Section 1 The results of treatment of pulmonary tuberculosis in communities in recent years

TUBERCLE SUPPLEMENT

S E C T I O N 1

T H E R E S U L T S O F T R E A T M E N T O F P U L M O N A R Y T U B E R C U L O S I S 1N C O M M U N I T I E S IN R E C E N T Y E A R S

(Cha i rman- -S in GEOFFREY MARSHALL)

Sir Geoffrey Todd: I wish to welcome you on behalf o f the Council and the consulting staff, and thank you all for coming. We are looking forward very much indeed to a very fruitful discussion today and tomorrow morning. I shall now hand you over to the Chairman of the Consulting Staff. Chairman: We have to thank the Council and Lord Portal, the Chairman, for arranging this for us.

The subject this morning is 'Results o f treatment of puhnonary tuberculosis in communities in recent years', and we shall ask Dr. Springett to start. His paper wilI be followed by one f rom Dr. H o m e from Edinburgh, and then that will be followed by a discussion which will be opened by Dr. Foster-Carter.

DR. V. H. S P R I N G E T T :

In discussing the subject of the results o f treatment of pulmonary tuberculosis to-day the chief problem is one of access to a sufficiently large group of patients. I should like to say right at the start that I am indebted to my colleagues in Birmingham for access to their material, for it will be mainly these results that I shall be discussing.

Just one word about the background: six of us work in Birmingham, dividing the city on a geo- graphical basis, and we deal with diagnosis, in-patient t reatment and after-care. I wanted to start with that point on organization because it may be important , in that one consultant is responsible for one patient right the way throughout treatment.

The last phrase in my title presents some problems because treatment has been rather different at different times in "recent years'. I f one takes too recent a period then there is no follow-up and the results you are dealing with are incomplete and not very interesting. On the other hand, if one goes back too many years the methods of t reatment employed at that time are so different f rom those that we are now employing that again the results are not really of current interest. So as a com- promise I have on the whole taken the years 1957 and later for study, taking cases coming under treatment for the first t ime during those years or later, rather than any earlier years.

The main difference, t think, in our methods o f t reatment between 1957 and now is that at that time approximately t0 % o f patients were having surgery as part o f their primary treatment and at the present time it is something under 1 % - - I do not know how small, but it is extremely small. So far as the medical t reatment is concerned, I do not think that there has been any very great difference between 1957 and now.

Now the middle phrase of my title is ' in communit ies ' ; al though it is in the plural in the title, I ~/m proposing to deal solely with the city of Birmingham or defined sub-divisions of it. Part o f what I have to say relates only to two teams in the city dealing with a third o f the total population.

The total population is 1,100,000 or rather more, and there ate one or two facts about this population which I think are worth mentioning. We have a very large immigrant group, over 100,000 probably, who were born in Ireland. This group has a slight excess o f tuberculosis, up to perhaps

R E S U L T S OF T R E A T M E N T

50% more than in the native-born population. There is quite a big West Indian born population, around 30,000 to 50,000; we do not know exactly until the last census figures are out. But the West Indians are no worry from the tuberculosis point of view; in fact, they seem to have rather less tuberculosis than the native-born. There is a substantial Asian born population, particularly from Pakistan; again, I do not know the number exactly, but there are probably around 10,000 or 20,000. This group is very important , because they do produce a quite disproportionate amount of the tuberculosis with which we have to deal. Although they form only 1% of the population, in recent years they have been supplying well over 10 % o f the cases of tuberculosis; but they are all included in the results I am to quote later on.

There is one other point in the background I would mention and that is the question of social class. We divided up our notifications for last year according to the social class, that is the occu- pation of the worker, and it is very interesting that out of some 700 notifications there was none in social class 1, the professional classes. There are two main reasons for that. Of course there is less tuberculosis in that social group, but there is also a selective factor to the city of Birmingham, in that on the whole, if you achieve social class l, you no longer live in Birmingham--unless you have to. The point o f this is that my material is not weighted with people with favourable social back- grounds; in fact, the weighting, if anything, is towards adverse factors.

TABLE ] . - - N E w NOTIFICATIONS IN RECENT YEARS OF RESPIRATORY TUBERCULOSIS IN

PERSONS AGED 15 YEARS AND OVER, WITH ESTIMATE OF NUMBERS BACTERIOLOGICALLY

POSITIVE, AND PERCENTAGE DRUG-RESISTANT AT DIAGNOSIS

I Year [ Notifications

i (Respiratory: aged 15 and over)

1956 I 849 1957 ! 731 1958 I 775 1959 i 613 1960 I 650 1961 _. 602

Total: , 4220

Estimated ,i Primary Drug Resistance Positives [ No. % of POS:

---;3T- 457 483 383 406 376

2635

7 1.3 13 2.8 8 1.7 7 1"8

10 2.5 11 2"9

56 2.1

(In addition, one boy under 15 years was found to be excreting drug-resistant organisms on diagnosis in 1961.)

I have put in Table I because I think it is important to know, in discussing results o f treatment of newly diagnosed patients, what is the position with reg~trd to drug resistance. I am not going into details o f bacteriological methods of testing sensitivity. I hope they are reliable; they seem to work in practice. I do no t think they would entirely satisfy Dr. Mi~chison, and he might have comments on this. But it does look as though we are running fairly steadily at about 2 % primary drug resistance, and it has no~ ~a}~y changed very much over the years, i t does vary between 7 and 13 cases, but it is not a very big variation and I am not sure that there is actually any real increase in recent years.

In Table I I I have put the pattern of pr imary drug resistance and I think it is impor tant to notice that such resistance as there is is almost entirely due to ofie' drug only and mainly to streptomycin. This no doubt goes back to the time when a good deal o f home treatment was being done from the start, with streptomycin being given by the district nurse and the patient being left to take the PAS and presumably he did not ; a good bit of induced streptomycin resistance occurred then and we are getting the results o f that now. The isoniazid figure seems to me very low, and I was very

T U B E R C L E S U P P L E M E N T

pleased that we had had no primary isoniazid resistant case for three years until last September when the first one turned up. When we went into the story, it was one of these Pakistanis, who had been in the country only six weeks on diagnosis. He had shared lodgings in Pakistan with a known case of tuberculosis who was getting his drugs through the post f rom England.

TABLE II.--RESiSTANCE PATTERN IN THOSE PRIMARILY RESISTANT 1956-1961.

To isoniazid only 6 To PAS only l0 To streptomycin only 36

Total to one drug 52 to two drugs 3 to three drugs 1

Total to one or more drugs 56

As to results, we* have previously published the fact that, to our own surprise when we came to study it, we were getting 100 ~ sputum conversion in in-patients who were co-operative in treatment, over a series of 530 patients. Rather than extend the size of that series by bringing in other years, I have for to-day taken a rather different form of extension, something we are engaged in doing for this series, and that is to include those who were excluded on certain definitions in that survey. Unfortunately, I have not been able to do this for all six teams, but only for the patients under the care of Dr. Harold Thomas and myself. The others are on the way, but just not advanced enough for presentation. So these results are to some extent provisional in that they have been put through rather quickly in the last two or three months.

Table III gives the basis of selection of the present group of 310 for study. There were 203 in the original study and on the next line there are 13 who fulfilled the criteria of the original survey and they should have been in but were not, for various reasons in the way the lists were compiled. The next 28 were purely technical exclusions, in that their positive spu tum was outside the defined times or for some reason there was no culture or sensitivity done, and that took them out of the first study. Then there is another group of 29 who were treated away from Birmingham because we had not got suficient beds; they were therefore not treated by any of the six physicians that [ have mentioned; again they were excluded from the original study. There was only one case of primary

TABLE III.--BAs[S OF SELECTION OF PRESENT GROUP OF 310 FOR STUDY.

Included in original survey 203 Fulfil criteria of original survey, but not included 13 Positive > 2/12 before or after admission: No culture or no sensitivity 28 Part or whole of hospital treatment not under any of the 6 physicians 29 Resistant to more than 1 drug 1 Refused admission, or self-dlscharge 36

Total 310

(Excluded because sputum negative throughout 181) (.Excluded because never under chest clinic care 15)

* Thomas, H. E., Forbes, D. E. P., Luntz, G. W. R. N., Ross, H. J. T., Smith, J. Morrison, and Springett, V. H. (1960), Lancet, it, 1185.

R E S U L T S OF T R E A T M E N T 9

resistance to more than one drug, and this has in fact been successfully treated with the aid of resection, Then there is the very impor tan t group, on the g rounds o f which mos t people have criticised the original study, o f 36 who either refused admiss ion to hospital al together or were excluded because they took their own discharge against medical advice,

For completeness, I have noted tha t there were 181 who were s p u t u m negative th roughout , notified in the same area and same years, and 15 who never came under chest clinic care if, for example, they were notified after death or because they were under t rea tment e l sewhere- -one o f them, interestingly enough~ under t rea tment at Midhurs t ; I a m not equat ing that with being notified after death.

TABLE IV.--STATUS DURING WINTER 1961-62 OF 3-HESE 310 PATIENTS,

No. % Well, no problems related to tuberculosis 201 64.9 Removed from city, or lost from supervision 68 21.9 Consistently sputum negative, but a complication of

tuberculosis or treatment 2 0-6 Have had sputum + relapse; alive 7 2-3 Dead; tuberculosis an important factor 10 3.2 Dead, other causes 22 7.1

Totals 310 100.0~

In Table IV I have used certain ma in headings to indicate what the posi t ion was dur ing this past w in te r - - I have not t aken any exact time. These are all cases notified and star t ing on t rea tment in 1957-58 and this is the posi t ion at their last a t tendance dur ing the winter of 1961-62. Just about two out o f three were well with no problems at all related to their tuberculosis, working and leading no rma l lives unless there was some quite unrelated condit ion. When I come to discuss some of the hor rors later on, please r emember tha t two out o f three o f the original series really are doing quite well.

The next group, ano ther 22 % w h o m I have listed as removed f rom the city or lost f rom supervision, I also regard as satisfactory. We have done no inquiry into patients who have moved out of the city. Quite a lot have been re-housed jus t outside the city borders and are no longer under our care, and I have had to count those as lost. There are, of course, some who are genuinely lost f rom supervision and are no t at tending. I th ink they are a smaller number , bu t in both these groups there is a tendency, I think, to hear abou t it i f things have gone wrong. So that on the whole I am fairly happy about including those amongs t the 'welt'. It is no t entirely satisfactory, but [ think they belong there rather t han anywhere else. Certainly one pat ient who was re-housed outside the city died subsequent ly : I hea rd abou t this, and instead o f put t ing him there, where he would be if he had done weir, I have included h~rn in the deaths, with tuberculosis as an impor tan t factor. [ sha[t be discussing tha t case in detail.

Now for some of the ones who have not done quite so well: two patients, both my own, were consistently s p u t u m negative following t reatment , bu t I feel that thmr course has not been an uncompl ica ted one, part ly because o f their tuberculosis, bu t really rather more because o f their t reatment . The first was a m a n aged 45 years when he first came under t rea tment in September, 1957; he had in fact been under observat ion for two years following mass radiography examinat ion; his s p u t u m was then positive and this was the first t ime definite evidence o f activity had been obtained; his organisms were fully sensitive. He came into hospital for jus t under one year and had all three p r imary drugs t h roughou t his stay. He was still in hospital in June, 1958, clinically very well and s p u t u m negative. There was still some cavitat ion at the left apex and we decided to carry out what migtlt be called an ' insurance resection' . This was done and he proceeded to an apical empyema and has had a drainage tube ever since, having had a thoracoplas ty and a shor tening o f the left

10 TUBERCLE SUPPLEMENT

clavicle. He is now working but is leading a 'drainage tube existence'. As I say, this I feel is a complicat ion o f his t reatment , one of the things that just does happen ; bu t he, I feel, would have been better had we left h im alone.

The second in this group of two is an engine driver aged 59 years, who in September 1958 presented with newly diagnosed s p u t u m positive pu lmonary tuberculosis, fully sensitive to the three main drugs. He was in hospital for only four months . He had three drugs for three months , and this then was followed with PAS and isoniazid for a total of 27 mon ths ' chemotherapy. He returned to work about a year after diagnosis; that would have been tile early part o f 1959. In January 1960 he was reasonably well and working, still taking his PAS and isoniazid. Then when 1 next saw him on a routine visit in April, 1960, I though t someth ing had happened in the left upper zone and I did not at all like the look of it. I t hough t there was a fresh lesion and the rather solid round focus was confirmed on tomography. I was concerned lest this was a neoplasm arising at the site o f his old tuberculosis; and he in fact had a resection. He took all this very calmly and quite smoothly. The whole thing was tuberculous, there was no quest ion of neoplasm, and 1 feel that he suffered from my lack o f confidence in what I was dealing with. He also would have been better wi thout his surgery. So these two I feel have had complicat ions o f their t rea tment rather than their disease.

Now we come to a group of seven, in which there has been a definite sputum-posi t ive relapse; these patients are alive at the present time. i f there is a point of interest amongs t them it is that it is in this group only that there seems to be any difference between Haro ld T h o m a s ' results and mine. Of the seven relapses, two are mine and they bo th broke down with resistant organisms. The remaining five, patients of Harold Thomas , broke down with sensitive organisms, and we wonder if there is some difference in our approach to these patients. Do I tend to make mine hang on a bit longer but a bit irregularly with their drugs so they break down resistant, if at all? Does Harold T h o m a s terminate t rea tment if he feels that they are not co-operat ing fully, and therefore, a l though he may have slightly more relapses, they tend to be with sensitive organisms? It is only a difference between two and five out o f roughly equal sized series, bu t it is the only sign of any suggest ion oF any difference between our results and we jus t wonder if there is some sort o f personal factor. It may be purely chance and with a longer series it might easily be reversed.

Now the other impor tan t group of failures is the group who have died with tuberculosis as the impor tan t major factor in their deaths. There are ten Of these; 3 ~ of the total series taken from the start of diagnosis through to this period four or five years after diagnosis.

The earliest death was a m a n of 50 years with very gross disease. He had a year 's history of cough and m a n y other symptoms and progressive weakness. In fact, he was first referred to Dr. Brian Taylor at the General Hospi ta l and he came a long to me and was admit ted within a mat ter o f a day or two; but he died ten days later f rom his gross tuberculosis. I th ink we jus t have to admi t tha t if the diagnosis is too desperately late there are going to be a small percentage w h o m we are not going to be able to save. We still get this sort of th ing occasionally, people who jus t will no t come up or are not sent up until they are very grossly ill. Whe the r with steroids we might save one or two more l do not know, but certainly there is a group like this where we are going to have one or two early deaths.

The other early death in the series was a w o m a n aged 37 years when she came under t rea tment in October, 1957. She was s p u t u m positive and fully sensitive, and she had three drugs t h roughou t her stay in hospital of some three months . She then died suddenly one night f rom a right spon taneous pneumothorax . This was correctly diagnosed by the du ty officer, bu t efforts at t rea tment were unavailing. Post mor t em confirmed that the cause of death was a right spon taneous pneumothorax , but added the observat ion that at the apices o f bo th lungs there were numerous emphysema tous bullae up to 2 cms. in diameter. It was though t that it migh t have been the rupture of one o f these rather than o f the tuberculous cavity that was responsible. However, I t hough t i~ fairer to regard this as a tuberculous death.

There was one other death about 15 m o n t h s f rom diagnosis which was definitely due to a rup-


tured cavity, a m a n in his thirties with very gross disease, left with two very large cavities, one at each apex. We did not know which one to tackle surg ica l ly- -and we decided to tackle neither. He in fact ruptured the rather less dangerous looking one some mon ths after leaving hospital, and again, when he got to hospital , efforts at t rea tment were unavai l ing and he died from the effects o f his ruptured cavity.

The next patient 1 feel really begins to show up why patients do not do well: it is undoubted ly physicians ' mistakes for the mos t part . In March, 1954, a man in his thirties was found by mass radiography to have moderately extensive tuberculosis which included some calcification. At tha t t ime a decision was made to keep h im under observat ion whilst he cont inued at work, t hough I do not th ink we would do so to-day in view of the extent of the disease. Certainly the policy of observat ion was main ta ined for far too long, until July, 1957, when he had gross disease with cavitat ion and was spu tum positive and fully sensitive. He was admit ted under my care, and I then made mistake number two, by treating him, in addition to the drugs, with postural retention, l am sure this was quite wrong, and a l though we got excellent control of his disease and he became spu tum negative, he got a grossly destFoyed and infected left lung. After some nine m o n t h s ' t reatment the left lung was removed and he had a thoracoplasty. W hen he was last seen in October, 1959, he had an empyema and a drainage tube, and he died shortly after that f rom a cerebral abscess which was certainly secondary to his empyema. 1 think there are at least two clear-cut mistakes in the manage- men t o f that man and these were the cause of his death. He, in fact, was the m a n who had been re-housed outside the city, and if he had done well he would have appeared in the second category as lost f rom supervision.

The final case-history in this series o f deaths is that of a man aged 50 on diagnosis in April, 1958, with relatively limited disease in the right upper zone and spu tum positive, though the culture was slow to grow and we only got it after he had been discharged f rom hospital. He was in less than three m o n t h s on three drugs for the time he was in hospital, cont inuing on PAS and isoniazid afterwards. He stopped chemotherapy in August , 1959. He seemed reasonably satisfactory when he was seen in March, 1960. In November , 1960, he failed to keep an appo in tmen t and unfor tunate ly was not sent for again. This I regard as a major error, tha t on one failure the machinery did not work sufficiently well to send for h im again fairly quickly. We did not see h im again until June, 1961, when he was very weak and ill indeed. There was spread o f disease and a positive spu tum, and he died ten days later f rom a massive pu lmonary embolism. I have always felt tha t tha t was a very sad result o f the administrat ive fault of our failing to send for h im again when he had failed on one occasion to attend.

Return ing to Table IV, you will see that 22 have died f rom other causes. 1 cannot be absolutely certain that tuberculosis did not play a part in some of these. 1 th ink there were some where the extensive fibrosis, and so on, had played some par t in causing the death. I th ink it was fair enough to regard them as essentially non- tuberculous deaths. They certainly included several cases of carc inoma of the bronchus, the other large group being cardiac failure.

TABLE V, - - SE x AND AGE AT NOTIFICATION, RELATED TO 1961-62 STATUS

Males Females

Well, no problems Removed or lost Sputum negative, with complications Sputtm~ positive reIapse Dead; tuberculosis Deed; other causes

Under 50 years

100 43

l I 3 3

50 y e a r s & o v e r

42 II

1 6 4

t7

Under 50 years

55 13 0 0 2 0

Totals i 152 81 70 8

50 years & over

12 T U B E R C L E S U P P L E M E N T

TABLE VL--EXTENT OF DISEASE AT NOTIFICATION, RELATED TO 1961-62 STATUS.

Well, no problems Removed, or lost Sputum negative, with complications Sputum positive, relapse Dead; tuberculosis Dead; other causes

Totals

Ministry o f Health classification

-I--I I i 2 f not recorded

43 2 3 22 1

I 0

i 12 0 7 0 1 6 0

I r 57 162 I 88 3

We have looked at these cases f rom two o ther points o f view in Tables V and VI. Table V gives the age and sex groupings of the patients, and summar izes the results in regard to these factors. Tile point I think 1 should emphasize here is that if we take the group o f 222 unde r 50 in bo th sexes, I th ink it is fair to claim that the results really are very good indeed, even when you take into account such drug resistance as we had, and such lack o f co-operat ion as there is. I th ink the dea th rate is about 3.5 ~ f rom all causes in the 4-5 year period, and only abou t 1 ~ relapsed or had any complication, if you restrict it to the under fifties. I f you look at the older ma le s - - t he re are very few of the older f ema le s - - t he results are not nearly so good; but I th ink it is largely due to the presence o f other complicat ing factors tha t you run into such difficulties there, and indeed I th ink the co-operat ion tends to be less satisfactory.

In Table V[, we are dealing with the extent o f disease at diagnosis, and the only i tem which I think shows any marked relationship is the fact o f death f rom tuberculosis : none with very l imited disease died in the follow-up period, bu t there was a considerable increase in the tendency to die with extensive disease, which o f course is someth ing which has been establ ished over a very long period and does appear still to persist even with the aid o f chemotherapy. I t is interest ing tha t the same relationship does not appear to hold with regard to sputum-posi t ive relapses, which are more or less evenly distributed, and I just wonder if this is perhaps due to the fact o f relapse depending less on the extent o f disease than on the extent to which the pat ients co-operate in taking their drugs. The extent o f disease is no t impor tan t in this respect, bu t the combina t ion o f drugs and the time for which they are taken is far more a control l ing factor in whether a relapse occurs or not.

Tha t is the end o f the material dealing with the follow-up of the defined series f rom the start. The numbers who have done badly are numerical ly ra ther small for any fur ther analysis, so I have switched to taking the whole o f the B i rmingham mater ia l for Tables VII and VIII which deal with deaths and acquired drug resistance.

TABLE VII . - - I 1 BIRMINGHAM PATIENTS NOTIFIED IST JANUARY 1957 OR LATER, AND TREATED FOR AT LEAST ONE MONTH, WHO DIED DURING 196I.

Sex

Age

Extent o f disease

Other disease

Co-operation

Drtlg resistotlce

9 males: 2 females. All over 50 years, 7 over 65 years. 9 had gross tuberculosis at notification. 7 had other major disease. 6 had discharged themselves, or repeatedly failed clinic appointments. (1 other, an alcoholic, died in hospital 5 weeks after notification.) 2 drug-resistant at time of death.


Table VII deals with the 11 patients who, having been notified in 1957 or later and survived on t r ea tment for at least one mon t h , died dur ing 1961 f rom tuberculosis. They were predominant ly males, nine out o f 11 ; they were all over 50, and seven of them over 65. The disease was gross in the major i ty o f them, and in seven there was other major disease present. In half of them there was a gross lack o f co-operat ion, no t jus t one occasional failure o f at tendance, but repeated failure to at tend, or they actually discharged themselves f rom hospital. On the whole, drug resistance as a factor in this group does not appear to have been o f major importance. Only two were drug resistant at the t ime of death.

TABLE Vl lL--12 BIRMINGHAM PATIENTS NOTIFIED IST JANUARY, 1957, OR LATEa, AND KNOWN TO EXCRETE FULLY SENSITIVE ORGANISMS, WHO HAD BY 31ST DECEMBER, 1961, PRODUCED ORGANISMS RESISTANT TO

ONE OR MORE OF THE THREE STANDARD DRUGS.

Sex: 11 males: 1 female. Age: 3 under 50:7 aged 50-64 years: 1 male and 1 female over 65 years. Extent of disease: 6 had 5 zones involved : ALL showed definite cavitation. Co-operation: 5 had discharged themselves from hospital. Possibility ofsurget:v: In 3, surgery might possibly have been helpful (I refused, 2 very doubtful). b~formation to general praetitioner about chemotherapy: could have been more explicit in 5.

Now these factors all completely reproduce themselves in Table VIII, dealing with patients who first came under care with sensitive organisms in 1957 or later, and we know that by the end of 196t under our care they had produced organisms which were resistant to one or more o f the three s t andard drugs. Again they are males, they are most ly over 50, they had gross disease and about ha l f were unco-operative. We looked at two other factors here. One was the possibility o f having a better result had we applied surgery. Th i s possibility arose only in three. One was a patient who refused and in the other two it is extremely doubtful whether surgery would have been feasible. The other factor, where we t hough t we might have done a little better, was to have been a little more explicit and precise abou t the drugs in the letters to the general practi t ioner concerning the drug regime and d rug prepara t ions to be used at home; but I do no t know how impor tan t that is with this group of patients who are no t very co-operative.

TABLE IX.--NuMBER OF PATIENTS ADDED TO DRUG RESISTANCE REGISTER IN EACH YEAR 1956-61.

,1956

Primary

1957 13 101 1958 8 39 1959 7 19 1960 10 18 1961 12 29*

Totals 57 296

Resistance

Acquired

90 97

26

41

Cumulative Total

97 211 258 284 312 353

* Includes 8 previously treated outside Birmingham.


TABLE X,--AssESSMENT ON' 3 l s r DECEMBER IN YEARS 1957-61 OF PATIENTS ON BIRMINGHAM

DRUG RESISTANCE REGISTER FOR MORE THAN I YEAR

Assessment 1957 1958 1959 1960 1961

Quiescent 12 46 67 73 96 Negative-active 20 36 37 26 30 Positive 46 67 61 67 47 Died 18 54 80 96 I 13 Left city ! 8 13 22 26

Totals 97 21 [ 258 284 312

Table IX shows tile position with regard to total drug resistance o f those who were on the drug resistance regi:'~ ~ in Birmingham. The first co lumn gives pr imary resistance cases and is merely repeat ing w~::~ ~,;s in Table 1. The next co lumn deals with the number s we have added each year who had re>i:,7 ...~ drug resistance, that is after previous t rea tment ; then we give the total, and the cumulat ive t.o~:,f, l ' h e last co lumn of Table X gives the present posi t ion o f these patients, when they have been on the register for at least a year, that is for all those who were found to be resistant up to the end of 1960. Roughly one-third o f the total o f 312 (the first two groups) are in a reasonably satisfactory state, roughly one-third are dead, and there is a much smaller group of 47 who remained positive a year or more after having been found to have drug resis tant organisms. Mos t of these pat ients date back to pre-1957, in fact to 1953 or 1954. A quest ion which is often asked is: what is the posit ion with regard to your t rea tment of drug-resis tant patients? F rom the poin t o f view of the communi ty , the factor that seems to me of greatest impor tance is to read Table X horizontal ly a long the line opposite 'positive' , which at least does not suggest tha t the n u m b e r known to be produc ing resistant organisms is increasing. I would hesitate to claim a decrease.

In conclusion, it does appear to me that the results o f t rea tment o f pu lmona ry tuberculosis o f adults with a positive spu tum can be a lmost unbelievably good. 1 still find it difficult to credit this, and I find it rather frightening, because it seems to me to bring great responsibilities in two aspects : we have got to go into any failure, that is death or d rug resistance, which occurs in our pat ients with very great care to try to find out what went wrong, and be prepared to produce them on occasions Iike this. Secondly, and this has more importance, it does mean a need for absolutely meticulous at tent ion in applying t reatment , and particularly in obtaining the co-operat ion o f pat ients in accepting drug therapy adequately.

D R . N. W. H O R N E :

I am presenting this account with my colleagues, Professor J. W. Crofton, Dr. I. W. B. Gran t and Dr. J. D. Ross, who have worked closely together on this problem dur ing the last decade.

One dict ionary defines a ' commun i t y ' as a 'collection o f individuals who live in the same locality and who are mutual ly dependent one on the other ' . It is in this sense tha t I propose to discuss the problem as it concerns the commun i t y in which I work - -E d i nbu rgh . Consequent ly , I am going to begin by looking at the c o m m u n i t y and then to consider the results o f t rea tment as they affect the individual. I shall then return to the c o m m u n i t y at the present t ime and see what our residual problems are.

The influence o f good chemotherapy on notifications in Edinburgh in recent years is shown in Fig. I. I am not pretending for a m o m e n t that good chemotherapy has been the only factor responsible, as I shall indicate subsequently. As you will see, and this was characterist ic o f Scotland as a

R E S U L T S O F T R E A T M E N T

c HEMOTHE~Ai:~Y ; GOOD: GOOD 5TAfiTED (HO$ PlTAL)(ALL PATIENTS}

IBO

160

g 1 4 0

~Q 129,

Z~ o O,oo

~ o ~ - O ua O BO p.vmNrS I I I I

_ KNOWN RESIST~NT ~

2o z

1946 '45 '50 '52 '54 '56 '58 '60

FIG. 1. Effect o f g o o d c h e m o t h e r a p y on no t i f i ca t ion ra te : E d i n b u r g h .

15

whole, between 1946 and the early fifties the situation was very depressing, and there was a consis- tent rise in notifications from a level of about 129 per 100,000 to 169 and 170 per 100,000 in 1953 and 1954. From 1954 there was a very dramatic fall down to 70 in 1957, and the rate of fall, perhaps somewhat naturally, slows down from 1957 onwards. The peak in 1958 is of course accounted for by the large community survey which we had.

Now, there are certain administrative aspects and also features in relation to the chemotherapy which we have used which are important, and which I feel I ought to mention specifically. We began using chemotherapy in 1948 and, like everyone else, we used single drug therapy for short courses; we used it badly. However, by 1952 we began to be a little better at it, I think, and, in particular, we began to use streptomycin daily. In 1952 the majority of patients in hospital had good chemotherapy. Then, with the advent of isoniazid, we had an additional and potent weapon in our armentarium. In 1954 there was an amalgamation between the chest services on an out-patient and in-patient basis and, as with Birmingham, it is the responsibility of one consultant to supervise the care of the patient fl'om diagnosis through hospital to cure.

Aa you will see in Fig. l, we were in the position at that time of having 375 sputum-positive patients at home, of whom 95 were known to be drug resistant. Within a year, and with very little in the way of expansion of beds, we had reduced that number to 46. We do not know the precise figure for the number of resistant cases in this year. In 1957 the number sputum-positive at home was reduced to 43, with 12 resistant eases, and in 1961 there were 27 with 3 resistant cases. At a snap survey which I did at the end of April this year to see what the position was, it seemed that there were in fact only 15 known patients with a positive sputum out of hospital, of whom 3 had resistant organisms.

Another feature which I think is important in understanding the background of results which we have achieved is the question of drug resistance standards. In the presence of Dr. Mitchison I


hesitate to talk bacteriology, but Rist & Crofton have shown the tremendous variation in techniques of resistance tests throughout the world. For instance, in respect of inoculum of bacilli you have anything from less than 10 a to 1W. If you look at the critical concentrations at which people accept streptomycin resistance, it varies from 1 to 200 ag./ml., the same with isoniazid from 0.08 to 10, and for PAS 0'2 ,ag./ml. right up to 10--a fifty-fold variation. In 1952 we set about trying to evaluate what was the important level of resistance in so far as its clinical application was concerned; and 1 think that this was one of tile important factors which enabled us to set an effective pattern of treatment at an early stage.

Since the beginning of 1955 all patients admitted to hospital have been treated with daily streptomycin, PAS and isoniazid, unless there has been suspicion in respect of previous drug therapy or a known exposure to resistant organisms. All patients have had treatment with all three drugs initially until such time as the drug resistance of the organism with which they have been infected was known, or until a series of negative initial cultures had been obtained.

The other obvious index which is partly related to the community, but also of vital importance obviously to the individual, is the death rate (Table XI). It will be seen that the death rate in Edin- burgh has cascaded down in the last decade, until in 1961, it was as low as 3 per 100,000. This is, of course, a very remarkable fall and is almost wholly attributable to chemotherapeutic treatment.

Now, if we turn away from the question of the community and consider the individual, the results which we have been able to obtain are shown in Tables XH, XIII, and XIV. Table XII shows the sputum conversion in 348 patients treated by Professor Crofton in Edinburgh between 1952 and 1958, the patient's organisms being sensitive to at least two of the standard drugs. He reported that he was able to obtain 100 per cent sputum conversion, the majority--98 ~ - - b y six months; and of course this work has been repeated, as we have heard, in Birmingham, where it was possible to

TABLE XI.--CITY OF EDINBURGH: DEATHS FROM RESPIRATORY TUBERCULOSIS.

Year

1946-50 (Av.) 1951 1952 1953 1954 1955 1956 1957 1958 1959 1960 1961

No.

283 156 125 109 88 49 42 34 29 20 24 16

Dea~s

Rate (per 100,000)

59 33 26 23 19 10 9 7 6 4 5 3

TABLE XI][.--SPUTUM CONVERSION IN 348 PATIENTS TREATED BETWEEN 1952 AND 1958. (Afte, Crofton).

Months of chemotherapy I 2 3 4 5 6 7 8 9 10+

Sputurnposi t ive(~) 50 33 18 10 4 2 1 0-2 0'2 "Nil.


obtain 100 per cent sputum conversion in co-operative patients with the same criteria. I am at present engaged in the analysis o f over 2,500 patients who have been admitted to our hospitals between 1955 and 1960, and from a provisional analysis it would seem that all have become negative with treatment, with one possible except ion- - though I cannot just at the moment find out why it should be a failure. During this period we have, in fact, induced drug resistance in only two of these patients, both o f whom developed isoniazid resistance during desentization to that drug, without having adequate chemotherapy as a cover during the desensitization procedttre. Neverthe- less both were rendered sputum-negative.

TABLE XIII.--PostTIVE ISOLATIONS OF TUBERCLE BACILLI FROM 215 RESECTED LUNG LESIONS, 1953-56 (After Stewart, Macgregor and Turnbull.)

Chemotherapy (months) <3 3-6 6-9 9-12 12-15 15-18 > 18

Positive isolations (~) 31 19 9 8 2 2 0

Table XIII shows the information which we have accumulated in relation to our problem as to how long chemotherapy ought to be given. It is taken from the detailed survey by Sheila Stewart, Agnes Macgregor and F. W. A. Turnbull o f 215 lung specimens resected at operation in the years between 1953 and 1956. It shows you the positive isolations which were obtained according to the length of chemotherapy which had been given prior to resection. You will see that there were 31 per cent positive in those who had under three months ' chemotherapy, with progressively fewer isolations, right through to 2 per cent between fifteen and eighteen months, and none in specimens resected from patients who had more than eighteen months.

TABLE XIV.--RELAPSE 1N 631 PATIENTS HAVING SENSITIVE TUBERCLE BACILLI ACCORDING TO DURATION OF CHEMOTHERAPY, 1953-54.

(After Ross, Crofton, H o m e and Grant )

Chemotherapy (Months) 0-5 6-11 12-17 18-}-

Relapse (~) 22 7 1 0.3

Table X1V shows the relapse in Edinburgh pat ients- -wi th a follow-up of a minimum of three and a maximum of five years- -wi th sensiI~ : organisms, o f whom there were 631 ; and you will see that this varies directly according to the (_~tJ~ lion of drug therapy which was given. The average relapse for the whole o f the 631 was 3.5 per cent. in so far as patients receiving under six months were concerned, we had a relapse rate of nearly 1 in 4; between six and twelve months, 7 per cent; between twelve and eighteen months, 1 per cent; and in those treated for eighteen months and over there were 261 patients with only 2 relapses. However, if you contrast the relapse rate in patients with sensitive organisms with those with resistant organisms the relapse rate at 10.4 per cent is nearly three times as great.

I want to say just a few words about the place of surgery in treatment, and I am grateful to my surgical colleagues for giving me the figures shown in Table XV, demonstrat ing the amount of surgery carried out in the south-east of Scotland during the years 1947 to 1961. You will see that the peak years for surgery with us were 1954 and 1955, and at that time we employed surgery in something like 35 or 40 per cent o f patients, and even in those who had become sputum-negative following chemotherapy. That, I think, was a very valid thing to do in the light o f our knowledge at that time. However, with the knowledge that we have accumulated over the years regarding the

B(s)

] 8 TUBERCLE SUPPLEMENT

TABLE XV.--SURGICAL OPERATIONS FOR PULMONARY TUBERCULOSIS: SOUTH-EAsT SCOTLAND.

Year Total No. o f Resections Thoraco- OperatioJts plastics

1947-49 1950 1951 1952 [953 1954 1955 1956 1957 1958 1959 1960 1961

35 56 85

224 253 531 440 393 181 113 29 26 13

8

12 34

I34 I49 345 290 312 140 92 19 21 11

27 44 51 90

, 104 j 186 '. 150

81 i 41

21 10 5 2

effectiveness of chemotherapy, provided it is given in proper combinations and for a proper length of time, our surgical attack ra te- - i f that is the right word in this audience--has fallen very considerably, and last year it was less than 2 per cent. In 1961, in Edinburgh there were ten operations carried out for tuberculosis, and of these, five were done purely for diagnostic reasons due to an uncertainty as to whether the /es ion we were dealing with was a tumoar or tuberculous, and the remaining ones illustrated, as it happens, the kind of indications which we believe are still important for the individual. There were two patients with drug-resistant organisms, one with recurrent infections and haemoptysis from a residual cavity, one unco-operative ne'er-do-well, and one patient who had a tuberculous empyema. There has been a pronounced fall in the number of patients whom we submit to surgery, but I do not think that we ought to allow ourselves to forget that in the middle fifties--I am talking about the century, not about the age of the pat ients - - surgery had a very significant contribution to make, not only to the individual but also to the community. Furthermore, a figure which is often not given sufficient emphasis is that the relapse rate at that time in people who had surgery was only one-fourth of that occurring in patients who had chemotherapy alone. Surgery has made a very significant contribution to this decrease in these years,

So much then for the shiny side of the coin: let us now look at the rather duller obverse; first of all, at the fate of patients with drug-resistant organisms. We believe that the fate of those with resistance to one drug only should not be different from that which is possible for people with fully sensitive organisms. As will be seen in Table XVI, o f the 7i patients who were resistant to two of the

TABLE XVL--FATE OF PATIENTS WITH RESISTANT TUBERCLE BACILLI

Resistance to

No. Dead %

Alive

T.B, Neg. T.B. Pos. % %

Two drugs 7l 31 66 3 Three drugs 64 56 38 6


s tandard drugs, 31 per cent died, all of them being sputum-posi t ive; 66 per cent were converted to s p u t u m negative and survived, m a n y of them operated upon; and 3 per cent are alive and still sputum-posi t ive.

I f we look, however, at the 64 pat ients with organisms resistant to all three s tandard drugs, we see tha t the death rate has risen from 31 to 56 per c en t - -ove r ha l f of them dead. One of t h e m - - o n l y one of t h e m - - d i e d sputum-negat ive , and he had the misfor tune to die o f post-operative pu lmonary embol ism. 44 per cent are still alive, and 6 per cent are still sputum-posit ive. A b o u t two-thirds o f them had surgical t reatment , with very striking success, bu t a large number o f the patients in this g roup had too extensive disease for surgical t rea tment to be considered.

Next--- this is a point which Dr. Springett made very wel l - -we still f ind that about 1 in every 6 patients comes to us with far advanced disease. A l though these patients become non-infectious, they nevertheless form a very considerable problem for us, because these are the sort of people who, a l though they are not a problem so far as the c o m m u n i t y is concerned, form a very significant problem so far as they themselves as individuals are concerned. A s tudy by Dr. Andrew Douglas and myse l f relating to 40 patients with advanced disease and a residual cavity over 5 cms. in diameter is summar ized in Tables XVII and XVIII. Of these, 6 are dead, 6 totally incapacitated, 20 fit for light work only, 6 slightly disabled and only 2, or 5 per cent, are completely well and symptom-free. 15 per cent are dead and only 5 per cent are completely well. 90 per cent o f them have respiratory

TABLE XVII,--FATE o r 40 PATIENTS WITH FAR ADVANCED DISEASE AND 'OPEN CAVITY HEALING'*

Dead Totally incapacitated 1_ ight work only Slightly disabled Well Sputum negative

No.

6 15 6 15

20 50 6 15 2 5

40 100

* Cavity diameter exceeding 5 cm.

TABLE XVIII.--COMPLICATIONS IN 40 PATIENTS

WITH FAR ADVANCED DISEASE AND 'OPEN CAVITY HEALING ~*

Respiratory insu~ciency'P" Bacterial infection Aspergillosis Haemoptysis ? Amyloid Symptom-free Relapse of tuberculosis

No.

* Cavity diameter exceeding 5 cm. 1" M.V.V. = 406/rain. or less.

36 90 29 72

3 7"5 6 15 1 2"5 2 5

nil nil


insufficiency with a m a x i m u m voluntary ventilation of 40 l/rain, or less. 6 o f them have died f rom a combinat ion o f respiratory insufficiency and bacteriological infection, and three-quarters have had recurrent respiratory infections. 3 o f them have been complicated by aspergillosis, 6 have had recurrent haemoptyses , f rom which 1 died, and 1 has amyloid. Only 2 are symptom-free , none laave relapsed, and all, o f course, are sputum-negat ive. These are the kind of figures which i think we should remember when we look at the problem of tuberculosis as it s tands at the present time.

Now, 1 want to pass back in the last few minutes to the c o m m u n i t y again. Table XIX shows a census o f drug-resistant cases between Augus t , 1957, and March, 1962. In 1957, 188 patients were in hospital and there were 43 sputum-posi t ive patients at home. In 1961, it was 106 in hospital and 27 at home, and in 1962 there are 73 in-patients and 15 sputum-posi t ive at home. I f we look at the drug-resistance problem, you will see that in 1957 there were 44 patients with drug-res is tant organisms, a total o f 18 per cent o f all the patients under t reatment , and, o f these, 28 per cent were at home. By comparison, there were only 8 resistant cases (6 per cent) in 1961, and 11 (12 per cent) in 1962. There are only 3 known resistant patients at home in 1962. It will also be seen tha t in 1957 we had 30 patients resis tant to all three drugs , but only 6 in 1961 and 3 in 1962, and the n u m b e r resistant to two drugs has fallen to 2 in 1962. Al though we have reduced the percentage o f persons sputum-posi t ive and resistant (to any drug) on the register f rom 0'83 in 1957 to 0'18 in 1961, it is 0.26 in 1962, and a l though the known drug-resistance per 100,000 to any drug has been reduced f rom 9.4 to 1.7 between 1957 and 1961, it is 2"3 in 1962. Again, 57 pe r cent o f pat ients are still coming to us with moderately advanced or far advanced disease, and our sputum-posi t ive isolation on diagnosis has risen between 1957 and 1960 f rom 53 per cent to 66 per cent.

We seem to be at the present time in ra ther a static phase, and this I submi t requires some careful thought .

TABLE X]X.--PATTERN OF DRUG RESISTANCE IN HOSPITAL AND AT HOME

1957 1961 1962

Patients in hospital 188 106 73

Sputum positive patients at home 43 27 15

231 133 88

Total resistant 44 8 11 (18%) (6%) (12%)

Hospital 32 5 8 At Home 12 3 3

Resistant to all three drugs 30 6 3 Hospital 21 3 1 At Home 9 3 2

2 drugs 10 0 2 Hospital 9 0 2 At Home 1 0 0

1 drug 4 2 6 Hospital 2 2 5 At Home 2 0 l

R E S U L T S O F T R E A T M E N T 21

In the light of what I have shown you, I think it is emphatically true that patients still require to be given the best chemotherapy at all points in their management so that no new drug-resistant cases are created. If we continue to employ this high standard of treatment, if we can take a good deal more thought and trouble in regard to securing the co-operation of recalcitrant patients, if we can also take a good deal more trouble in seeking out the patients who have positive sputum and who are going about infecting the community, and if we are able to bring them into hospital and give them proper treatment until such time as we are able to convert them to sputum-negative, then it would seem reasonable that the eradication of tuberculosis in our community is possible in the foreseeable future.

D R . A. F. F O S T E R - C A R T E R :

I cannot produce big figures for you. My experience has been that of a physician in a chest hospital--the Brompton Hospital and its Frimley branch. One might almost call it the experience of a sanatorium physician. My figures, as I say, are small, and I am not claiming any great statistical value for them. But perhaps they may have an intimate character which will help to promote discussion by encouraging others to talk from their experience.

It was suggested to me that we might usefully discuss the pros and cons of each method of treatment in use to-day; but before we do so I think it is very essential to establish the background against which our discussion is taking place. This has already been dealt with to a large extent by Dr. Springett and Dr. Horne, but the tuberculosis situation has changed radically and extremely rapidly in the past 10 years; and I want to give you just two examples of the changed position in order to set the background to our discussion before we discuss treatment.

First, I want you to look at this graph which was recently published in the 'British Medical Journal'* (Fig. 2). It is based on the Registrar General's figures for England and Wales, and it shows the annual death rate from tuberculosis since 1900. From 1900 to 1950 there was a gentle fall in the death rate, which we regarded, I remember, with some satisfaction. We liked to think that our efforts to control and treat tuberculosis were contributing to this gradual improvement. In 1950, coincident with the coming of two-drug chemotherapy, the graph suddenly plunges and since then the fall has been precipitate. The mortality dropped from more than 20 per thousand to 3 per thousand in 10 years--a fall which might have been expected to take 80 years at the former rate.

The second example which I wish to quote in order to set the scene is the Madras experiment, which is one of the most significant things published about tuberculosis in recent years. Wallace Fox and his colleagues in Madras took 130 patients and treated them all with chemotherapy for one year; half were kept in a sanatorium for the whole year, doing no work and away from their families. The other half were treated at home, and the only thing that the team was able to do for these patients was to ensure, as far as possible, that they took their drugs regularly. Apart from this they led normal lives; they were quite unable to rest--in fact they were so poor that they had to work and work very hard. Their living conditions were not good, their diet was meagre and they were not separated from their families. At the end of a year, the patients treated at home had fared, if anything, slightly better than those kept in a sanatorium. And, most surprising of all, the attack rate in the contacts was the same in the two groups.

What is the significance of these two examples and the figures we have heard earlier? Above all they emphasize the immense power of chemotherapy. It is quite fantastic what these drugs will do. And in view of this we can now take absolutely nothing for granted. All of our previous ideas about the principles of treatment must be questioned, examined critically and re-assessed. In fact, I think we must ask ourselves whether any treatment at all, other than chemotherapy, is necessary for the vast majority of tuberculous patients.

* Scale, J. R. Brit. med. J., 196!, ii, 1285.

2 2 T U B E R C L E S U P P L E M E N T

60. :SO" 40.

30-

~ ,o:

~ 6 -

~ 4 ' N 3-

2 0

I 0 "

1950 1951

YEAR,

/ /

/ /

/ / - - ~ - - CHEMOTHERAP~ /

I - - A . P . & P.P. /

/ / . . . . . . . . . . SURGICAL COLLAPSE.

/ . . . . . . . RESECTION. / /

1 /

//" ./ .~ "x

1952 1953 1954 1955 1956 1957 1958 1959 19q'O 1961

FIG. 3. Types of treatment. 1950-19fil

P E ~ CEN~ I 0 0 '

9 0 '

B O ~

7 0

6 0

50

4 0

3 0

l~oo 19"Io Ig"ao 4~30 i~'ao i$so ~q60 Fm. 2

Deaths per year from tuberculosis, England and Wales, 1900-1960. Source: Registrar General, Stastic,al Revieu, o]'Englcmd arid Wales. (Reproduced by permission of the

editor of the British Medical Journal,) m


Figure 3 is a graph showing the types of treatment in vogue at Brompton and Frimley since t950. I ought first of all to say just a word about the Brompton organization, because in some ways it is very different from the two organizations about which you have been hearing. The Brompton system may be described, without disrespect, as a benevolent anarchism. There is no central control of treatment policy; complete individual autonomy is allowed and each clinician is a law unto himself. Therefore, the Brompton results represent the average opinion of a number of clinicians, and any trends which emerge over the years have evolved as the result of experience rather than from a policy which has been deliberately planned.

The graph shows that medical collapse therapy--A.P, and P.P. had been abandoned almost completely by 1959. Surgical collapse therapy also is hardly ever used nowadays. The frequency of resection is interesting. It started very low because, of course, resection only became possible as effective chemotherapy was introduced. Then it rose to a peak of enthusiasm in 1953 and from 1954 to 1959 it remained almost constant at about 15~, falling off by about half in the last two years from 1960.

Finally, the use of chemotherapy. This had a slow start. I am surprised at this myself. You see that in 1950, half the patients had no chemotherapy at all, and it was not until 1955 that 100~ of patients were baying chemotherapy.

In 1951 the average duration of chemotherapy was very short--about three months on streptomycin and PAS (Fig. 4). In 1952, a little longer--about four months. In 1953 some patients were

N s l iP. r--IH. MONTHS

31 ,: ! ! i " i i !

3

1951 1952 1953 1954 1955 3 months 4 months 4 months 0o9 months 12-24 months

S.R S,R S,R S. RH, RH.with early

Ocr H, Oce. long term. S, in majorny

Fm. 4. The duration of chemotherapy.

having isoniazid as well, but Still only for a short period. In 1954 the average period of treatment had gone up to about six or nine months on all three drugs, and some patients were starting to have long-term treatment up to about I8 months ofisoniazid and PAS. By 1955, the present pattern was becoming established ; quite a large number of patients were having long-term chemotherapy with PAS and isoniazid up to two years and many were starting with streptomycin as well.

I have chosen for my small survey a group of patients discharged from Frimley in 1955, because by that time long-term chemotherapy was becoming established and it is sufficiently long ago for us


to have a 4-5 year follow-up after the two years' chemotherapy finished. This, I think, is very important, because most patients do well while taking the drugs. What we want to know is what happens to them after chemotherapy has stopped.

Very briefly, the criteria by which I selected this group of patients were: that they were all discharged in 1955; they all had a positive sputum ( I thought that one would get a more clearly defined �9 group by taking only the positive sputum patients and discarding the negative ones) ; and that none of them had had any previous chemotherapy or surgery. Some had had other t rea tment-- for example, hospital treatment or even an A.P. before, but no chemotherapy or surgery.

TABLE XX.--SEX AND AGE DISTRIBOTJON

Group

A�9 Chemotherapy only B. A , P . C. P.P. D. Plombage E. Thoracoplasty F. Resection

M.

54 2

11 6

14 16

F. 15-25 yrs.

36 33 4 1

13 8 6 2 5 4

13 7

77 55

Age

26-35 yrs. 36-50 yrs. 50 +yrs.

25 25 7 3 2 - - 7 5 4 3 6 1 5 8 2

l0 6 6

Total 103 53 52 20

TABLE XXI.--EXTENT OF DISEASE

Group

�9 A. Chemotherapy only B. A . P . C. P.P. D. Plombage E. Thoracoplasty F, Resection

Total

3O 3 3 2

t l 12

51

Number o f Zones Involved

2 - - i - - 2 3 I 4 5 f

34 7 - 7 ; - 2 - 7 - ! , l '3 7 5 3 l 2 1 6 6 4 2

11 4 --

62 24 22

1 z o n e = 51 ( 2 8 % ) . 2-3 zones = 86 (48 %). 4 or more zones = 42 (24%).

6

4

3 3

2

10 10

Tables XX and XX1 show the age and sex distribution and the extent of disease in these patients. They were a fairly representative, mixed group. Half the patients had moderately advanced disease (2 to 3 zones involved) and one quarter of them had far advanced disease.

Table XXII shows i:" more detail the amount of chemotherapy which these patients were given�9 There were 171 patient~ lnd nearly half of them (45 ~ ) had chemotherapy for more than 18 months. All the same, no less than 38 ~ had treatment for less than a year.

�9 Table XXII I shows the results. This is a comparatively simple table when you think of what they used to be like in the pre-chemotherapy days. We start with 17t patients and at the end of 5 years, 169--no less than 99 ~ - - w e r e not merely well but working�9 Only 2 patients died; both from causes unconnected with tuberculosis�9

R E S U L T S OF T R E A T M E N T

TABLE XXII.--DURATION OF CHEMOTHERAPY.

25

.41l Medical Surgical Resection groups collapse

Total 171 114 31 26

< 1 year 65 (38~) 40 (35~) I0 (32%) 15 (58~)

1-1�89 years 29 (17~) 18 (16~) 7 (23 ~) 4 (15~)

1�89 years 40 (23%) 31 (27~) 4 (13%) 5 (19%)

2-3 years 26 (15~) 18 (16%) 6 (19~) 2 (8%)

> 3 years I1 (7~) 7(6%) 4 (13~) - -

TABLE XXIII.--RESUL'IS OF TREATMENT

All Chemotherapy groups only

Resection A.P. & P.P, Surgical collapse

27 31

25 31

-~ Both died from other causes: 1 emphysema; t after operation for hernia.

There were only 2 relapses and one of those was pretty doubtful. The first was a definite relapse; a patient w h o only had 6 months ' chemotherapy. Two or three months later, a small spread of disease was shown by x-ray; the sputum was again positive and he was put back on the drugs for 2 years and there was no further relapse. The other patient, whom I have had to count as a relapse, had only B months ' chemotherapy but kept very well for 2 years and then developed urinary symptoms and was said to have had tubercle bacilli in the urine on one occasion. She was admitted to hospital and investigated; nothing was found but she was given a course of isoniazid and PAS as a precaution. Whether she really relapsed or not I do n.~,~ k~ow, but certainly there were no more than these two. This is a relapse rate of one per cent. And you see all the groups did equally well. The two deaths happened to occur in the medical collapse group, but I do not think there is any significance in that at all.

This is such a very different picture, is it not, f rom the pre-chemotherapy days when we used to judge the efficacy of our treatment by the 5 year survival rate? All the patients are doing well, whatever group you take. For comparison, the results of our large-scale follow-up investigation, covering the years 1937 to 1942, before the advent of chemotherapy*, showed that even in the most favourable group, 20 ~ of the patients died in the first 5 years, and 25 ~ relapsed. Now we cannot

* Foster-Carter, A. F., Myers, M., Goddard, D. L. H., Young, F. H., and Benjamin, B. Brompton Hospital Reports, 1952, 21, I.

Total 171 87 26

Well at 169 (99 %) 87 26 5 years

Relapsed 2 (1%) 2*

D i e d 2 (1 ~ ) - -

* Chemotherapy 6- 8 months, 1 true relapse, doubtful.


even get large enough figures to use the relapse rate to differentiate between different forms of treatment and judge their efficacy.

It seems to me that there are two big questions to discuss, each of which involves a number of subsidiaries:

The first question, which I mentioned earlier, is: do we need to prescribe any treatment other than chemotherapy for the vast majority of tuberculous patients? We have to consider whether rest, which used to be our 'sheet-anchor' (to use R. C. Wingfield's phrase), has any longer any part to play. And also l think we might discuss what is the place, if any, of hospital treatment in the treatment of tuberculosis?

The second question concerns chemotherapy itself. Ought we to modify our scheme of chemotherapy in the light often years' experience? For instance, an arbitrary period of two years has been widely accepted as the optimum for long-term treatment. Can we safely reduce this for patients who have minimal disease and respond to treatment, or those patients who have had a successful resection? I know this is controversial.

Since the original Medical Research Council trials, most of us have believed and have preached that the only safe way to treat pulmonary tuberculosis is by regular and prolonged administration of at least two drugs. We taught that any deviation from this is likely to produce resistant bacilli and this is the worst tragedy which can befall a tuberculous patient. It cannot be denied that resistance does occur when the drugs are given in a haphazard way. We have seen the evidence of it, and we have seen that some patients whose bacilli are insensitive die as they used to do before the days of the drugs.

But the really dramatic feature nowadays is the success of chemotherapy, not its failure. It may be argued that this is because we have adhered faithfully to ou r principles of treatment. But is this really true? l think we have to admit that the remarkable success of chemotherapy has not depended as much as we thought it would upon strict adherence to a prolonged drug routine. The good result in my small series was achieved in spite of the fact that nearly 40 % of the patients had chemotherapy for less than one year. And recent work has proved beyond all doubt that many patients do not take their drugs regularly. We prescribe long-term chemotherapy but there are probably quite a number of patients who are not having long-term chemotherapy as we prescribed it. In view of this, may not the optimum period of chemotherapy be shorter? Are we perhaps penalising the conscien- tious patients by making them endure the discomforts of PAS for two years? May it not be safe after a certain period of time (perhaps one year) to change over to isoniazid and thiacetazone?

My own impression is that the first six months of chemotherapy are the most important and that the reason why my patients did so well was that most of them spent those first six months in hospital. They would probably have done just as well at home, leading normal working lives, if only regular drug treatment could have been ensured during at least that period.

The figures certainly suggest that if one does one's best, by indoctrination and supervision,to impress upon patients the importance of regular chemotherapy, the large majority of them will take enough drugs to ensure a satisfactory result.

DR. E. RHYS JONES:

In presenting our experience in the long-term medical treatment of pulmonary tuberculosis at Midhurst we are aware that our cases represent a highly selected group. Of course, no general conclusions can be drawn from a survey of such a group. It is interesting, however, to see how these cases illustrate the changed role of this chest hospital.

Previously, sanatoria tended to accept only those cases with a favonrable prognosis. Nowadays the situation appears to be reversed.

Apart from short-term cases admitted for investigation and to start treatment, we admit many

R E S U L T ~ OF T R E A T M E N T 27

patients for tong-term treatment because their course has not been straightforward. Difficulties may have been encountered in treatment because of reaction to the drugs or the finding of resistant organisms. The patient may have accessory respiratory disease such as bronchitis, or some other medical complaint such as diabetes. Psychological or social factors may be playing a part, so that some form of hospital discipline is necessary in order to make sure that they follow their treatment.

TABLE XXIV. Chemotherapy alone 283 (56 ~) Resection 159 (31%) Thoracoplasty 21 (4 %) Cases of pleural effusion only 15 (3 %) Other cases 29 (6 %)

Total: 507

We took the cases having long-term treatment in 1957-58 and found that out of the total of 507, chemotherapy was given alone to 283, that is over half of them (Table XXIV). But you see that in those years quite a proportion also had resections and thoracoplasties.

We propose to analyse the cases which have been treated here in the two years in order to give some idea of the clinical material on which we were working and the problems encountered, and then to give the three-year follow-up results.

In order to analyse these cases a little further the severity of the disease was assessed by a classification using three criteria:

(a) Extent of disease as assessed by the Foster-Carter g roup ings : - Group 1 (1 zone) 87 cases (31 ~) Group 2 (2 or 3 zones) 107 cases (38~) Group 3 (4 or more zones) 89 cases (3 l ~)

154 (54 ~) were bilateral and 129 (46 ~) were unilateral. (b) Cavitation (t27 cases) or non-cavitation (156 cases). (c) Positive sputum (176 eases) or negative (107 cases). The result was that a rough scale of severity could be drawn up ranging from Group t negative

non-cavitated cases at the one end of the scale to Group 3 cavitated and positive cases at the other end of the scale.

Of the 283 cases treated with long-term medical treatment, 256 could be regarded as successfully treated; 8 died in hospital (one a non-tuberculous death); 19 failed to convert their sputum. Excluding the non-tuberculous death, there were 26 (19 and 7) cases of failure to treat successfully while in hospital.

This group of 26 'treatment failures' seems to have a very poor outlook; nearly half of them have died.

Of 26 cases, 12 have died (7 in hospital and 5 within 3 years of leaving hospital); 7 have had extension of their disease; 5 are still active and positive but without extension of disease; 2 converted sputum to negative following discharge on continued chemotherapy.

When this group of failures was analysed according to severity we found: No. o f cases

Group 1-- Nil Group 2--non-cavitated : Nil

cavitated: 4 with 1 death Group 3--non-cavitated : 2

cavitated: 20 with 6 deaths.

28 TUBERCLE SUPPL E ME NT

A n a l y s i n g the fa i lures a n d t o t a l cases by age g r o u p s s h o w e d : Age (years) Total cases Failures

- - 3 0 73 1 ( 1 . 4 % ) 30---39 128 7 ( 5 " 6 % ) 40 or o v e r 82 18 (21 .0%)

S tudy o f the g r o u p o f fa i lu res p resen t s a p i c tu r e of ageing, c h r o n i c cases. Th i s is b r o u g h t ou t fu r the r i f the G r o u p 3 cav i t a ted , pos i t ive cases ( the wor s t cases) are t a k e n a n d the ' f a i lu res ' a n d ' successes ' in t h a t pa r t i cu l a r g r o u p c o m p a r e d .

The re were 19 ' f a i lu res ' in th i s ca t ego ry a n d 38 ' successes ' (Tab le XXV). The difference in these

TABLE XXV.--GROUP 3 CAVITATED POSITIVE CASES

Total eases = 57 Failures Successes

Total cases 19 38

Previous treatment Previous treatment other than chemotherapy 9 (47 ~ ) 10 (26 %) Previous chemotherapy 14 (74~) 8 (2t ~ ) No previous treatment 3 (16 ~ ) 27 (71 ~)

Age Cases 50 years old or over 12 (63 ~ ) 26 (53 ~ )

Sensitivities Resistant to 2 or more drugs 14 4 Sensitive to 2 or more drugs 5 31 Sensitivities not known - - 3

Results Death 8 5 N.T.B.

I T.B,

Further extension of disease 5 - - Persistently positive without extension of disease 4 - - Apparently converted (1 with sensitive organisms;

1 with resistant organisms) 2 - - Relapse - - 2 No relapse at 3 years - - 28 No relapse at 2 years - - 2

two g r o u p s is appa ren t . O u t of 26 ' t r e a t m e n t f a i lu res ' there were 5 pa t i en t s w i t h o r g a n i s m s sens i t ive to a l t th ree d r u g s a n d one w i t h o r g a n i s m s sens i t ive to two drugs . The fate o f these 6 cases was as fo l lows :

.Result C a s e 1. N o d r u g s g iven ( in to l e ran t ) T u b e r c u l o s i s d e a t h in hosp i t a l .

,, 2. A d e q u a t e c h e m o t h e r a p y fo r 3/12 u p to T u b e r c u l o s i s dea th . ,, 3, , . . . . . 18/12 N o w nega t ive , ,, 4 . . . . . . , 24/12 N o w negat ive . ,, 5 . . . . . . . 24/12 (15/12 in hosp i t a l ) C a v i t a t e d a n d posi t ive . ,, 6. ,, ,, ,, 24/12 (1/12 in hosp,.'tal) Re lapse .

In two cases, there fore , the d r u g s a p p e a r t o h a v e fa i led to inf luence the cou r se o f the d isease .

Case 5--Bilateral cavitation. Intermittent positive. Last sensitivities 13.4.61. Culture positive and resistant to all three drugs. Now on pyrazinamide and eycloserine.

Case 6---PAS and isoniazid over two years; still sensitive Nov. 1961 ; now on pyrazinamide for past 7 months. Positive last in Jan. 1962 but recent negative. Also a diabetic.


The majority of the ' treatment failure' group were chronic cases with extensive disease who had had various treatments in the past, and in the whole group only 8 ~ had not had some form of previous treatment. In consequence, the rate of resistant organisms was high. In contrast, the successfully treated cases with extensive disease had only recently been diagnosed. Many of them had organisms sensitive to two or more of the three common drugs, and this fact appeared to be the most significant difference affecting the prognosis in the two groups.

The proportion having newer drugs in 1957 and 1958 was, of course, considerably lower than it would be at present, so perhaps some of these could be successfully treated to-day.

Nevertheless, patients of tl~is type make a smali 'hard core' with considerable problems in care and disposal, and, of course, they are a hazard to the public health. We believe it important to care for these unfortunate people, encouraging them to stay in hospital if necessary. Many are willing, because they are getting on in life and need medical and nursing care. By adopting this policy there is a hope that this particular generation of patients will not pass on their resistant organisms to the younger generation and in a decade or so this problem may be less as this group of much-treated cases becomes fewer.

Finally, I should just like to give you the results of the *treatment successes' and tell you how they got on (Table XXVl).

TABLE XXVI

DEATHS: Tuberculous . . . . Non-tuberculous ..

N O RELAPSE: Followedup for: 3 years

2 years 1 year

2 (0.8 ~) 18 (7-0%)

. . . . 215 (84'0%)" /

. . . . 7 ( 2.7%)~ 87.5%

. . . . 2 ( 0"8~)J

R E L A P S E D : 10 (3 .9~)

L O S T S I G H T OF: 2 ( 0'8~) In those cases which were apparently successfully treated the relapse rate was:

At one year . . . . . . . . 2-1 At two years . . . . . . . . 3.0 At three years . . . . . . . . 4.4

RELAPSES: The x-ray appearances on admission of the ten relapses were:

GROUP 1: Non-cavitated, unilateral 2 G R O U P 2: Non-cavitated, unilateral 3

Non-cavitated, bilateral t Cavitated, bilateral l 5

G R O U P 3: Non-cavilated, bilateraI i Cavitated, bilateral 2 3

The discharge x-rays of 9 of these cases showed improvement and 1 was unchanged.

Seven of the cases had had a positive finding during the current illness and 3 had been negative. Three were sensitive to all 3 drugs and 2 showed some initial resistance.

Chemotherapy: Of the 10 relapses, 5 occurred in patients still on drugs; at the time of relapse

1 had had nine months' drugs 2 ,, twelve months' drugs 1 twenty-eight months' drugs 1 ,, threeyears'drugs.


T h e total re lapse ra te in 3 years in this pa r t i cu la r g r o u p has been 4 .4 ~ .

D I S C U S S I O N

Chairman: Thank yon, Dr. Rhys Jones. The subject is now open for discussion. Dr. Mitehisnn: There is, l think, one rather important aspect of what has been said this morning and that is that the

reviews which have been given are from communities where standards of organization of the tuberculosis service are very high and where tile clinical results may well he more impressive than they are over the country as a whole. Dr. Springett and subsequent speakers have said that they believe that the problem of primary drng resistance is at present a small one. We have quite recentIy been Iooking a: data from a variety of sources in Britain. This was not a proper survey, in the sense that it was not doge on a proper sampling basis, but it was repre~sentative of a pretty large number of clinics, and the total figure for primary drug resistance was somewhere in the region of 10-11 ~ of positive cultures, by our particular methods. These methods have not altered since we did a survey on a national basis about four years ago when the figure was 4"5 ~ , and it therefore seems probable that primary drug resistance has increased by a factor of well over twofold during those past four years. ] am doubtful, of course, of putting this forward as fully proved. To get a fully proved answer you need to do a proper survey of tile problem. We found, as did Dr. Springett, that the majority of these cases of primary drug resistance showed resistance to only 1 drug, with resistance to streptomycin being the most common type of resistance. These patients, &course, respond very well to treatment if it is started, as is usual, with 3 drugs; but the incidence of resistance to isoniazid is rising, and resistance to more than I drug. though still only occurring in a very small proportion of cases, is also rising. We are, I think, still in quite a safe position; very little trouble is caused by this primary resistance, but what I am not sure is whether we could afford to relax our standard appreciably.

Dr. Oswald: What has been said does make one wonder whether to give 3 drugs or 2 to start with. I notice that up in Scotland, I think it was, 3 drugs are given routinely until the results of sensitivity tests are known. T think that, in common with quite a number of other people, I have tended in the last year or two to reduce the drugs to 2, except in people with obviously active or advanced tuberculosis, mainly because of the c9mplications of giving all 3 drugs. But the other thing I would say, in regard to Dr. Mitchison's comments, is that I do not like accepting this figure of 1 0 ~ too readily at tile moment because, from my very limited experience at the Brompton, out of 157 patients with tubercle bacilli in the sputum, I have only had 3 with primary drug resistance, 1 English, I Pakistani and I Italian. I think I should rather like to see where his patients came from before we accepted this figure of ] 0 ~. We seem to have so many immigrants.

Dr. Seadding: I was a little reassured last year by the Public Health Laboratory Service survey which Marks published ; this seemed to suggest that the rate of primary drug resistance in this country was about the same as it was in Dr. Mitchison's survey about five years ago. Of course I am aware that the bacteriological methods were slightly different and also that the figures were not derived, as his were, from a carefully selected sample survey of cases at selected representative clinics. But it did rather shock me this morning to hear that this reassurance may not be justified. ] wonder whether Dr. Mitchison would make some comment on this important matter, that is, the exact significance of the survey which Marks published last year.

Dr. Mitchison: There are two comments, if I may answer both speakers on this. The first is that it is not the usual experience to find such a high rate. We have had experience of a comparison between the results of sensitivity tests done by our laboratory and in Edinburgh which give very closely similar results, and it is certainly true that we find drug resistance more commonly than do some other laboratories in the country. This would by no means account for all the differences in these prevalence estimates, but I would again emphasize that there may be quite important differences in the prevalence of primary drug resistance from one area to another. Birmingham and Edinburgh in particular, I think, have very high standards of looking after and segregating their tuberculous patients with acquired drug resistance. Other parts of the country may not do this with such thoroughness. The second point, about the Public Health Laboratory Service survey, is that the bacteriologicaI methods used by Dr. Marks are rather different from ours in several important respects. One of these is the use of a very much smaller inoeulum in the sensitivity tests, a shorter period of incubation, and the deliberate exclusion, which Dr. Marks pointed out, of quite a large proportion of his patients in whom he felt that the growth on drug-containing medium was not of clinical significance. He is, in fact, using a criterion of drug resistance very different from that of our original survey. I am not prepared at this stage to argue about the clinical significance because it is a very complicated point, but purely from the point of view of making a temporal comparison between 4 years ago and now, I think the prevalence of drug resistance is rising. The figure is based on not very large numbers; it might be 8 ~ or it might be even higher, 12 ~ or 14 ~ .

Chairman: Thank you, Dr. Mitchison. Does anybody want to comment further on the use of the 3 drugs, or the rather difficult medico-legal aspect of streptomycin and its effect on the 8th nerve which cramps some of us in treating elderly oatients.

Dr. Home: I am very grateful to Dr. Mitchison for having emphasized this particular problem in this way. I think we are not at the stage at which it would be justifiable to relax our chemotherapeutic measures at all. In so far as drug


dosage is concerned, part icularly in relation to s treptomycin, our recent experience of giving 0,75 g. in older patients has vastly reduced our own incidence of s t reptomycin toxicity on the 8th nerve and does not seem to have interfered with our results, provided PAS and isoniazid were given as well, We are giving 0,75 g, daily, and I think in our view it would be unjustifiable to reduce this dosage. I agree with Dr . Oswald that the complicat ions of t reatment are, i f anything, increasing; our hypersensit ivity rate to drugs last year was no less than 16 ~ , But I think that the troubles associated with these are as nought compared with the risks of d rug resistance.

Chai rman: T h a n k you very much, Dr . H o m e . Dr . Springett , would you like to add anything? Dr . Springett : W e employ 3 drugs routinely, certainly until sensitivities are known o r untit we obtain a negative

eutture, and indeed in patients with extensive gross disease we mainta in the 3 drugs throughout the hospital stay at least and somet imes even after discharge. W e t o e have reduced the dose to 0-75 g. in those aged over 45-50 w{th no obvlous falIing off in bacter{oiog{ca[ results, and witI~ a good deal o f sav ing of trouble wi th toxic effects. I did not go into what we did in terms o f t reatment , but in view of some of~he discussion perhaps I should say that we do have all our patients in hospital for the first 3 months. With tile social background in this country people who are seriously ill, and 1 sli]l th ink tubereulosis is a serious disease, expect to be in hospital, and 1 th ink it is the right place to have them to get t rea tment started. I am not really th inking in terms of sanatoria , a l though I would not entirely ignore the value of that approach, but nevertheless I do believe that hospital is the r ight place for those first two or three months. There are two other points I would like to take tip. Dr . Fos ter -Car ter spoke about perhaps relaxing our s tandards a little~ I would be very unhappy to relax them at all in the first year of treatment, but I admi t to having similar thoughts to his about the long-term phase when you have reached a reasonable degree of control and you need that extra little safety factor to finish off. 1 would dearly love somebody else to do this, but 1 have not the nerve to do it mysel f though [ have a feeling that it might be all right. There is realb; one quest ion I wanted to ask Dr . H o m e . He showed us a group of 40 patients with far-advanced disease and persistent cavi tat ion who had done perhaps not too well. I have had quite a lot of patients in these last few years who are not far-advanced but who have a persistent cavity and so far they seem to be all right. I am a bit worried about them and I would like to kt~ow whether Dr . H o m e thinks the ra ther less sat isfactory results in his group are because the disease was far-advanced or because of the persistent cavitat ion. [ should like to think it was the former.

Dr . H o m e : The answer is entirely that they were patients with far-advanced disease who happened to be left with a large cavity.

Section 1 The results of treatment of pulmonary tuberculosis in communities in recent years

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Transcript of Section 1 The results of treatment of pulmonary tuberculosis in communities in recent years