Saturday
SHORT-COURSE CHEMOTHERAPY IN PULMONARY TUBERCULOSIS
by the British Thoracic and Tuberculosis Association*
A Controlled Trial
The results of short
courses
of chemo-
Summary therapy using rifampicin plus isoniazid, supplemented for the first two months by streptomycin or ethambutol, in patients with newly diagnosed 174 pulmonary tuberculosis, have been studied.
patients with little or no cavitation received six months chemotherapy. 1 (0·6%) failed to convert to culture negative during treatment and 5 (3%) relapsed in the twelve months after the end of treatment. In 177 patients with similar disease, twelve months chemotherapy was 100% effective in rendering the sputum culture negative and in preventing relapse in the six months after the end of treatment. 151 patients with more extensive cavitation received chemotherapy for nine months: this was 100% effective in sputum conversion and in preventing relapse in the nine months after the end of treatment. In 155 patients with similar disease, the eighteen-month regimen was uniformly successful in sputum conversion. The isoniazid was well tolerated, rifampicin plus regimen producing adverse effects which warranted withdrawal from the study in only 3·6% of patients. Comparison of ethambutol with streptomycin as a third drug given for the first eight weeks showed no significant difference in the rate of sputum conversion nor in the incidence of relapse. Streptomycin produced significant adverse effects in 8% of patients whilst ethambutol caused none. Chemotherapy with rifampicin plus isoniazid for nine months, supplemented initially by ethambutol, is more acceptable than standard chemotherapy for eighteen months, is highly effective in sputum conversion, and has resulted in no relapses over a nine-month follow-up period. Further followup is being continued to confirm that relapse does not occur.
Introduction
January 1975
p-aminosalicylic acid (P.A.S.), supplemented initially by streptomycin, is of confirmed efficacy in pulmonary tUberculosis,l-4 and provided chemotherapy is taken as prescribed relapse is exceptiona1.4 The same for one been shown regimen given year has, however, to be associated with appreciable relapsed Consequently, a minimum of eighteen months chemotherapy is now standard practice in Britain. However, prolonged chemotherapy has disadvantages which include inconvenience to the patient, the tendency of patients not to take their drugs,6,7 and the need for treatment services to monitor patients closely for long periods of time. Moreover, both P.A.S. and streptomycin have a high incidence of adverse effects.5 Rifampicin is a powerful, bactericidal antituberculosis drug, and in combination with isoniazid it forms a highly potent regimen. The good results 8-10 of a study in which rifampicin, isoniazid, and streptomycin were given for six months to patients with extensive disease suggested that it might now be possible to reduce the duration of chemotherapy in Britain with regimens including rifampicin. To investigate this possibility the British Thoracic and Tuberculosis Association initiated a study in October, 1972, the aims of which were to compare the efficacy of different durations of rifampicin plus isoniazid, supplemented initially by a third drug, in the treatment of newly diagnosed cases of pulmonary tuberculosis, and to compare the efficacy of initial eight-week supplements of either ethambutol or streptomycin when combined with the basic regimen of rifampicin plus isoniazid. .
Patients and Methods Patients Patients
aged between fifteen and seventy years, with culture-positive pulmonary tuberculosis, who had not received more than two weeks antituberculosis therapy at any time, were eligible for inclusion, provided they were not known to be pregnant or to have impaired renal, hepatic, or visual function. and Dosages Two separate comparisons of duration of chemotherapy were made, depending on the severity of the disease: (a) Patients with no cavitation or with no single cavity larger than 2 cm. in diameter evident on the plain chest radiograph were allocated at random to either six months or twelve months rifampicin plus isoniazid. (b) Patients with any cavity larger than 2 cm. in diameter evident on the plain chest radiograph were
Design
EIGHTEEN months treatment with isoniazid andl The trial was organised by a subcommittee of the ResearchI Committee of the British Thoracic and Tuberculosis Association whose members were: Dr K. M. CITRON (chairman), Dr J. H. ANGEL (secretary and coordinator), Dr 1. A. CAMPBELL (coordinator), Dr A. R. SOMNER (coordinator), and Dr P. A. JENKINS, Dr S. LAL, Dr J. B. SELKON, and Dr I. SUTHERLAND. The report was pre-: pared by Dr Campbell. ’
r
7899
I8
c
120 allocated at random to either nine months or months rifampicin plus isoniazid. Patients were placed in one or the other group on the basis of the physician’s reading of the pretreatment plain chest radiograph. In addition, there was, for all patients under the age of sixty, a further random allocation to ethambutol or streptomycin as the third drug for the first eight weeks. Patients aged sixty or more received ethambutol as the third drug for eight weeks. The random allocations of treatment were made centrally by the coordinators. The dosages used were as follows: Rifampicin (R).-600 mg. daily, orally (or 450 mg. if the patient weighed less than 50 kg.). Isoniazid (H).-300 mg. daily, orally. Ethambutol (E).-25 mg. per kg. daily, orally. Streptomycin (S).-0’75 g. intramuscularly, 6 days a week. The oral drugs were taken all together, in a single daily dose, on an empty stomach. Chemotherapy was administered on an outpatient or inpatient basis, according to the usual practice of the physician. Thus patients without cavities or no cavity larger than 2 cm. received either six months or twelve months rifampicin and isoniazid, supplemented initially by ethambutol
eighteen
(EHR6
or
EHR12)
or
by streptomycin (SHR6
or
SHR12).
Patients aged sixty or more were allocated only to the EHR6 or EHR12 groups. Patients with any cavity larger than 2 cm. received either nine months or eighteen months rifampicin and isoniazid, supplemented initially by ethambutol (EHR9 or EHR18), or by streptomycin (SHR9 or SHR18). Patients aged sixty or more were allocated only to the EHR9 or EHR 18 groups.
Bacteriology Before chemotherapy
was started two sputum specithe Tuberculosis Reference Laboratory, Public Health Laboratory Service, Cardiff, for culture and sensitivity testing.ll.UI During chemotherapy one specimen of sputum was examined monthly at the local laboratory, except for the last three months of treatment, when two specimens were In the first sent each month to the Cardiff laboratory. year after stopping treatment, two specimens of sputum were examined every two months at the local laboratory. mens were sent to
Radiology Pretreatment and end-of-treatment
plain
chest radio-
graphs were collected and assessed, using standard gradings,l3.l4 by an observer (Dr G. Simon) who did not know what regimen the patient had been taking. Definitions Failure of chemotherapy
was
defined
as
the presence of
different months during The finding of two cultures one at month in the last three only positive months was not classed as a failure of chemotherapy. Relapse after chemotherapy was defined as two or more positive cultures in any period of four months in specimens taken at least two weeks apart. two or more
positive cultures
at
the last three months of treatment.
Results Of the 913 patients who were considered in the eight months of the intake, 111 patients did not satisfy the requirements of the trial design (table I). Of the 802 eligible patients 106 did not complete the allocated treatment. 37 did not cooperate, 29 developed rifampicin and/or isoniazid toxicity, and 6 patients emigrated. 11 patients were withdrawn by their physicians for reasons other than lack of cooperation, but unconnected with their response to chemotherapy. 4 patients (2 EHR9 and 2 SHR18) were withdrawn because their physicians were dissatisfied with their response to chemotherapy. 19 patients died: 9 because of pulmonary tuberculosis, between two days and two months after entry (6 SHR and 3 EHR) Thus 696 patients remain for analysis and are described in table 11 in terms of mean age, sex, and pretreatment radiographic characteristics; in these respects the random allocations have yielded similar treatment groups. FAILURE OF CHEMOTHERAPY AND RELAPSE
All patients have completed eighteen months in the study. Thus patients in the six-months group have been followed up for one year after the end of chemotherapy, those in the twelve-months group have had six months of follow-up. Patients in the nine-months group have been followed up for nine months, and the eighteen months group have com-
pleted chemotherapy. Patients without Cavities or no Cavity Larger than 2 cm. (Six or Twelve Months Chemotherapy) The results of six and twelve months chemotherapy in patients with little or no initial cavitation are shown in table III. Six months group.-Of the 194 patients who completed chemotherapy 20 are not eligible for analysis for the reasons given in table iv. Of the 174 remainwas a failure of chemoing patients 1 (EHR6>60) therapy and produced positive cultures at the ends of
TABLE I-POPULATION IN THE STUDY
* Reasons: Pretreatment cultures negative 60; not tuberculosis 16; opportunist mycobacteria 16; pretreatment isoniazid resistance 12; previous chemotherapy 3; abnormal hepatic function 3; aged more than seventy 1.
121
months 5 and 6, the cultures at the end of the four previous months having been negative. During the last three months of treatment 12
TABLE III-FAILURE OF CHEMOTHERAPY AND RELAPSE: PATIENTS WITHOUT CAVITIES OR NO CAVITY > 2 cm. (6 OR 12 mo. CHEMO-
THERAPY)
patients produced
sputum which was positive on smear but negative on culture and 4 patients each produced a single positive culture. By definition, these patients were not considered to be failures of chemotherapy, although 1 1 subsequently relapsed. 5 patients (2 EHR660) months since the end of treatment, of whom 3 did 1 of the relapsed so within the first six months. patients had produced a single positive culture as well as a positive smear with negative culture in the last three months of treatment. 2 of the relapsed patients were thought, by their physician, to have been irregular with their chemotherapy. The mycobacteria re-emerging in the patient who was a failure of chemotherapy and in the 5 relapses were all fully sensitive to the antituberculosis drugs used in treatment. During the twelve months since the end of treatment, 3 patients have produced sputum which was positive on smear but negative on culture and 9 patients have produced isolated positive cultures. By definition, these patients were not considered to be relapses and none of them has subsequently relapsed. (1 of these patients was restarted on chemotherapy by the physician after a positive culture was found: two further specimens of sputum, taken before treat-
restarted, proved negative
ment was
on
culture,
as
Patients with
streptomycin toxicity or resistance who were changed to
ethambutol.
subsequent cultures; there had been no clinical radiological deterioration and he has not been classed as a relapse.) Twelve months group.-Of the 190 patients who completed chemotherapy 13 are not eligible for analysis (table iv). None of the 177 remaining patients was a failure of chemotherapy. During the
have or
TABLE II-POPULATION IN THE ANALYSIS: CONDITION ON ADMISSION
.
*
I
As determined by the patient’s 2 radiographs not yet read.
clinician;
II
the radiographic extent of cavitation " was graded by "
t t1 radiograph not yet read.
TABLE IV-PATIENTS NOT ELIGIBLE FOR ANALYSIS OF RELAPSE
...
an
independent observer.
122
last three months of treatment 2 patients produced sputum which was positive on smear but negative on culture and no single positive culture was found. In the six months since the end of treatment no patient has relapsed. 3 patients have produced sputum which was positive on smear but negative on culture and 1 patient has produced an isolated positive culture. By definition, none of these patients was classed as a relapse and they have continued to do well clinically and radiologically, further specimens of sputum
being negative
on
cm.
(Nine
Nine months group.-Of the 157 patients with large cavities who completed nine months chemotherapy 6 are not eligible for analysis (table iv). None of the 151 remaining patients was a failure of chemotherapy. During the last three months of treatment 6 patients produced sputum which was positive on smear but negative on culture and no single positive culture was found. No patient has relapsed in the nine months since the end of treatment. 6 patients have produced sputum which was positive on smear but negative on culture and 2 patients have each produced an isolated positive culture: these patients have continued to do well clinically and radiologically, further specimens of sputum being negative on culture. Eighteen months group.-155 patients have completed chemotherapy and are eligible for analysis of failure of chemotherapy. There were no failures of chemotherapy. Positive smears with negative cultures and single positive cultures did not occur during the last three months of treatment. COMPARISON OF STREPTOMYCIN AS
ETHAMBUTOL THE
THE FIRST
8
THIRD
AND
DRUG
FOR
WEEKS
This comparison is restricted to those groups in which the allocation of the third drug was random (i.e., to patients aged less than sixty). None of the 286 patients who received ethambutol experienced adverse effects which warranted discontinuation of the drug. Of the 298 patients who received streptomycin 23 (8%) experienced adverse effects which warranted discontinuation of streptomycin and substitution of ethambutol: in 10 patients the adverse effects were of the hypersensitivity type, in 11 patients the adverse effects were vestibular, and 2 patients refused injections.
of
Conversion
(6
THERAPY)
culture.
Patients with any Cavity Larger than 2 or Eighteen Months Chemotherpy)
Rate
TABLE V-SPUTUM CONVERSION DURING CHEMOTHERAPY: PATIENTS WITHOUT CAVITIES OR NO CAVITY > 2 cm. OR 12 010. CHEMO-
of Sputum
Culture
to
of each month are shown in table v. The rates of culture conversion in the EHR and the SHR groups are similar. 2 patients in the EHR6 group relapsed and 1 patient in the SHR6 group relapsed, giving a similar incidence of relapse in each group. Patients with any cavity larger than 2 cm. (nine or eighteen months chemotherapy).-After exclusion of 1 EHR patient and 8 SHR patients because of errors in chemotherapy and adverse reactions to streptomycin, 131 patients allocated at random to the ethambutol group (65 EHR9 and 66 EHR18) and 126 patients allocated at random to the streptomycin group (68 SHR9 and 58 SHR18) remain eligible for comparison. The percentages of patients whose sputum converted to negative on culture by the end of each month are shown in table vi. The rates of conversion are again much the same in the two groups. ADVERSE
EFFECTS
OF RIFAMPICIN AND
ISONIAZID
Adverse effects caused by rifampicin and/or isoniazid and which were severe enough to warrant discontinuation of treatment occurred in 29 (3-6%) of the 802 patients accepted for the study (table vil). The psychoses attributed to isoniazid occurred in the third month of chemotherapy and the peripheral neuropathies in the second month. 2 of the rashes developed in the first month of chemotherapy and 1 in the fourth month. After the isoniazid was stopped the adverse effects subsided. TABLE VI-SPUTUM CONVERSION DURING CHEMOTHERAPY: PATIENTS WITH ANY
CAVITY > 2
Cril.
(9
OR
18
mo.
CHEMOTHERAPY)
Negative
Patients without cavities or no cavity larger than 2 cm. (six or twelve months chemotherapy).-After exclusion of 4 EHR patients and 23 SHR patients because of errors in chemotherapy, adverse reactions to streptomycin, and pretreatment streptomycin resistance, 150 patients allocated at random to the ethambutol group (78 EHR6 and 72 EHR12) and 141 patients allocated at random to the streptomycin group (70 SHR6 and 71 SHR12) remain eligible for comparison. The percentages of patients whose sputum converted to negative on culture by the end
TABLE
VII-PATIENTS EXCLUDED FROM ANALYSIS BECAUSE RIFAMPICIN AND/OR ISONIAZID TOXICITY
OF
123
With 2 exceptions the adverse effects due
to
rifampicin occurred in the first month of chemotherapy. 1 patient had a rash in the second month and 1 patient was noticed to be jaundiced in the fourth month. Of the 8 patients who became jaundiced (bilirubin range 2-5-5 mg. per 100 ml.) and of the 6 patients whose disturbance of hepatic function was primarily manifested as raised transaminases, only 1 patient failed to regain normal hepatic biochemistry after rifampicin was stopped: he was an alcoholic who continued to drink heavily. The 5 patients with rifampicin-induced rashes, pyrexia, or gastrointestinal upset recovered on stopping rifampicin. In 2 other patients it was the combination of rifampicin and isoniazid which caused the rash and pyrexia, the reactions failing to occur when either drug was given singly. PRETREATMENT DRUG RESISTANCE
Of the 822 positive cultures examined at the Tuberculosis Reference Laboratory 3-4% showed resistant organisms: 2% were resistant to streptomycin, 1 % to isoniazid, and 0-4 % to both streptomycin and isoniazid. There were no organisms resistant to rifampicin or ethambutol.
Discussion aim of the study was to compare different durations of chemotherapy, and two major comparisons were incorporated into the design-a comparison of six months and twelve months chemotherapy for patients with little or no cavitation, and a comparison of nine months and eighteen months chemotherapy for patients who had any cavity greater than 2 cm. in diameter. The chemotherapy used for all four groups was rifampicin plus isoniazid, supple mented for the first eight weeks by a third drug, either streptomycin or ethambutol. The
primary
Among was
174
patients in the six months group there chemotherapy, and there were 5
1 failure of
in the first year after the end of treatment. In contrast, there was no failure of chemotherapy among 177 patients in the twelve months group and there were no relapses in the six months after the end of treatment. These results are in line with those of other studies. The East Africa/British Medical Research Councils study," using daily streptomycin, isoniazid, and rifampicin, all for six months, yielded no failure of chemotherapy and a 3% incidence of bacteriological relapse in the 156 patients followed up for a year after the end of treatment. No further relapses occurred in the subsequent twelve months. In the study reported by Brouet Mid Roussel,15 using rifampicin plus isoniazid daily for six, nine, or twelve months, supplemented in the first three months by
relapses
streptomycin or ethambutol, no relapse occurred among 46 patients in the six months group in the first year after the end of treatment; however, 3 relapses (6-5%) occurred in the subsequent eighteen months. No relapses occurred among 49 patients treated for twelve months and followed for a further two years. In a second East African study 16 a comparison was made of the relapse-rates after six months
chemotherapy with rifampicin and isoniazid, supplemented in one group with daily streptomycin (SHR) but given without a supplement in a second group (HR): the relapse-rates in the first six months after stopping treatment were 2% for the 166 SHR patients and 5 % for the 170 HR patients. Poppe de Figueiredo et al.17 using the combination of rifampicin, isoniazid, and ethambutol daily for six months in 89 patients with sensitive organisms, found a relapserate of 3 % : all the relapses occurred in the first six months of the two-year follow-up. Considering the patients in the present study with a cavity greater than 2 cm. in diameter, no failure of chemotherapy occurred in any of 151 patients in the nine months group or in any of 155 patients in the 18 months group. No relapse has occurred in the nine months group in the nine months after the end of treatment. These results are in accord with those of Brouet and Roussel,15 who found no relapse in the nine months after the end of chemotherapy among 59 patients treated for nine months. A 3 % relapse-rate has been found among patients with little or no cavitation treated for six months and followed up for a further twelve months. However, in patients with more advanced disease, treated for nine months and followed up for a further nine months, no relapse occurred. It would appear, therefore, that six months chemotherapy with rifampicin plus isoniazid, supplemented initially by ethambutol or streptomycin, is not enough to achieve 100 % success, whereas nine months may prove sufficient both in cavitated and non-cavitated disease. At present this conclusion can only be tentative because of the limited period of follow-up. However, most studies of short-course chemotherapy have shown that the majority of relapses occur in the first six months after stopping chemotherapy, and it seems reasonable to expect few, if any, relapses in the nine-month group. These satisfactory results were obtained employing the normal prescribing practice of the attending
physician. Another aim of the study was to compare the efficacy of ethambutol and streptomycin as an initial third drug in patients under the age of sixty. Comparison of the two series of patients showed no difference in the rate of sputum conversion, whatever the extent of cavitation, and a similar relapse-rate in the EHR6 and the SHR6 groups (3% v. 1-5%). No toxic reaction to ethambutol was reported whereas 8 % of the 298 patients in the streptomycin series experienced adverse effects which led the physician to discontinue streptomycin and to substitute ethambutol. The rifampicin/isoniazid regimen was associated with a low incidence of toxicity. Although 1-75% of the patients developed abnormal liver-function tests and were withdrawn from the study on this account, recent publications 18,19 have emphasised that disordered liver function at a purely biochemical level is unlikely to be of significance and that the raised transaminase and bilirubin levels tend to return to normal even though rifampicin is continued. It is likely that, in the light of this new knowledge, fewer patients would have had their rifampicin discontinued.
124
LEUKÆMIA AND LYMPHOMA PATIENTS INTERLINKED BY PRIOR SOCIAL CONTACT *
As in previous studies 5,9 some patients continue to produce sputum which is positive on smear but negative on culture, both during and after chemotherapy. Such results have been held to signify non-viable bacilli and to be of no clinical importance. This finding in the last three months of chemotherapy was not taken to indicate a failure of chemotherapy : however, 1 of the 12 patients in the six months group who had shown this feature did relapse. He had also produced a single positive culture in the last three months of chemotherapy. Isolated positive cultures occurred after the cessation of chemotherapy, as in other studies,5,9 but the frequency of bacteriological examination in the present study has allowed differentiation from true bacteriological relapse. In only 1 patient was chemotherapy restarted by the physician on the basis of an isolated positive culture. The appearance of this positive culture was not supported by any radiological or clinical deterioration and two subsequent sputum cultures produced before the reinstitution of chemo-
negative: this patient has not been having relapsed. The 5 patients who relapsed after stopping treatment at six months did so with organisms sensitive to streptomycin, isoniazid, rifampicin, and ethambutol, suggesting that the duration of chemotherapy had been inadequate to kill off all sensitive bacilli.5 2 were thought not to have taken their full course of chemotherapy. All 5 have responded to reintroduction of chemotherapy. therapy regarded
REFERENCES
2. 3. 4.
5. 6. 7. 8.
Ross, J. D., Horne, N. W., Grant, I. W. B., Crofton, J. W. Br. med. J. 1958, i, 237. Ross, J. D. Bull. Un. int. Tuberc. 1959, 29, 710. Crofton, J. W. Br. med. J. 1960, ii, 679. Pearce, S. J., Horne, N. W. Lancet, 1974, ii, 641. Report to the Medical Research Council by their Tuberculosis Chemotherapy Trials Committee. Tubercle, 1962, 43, 201. Pande, B. R., Martischnig, K. M., Feinmann, L. ibid. 1970, 51, 39. Lal, S. ibid. 1969, 50, 269. East African/British Medical Research Councils. Lancet, 1972, i,
1079. 9. East African/British Medical Research Councils. ibid. 1973, i, 1331. 10. East African/British Medical Research Councils. ibid. 1974, ii, 237. 11. Marks, J. Publ. Hlth Serv. Monogr. Ser. no. 5; laboratory methods, I, 14. H.M. Stationery Office, 1974. 12. Leat, J. L., Marks, J. Tubercle, 1970, 51, 68. 13. Tuberculosis Chemotherapy Centre, Madras. Bull. Wld Hlth Org.
1960, 23, 535. 14. Simon, G. Br. med. J. 1966, ii, 491. 15. Brouet, G., Roussel, G. in XVII Congres national de la tuberculose et des maladies respiratoires; p. 27. Paris 1974. 16. East African/British Medical Research Councils. Lancet, 1974, ii, 1100. 17. Poppe de
either leukæmia or asked if they had close personal associations with other patients before the onset of disease. Initial interviews indicated that several patients could be interlinked into social clusters. Tumour-registry records were used to contact each patient (or a surviving relative) diagnosed during the years 1964-73 in three areas of West Virginia. Close personal associations, antedating the onset of disease in 1 or both individuals of each linkage pair, were detected in 14 of 23 (61%), 14 of 22 (68%), and 6 of 8 (75%) patients from these three areas during this In addition, among 28 randomly ten-year period. selected patients with Hodgkin’s disease from various parts of the United States, 10 (36%) had direct or indirect close personal associations with 17 other patients with leukæmia or lymphoma. Patients with leukæmia or lymphoma frequently are interlinked by prior close personal associations to other patients with these diseases.
Summary
as
Requests for reprints should be addressed to Dr I. A. Campbell, Department of Respiratory Diseases, City Hospital, Edinburgh EH10 5SB.
1.
Section of Medical Oncology, Baltimore Cancer Research Center, National Cancer Institute, University of Maryland Hospital, Baltimore, Maryland 21201, U.S.A.
were
The Research Committee of the British Thoracic and Tuberculosis Association acknowledges with gratitude the cooperation of the many participating physicians and hospital staff in England, Scotland, Wales, and Ireland; CIBA Laboratories and Lepetit Pharmaceuticals for financial support ; and Mrs C. P. Davison, Mrs P. Hindshaw, Mrs F. Hoare, and Mrs L. Hunt for their assistance.
Figueiredo, F., Brito, A. A., Valle, J. H. L., Tavares, P. M., Trannin, P. L. Proc. XXIInd Tuberc. Conf. 1973. (In the press.) 18. Lal, S., Singhal, S. N., Burley, D. M., Crossley, G. Br. med. J. 1972, i, 148. 19. Baron, D. N., Bell, J. L. Tubercle, 1974, 55, 115.
CAROL R. SCHIMPFF PETER H. WIERNIK
STEPHEN C. SCHIMPFF DORAH M. BRAGER
Patients
with
lymphoma
were
Introduction THERE is increasing interest in the possibility of person-to-person transmission of leukarmias or lymphomas in a manner similar to that shown for fowl and cats.1-3 Most human studies have concentrated on one disease entity such as Hodgkin’s disease or acute lymphocytic leukaemia.H2 For example, Vianna’s group 4,5 has linked together 31 patients with Hodgkin’s disease on the basis of prior personal associations, and Kemmoonahas found 5 patients with acute lymphocytic leukaemia and another with lymphosarcoma who could be interlinked through their social contacts. Our investigations of Hodgkin’s disease in one area and leukaemia in another resulted in the detection of large numbers of socially interlinked patients. In these and other areas, however, multiple social linkages found among patients with all forms of leukxmia and lymphoma rather than with only a single These findings indicate that many tumour type. individuals with either leuksemia or lymphoma can be interlinked into social clusters based on prior personal associations. were
Methods Three separate areas of West Virginia were studied. In each area, patients with leukaemia or lymphoma from the Baltimore Cancer Research Center had reported knowledge of one or more close personal friends with leukaemia or lymphoma living near their homes. The West Virginia *
Based on a paper presented at the Fourteenth Interscience Conference on Antimicrobial Agents and Chemotherapy, held in San Francisco in September, 1974.
SHORT-COURSE CHEMOTHERAPY IN PULMONARY TUBERCULOSIS
by the British Thoracic and Tuberculosis Association*
A Controlled Trial
The results of short
courses
of chemo-
Summary therapy using rifampicin plus isoniazid, supplemented for the first two months by streptomycin or ethambutol, in patients with newly diagnosed 174 pulmonary tuberculosis, have been studied.
patients with little or no cavitation received six months chemotherapy. 1 (0·6%) failed to convert to culture negative during treatment and 5 (3%) relapsed in the twelve months after the end of treatment. In 177 patients with similar disease, twelve months chemotherapy was 100% effective in rendering the sputum culture negative and in preventing relapse in the six months after the end of treatment. 151 patients with more extensive cavitation received chemotherapy for nine months: this was 100% effective in sputum conversion and in preventing relapse in the nine months after the end of treatment. In 155 patients with similar disease, the eighteen-month regimen was uniformly successful in sputum conversion. The isoniazid was well tolerated, rifampicin plus regimen producing adverse effects which warranted withdrawal from the study in only 3·6% of patients. Comparison of ethambutol with streptomycin as a third drug given for the first eight weeks showed no significant difference in the rate of sputum conversion nor in the incidence of relapse. Streptomycin produced significant adverse effects in 8% of patients whilst ethambutol caused none. Chemotherapy with rifampicin plus isoniazid for nine months, supplemented initially by ethambutol, is more acceptable than standard chemotherapy for eighteen months, is highly effective in sputum conversion, and has resulted in no relapses over a nine-month follow-up period. Further followup is being continued to confirm that relapse does not occur.
Introduction
January 1975
p-aminosalicylic acid (P.A.S.), supplemented initially by streptomycin, is of confirmed efficacy in pulmonary tUberculosis,l-4 and provided chemotherapy is taken as prescribed relapse is exceptiona1.4 The same for one been shown regimen given year has, however, to be associated with appreciable relapsed Consequently, a minimum of eighteen months chemotherapy is now standard practice in Britain. However, prolonged chemotherapy has disadvantages which include inconvenience to the patient, the tendency of patients not to take their drugs,6,7 and the need for treatment services to monitor patients closely for long periods of time. Moreover, both P.A.S. and streptomycin have a high incidence of adverse effects.5 Rifampicin is a powerful, bactericidal antituberculosis drug, and in combination with isoniazid it forms a highly potent regimen. The good results 8-10 of a study in which rifampicin, isoniazid, and streptomycin were given for six months to patients with extensive disease suggested that it might now be possible to reduce the duration of chemotherapy in Britain with regimens including rifampicin. To investigate this possibility the British Thoracic and Tuberculosis Association initiated a study in October, 1972, the aims of which were to compare the efficacy of different durations of rifampicin plus isoniazid, supplemented initially by a third drug, in the treatment of newly diagnosed cases of pulmonary tuberculosis, and to compare the efficacy of initial eight-week supplements of either ethambutol or streptomycin when combined with the basic regimen of rifampicin plus isoniazid. .
Patients and Methods Patients Patients
aged between fifteen and seventy years, with culture-positive pulmonary tuberculosis, who had not received more than two weeks antituberculosis therapy at any time, were eligible for inclusion, provided they were not known to be pregnant or to have impaired renal, hepatic, or visual function. and Dosages Two separate comparisons of duration of chemotherapy were made, depending on the severity of the disease: (a) Patients with no cavitation or with no single cavity larger than 2 cm. in diameter evident on the plain chest radiograph were allocated at random to either six months or twelve months rifampicin plus isoniazid. (b) Patients with any cavity larger than 2 cm. in diameter evident on the plain chest radiograph were
Design
EIGHTEEN months treatment with isoniazid andl The trial was organised by a subcommittee of the ResearchI Committee of the British Thoracic and Tuberculosis Association whose members were: Dr K. M. CITRON (chairman), Dr J. H. ANGEL (secretary and coordinator), Dr 1. A. CAMPBELL (coordinator), Dr A. R. SOMNER (coordinator), and Dr P. A. JENKINS, Dr S. LAL, Dr J. B. SELKON, and Dr I. SUTHERLAND. The report was pre-: pared by Dr Campbell. ’
r
7899
I8
c
120 allocated at random to either nine months or months rifampicin plus isoniazid. Patients were placed in one or the other group on the basis of the physician’s reading of the pretreatment plain chest radiograph. In addition, there was, for all patients under the age of sixty, a further random allocation to ethambutol or streptomycin as the third drug for the first eight weeks. Patients aged sixty or more received ethambutol as the third drug for eight weeks. The random allocations of treatment were made centrally by the coordinators. The dosages used were as follows: Rifampicin (R).-600 mg. daily, orally (or 450 mg. if the patient weighed less than 50 kg.). Isoniazid (H).-300 mg. daily, orally. Ethambutol (E).-25 mg. per kg. daily, orally. Streptomycin (S).-0’75 g. intramuscularly, 6 days a week. The oral drugs were taken all together, in a single daily dose, on an empty stomach. Chemotherapy was administered on an outpatient or inpatient basis, according to the usual practice of the physician. Thus patients without cavities or no cavity larger than 2 cm. received either six months or twelve months rifampicin and isoniazid, supplemented initially by ethambutol
eighteen
(EHR6
or
EHR12)
or
by streptomycin (SHR6
or
SHR12).
Patients aged sixty or more were allocated only to the EHR6 or EHR12 groups. Patients with any cavity larger than 2 cm. received either nine months or eighteen months rifampicin and isoniazid, supplemented initially by ethambutol (EHR9 or EHR18), or by streptomycin (SHR9 or SHR18). Patients aged sixty or more were allocated only to the EHR9 or EHR 18 groups.
Bacteriology Before chemotherapy
was started two sputum specithe Tuberculosis Reference Laboratory, Public Health Laboratory Service, Cardiff, for culture and sensitivity testing.ll.UI During chemotherapy one specimen of sputum was examined monthly at the local laboratory, except for the last three months of treatment, when two specimens were In the first sent each month to the Cardiff laboratory. year after stopping treatment, two specimens of sputum were examined every two months at the local laboratory. mens were sent to
Radiology Pretreatment and end-of-treatment
plain
chest radio-
graphs were collected and assessed, using standard gradings,l3.l4 by an observer (Dr G. Simon) who did not know what regimen the patient had been taking. Definitions Failure of chemotherapy
was
defined
as
the presence of
different months during The finding of two cultures one at month in the last three only positive months was not classed as a failure of chemotherapy. Relapse after chemotherapy was defined as two or more positive cultures in any period of four months in specimens taken at least two weeks apart. two or more
positive cultures
at
the last three months of treatment.
Results Of the 913 patients who were considered in the eight months of the intake, 111 patients did not satisfy the requirements of the trial design (table I). Of the 802 eligible patients 106 did not complete the allocated treatment. 37 did not cooperate, 29 developed rifampicin and/or isoniazid toxicity, and 6 patients emigrated. 11 patients were withdrawn by their physicians for reasons other than lack of cooperation, but unconnected with their response to chemotherapy. 4 patients (2 EHR9 and 2 SHR18) were withdrawn because their physicians were dissatisfied with their response to chemotherapy. 19 patients died: 9 because of pulmonary tuberculosis, between two days and two months after entry (6 SHR and 3 EHR) Thus 696 patients remain for analysis and are described in table 11 in terms of mean age, sex, and pretreatment radiographic characteristics; in these respects the random allocations have yielded similar treatment groups. FAILURE OF CHEMOTHERAPY AND RELAPSE
All patients have completed eighteen months in the study. Thus patients in the six-months group have been followed up for one year after the end of chemotherapy, those in the twelve-months group have had six months of follow-up. Patients in the nine-months group have been followed up for nine months, and the eighteen months group have com-
pleted chemotherapy. Patients without Cavities or no Cavity Larger than 2 cm. (Six or Twelve Months Chemotherapy) The results of six and twelve months chemotherapy in patients with little or no initial cavitation are shown in table III. Six months group.-Of the 194 patients who completed chemotherapy 20 are not eligible for analysis for the reasons given in table iv. Of the 174 remainwas a failure of chemoing patients 1 (EHR6>60) therapy and produced positive cultures at the ends of
TABLE I-POPULATION IN THE STUDY
* Reasons: Pretreatment cultures negative 60; not tuberculosis 16; opportunist mycobacteria 16; pretreatment isoniazid resistance 12; previous chemotherapy 3; abnormal hepatic function 3; aged more than seventy 1.
121
months 5 and 6, the cultures at the end of the four previous months having been negative. During the last three months of treatment 12
TABLE III-FAILURE OF CHEMOTHERAPY AND RELAPSE: PATIENTS WITHOUT CAVITIES OR NO CAVITY > 2 cm. (6 OR 12 mo. CHEMO-
THERAPY)
patients produced
sputum which was positive on smear but negative on culture and 4 patients each produced a single positive culture. By definition, these patients were not considered to be failures of chemotherapy, although 1 1 subsequently relapsed. 5 patients (2 EHR660) months since the end of treatment, of whom 3 did 1 of the relapsed so within the first six months. patients had produced a single positive culture as well as a positive smear with negative culture in the last three months of treatment. 2 of the relapsed patients were thought, by their physician, to have been irregular with their chemotherapy. The mycobacteria re-emerging in the patient who was a failure of chemotherapy and in the 5 relapses were all fully sensitive to the antituberculosis drugs used in treatment. During the twelve months since the end of treatment, 3 patients have produced sputum which was positive on smear but negative on culture and 9 patients have produced isolated positive cultures. By definition, these patients were not considered to be relapses and none of them has subsequently relapsed. (1 of these patients was restarted on chemotherapy by the physician after a positive culture was found: two further specimens of sputum, taken before treat-
restarted, proved negative
ment was
on
culture,
as
Patients with
streptomycin toxicity or resistance who were changed to
ethambutol.
subsequent cultures; there had been no clinical radiological deterioration and he has not been classed as a relapse.) Twelve months group.-Of the 190 patients who completed chemotherapy 13 are not eligible for analysis (table iv). None of the 177 remaining patients was a failure of chemotherapy. During the
have or
TABLE II-POPULATION IN THE ANALYSIS: CONDITION ON ADMISSION
.
*
I
As determined by the patient’s 2 radiographs not yet read.
clinician;
II
the radiographic extent of cavitation " was graded by "
t t1 radiograph not yet read.
TABLE IV-PATIENTS NOT ELIGIBLE FOR ANALYSIS OF RELAPSE
...
an
independent observer.
122
last three months of treatment 2 patients produced sputum which was positive on smear but negative on culture and no single positive culture was found. In the six months since the end of treatment no patient has relapsed. 3 patients have produced sputum which was positive on smear but negative on culture and 1 patient has produced an isolated positive culture. By definition, none of these patients was classed as a relapse and they have continued to do well clinically and radiologically, further specimens of sputum
being negative
on
cm.
(Nine
Nine months group.-Of the 157 patients with large cavities who completed nine months chemotherapy 6 are not eligible for analysis (table iv). None of the 151 remaining patients was a failure of chemotherapy. During the last three months of treatment 6 patients produced sputum which was positive on smear but negative on culture and no single positive culture was found. No patient has relapsed in the nine months since the end of treatment. 6 patients have produced sputum which was positive on smear but negative on culture and 2 patients have each produced an isolated positive culture: these patients have continued to do well clinically and radiologically, further specimens of sputum being negative on culture. Eighteen months group.-155 patients have completed chemotherapy and are eligible for analysis of failure of chemotherapy. There were no failures of chemotherapy. Positive smears with negative cultures and single positive cultures did not occur during the last three months of treatment. COMPARISON OF STREPTOMYCIN AS
ETHAMBUTOL THE
THE FIRST
8
THIRD
AND
DRUG
FOR
WEEKS
This comparison is restricted to those groups in which the allocation of the third drug was random (i.e., to patients aged less than sixty). None of the 286 patients who received ethambutol experienced adverse effects which warranted discontinuation of the drug. Of the 298 patients who received streptomycin 23 (8%) experienced adverse effects which warranted discontinuation of streptomycin and substitution of ethambutol: in 10 patients the adverse effects were of the hypersensitivity type, in 11 patients the adverse effects were vestibular, and 2 patients refused injections.
of
Conversion
(6
THERAPY)
culture.
Patients with any Cavity Larger than 2 or Eighteen Months Chemotherpy)
Rate
TABLE V-SPUTUM CONVERSION DURING CHEMOTHERAPY: PATIENTS WITHOUT CAVITIES OR NO CAVITY > 2 cm. OR 12 010. CHEMO-
of Sputum
Culture
to
of each month are shown in table v. The rates of culture conversion in the EHR and the SHR groups are similar. 2 patients in the EHR6 group relapsed and 1 patient in the SHR6 group relapsed, giving a similar incidence of relapse in each group. Patients with any cavity larger than 2 cm. (nine or eighteen months chemotherapy).-After exclusion of 1 EHR patient and 8 SHR patients because of errors in chemotherapy and adverse reactions to streptomycin, 131 patients allocated at random to the ethambutol group (65 EHR9 and 66 EHR18) and 126 patients allocated at random to the streptomycin group (68 SHR9 and 58 SHR18) remain eligible for comparison. The percentages of patients whose sputum converted to negative on culture by the end of each month are shown in table vi. The rates of conversion are again much the same in the two groups. ADVERSE
EFFECTS
OF RIFAMPICIN AND
ISONIAZID
Adverse effects caused by rifampicin and/or isoniazid and which were severe enough to warrant discontinuation of treatment occurred in 29 (3-6%) of the 802 patients accepted for the study (table vil). The psychoses attributed to isoniazid occurred in the third month of chemotherapy and the peripheral neuropathies in the second month. 2 of the rashes developed in the first month of chemotherapy and 1 in the fourth month. After the isoniazid was stopped the adverse effects subsided. TABLE VI-SPUTUM CONVERSION DURING CHEMOTHERAPY: PATIENTS WITH ANY
CAVITY > 2
Cril.
(9
OR
18
mo.
CHEMOTHERAPY)
Negative
Patients without cavities or no cavity larger than 2 cm. (six or twelve months chemotherapy).-After exclusion of 4 EHR patients and 23 SHR patients because of errors in chemotherapy, adverse reactions to streptomycin, and pretreatment streptomycin resistance, 150 patients allocated at random to the ethambutol group (78 EHR6 and 72 EHR12) and 141 patients allocated at random to the streptomycin group (70 SHR6 and 71 SHR12) remain eligible for comparison. The percentages of patients whose sputum converted to negative on culture by the end
TABLE
VII-PATIENTS EXCLUDED FROM ANALYSIS BECAUSE RIFAMPICIN AND/OR ISONIAZID TOXICITY
OF
123
With 2 exceptions the adverse effects due
to
rifampicin occurred in the first month of chemotherapy. 1 patient had a rash in the second month and 1 patient was noticed to be jaundiced in the fourth month. Of the 8 patients who became jaundiced (bilirubin range 2-5-5 mg. per 100 ml.) and of the 6 patients whose disturbance of hepatic function was primarily manifested as raised transaminases, only 1 patient failed to regain normal hepatic biochemistry after rifampicin was stopped: he was an alcoholic who continued to drink heavily. The 5 patients with rifampicin-induced rashes, pyrexia, or gastrointestinal upset recovered on stopping rifampicin. In 2 other patients it was the combination of rifampicin and isoniazid which caused the rash and pyrexia, the reactions failing to occur when either drug was given singly. PRETREATMENT DRUG RESISTANCE
Of the 822 positive cultures examined at the Tuberculosis Reference Laboratory 3-4% showed resistant organisms: 2% were resistant to streptomycin, 1 % to isoniazid, and 0-4 % to both streptomycin and isoniazid. There were no organisms resistant to rifampicin or ethambutol.
Discussion aim of the study was to compare different durations of chemotherapy, and two major comparisons were incorporated into the design-a comparison of six months and twelve months chemotherapy for patients with little or no cavitation, and a comparison of nine months and eighteen months chemotherapy for patients who had any cavity greater than 2 cm. in diameter. The chemotherapy used for all four groups was rifampicin plus isoniazid, supple mented for the first eight weeks by a third drug, either streptomycin or ethambutol. The
primary
Among was
174
patients in the six months group there chemotherapy, and there were 5
1 failure of
in the first year after the end of treatment. In contrast, there was no failure of chemotherapy among 177 patients in the twelve months group and there were no relapses in the six months after the end of treatment. These results are in line with those of other studies. The East Africa/British Medical Research Councils study," using daily streptomycin, isoniazid, and rifampicin, all for six months, yielded no failure of chemotherapy and a 3% incidence of bacteriological relapse in the 156 patients followed up for a year after the end of treatment. No further relapses occurred in the subsequent twelve months. In the study reported by Brouet Mid Roussel,15 using rifampicin plus isoniazid daily for six, nine, or twelve months, supplemented in the first three months by
relapses
streptomycin or ethambutol, no relapse occurred among 46 patients in the six months group in the first year after the end of treatment; however, 3 relapses (6-5%) occurred in the subsequent eighteen months. No relapses occurred among 49 patients treated for twelve months and followed for a further two years. In a second East African study 16 a comparison was made of the relapse-rates after six months
chemotherapy with rifampicin and isoniazid, supplemented in one group with daily streptomycin (SHR) but given without a supplement in a second group (HR): the relapse-rates in the first six months after stopping treatment were 2% for the 166 SHR patients and 5 % for the 170 HR patients. Poppe de Figueiredo et al.17 using the combination of rifampicin, isoniazid, and ethambutol daily for six months in 89 patients with sensitive organisms, found a relapserate of 3 % : all the relapses occurred in the first six months of the two-year follow-up. Considering the patients in the present study with a cavity greater than 2 cm. in diameter, no failure of chemotherapy occurred in any of 151 patients in the nine months group or in any of 155 patients in the 18 months group. No relapse has occurred in the nine months group in the nine months after the end of treatment. These results are in accord with those of Brouet and Roussel,15 who found no relapse in the nine months after the end of chemotherapy among 59 patients treated for nine months. A 3 % relapse-rate has been found among patients with little or no cavitation treated for six months and followed up for a further twelve months. However, in patients with more advanced disease, treated for nine months and followed up for a further nine months, no relapse occurred. It would appear, therefore, that six months chemotherapy with rifampicin plus isoniazid, supplemented initially by ethambutol or streptomycin, is not enough to achieve 100 % success, whereas nine months may prove sufficient both in cavitated and non-cavitated disease. At present this conclusion can only be tentative because of the limited period of follow-up. However, most studies of short-course chemotherapy have shown that the majority of relapses occur in the first six months after stopping chemotherapy, and it seems reasonable to expect few, if any, relapses in the nine-month group. These satisfactory results were obtained employing the normal prescribing practice of the attending
physician. Another aim of the study was to compare the efficacy of ethambutol and streptomycin as an initial third drug in patients under the age of sixty. Comparison of the two series of patients showed no difference in the rate of sputum conversion, whatever the extent of cavitation, and a similar relapse-rate in the EHR6 and the SHR6 groups (3% v. 1-5%). No toxic reaction to ethambutol was reported whereas 8 % of the 298 patients in the streptomycin series experienced adverse effects which led the physician to discontinue streptomycin and to substitute ethambutol. The rifampicin/isoniazid regimen was associated with a low incidence of toxicity. Although 1-75% of the patients developed abnormal liver-function tests and were withdrawn from the study on this account, recent publications 18,19 have emphasised that disordered liver function at a purely biochemical level is unlikely to be of significance and that the raised transaminase and bilirubin levels tend to return to normal even though rifampicin is continued. It is likely that, in the light of this new knowledge, fewer patients would have had their rifampicin discontinued.
124
LEUKÆMIA AND LYMPHOMA PATIENTS INTERLINKED BY PRIOR SOCIAL CONTACT *
As in previous studies 5,9 some patients continue to produce sputum which is positive on smear but negative on culture, both during and after chemotherapy. Such results have been held to signify non-viable bacilli and to be of no clinical importance. This finding in the last three months of chemotherapy was not taken to indicate a failure of chemotherapy : however, 1 of the 12 patients in the six months group who had shown this feature did relapse. He had also produced a single positive culture in the last three months of chemotherapy. Isolated positive cultures occurred after the cessation of chemotherapy, as in other studies,5,9 but the frequency of bacteriological examination in the present study has allowed differentiation from true bacteriological relapse. In only 1 patient was chemotherapy restarted by the physician on the basis of an isolated positive culture. The appearance of this positive culture was not supported by any radiological or clinical deterioration and two subsequent sputum cultures produced before the reinstitution of chemo-
negative: this patient has not been having relapsed. The 5 patients who relapsed after stopping treatment at six months did so with organisms sensitive to streptomycin, isoniazid, rifampicin, and ethambutol, suggesting that the duration of chemotherapy had been inadequate to kill off all sensitive bacilli.5 2 were thought not to have taken their full course of chemotherapy. All 5 have responded to reintroduction of chemotherapy. therapy regarded
REFERENCES
2. 3. 4.
5. 6. 7. 8.
Ross, J. D., Horne, N. W., Grant, I. W. B., Crofton, J. W. Br. med. J. 1958, i, 237. Ross, J. D. Bull. Un. int. Tuberc. 1959, 29, 710. Crofton, J. W. Br. med. J. 1960, ii, 679. Pearce, S. J., Horne, N. W. Lancet, 1974, ii, 641. Report to the Medical Research Council by their Tuberculosis Chemotherapy Trials Committee. Tubercle, 1962, 43, 201. Pande, B. R., Martischnig, K. M., Feinmann, L. ibid. 1970, 51, 39. Lal, S. ibid. 1969, 50, 269. East African/British Medical Research Councils. Lancet, 1972, i,
1079. 9. East African/British Medical Research Councils. ibid. 1973, i, 1331. 10. East African/British Medical Research Councils. ibid. 1974, ii, 237. 11. Marks, J. Publ. Hlth Serv. Monogr. Ser. no. 5; laboratory methods, I, 14. H.M. Stationery Office, 1974. 12. Leat, J. L., Marks, J. Tubercle, 1970, 51, 68. 13. Tuberculosis Chemotherapy Centre, Madras. Bull. Wld Hlth Org.
1960, 23, 535. 14. Simon, G. Br. med. J. 1966, ii, 491. 15. Brouet, G., Roussel, G. in XVII Congres national de la tuberculose et des maladies respiratoires; p. 27. Paris 1974. 16. East African/British Medical Research Councils. Lancet, 1974, ii, 1100. 17. Poppe de
either leukæmia or asked if they had close personal associations with other patients before the onset of disease. Initial interviews indicated that several patients could be interlinked into social clusters. Tumour-registry records were used to contact each patient (or a surviving relative) diagnosed during the years 1964-73 in three areas of West Virginia. Close personal associations, antedating the onset of disease in 1 or both individuals of each linkage pair, were detected in 14 of 23 (61%), 14 of 22 (68%), and 6 of 8 (75%) patients from these three areas during this In addition, among 28 randomly ten-year period. selected patients with Hodgkin’s disease from various parts of the United States, 10 (36%) had direct or indirect close personal associations with 17 other patients with leukæmia or lymphoma. Patients with leukæmia or lymphoma frequently are interlinked by prior close personal associations to other patients with these diseases.
Summary
as
Requests for reprints should be addressed to Dr I. A. Campbell, Department of Respiratory Diseases, City Hospital, Edinburgh EH10 5SB.
1.
Section of Medical Oncology, Baltimore Cancer Research Center, National Cancer Institute, University of Maryland Hospital, Baltimore, Maryland 21201, U.S.A.
were
The Research Committee of the British Thoracic and Tuberculosis Association acknowledges with gratitude the cooperation of the many participating physicians and hospital staff in England, Scotland, Wales, and Ireland; CIBA Laboratories and Lepetit Pharmaceuticals for financial support ; and Mrs C. P. Davison, Mrs P. Hindshaw, Mrs F. Hoare, and Mrs L. Hunt for their assistance.
Figueiredo, F., Brito, A. A., Valle, J. H. L., Tavares, P. M., Trannin, P. L. Proc. XXIInd Tuberc. Conf. 1973. (In the press.) 18. Lal, S., Singhal, S. N., Burley, D. M., Crossley, G. Br. med. J. 1972, i, 148. 19. Baron, D. N., Bell, J. L. Tubercle, 1974, 55, 115.
CAROL R. SCHIMPFF PETER H. WIERNIK
STEPHEN C. SCHIMPFF DORAH M. BRAGER
Patients
with
lymphoma
were
Introduction THERE is increasing interest in the possibility of person-to-person transmission of leukarmias or lymphomas in a manner similar to that shown for fowl and cats.1-3 Most human studies have concentrated on one disease entity such as Hodgkin’s disease or acute lymphocytic leukaemia.H2 For example, Vianna’s group 4,5 has linked together 31 patients with Hodgkin’s disease on the basis of prior personal associations, and Kemmoonahas found 5 patients with acute lymphocytic leukaemia and another with lymphosarcoma who could be interlinked through their social contacts. Our investigations of Hodgkin’s disease in one area and leukaemia in another resulted in the detection of large numbers of socially interlinked patients. In these and other areas, however, multiple social linkages found among patients with all forms of leukxmia and lymphoma rather than with only a single These findings indicate that many tumour type. individuals with either leuksemia or lymphoma can be interlinked into social clusters based on prior personal associations. were
Methods Three separate areas of West Virginia were studied. In each area, patients with leukaemia or lymphoma from the Baltimore Cancer Research Center had reported knowledge of one or more close personal friends with leukaemia or lymphoma living near their homes. The West Virginia *
Based on a paper presented at the Fourteenth Interscience Conference on Antimicrobial Agents and Chemotherapy, held in San Francisco in September, 1974.
