Relapse in tuberculosis

Brit. J. Dis. Chest (1973)

67, 33

RELAPSE IN TUBERCULOSIS A Report

from

the

Research

Committee Thoracic

of the South-East Society

Metropolitan

Regional

MANY chest physicians keep their tuberculous patients under observation indefinitely. This custom is a legacy of the prechemotherapy days, when relapses were so common that cautious words like ‘quiescent’ and ‘arrested’ were used for apparently cured tuberculosis. Although the disease was eventually labelled as healed, neither the physician nor the patient had enough confidence to part company. Certain residual lesions were thought to be more likely to relapse than others; experience had suggested that age, sex and social conditions were among the most important of the factors affecting prognosis. The success of chemotherapy changed all this. At first, physicians were naturally cautious in accepting recovery as permanent, and were slow to discard rest, collapse therapy, resection and other ancillary measures. This attitude is still reflected by the tradition that few patients are ever discharged from observation. A more rational policy could be formulated if it were known what proportion of patients do in fact relapse, and if it were possible to identify in advance those who are likely to relapse. This study, designed by the Research Committee of the South-east Metropolitan Thoracic Society, tries to answer these questions.

Procedure Relapses All chest clinics in the region were asked to report every patient in whom a relapse occurred after not less than 2 years of quiescence. Patients who had completed their treatment by I January 1962, or who had been under observation on that date, and had relapsed in the year May 1g64-April 1965, were reported. Relapse was defined as the reappearance of Mycobacterium tuberculosis in the sputum or a radiological change attributed to reactivation of tuberculosis. The previous medical history, the previous treatment, including standard chemotherapy (streptomycin, PAS, isoniazid), the social background and other personal details were entered on a standard questionnaire, and the following four films were extracted from the complete set of chest radiographs: I. A film showing the greatest extent of the disease. 2. A film at completion of treatment.

3. The last film taken before relapse. 4. A film when relapse was diagnosed. Films 3 and 4 were used only to confirm (Received,for

jmblication

the radiological October

1972)

diagnosis of relapse.

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34

THORACIC

SOCIETY

Controls Chest physicians were asked to extract every tenth name in sequence from a list containing the names of all their tuberculous patients. These names were forwarded to the coordinator, who selected a total of 404 names drawn at random from each clinic in proportion to the total number of patients on their lists. These names were submitted to the chest physician concerned, who then completed a questionnaire similar to that used for the relapses. The complete set of radiographs was obtained and the following films, comparable to those of the relapse group, were selected: A film showing the greatest extent of the disease. A film at completion of treatment. 3. A film taken during the year May Ig64-April 1965, used only to confirm that no radiological relapse had occurred.

I.

2.

Examination of radiographs All the films at the greatest extent of disease (No. I) of both study and control cases were put together in random order. This collection was sorted by the film reader at one sitting into appropriate groups by one criterion, for example, the presence of cavitation. Each pile was then checked through by the film reader until a final check confirmed its homogeneity. The relapse and controls in each pile were then recorded by the co-ordinator before amalgamating and sorting for the next criterion. The procedure was repeated for the films taken on completion of treatment (No. 2). At no time was the film reader aware of which films belonged to relapses and which to controls. The diagnosis of relapse The number of relapses reported was 164. Of these, IOO were confirmed by a positive sputum at the Tuberculosis Reference Laboratory at Cardiff, 28 were confirmed by a positive sputum at a local laboratory only and 36 were not confirmed bacteriologically. The following steps were taken to confirm relapse in the 36 cases where bacteriological proof was lacking: I.

2.

The physician who had submitted the case was asked if any further sputum test had been positive and, if not, whether he still considered that the radiological change had been due to a relapse of tuberculosis. The prerelapse film No. 3 and the postrelapse film No. 4 were submitted to an independent physician for a further opinion.

In a group of 12 patients, where relapse had been diagnosed on radiographic grounds only, the diagnosis was confirmed both by the independent assessor and by the submitting physician in retrospect. In another group of 18 patients, despite disagreement between the independent assessor and the submitting physician, there was thought to be sufficient evidence for the diagnosis of relapse to be accepted. In 2 patients, both had agreed that evidence of relapse was unconvincing. To these were added 4 patients subsequently known to have

RELAPSE

IN

TUBERCULOSIS

35

had non-tuberculous diseases, carcinoma of the lung (2) and aspergilloma These 6 patients were excluded, leaving 158 relapses to be studied.

(2).

The incidence of relapse In 1964 the total number of tuberculosis patients under observation at the chest clinics in the South-east Metropolitan region was 32 989. The number of relapses reported during the twelve months of the study was 158, representing 0.5% of the tuberculous population known to the clinics. Exclusions jiiom the control series The controls were patients previously treated or under observation for tuberculosis who, in the opinion of their physician, did not now have active tuberculosis. This opinion was confirmed by a review of radiographs by an independent physician and by sputum tests carried out at the Tuberculosis Reference Laboratory. Since the lists were compiled at random, they included patients whose treatment had been completed less than two years before the study. To match the control group with the relapse group, all of whom had completed treatment at least two years before the study, these patients were excluded. Another 7 controls who had extrapulmonary tuberculosis and one who had relapsed after the lists of controls had been compiled, were also excluded. Of the 333 patients remaining, completed questionnaires were received for 244. Radiographs showing the maximum extent of the disease were collected from 240, and those showing the state of the lungs at the end of treatment from 242. This left 89 about whom information was lacking. It was desirable to show that this group did not contain unreported relapses. Enquiries showed that many of these patients were no longer attending, although their names were still on the chest clinic registers. Records of subsequent attendance and home visits by health visitors confirmed that 34 of these patients were keeping well, or were known to have been well in 1965. Twelve patients had died of diseases other than tuberculosis. There remained only 43 (or 13% of 333) about whom no information could be obtained.

Analysis

of Factors

with

Possible Bearing to Relapse

on the Liability

The sex and age of patients, the treatment received in the past, other diseases and certain radiological features of the disease were believed a priori to affect the probability of relapse. A comparison of the relapse and control groups in respect of each of these data will show how far this prediction proved to be valid. Sex and age Although controls were chosen entirely at random, the number of males and females in the control group happens to be exactly the same (Table I). Among

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36

THORACIC

SOCIETY

relapses, on the other hand, there is a significant excess of males over females (P= 0.004). The age distribution is shown in Table 2. TABLE

I.

RELAPSE

AND

CONTROL

GROUPS

Relaflses Males Females Total

TABLE

2.

AGE

DISTRIBUTION

Control.7

103 (65%) 55 (35%)

122 (5o%) 122 (50%)

158

244

OF RELAPSES

AND

CONTROLS

Relapses

IN

1965)

Females

Males

Age

(AGE

Controls

Relapses

Controls

-

5-14 ‘4-24 25-34 35-44 45-54 55-64 65-74 75-84 Total

4 (4%): 5 (5%) ‘4 (14%)

3 2 0 28 28

Go/o) (1695%) (23%) (23%)

4 (7/o) JF ‘1 (20%) 43 27 ‘I 6

Q (2%)

2 (2%)

103

TABLE Duration chemotherapy

3.

122

55

DURATION

OF CHEMOTHERAPY

of

None I -6 months 7-12 months More than 12 months Total

(35%) (22%) (9%) (5%)

122

Controls 67 43 24 24 158

(43%) (27%) (15%) (15%)

56 47 4’ ‘00

(23%) (‘9%) (17%) (41%)

244

Chemotherapy The distribution of relapses and controls according to the length of standard chemotherapy received in the past is shown in Table 3. The proportion of patients who received by present standards insufficient or no chemotherapy is much higher in the relapse group. The difference between the distribution of patients in the two groups is highly significant (P= O*OOOOI). The higher relapse rate for those who received no chemotherapy could mean simply that they are older and that they came under treatment before drugs were introduced. To test this hypothesis the patients were divided into two groups, one group aged 45 years and over, and the other less than 45 years

RELAPSE

IN

TUBERCULOSIS

37

when first under observation. this difference still held. 4.

TABLE

AGE

WHEN

FIRST

Duration of chemotherapy

None r-6 months More than

6 months

Total

When

these groups were compared

UNDER OBSERVATION CHEMOTHERAPY

Age

RELATED

of observation

TO

Age

over45 Controls

Relapses

18 (41%) 12 (27%) ‘4 (32%)

11 (23%) 5 (10%) 32 (67%)

49 (43%)

44

DURATION

48

;; “4

[;#

4)

OF

of obseruation under

Relapses

(Table

45 Controls

0

45 (23% 42 (21%) 109 (56%) 196

Drug resistance The incidence of strains of Mycobacterium tuberculosis resistant to streptomycin, PAS or isoniazid among the relapse patients was based on series of sputa tested for drug sensitivity at the Tuberculosis Reference Laboratory at Cardiff, sputa studied at other laboratories being omitted. Ten of the 89 positive cultures (I I %) grew organisms resistant to one or more of these first line drugs. Thirteen of the 158 relapses had received single drug chemotherapy. In these, susceptibility tests were not carried out in I, susceptible organisms to all 3 first line drugs were grown in I I, and only I of these patients was found to harbour a drug resistant strain. Surgery Resection had been performed on 6 (4%) of the relapse patients and 27 (I I %) of the controls. At first sight this difference appears to show a significant protective effect of the operation (P= o-OI), but the numbers are small and the sex distribution and the chemotherapy given in the past was not comparable in the two groups, although the extent of original disease was similar. On statistical treatment of these data by multiple regression analysis it became evident that the apparent advantage of resection may well have been due to longer chemotherapy and the larger proportion of males amongst the controls treated by resection. Thoracoplasty had been performed on I 3 (8%) relapses and 16 (7 %) controls. The difference between these two figures is not significant. Radiological,features The maximum extent of the disease. The radiograph showing the largest total area of abnormal shadows was selected from the dossier of all patients and classified into I of the following 5 categories: I.

2.

Trivial : less than the area of one segment. Slight: more than the area of one segment, but less than the area ofone lobe.

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38

THORACIC

SOCIETY

3. Limited: the area of one lobe. 4. Moderate: the area of one lung. 5. Extensive: more than the area of one lung. These films were also examined for cavitation. The extent of lung involvement and the incidence of cavitation at the height of the disease in the relapse and control groups is shown in Tables 5 and 6 to be almost identical. It seemed possible that the originally unfavourable prognosis of extensive disease was balanced by more effective treatment given to these patients, but a division of patients in each of the 5 radiological categories into those who did or did not receive adequate chemotherapy gives no support to this hypothesis. TABLE

5.

MAXIMUM

Maximum extent of disease

Present Absent Total

DISEASE

Controls

5 (4%) 3’ (21%) 43 (30%) ;‘;

Total

Cavitiation

OF

Relapses

Trivial Slight Limited Moderate Extensive

TABLE

EXTENT

‘(gy

4 ;;

PRESENCE MAXIMUM

240

OF CAVITATION DISEASE

Relapses

18 (12%) I27 ‘45

(88%)

[;@

26 (I&

0

145

6.

(2%)

62 (26%)

AT

Controls 34 (14%) 206 (86%) 240

Distribution of the disease according to lung zones. Classification of the films showing the greatest extent of the disease according to lung zones showed that the upper zones were involved in approximately three-quarters of the patients, the middle zones in one-third and the lower only in about I in IO. The right lung was rather more often affected than the left. There was no difference in the distribution of the disease between the relapse and the control groups. Gaseousnodules and cavitation. A film chosen as near as possible to the date of completion of treatment was examined for cavities and for caseous nodules, classified as large (over I cm in diameter) or small (up to I cm in diameter). The incidence of these residual lesions in the relapse and control groups was similar. General radiological assessment. It was thought possible that an analysis of the radiographs according to individual features, such as extent, distribution and nature of residual lesions, might conceal the prognostic value of a general assessment of the radiological appearances. A further analysis of the films taken on completion of treatment was therefore carried out, taking all these factors

RELAPSE

IN

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39

simultaneously into account, and dividing the films into three groups regarded as ‘cured’, ‘good risks’ and ‘bad risks’, according to the personal impression of the independent assessor. The proportion of patients so classified proved to be almost identical amongst those who relapsed and those who remained well. Other prognostic factors The number of patients with diabetes, gastrectomy or a history of excessive consumption of alcohol was too small to show whether these factors influenced the likelihood of relapse. The proportion of women who had borne children was exactly the same in the relapse and control groups. Discussion The information collected in this study came from chest clinics in Kent, part of East Sussex and the south-east suburbs of London. It is a prosperous part of the country with a relatively small immigrant population, so that conclusions drawn from these data may not apply to other parts of the British Isles or to other countries of Western Europe. They may, however, be used as a guide in deciding which, if any, of the patients who have had pulmonary tuberculosis, could be discharged from observation. The relapse rate of 0.5% revealed by this study is too high for unselective wholesale discharge of ex-tuberculous patients from the chest clinics. However, as certain groups of patients were shown to be at greater risk than others, it would be reasonable to keep under continued observation only those with a relatively unfavourable prognosis. The greater liability to relapse of males over the age of 40 was to be foreseen from the regional notification and mortality figures (Registrar General 1964; Greater London Council 1966). Chronic tuberculosis in this section of the population now accounts for a large proportion of patients coming under treatment for the first time. As was to be expected, patients who had received no chemotherapy in the past, or who were given antituberculous drugs for too short a time by present standards, were much more liable to break down. Although the incidence of drug resistant strains after relapse (I I %) was more than three times the national average of 3% in pretreatment cases (Miller et al. 1g66), this was not the main reason for failure of previous treatment to effect a permanent cure, but was probably the result of unsatisfactory chemotherapy. It is suprising that in I I of the 13 patients who had received single drug chemotherapy’, the tubercle bacilli were still susceptible to all three first line drugs at the time of relapse Chemotherapy given for less than 18 months is now considered to be insufficient (Crofton 1960) and accounts for a substantial number of relapses. But relapse some years after continuous treatment for 12 months or more was unexpected. An attempt was made to discover the reason for this in 24 patients. An enquiry addressed to the chest physician concerned sought to establish in retrospect whether these patients had been treated with unconventional

40

SEMR

THORACIC

SOCIETY

preparations or a low dosage, whether they had shown any intolerance to PAS and whether they were thought to have been reliable in carrying out their chemotherapy. The answers, when compared with those to a similar enquiry relating to 24 patients chosen at random from the controls, were similar as far as details of the chemotherapy were concerned, but 15 of the 24 relapses, in contrast with I of the 24 controls, were thought to have been unreliable. However, as the identity of relapsed patients was known to the physician, such a retrospective judgement may have been coloured by subsequent events. In the days before chemotherapy the radiological features of tuberculosis were regarded as of paramount importance in forecasting the likelihood of a permanent recovery. Widespread involvement of the lungs was rightly thought to be more dangerous. Apical residual lesions relapsed more often than basal ones, caseous nodules often harboured live bacilli and, above all, persistent cavities usually spelt disaster sooner or later. However, after ten years’ experience with chemotherapy, it became evident that, providing the treatment was conscientiously taken, some prognostic features such as open cavitation had lost their importance (Arblaster et al. 1961). On the other hand, the extent of initial disease still seemed to be important (Ross rgsg), and a higher initial death rate in patients with more extensive disease is shown in studies by the anniversary method (Alling & Bosworth 1960). The correlation between the extent of disease at the height of the illness and the extent and nature of the residual lesions on completion of treatment was therefore studied with particular care in this survey. Evidently none of these features, whether assessed singly or together, has any bearing on the prognosis of relapse as judged in the patient who has completed treatment. The study failed to show any adverse effect of diabetes, gastrectomy or excess consumption of alcohol, traditionally regarded as unfavourable prognostic factors, but the numbers were very small. The proportion of women who had borne children during the period of observation was identical in the two groups. In deciding the order of priorities in the light of this survey, it would therefore be reasonable to start by discharging women before men and the younger before the middle-aged or elderly patients. Those who have received adequate chemotherapy for at least 18 months could all be regarded as cured, if it were not for the lesson, brought home again by this study, that patients do not always take their drugs as regularly, or for as long as prescribed. All other forms of past treatment and past pregnancies may be disregarded, but it might be wise to treat diabetes, gastrectomy and excessive drinking as adverse prognostic factors. The findings suggest that the extent of the disease at the height of the illness, the distribution and nature of the residual lesions, in fact any of the old radiological criteria, may be disregarded in estimating the probability of relapse. The patients with severely damaged lungs run other serious risks; they are more prone to secondary infections with pyogenic organisms and Aspergillus (British Thoracic and Tuberculosis Association Report 1970) and are at risk from respiratory and cardiac failure. For this reason it may be wise to keep patients with widespread tuberculous fibrosis, a history of thoracoplasty or extensive resection and persistent cavities under observation, although not

RELAPSE

IN

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41

primarily for tuberculosis. The greater risk of relapse of tuberculosis in middleaged and elderly men was confirmed once again. Even when the majority of tuberculous patients now attending the chest clinics is eventually recognized as cured and discharged, there seems to be a good case for keeping this group under observation. Summary This is a study of pulmonary tuberculosis in South-east England and, in particular, an attempt to discover whether certain groups of patients are more liable to relapse than others. The chest clinics in the South-east Metropolitan region were asked to report during a period of 12 months all patients with bacteriological or radiological evidence of reactivation of pulmonary tuberculosis after not less than 2 years of quiescence. The number of relapses reported was I 58, representing 0*50/O of the tuberculous population known to the clinics. These patients were compared with 244 controls drawn at random from the tuberculosis register of the same clinics in respect of sex, age, previous treatment and certain radiological features. Among the relapses there was a significant excess of males, especially in the older age groups, and a significantly higher proportion of patients who had received insufficient or no chemotherapy. Nevertheless, 24 patients who relapsed were said to have received more than I 2 months’ treatment with two or three first line antituberculosis drugs. Amongst the 89 positive sputum cultures examined by the Tuberculosis Reference Laboratory at Cardiff IO strains resistant to streptomycin, isoniazid or PAS were found. There was little difference between the relapse and control groups in respect of the number of patients treated by surgery. The radiological extent and distribution of the disease at the height of the original illness and just before relapse was similar in the two groups. Cavitation and caseous nodules were not shown to carry increased risk of relapse. Future policy in keeping tuberculosis patients on long continued observation at chest clinics is discussed in the light of these observations.

ACKNOWLEDGEMENTS

The study was made possible by a grant from the South-east Metropolitan Regional Board’s Research Grants Committee. Bacteriology was carried out at the Tuberculosis Reference Laboratory, Cardiff by Dr J. Marks. The radiographs were read by Dr R. H. Andrews, Dr N. F. Crofts, Dr P. Forgacs and Dr J. Spencer Jones. The study was coordinated and the report was written by Dr A. P. Bentley. The committee was made up as follows: Research Sub-Committee Chairman: D. G. Madigan; Coordinator and Secretary: A. P. Bentley; Members: R. H. Andrews, J. A. Chamberlin, Owen Clarke, N. F. Crofts, Ma ry Farquharson, P. Forgacs, J. Spencer Jones, F. B. Meade, D. L. Pugh, D. G. Wraith. The following physicians cooperated in the investigation: A. W. Anderson, R. H. Andrews, A. P. Bentley, H. Broderick, H. C. Calvey, F. E. Cayley, J. A. Chamberlin, Owen Clarke, F. Temple Clive, N. F. Crofts, B. Dyer, M. Farquharson, P. Forgacs, A. H. Ferguson Gow, J. D. Hall, J. Spencer Jones, G. M. Lewis, A. MacManus, A. Macfarlane, D. G. Madigan, Brendan J. Malley, J. K. M. Marsh, R. G. May, F. B. Meade, W. E. D. Moore, M. M. Nagley, C. F. Price, M. Price, E. K. Pritchard, D. L. Pugh, G. I. Rees-Jones, J. P. V. Rigby, B. G. Rigden, H. J. Robinson, J. E. Stokes, E. W. Street, S. J. Sutton, B. R. Turner, V. St G. Vaughan, G. H. C. Walmsley, D. G. Wraith. 4

SEMR

42 Tables showing on request: I. z. 3. 4. 5. 6.

the following

statistical

data

in greater

detail

THORACIC

will be provided

SOCIETY by the coordinator

Duration of chemotherapy related to age of patients in year I 965” Drug resistant strains in relapses. Extent of disease related to chemotherapy. Extent of disease related to age. Other prognostic factors. Relationship of relapse to the 4 factors, resection, sex, smoking and therapy (multiple regression analysis).

duration

of chemo-

REFERENCES ALLING, D. W. & BOSWORTH, E. B. (1960) The after history of pulmonary tuberculosis. Am. Rev. resp. Dis., 81, 830. ARBLASTER, P. G., CROSS, K. W., MCWHINNEY, I. R. & YATES, J. (1961) Caviatated pulomnary tuberculosis: a long-term follow-up of 283 patients with special reference to the significance of the persistent cavity. Tubercle, Lond., 42, 428. BRITISH THORACIC AND TUBERCULOSIS ASSOCIATION (1970) Aspergilloma and residual tuberculous cavities; the results of a resurvey. Tube&e, Lond., 51, 227. CROFTON, J. (1960) Tuberculosis undefeated. Br. med. J., ii, 679. GREATER LONDON COUNCIL (1966) Report of the County Medical Oficer of Health for the London County Councilfor the Year 1964, pp. 28-g. London. MILLER, A. B., TALL, R., Fox, W., LEFFORD, M. J. & MITCHISON, D. A. (1966) Primary drug resistance in tuberculosis in Great Britain. Second national survey (I 963). Tubercle, Lond.,

47, 92. REGISTRAR GENERAL (1964) London : HMSO. Ross, J. D. (1959) Relapse int. Tuberc., zg, 710.

Statistical during

Review and

after

for

England

treatment

and Wales for the of pulmonary

Year

tuberculosis.

1964,

p. 236. Bull.

Un.