cont. positive (indicating
prc~sence
of INH),
five per cent. doubtful, and 76 per cent. negative, (indicating absence; of INH). 1\lhc;n the data are broken down according to the pl;riod during which administered, the percentages of positive results are ns follows: months: 27 per cent; four to six months: 23 per c\mt; t~eatment
had been
Less than three
and seven to 12 months:
16 per cent. It appears from·thEose data that the taldng of the tablots was very incomplete; furthermore, the proportion of tablets taken decreased as the treatment lengthened. Unfortunately, urine was never examined mor0 than once for each person and it is thus impossible to know whether th0 poor results reflect regular intake of tablets by a small group of persons and no tablet taking at all by a large group, or occasional taking of tabl\Jts by a l:J.rgc.: group. Attcmdance at follovr-up r:md final examinations Nearly throe-quarterc~
of the p·-.:rson:.:; initially found eligible for final
examination .were so examined, o.ttendance being nearly the; same in the INH group (73.4 per cont.) as in the control group (73.2 ner cent.). It has not been possible
WHO/TB/Techn.Information/10 page 17 to analyse the reasons for not attending the final examination, mainly because reliable information about movements was not obtained and would indeed have been difficult to obtain. Often when a complete household or a member of a household
left the project area it was not known - even to the persons themselves - whether their absence would be temporary or permanent. Attendance at the periodic examinations (among persons with abnormal shadows on the initial photofluorogram) is shown in Table 5. TABLE 5. COMPLETENESS OF ATTENDANCE IN PER CENT• AT PERIODIC EXAMINATIONS Persons eligible f8r examination every six months INH group Control group 76.8 73.2 48.7 16.8 76.7 73.8 51.0 15.0 Persons eligible for examination every 12 months INH group Control group
Examination at
6 months 12 18 24 11 If
79.7
78.2
23.3
21.5
If
Again~
the results are nearly the same in the INH group as in the control group.
The reason for the rapid decrease in attendance is mainly that the observation period came to an end (persons were only called in for periodic observations scheduled to take place before l January 1961). Some information about the reasons for non-attendance at the half-yearly examinations is given in Appendix Table 12. (In this smali but important group, '
many visits were made to homes, and information about movements is therefore fairly reliable.) It appears from the appendix table that attendance was about 80 per cent.; '.
among those who were able to report it was somewhat higher at tho beginning than towards the end of the observation period. A comparison of tho length of the observation periods for persons in the INH group and in the control group is shown in Table 6 below.
WHO/TB/Techn.Information/10 page 18 TABLE 6. LENGTH OF OBSERVATION PERIOD (INTERVAL BETWEEN INITIAL AND FINAL - OR LAST PERIODIC EXAMINATIONS) Number of months Per cent. of persons INH group Control group 0.8 2.0 8.8 19.0 22.0 29.2 15.5 1.8 0.6 0.3 100.0 0.6 2.1 8.7 19.0 22.4 27.4 17.2 1.6 0.6 0.4 100.0
Less than 13 13-15 16-18 19-21 22-24 25-27 28-30 31-33 34-36 37 and over Total
The two distributions are very similar, the average observation period being 23.6 months in the INH group and 23.7 months in th0 control group. Because of the similarity of the distributions, it has been assumed in the following that the observation periods for various sub-groups of the study population (e.g., ntuberculinnegativesn) are not appreciably different in the INH group and in the control group. Effects of distributing INH The general question of the effect of giving INH may be divided into several more specific questions. bacilli? To what extent did it prevent new infection with tubercle To what To
To what extent did it prevent the development of lung lesions?
extent did it prevent deterioration, or promote improvement, of lung lesions? what extent did it prevent the development of bacteriologically positive cases?
In the following, these questions have been studied by comparing the ·frequencies of the various phenomena in the INH group and in the control group.
WHO/TB/Techn.Information/10 page 19 Information about new infection is shown in Appendix Table 13, and a summary is given in Table 7 below. TABLE 7. OBSERVED INFECTION RATE BY AGE IN THE INH GROUP AND IN THE CONTROL GROUP Age in ye:ars Rate in per cent. Control group INH group
2-4 5-9 10-14 Total
7.8 8.8 23.6 10.8
6.7 14.0 20.8 11.7
(It should be noted that the rates given in this table are expressed in terms of persons, not in terms of person-years; however, the rates are still comparable
because the length of the observation period may be assumed to be equal in the two study groups. ) The average rate is slightly higher in the control group than in the INH group but the difference does not attain statistical significance. The data concerning the development of lung shadows show that, among 4585 persons in the Iffl1 group with a normal initial photofluorogram, 54 (1.2 per cent.) were found to have developed abnormal lung or pleural shadows at the final examination. The corresponding figures among 4785 persons in the control group are 89 (1.9 per cent.). 'rhis diffcrenc~:;
is statistically highly significant.
In order to anal:¥SC the possible effect of INH on persons found to have pulmonary or pleural lesions initially, the data pertaining to the comparisonbetween the initial and the last periodic photofluorogram were used. The data for persons f~w
with calcified lesion were analysed separately beco.use there were very in this group. 11 11
chang12s
Among 298 persons of this category (calcified lesions) in the INH improvements" and no deteriorations", and,among 312 No
group, there were thrue
persons in the control group there was ,oqe deterioration and no improvements. conclusions can be drawn from these f8w observations. other types of lesion are gi v0n belmv.
The data for persons with
WHO/TB/Techn.Information/~0
page 20 TABLE 8. CHANGES IN THE CLASSIFICATION OF PULMONARY AND PLEURAL LESIONS (OTHER THAN CALCIFICATIONS) IN THE INH GROUP AND IN THE CONTROL GROUP Classification of shadows seen at the last periodic examination in comparison with those seen at the initial examination Improved Identical Deteriorated Total Number of persons INH group Control group
55 261 4 320
49 275 10
I
334
Although there are relatively more improvements and fewer deteriorations in the INH group than in the control group, the differences are not statistically significant. Finally, it was found that some persons taking part in the investigation became bacteriologically positive. Th0ir total number was 43, of whom 18 came from The incidence in the two groups was the INH group and 25 from the control group.
2,3 per thousand (persons) and 3.1 per thousand respectively, but this difference is not statistically significant. Both in the INH group and in the control group
10 cases developed within: one ye·ar after the beginning of treatment, whereas the remainder was found after this period. Conclusions One of the most significant findings of the present investigation was that, despite all efforts to make people take their tablets constantly, the results of testing urine specimens for the presence of INH showed that four-fifths of those examined had not taken the INH tablets on the day of examination. This observation is very discouraging and yet it cannot be concluded from the present investigation that it is impossible to apply INH as a prophylactic on a mass scale in this or a similar population. The study was designed to provide information on the effect of I
both primary and secondary INH prophylaxis, i.e., both in persons uninfected and
WHO/TB/Techn.Information/10 page 21
persons infected with tubercle bacilli.
But it is ce;rtainly possible that the
distribution of tablets to nearly everyone living in th(; project area diminished to a large extent the importance of taking the tablets, in the opinion of the population. It is still possible, therefore, that if a selected group of the
population (for example persons with very large reactions to the loTtr-dose tuberculin test) were given INH prophylactically the tablets might be taken with greater regularity. It is in the light of this v?rY incomplete tablet-taking that the data on the biological effects should be evaluated. These data all point in the di.rection of a
beneficial effect of INH, but in most instances the difference between the rates observed in the INH group and the control group is either statistically-insign'ificant or biologically unimportant. It seems justified to conclude that, if better results
cannot be obtained,. INH prophylaxis as practised in this investigation does not yield a reasonable dividend.
WHO/TB/Techn.Information/10 page 22 APPENDIX TABLE l. COMPLETENESS OF INITIAL EXAMINATIONS All blocks Tuberculin testing Eligible Examined Per cent. X-ray examination Eligible Examined Per cent. Bacteriological examination Eligible Examined Per cent. l 039 l 005 96.7 521 503 96.5 518 502 96.9 19 470 18 399 94.5 9 570 9 025 94.3 9 900 9 374 94.7 24 396 23 276 95.4 11 952 11 362 95.1 12 444 11 914 95-7 INH blocks Placebo blocks
WHO/TB/Techn.Information/10 page 23 Jl.ppen~ix
TABLE 2.
COMPlETENESS OF TUBERCULIN TESTING 1 BY AGE AND SEX -·~
Age 1n years Eligible 0-4 5-9 10-14 15-19 20-29 30-39 40-49 50-59 60-69 70 and over Unknown Total 2 452 1 847 1 192 772 1 860 1 664 1 310 673 302 160 213 12 445
Males Tested 2 408 1 818 1 136 712 1 624 1 525 1 244 648
---·
Per cent. 98.2 98.4 95.3 92.2 87.3 91.6 95.0 96.3 95.7 93.1 0.0 92.8
All blocks Females Eligible Tested Per cent. 2 398 17r;r( 1 116 861 2 437 1 462 938 468 296 148 30 2 371 1 774 1 098 836 2 391 1 443 919 464 289 138 98.9 98.7 98.4 97.1 98.1 98.7 98.0 99.1 97.6 93.2
-
'
·-. ·-·
,,,,
Both
Eligible 4 850 3 644 2308 1 4 3 2 1 633 2r;r( 126 248 141 598 3o8 243 24 396
sexes Tested Per cent. 779 592 234 548 015 968 163 112 578 287 98.5 98.6 96.8 94.8 93.4 94.9 96.2 97.5 96.7 93.2
INH blocks Both sexes Eligible i Tested ·Per cent.
Placebo'blocks Both sexes Eligible Tested Per cent. 2 474 1 943 1 177 825 2 144 1 611 1138 574 299 152 107 12 444 2 443 1 922 1 135 777 2 012 1 538 1 098 560 289 140 98.7 98.9 96.4 94.2 93.8 95.5 96.5 97.6 96.7 92.1
4 3 2 1 -4 2 2 1
I
2 376 1 701 1 131 808 2 153 1 515 1 110 567 299 156 136 11 952
2 336 1 670 1 099 771 '2 003 1 430 1 o65 552 289 147
'
98.3 98.2 97.2 95.4 93.0 94.4 95-9 r;rr.4 96.7 94.2
"
289 149
11 553
11 723 I
o.o 98.1
23 276
o.o 95.4 i
11 362 '
o.o 95.1
11 914
o.o 95.7
I
11 951
WHO/TB/Techn.Information/10 page 24
TABLE 3.
DISTRIBUTION BY SIZE OF REACTIONS TO THE MX 1-TU OR 5-TU ·-··
TEST~
ACCORDING TO AGE AND SEX
A. ...
Males .
..
··-·
..
···-··--
·Age in. years Less than 1 1 2 3 4 5 6 7 8 9 J,.0-14 -·
-·
---···-·--·----·-···----------
..
-- -------- ···------------··· -·
0-1 406 284 311 266 238 201 183 156 109 77 234 49 44 18 10 7 4 3 2 600 I
2-3 102 121 139 174 175 151 151 102 88 61 216 58 66 29 16 12 11 9 1 681
4-5 2 9 11 13 5 5 6 6 8 4 31 20 26 13 15 17 11 5 2CJ7
6-7 2 1 2 5 4 5 1
8-9
10:11 2
-·-
Diameter of induration-;-(mrn) 18-19 14-15 1 16-17.. . _ 12-13-· i ·····--
---·-··
20-21 1 1 5 7 8 15 11 27 19 24 119 70 172 132 105 60 ,
22-23
24-25 •··
26-27
28-29 I
30 and ···over
Total 519 426 I
1
3 3
2
1 1 7 4 4 9 6 5 14 12 70 84
2 1 4 7 18 19 18 18 25 19 124 145 373 -· 400 .
4 1 1 3 2 4 19 8 22 15 16 11 7 3 117 I
1 6 4 9 10 12 24 24 34 23 151 125 --···-·
I
2 2 6 3 13 14 14 10
1 2 1 2 3 6
1 2
'
1 1 1
-
-
2 5
1 5 3 3 5 14 25 59 ---44 60 24 ...
-
-
5 10 3 41 39 90 133 123 75 24 12 564 !
4 9 13 7 18 ... .. .. 12 12 13 3 5 116
3 4
3 1
-
. -· __ ;
15-19 .20:-.29 30-39 40-49 50-59 60-69 70 and over Total
65 . 61··--·-- . . -. 16 102 101 ... 80 25 12 9
5 32
4 4 8 10 3 3 1 .....
I I
..
-
. l
-
493 493 477 431 426 369 335 257 1 136 712 l 624 1 525 1 244 648 I
3 1 4 7 2 3
I
--·
..
I
21 10 282 i
I
?79 287 227 116 60 28
307 150 41 29 11 700 ! I
323 287 238 115 I
37 36 28 17 8 4 I
'
1 1 2 ,.... c:.
I i I
I
59 20 1 465
27 8
,
I I i !
I
1
l I
i
289 149 11 553
\
11 214
811
! !
519
I I
205
I
i
41
24 I
7
WHO/TB/Techn.Information/10 page 25 Appen<ix
TABLE
3.
'"'ISTRIBUTION BY SIZE 0? REACTIONS TO TEE MX l-·1'U OR 5-Tl! 'rE:S'.i',
:~CCOJh::U~G
TO :\CE .L\1'8 ::3EX (continue-1 )
B.
Females Age in -···-·--·
Diameter of induration (mm) .. -
years Less than 1 1 2 3 4 5 6 7 8 9 10-14 15-19 20-29 30-39
0-1 459 291 280 247 217 180 177 120 140 77 211 90 181 37
2-3 81 102 167 172 160 148 122 104 99 65 260 137 240 99
4-5. ·····6:..7 5 9 5 11 9 12 12 14 8 3 40 30 81 70 34 16 11 4 374 1
8-9 1 2 2 2 1
10-11 1 I
12-13 1 2 1 1 3 7 5 4 7 5 33 31 103 69 66 31 20 19 4o8
14-15 2 1 1 4 4 4 3 5 8 12 55
16-17 l
18-19 .. l
20-21 I' l I
22-23 1 1 2 9 11 7 16 16 20 15 76 84 232 158 86 44 34 17 829
I
I
24-25 l
I
26:..27
·····-....
28.:."-29 .....
30 and over
Total 557 414 483 473 444 411 418 330 367 248 1 098 836 2 391 1 443 ..
2 l
1 3. 3 2 2 1 2 2 15 12 37 20 22 13 7 4 147
1
2 2 3 4 2 3 1 20 17 56 51 41 19 13 6 242
3 3 1
2 8 8 8 11 25 11 14 18 114 109 389 253 151 75 48 17 1 262
2 10 5 16 17 24 '
I
1 4 1 5 4 7 8 3 43 40 133 72
5 2 8 13 20 13 25 17 79 73 267 181 111 58 40 17 932
2
-
:L
-
2
-
1
1 2 1 4 14 8 29 23 21 13 5 2 125
1 1 1 3 2 10 12 9 5 3
27
5 16 23 27 22 19 11 3 141
30 25 129 105 382 225 171 71 42 20 1 302
1 2 5 3 4 1 1
So 223 143 89 65 18 8 725
40:49 50-59 60-69 70 and over Total
··Is·· 4 4 3 2 733
41 13 11 8 2 029
36 17 21 10 400
.. ·-
919 464 289 138
50
18
11 723
WHO/TB/Techn.Information/10 page 26 Appendix TABLE 4. ·······-··
ESTIMATED PREVALENCE OF TUBERCULOUS INFECTION# BY AGE AND SEX . . --~
.. -
..
--··- . -· --·-
····-
...
----
Age in · -- - - .years Males Less than 1 1 2 3 4 5 6 ·7 8 9 ·10-14 15-19 20-29 30-39 1.3 2.3 6.1 7-1 10.7 15.8 19.7 27.6 37.0 39-7 54.8 80.1 89.2 94.3
..
. --
------
··- -·------~- - - -
All blocks Females 1.8 2.4 5.8 8.0 12.2 16.8 24.4 26.7 31.9 40.7 51.6 65.9 76.5 82.5
-- -- .
. ··-
-·-·
I Both- -sexes -· 1.6 2.4 5-9 7-6 11.4 16.3 22.0 27.2 34.3 40.2 53.3 72.4 81.6 88.5 . j
;
Males 1.5 2.2 6.4 8.3 12.8 18.9 18.8 26.0 42.1 38.9 52.8
Per cent. infected INH blocks Females
----·---
------
··-· .. ·-·-
--- ...
-----
... _.,. _____________
................
...
..
.
····--
.
'"•4··-····
....
·-·------ . ·-- ... ·--------~
.....
····--------
.
I '
I
i ··----
~-.,-
Both sexes .. ---
- --- -.---- -Males -~
Placebo blocks Females· ··-.. ....
.......... -
··Both· sexes L-3 2.4 5-5 5-5 10.5 . '14.8 21.9 27.8 31.7 38.1 ·- ------ --··--·-·· -
--
········
....
-- ----
.....
...
2.2 2.5 6.3 11.1 11.9 16.8 25.2 27.2 33-9 46.0 53·7 65.4 75.2 82.0
······
1.9 2.3 6.4 9.6 12.4 17.9 22.2 . 26.5 37.6 42.6 53.2 72.0 80.7 88.3
1.2 2.6
. ·T:4
·-
....
---·-··
2.3 5.3 5.0 12.4 16.7 23.6 26.3 30.1 35-5 49.6 66.4
5.8 6.0 8.8 12.9 20.4 29.2 33-3 40.3 56.9 80.9 89.6 94.3
1
I
79.2 88.8 94.3
I [
77.8 82.9
I
'
53-3 72.8 82.6 88.8
I
.. ----------
.. --- ------- -·--
.;
·-·---- --··· ··--------
WHO/TB/Techn.Inform tion/10 page 27/28 Appenrix TABLE 5. RESULTS OF X-RAY EXAMINATION, BY AGE, SEX, AND TYPE OF PATHOLOGY
Age in years
Examined
healed lesion Calcif. Pleurisy seq. 1 31 48 45 78 104 86 45 33
.''~~.
Males Apparently active lesion Enlarged Pleurisy ! Other active, rOther active, hilus gl. no cavity cavity
! App. Examined 1
healed ~esion Calcif. i Pleurisy seq. 1 37 53 33 95 86 57 31 45
l
Enlarged hilus gl.
Females active lesion Apparently Pleurisy Other active, Other act!> e., No cavity cavity
4 5-9 10-14 15-19 20-29 30-39 40-49 50-59 60 and over
179 1 564 1 147 723 1 643 1 540 1 253 649 436
1 13
-
16 1
2 4 5 2 2 1 3 1 3 I
1 28 22 15 74 86 105 78 59
1 5 10 8 13 5 6
171 1 516 1 099 834 2395 1 443 922 462 423
l
10 3
2
4 26 17 14 59 46 66 36 42
-
1 5 9 4 3 2
1 1 7 4 4 3 8
-
1 1 1 1 1
1
5 1 1 2 2
27 16 20 8
1 1
TABLE 6. ' Age in years
COMPARISON OF THE RESULTS OF TUBERCULIN TESTING AN'D X-RAY EXAMINATION Number examined by X-ray and tuberculin test negative ! positive I not made 1 1
I 1
Number with lung pathology j and tuberculin test ... _ _ _ j neg2tive l positive not made 2
I
4
5-9 10-14 15-19 20-29 30-39 40-49 50-59 60 and over
\ 308 . 2 208 l 043 11 l
39 864 189 115 l
!
3
8
24 10 2
7 130
l
I
14 17 39 23 12 2
139 114
2
425 736 340 203 125 126
l l
3 263 2 620 l
15 16 19 17 28 j
334 354 335 209 182
3 2
960 984 730
3
I ._
Total
\
5 514 __J 12 764
I
121
133
I
l
804
I
10
'0 '0 (])
;:r::.
'0
PJ
(Jq
(\)'-.._. [\) IJj
0
::r:: 8
~
0.. 1-'·
::J
:X:
\0 "-..
8 0
(])
g . ~ 'i H.> 0 Ill
3
1-'•
c+
~ 0
;t>
'0 '0
~ (jq
u
TABLE 7 •
RESULTS OF X-RAY EXAMINATION, BY AGE
(!)
··~:
~ ~
Age in years
All blocks Number i'ri th Number lung pathology examined
INH blocks Number with Number lung pathology examined
Placebo blocks Number Number with examined lung pathology
~! CD ()
CD"'-.
0
~ ~
if . 1; 'i ~
H
0
4 5-9 10-14 15-19 20-29 30.::)9 40-49 50-59 60 and over Total
350 3 080 2 246 l 557
9 155 151 117 350 373 356 226 210 l 947 ....
184 l 455 l 103
8 76 68 64 180 170 .188 106 99 959
166 l 625 l 143
l
a
79 83 53 170 203 168 120 lll
1-'·
c+
~
I-' ()
4 038 . 2 983 .2 -175 llll
777 2 014 l 439 l 069
780 2 024 1
544 l 106 560 426
551 433 9 025
859 18 399
9 374
988
I
TABLE 8.
ATTENDANCE AT, AND RESULT OF, BACTERIOLOGICAL EXAMINATION, BY AGE AND SEX
Age in years
Males Eligible for bacteriological examination . --~
Examined bacteriologically
Positive
Females Eligible for Examined bacteriological bacteriologically examination """
Positive
4
.
5-9 l0-14 15-19 20-29 30-39 40-49 50-59 60 and" over --------------
3 48
3-46 28
.. ---.
--
1 6 23 18 16 8 5
. ---
-"
·---···-·
4 -·- .
"-3- -
29 23 lOO
123 138 105 77 ---------
23 96 119 132 102 76 -----
39 21 16 78 60 75 45 55
4 38 21 15 74 59 72 44 53 ~-
1 3 1 17 13 5 4 4 -------------------
:g CD ><
~
~
'0
.....
5_
\.>JbJ 1-'""'-. ~ \.)
8 CD"'-g
::e:
•
~ 0 ..... 0
l 0
~ 1-'
);:>
TABLE
9.
DISTRIBUTION OF THE REGISTERED POPULATION7 BY AGE AND SEX INH blocks Male Female Both sexes Male Placebo blocks Female Both sexes
i::l ~
"0
'0 I» (JQ
1-'•
0.
~I! 1-3 (I)
(!)',_
::r: 0
:E:
Age in years Male
All blocks Female Both sexes
•
g
0
t:i
H)
2 517 5-9 1 847 10-14 1192 15-19 772 20-29 1 860 30-39 1 664 40-49 1 310 50-59 60-69 70and over Unhwtm
0-4
2 442 1797 1 116 861 2 437 1 462 938 468 296 148 30 11 995
4 959 3 644 2 308 1 633 .. 4297 3 126 2 248 1 141 598 3o8 243 24 505
1 251 840 587 390 936 8o8 631 327 155 82 118 6 125
1 177 861 544 418 1 217 .. ".--· .. -·--
-
2 428 1 701 1 131 808 2 153 1 515 1 110 567 299 156 136 12 004
1 266 1 007 605 382 924 856 679 346 147 78 95 6 385
1 265 936 572 443 1 220 755 459 228 152 74 12 6 116
2 531 1 943 1 177 825 2 144 1 611 1 138 574 299 152 107 12 501 I
c+ .....
~
0
g 0
--........ 1-'
I
673 302 160 213
707 479 240 144 74 18 5 879
Total
? 510
vffiO/TB/Techn.Information/10 page 33
TABLE 10.
EXCLUSIONS FROM STUDY
All blocks Registered p..)pulat.ion Exclusions: Persons less than 2 years of age Persons not attending or not completing examinations Persons given BCG vaccination Persons given specific antituberculosis treatment from the beginning, because: (1) they had already begun such treatment
INH blocks
Placebo blocks
24 _505
12 004
12 501 1 016 622 1 449
2 063 1 271 2 693
2 047 649 1 244
124 123 2 565 1 754 15 910
53 63 1 . 289 889 7 769 - ..
71 60 1 276 865 8 141
(2) they were found bacteriologically positive cli~ico.l reasons
(3)
it was considered necessary for . t,rc.·~;tment
I
Pr:rs.ons who cha.ngeq h;r;Jons w;10 r~ic1
b0cc;.use
of a change of residence not begin tr'-'::ttmcnt
until 1960 ~ligible
for study
WHO/TB/Techn.Information/10 page 34 Appendix TABLE 11. COMPLETENESS OF TABLET DISTRIBUTION IN THE INH AND CONTROL GROUPS
.. Effective number of weeks for which tablets were distributed
Number of persons ··Total· ·· · INH group 641 186 319 361 185 297 320 407 2 329 10 706 159 15 910 288 87 163 196 83 148 150 215 1 126 5 218 67 7 741 Control group 353 99 156 165 102 149 170 192 1 203 5 488 92 8 169
..
0-9 10-14 15-19 20-24 25-29 30-34 35-39 40-44 45-49 I
50-54 55 and over Total
WHO/TB/Techn.Information/10 page 35/36 Appendix TABLE 12. REASONS FOR NON-ATTENDANCE AT THE PERIODIC HALF-YEARLY EXAMINATIONS
INH Group Eligible for examinations Without record of follow-up With record of follow-up Died ) during Moved ) first six Observation ended ) months Non-attendance at six months not explained Attendance at six months Died ) between Moved ) six and 12 Observation ended ) months at 12 months not explained Attendance at 12 months Non~attendance
Control group 386
380 15 365 2 15
9
377 1
12 1
56 292 2
67 296 2
10
22
58 278 1
54 285 2
Died ) between Moved ) 12 and 18 Observation ended ) months Non-attendance at 18 months not explained Attendance at 18 months Died ) between Moved ) 18 and 24 Observation ended ) months Non-attendance at 24 months not explained Attendance at 24 months
9 79 62 185
85 55 197 1 2
155 28 64
158
33 58
WHO/TB/Techn.Information/10 page 37
_Appendix TABLE 13. DISTRmUTIONS BY SIZE OF REACTIONS TO THE FINAL MX 1-TU TEST AMONG PERSONS WITH REACTIONS MEASURING LESS THAN 10 mm TO THE INITIAL TEST, ACCORDING TO AGE AND STUDY GROUP r--.-·-·· -·---·-.
Age ia yea:2s
Diameter of induration (mm) 0-l
2-3
4-5
6-7
8-9
10-11
12-13
14-15
16-17 INH GROUP
18-19
20-21
22-23
24-25
26-27
28-29
2-4 5-9 10-14
30 and over
Total
126 136 30
300 299 88
29 43 23
5 9 12
1 2 2
3 7 8
2 5
2 4 4
2
4 5 7
14 8 6
8 7 6
2 7 4
2 7 CONTROL GROUP
3 1
1 4
1
500 536 203
2 1
2 2
2-4
140 148 17
349 277 78
1.~2
11 10
4 2 2
4 7 4
1 3 4
1
5-9 10-- JA
54 30
4
3 10 5
10
5 13 1
12 15 7
8 12 3
3 16 6
1
585 571 173
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I
The purpose of the WHO/TB/Techn.Information series of documents is to acquaint WHO staff and interested individual research and public health workers with the progress of tuberculosis research and control~ by means of: (1} summaries of some relevant problems;
(2) field reports and other communications which are of particular interest but which would not normally be printed in any WHO publication; (3) papers that may eventually appear in print but which, on account of their immediate interest or importance, deserve to be made known without delay.
The issue of a paper in this series does not~ therefore, constitute formal publication, and a paper so issued may, with the agreement of the author and WHO, be published in a WHO periodical or elsewhere. Authors alone are responoible for views expressed in signed articles. The mention of manufacturing companies or of their proprietary products does not imply that they are recommended or endorsed by the World Health Organization.