Tubercle
A TUBERCULOSIS
TREATMENT RESULTS
SURVEY
57 (1976),
131-I
IN SINGAPORE:
AT FIVE-YEARS C. H. Chew
Tan Tack Seng Hospital. Singapore
I I
Summary A National Tuberculosis Treatment Survey was instituted in the Republic of Singapore in 1969 with the aim of evaluating the Tuberculosis Treatment Services in Singapore. This five-year follow-up study of the 1969 survey was based on the assessment of the first 1000 consecutive patients who were registered for treatment during the year. Two hundred and forty-six cases were excluded for various reasons, leaving 754 cases for analysis. At the end of 5 years, only 2 (0.3 %) were culture positive, 677 (89.8 %) were culture negative, 48 cases (6.4 %) had died from tuberculosis and 27 cases (3.6 %) were lost. The most notable factor which influenced bacteriological positivity was lack of co-operation leading to interruption of chemotherapy. It is concluded that with an efficient organisation highly satisfactory results can be achieved by routine treatment services and prolonged observation of adequately treated patients is not necessary. RBsum6 Une enquete nationale sur le traitement de la tuberculose a 6th entreprise en 1969 dans la Republique de Singapour dans le but d’evaluer les Services de Traitement de la Tuberculose. Cette etude Porte sur I’observation pendant cinq ans des donnees de I’enquete de 1969 et repose sur I’btude des 1000 premiers malades enregistres pour traitement au tours de cette premiere an&e. Deux cent quarante six cas ont ete exclus pour diverses raisons, laissant 754 sujets pour I’analyse. Au bout de 5 ans, 2 sujets (soit 0,3 %) etaient positifs a la culture, 48 (soit 6,4 %) Btaient morts de tuberculose et 27 (3,6 %) etaient perdus de vue. Le facteur le plus important a noter dont la presence a eu une influence sur le maintien de la positivite bacteriologique a ete le manque de cooperation conduisant a I’interruption de la chimiotherapie. L’auteur conclut qu’une organisation efficiente permet aux services de traitement de routine d’obtenir des resultats hautement satisfaisants et I’observation prolongde des malades qui ont recu un traitement correct n’est pas necessaire. Resumen En la Republica de Singapur se instituyo una Encuesta National de Tratamiento de Tuberculosis en 1969 con el objetivo de evaluar 10s Servicios de Tratamiento de la Tuberculosis de Singapur. El seguimiento durante 5 adios de la encuesta de 1969 se basd en la evolution de 10s primeros 1 .OOOpacientes registrados para su tratamiento durante el aiio. Se excluyeron 246 case por diversas razones, y quedaron 754 para analizar. Al cabo de 10s 5 aAos solo 2 (0,3 %) tenian cultivos positivos, 677 (89,8 %) tenian cultivos negativos, 48 cases (6,4 %) habian muerto por tuberculosis y 27
36
132
Chew cases (3,6 %) se perdieron. El factor m&s importante que influyo en la bacteriologia positiva fue la falta de cooperacidn que llevo a la interruption de la quimioterapia. Se concluye que con una organization eficiente pueden alcanzarse resultados muy satisfactorios con 10s tratamientos de rutina, y que la observation prolongada de 10s pacientes bien tratados no es necesaria. Introduction
Singapore is an island republic situated at the southern tip of the Malay peninsula, about 137 km north of the equator. It has a land area of approximately 586 km2 and its population in 1969 was approximately 2 million. This relatively high population density is particularly suitable for mass control health and treatment programmes. Resources for treatment are good and the estimated prevalence of active tuberculosis is approximately 0.5 %. In 1969, a prospective National Tuberculosis Treatment Survey was instituted with the aim of evaluating the country’s tuberculosis treatment services. Thus from 1 January to 31 December 1969, a common system of documentation and a standardized procedure for bacteriological and radiological examinations were introduced. The number of patients registered for treatment for the year approximated very closely to the number of patients notified (Tuberculosis Control Unit, Ministry of Health, Singapore, 1969). The findings of the one-year and two-year follow-up of this national treatment evaluation have been reported (Chew, 1972; 1974) and it was shown that highly satisfactory results could be achieved by the routine treatment services. The purpose of this paper is to ascertain : whether the good results obtained at the end of one year and two years from registration could be maintained at the end of five years; whether prolonged follow-up of adequately treated patients was necessary; and to identify factors which might have influenced bacteriological failures, deaths due to tuberculosis and losses from the treatment services by studying the case records of the first 1000 consecutive patients registered for treatment in 1969. Material and Methods These have been dealt with in detail in previous communications (Chew, 1972; 1974). Briefly, identification details, extent of disease and any history of prior antituberculosis chemotherapy were recorded. Two sputum specimens were collected in consecutive clinic days before commencement of treatment, at one year and at two years after registration. For this study two specimens were collected five years after registration. These specimens were subjected to smear and culture examinations, and if tubercle bacilli were isolated, susceptibility to streptomycin, PAS and isoniazid was assessed. Niacin test was also carried out. The initial PA chest radiographs were assessed for extent of disease (National Tuberculosis 8 Respiratory Diseases Association, 1969) and for extent of cavitation (Veterans Administration, 1958). A procedure for retrieving defaulting patients was also formalized : all defaulting patients who did not respond to letters were home visited approximately one week after a missed attendance. Details of all deaths were obtained from the Registrar of Deaths. In all other respects the treatment services operated in the routine way. Chemotherapy The vast majority of patients ‘standard’ in 1969 : 1 Daily isoniazid
received the following
(300 mg) plus PAS (10 g) ;
regimens which
were considered
as
Tuberculosis 2 streptomycin (1 g) plus high dosage of isoniazid supervision twice a week.
Treatment in Singapore
(15 mg/kg)
administered
133
under full
Both these regimens followed an initial intensive phase of 12 weeks of daily streptomycin (1 g). PAS (10 g) and isoniazid (300 mg). The total duration of chemotherapy was between 18 months to 2 years. Treatment was administered mostly on an ambulatory basis. Thiacetazone-containing regimens were not used, as it has been found that this drug was unduly toxic for Singaporeans of all races (Singapore Tuberculosis Services/Brompton Hospital/ British Medical Research Council Investigation, 1971). For failure patients with drug resistant cultures to primary drugs, ‘reserve’ drugs which included ethambutol and rifampicin among others were used in combination and the regimens were left to the discretion of the patients’ physicians. This small group of patients received chemotherapy for at least two years. Initial population
Details of the entire initial population of the survey are shown in Table I. A total of 3422 patients were registered for anti-tuberculosis treatment during the year. The population is sub-divided according to results of smear examinations, culture examinations, the niacin test and history of prior treatment. Thus, 1176 of those assessed were smear positive (34.6 %), 1713 had a positive culture (51 %) and excluding those yielding only niacin-negative strains and those with no niacin test results, there remained 1631 culture-positive cases including 121 with a history of prior treatment exceeding one month’s duration and 1510 with no such history. Table I. ----__
Initial population
(Chew, 1972; 1974)
Smear examination
Culture examination
Niacin test result
History of prior treatment
Total assessed Negative Positive Not assessed Total -~--
3399 2223 1176 23 3422
3356 1643 1713 43 3399
1677 46 1631 36 1713
1631 1510 121 0 1631
Culture-positive
cases
Results
Although the number of culture-positive cases corresponded to a case rate of 85 per 100 000 of the estimated mid-year population of 1969, the overall rate observed in males (121) was over twice that of females (47) and the highest rate of all was in males over the age of 40 (Table rl). Table II. -.__
Culture-positive
Age group (in years)
cases by sex and age (Chew, 1972; 1974)
Culture-positive cases
Culture-positive
cases /
100,000popolation
Total
Male
Female
Total
Male
Female
1713 175 536 1002
1256 103 355 798
457 72 181 204
85 16 100 237
121 19 128 356
47 14 69 103
--Total Less than 20 20 to 39 40 or more
134
Chew
Method of assessment at five years The assessment of the five-year status was principally made in bacteriological terms consisting of culture examinations of patients who were available for the examination from the first 1000 consecutive cases registered for treatment in 1969 (29 % of the initial population). In the analysis, particular attention was also given to prognostic factors which might have influenced bacteriological failures and deaths due to tuberculosis such as extent of disease, presence or absence of cavitation, irregularity and interruption of chemotherapy, diabetes mellitus, corticosteroid therapy or alcoholism. Reasons for non-attendance of patients for their 5 year examination were analysed. Results Two hundred and forty-six patients were excluded from the five-year assessment: 116 died from non-tuberculous causes (14 from bronchial carcinoma), 67 migrated (42 after completing treatment), 37 failed to yield the requisite sputum specimens and 26 were transferred to other treatment agencies ; thus leaving 754 cases for assessment. The results of this treatment survey five years after registration were as follows. Of the 754 cases available for assessment, it is gratifying to note that only 2 cases (0.3 %) were culture positive and 677 (89.8 %) were culture negative. Forty-eight (6.4 %) died from tuberculosis, although the great majority of deaths occurred shortly after the detection of the disease, and only 4 (0.5 %) died after the second year of registration. Twenty-seven (3.6 %) were considered as lost. Of the two culture-positive cases, one patient with initial moderately advanced disease with cavitation admitted to stopping regular oral chemotherapy (PAS and isoniazid) after 8 months and he relapsed with drug-sensitive cultures to streptomycin and isoniazid. He has since been commenced on fully supervised chemotherapy and has converted. The second patient admitted to repeated interruptions of chemotherapy as his occupation required his frequent visits to other countries. His cultures were resistant to streptomycin, PAS and isoniazid and he is being persuaded to go on a reserve regimen. Both were not diabetics and were not on corticosteroid therapy. With regard to the 4 who died after the second year of registration, all were males over the age of 45, all had far advanced disease with multiple cavitation and death occurred between the 25th and 37th month of registration. Three were unto-operative and had frequent interruptions of treatment as a result of irregularity of attendance. One had a history of prior unsatisfactory treatment for several months before registration and the cultures were resistant to isoniazid, streptomycin and PAS. This patient also had diabetes mellitus, which was complicated by nephropathy and hypertensive heart disease. None were on corticosteroid therapy. With regard to losses from the treatment services, 9 could not be located because they had left no forwarding addresses and 18 refused to attend further follow-up examinations despite repeated home visits as they felt quite well and had no symptoms. A further analysis of their records showed that they had negative sputum examinations and had radiologically inactive disease on their last attendances. Discussion Too little is known about the results of treatment in ordinary clinical practice as opposed to controlled trials (Leading Article, 1971). The most significant and gratifying finding of this tuberculosis treatment survey under routine conditions 5 years after the registration of patients is the bacteriological culture status of the cases that were analysed; only 2 of 754 patients
Tuberculosis
Treatment in Singapore
135
(0.3 %) were found to have positive cultures and the great majority were culture-negative (89.8 %). By comparison, at the end of one year and two years, 3 % and 2 % were culture positive and 88 % and 82 % were culture negative respectively (Chew, 1972 ; 1974). Of the two bacteriological failures one had sensitive cultures and the other resistant. Both had had major interruption of chemotherapy. Neither were diabetics, alcoholics or had received corticosteroid therapy. The percentages of deaths due to tuberculosis were 4 % and 6 % at one year and two years respectively (Chew, 1972; 1974). Throughout the 5 years of follow-up, 48 cases (6.4%) died from tuberculosis and only 4 died after the second year (0.5 %), thus emphasizing the fact that the majority of deaths due to the disease occurred during the first year of follow-up; indeed, most of them shortly after the detection of the disease. It is well known that desperately ill patients may die before even the best chemotherapeutic regimens can have an effect; thus underlining the importance for earlier detection of such cases (Chew, 1974; Fox and Mitchson, 1975). Of the four cases who died, all were over the age of 45 and had multiple cavitation. In addition three were unto-operative while the other had diabetic nephropathy and hypertensive heart disease. All had electrocardiographic evidence of right ventricular hypertrophy and indeed it was surprising that death had not occurred earlier in these cases. It is interesting to note, in passing, that of the 116 non-tuberculous deaths, 14 (12 %) were due to bronchogenie carcinoma. The high incidence of bronchogenic carcinoma in tuberculosis has been noted previously (Springett, 1971 ; Pearce & Horne, 1974; Ong and others, 1975). Twenty-seven patients (3.6 %) were considered as lost at the end of 5 years of registration. Two-thirds of this group refused further follow-up in spite of repeated home visits; they were in good health and were attending their own general practitioners or their firms’ medical services for follow-up. The others had moved without informing the registry of their change of address. It has been shown that if cases were precisely documented, such losses should be rare (Chew, 1972). A review of the records of all these cases showed that they had radiologically inactive disease when last seen and had negative sputum examinations. It is unlikely that any in this small group of patients has relapsed without the knowledge of the tuberculosis services if they remained in Singapore. Tuberculosis is a disease which is well known for its relapsing nature and prolonged follow-up of treated patients, sometimes even for life, has in the past been commonly advocated in some countries. However, the results of this prospective survey clearly show that prolonged follow-up of adequately treated patients is not necessary. Further, in agreement with Pearce and Horne (1974) who studied 825 patients in Edinburgh, it is considered that each patient requiring continued observation should be assessed individually. As has been found in this study, the only important factor which justifies continued supervision is lack of co-operation of the patient. This policy would lessen the demands on the health services (Edsall and Collins, 1973), which is of outstanding importance for developing countries with poor economic resources (Ramakrishnan and others, 1969). It can thus be concluded that the results of this prospective survey not only confirm the observations in previous reports (Chew, 1972, 1974) but more importantly support the findings of other prospective and retrospective studies (Ramakrishnan and others, 1969; Stead and Jurgens, 1973; Pearce and Horne, 1974; British Thoracic and Tuberculosis Association Joint Tuberculosis Report, 1975; Poh and Chew, 1975) that, with an efficient treatment organization, good and inexpensive regimens and good patient co-operation, gratifying results can be achieved by routine treatment services, even in developing countries, the number of relapses is negligible and prolonged observation of adequately treated patients is not necessary.
136
Chew
Acknowledgements This survey is a project of the Tuberculosis Research Committee of the Ministry of Health, Singapore. I wish to thank my colleagues in the Committee and the staff of Tan Tack Seng Hospital for their assistance in the preparation of this report. I am particularly grateful to Dr D. M. Macfadyen and Dr W. Chan for their help in analyzing the one-year and the twoyear results respectively. References British Thoracic and Tuberculosis Association Joint Tuberculosis Committee Report (1975). An assessment of the need for follow-up of patients with pulmonary tuberculosis adequately treated by chemotherapy. British Medica/Joorna/, 2,28. Chew, C. H. (1972). A national treatment survey in Singapore. Bulletin of the International Union Against Tuberculosis, 47,94. Chew, C. H. (1974). A national treatment survey in Singapore-A two year follow-up. Bulletin of the lnternationai Union Against Tuberculosis, 46, Supplement 1,236. Edsall, J., 8 Collins, G. (1973). Routine follow-up of inactive tuberculosis, a practice to be abandoned. American Review of Respiratory Disease, 107,851. Fox, W., & Mitchison, D. A. (1975). Short course-chemotherapy for pulmonary tuberculosis. American Review of Respiratory Disease, 111,326. Leading Article (1971). The Twenty-first International Tuberculosis Conference. Tubercle, 52, 242. National Tuberculosis and Respiratory Disease Association (1969). Diagnostic Standard and Classification of Tuberculosis, New York. Ong, Y. Y., Nadarajah, K. 8 Chew, C. H. (1975). A study of primary lung cancer in Singapore. Anna/s of the Academy of Medicine, Singapore, 4. 386. Pearce, S. J., 8 Horne, N. W. (1974). Follow-up of patients with pulmonary tuberculosis adequately treated by chemotherapy: is this really necessary? Lancer, 2,641. Singapore Medical Poh, S. C., Et Chew, S. E. (1975). Routine follow-up of patients with treated pulmonary tuberculosis. Journal, 16,200. Ramakrishnan, C. V., Devadatta, S., Evans, C., Fox, W., Menon, N. K., Nazareth, 0.. Radakrishna, S., Sambamoorthy, S., Stott, H., Tripathy, S. P., & Velu, S. (1969). A four-year follow-up of patients with quiescent pulmonary tuberculosis at the end of a year of chemotherapy with twice-weekly isoniazid plus streptomycin or daily isoniazid plus PAS. Tubercfe, 60,115. Singapore Tuberculosis Services/Brompton Hospital/British Medical Research Council Investigation (1971). A controlled clinical trial of the role of thiacetazone-containing regimens in the treatment of pulmonary tuberculosis in Singapore. Tobercfe, 52,88. Springett, V. H. (1971). Ten-year results during the introduction of chemotherapy for tuberculosis. Tubercle, 62,73. Stead, W. W. Et Jurgens, G. H. (1973). Productivity of prolonged follow-up after chemotherapy for tuberculosis, American Review of Respiratory Disease, 106.314. Tuberculosis Control Unit, Ministry of Health, Singapore (1969). Annual Report. Veterans Administration (1958). Protocols for the chemotherapy of tuberculosis, p. 481, Transactions of the 17th Conference on the Chemotherapy of Tuberculosis, Washington.
A TUBERCULOSIS
TREATMENT RESULTS
SURVEY
57 (1976),
131-I
IN SINGAPORE:
AT FIVE-YEARS C. H. Chew
Tan Tack Seng Hospital. Singapore
I I
Summary A National Tuberculosis Treatment Survey was instituted in the Republic of Singapore in 1969 with the aim of evaluating the Tuberculosis Treatment Services in Singapore. This five-year follow-up study of the 1969 survey was based on the assessment of the first 1000 consecutive patients who were registered for treatment during the year. Two hundred and forty-six cases were excluded for various reasons, leaving 754 cases for analysis. At the end of 5 years, only 2 (0.3 %) were culture positive, 677 (89.8 %) were culture negative, 48 cases (6.4 %) had died from tuberculosis and 27 cases (3.6 %) were lost. The most notable factor which influenced bacteriological positivity was lack of co-operation leading to interruption of chemotherapy. It is concluded that with an efficient organisation highly satisfactory results can be achieved by routine treatment services and prolonged observation of adequately treated patients is not necessary. RBsum6 Une enquete nationale sur le traitement de la tuberculose a 6th entreprise en 1969 dans la Republique de Singapour dans le but d’evaluer les Services de Traitement de la Tuberculose. Cette etude Porte sur I’observation pendant cinq ans des donnees de I’enquete de 1969 et repose sur I’btude des 1000 premiers malades enregistres pour traitement au tours de cette premiere an&e. Deux cent quarante six cas ont ete exclus pour diverses raisons, laissant 754 sujets pour I’analyse. Au bout de 5 ans, 2 sujets (soit 0,3 %) etaient positifs a la culture, 48 (soit 6,4 %) Btaient morts de tuberculose et 27 (3,6 %) etaient perdus de vue. Le facteur le plus important a noter dont la presence a eu une influence sur le maintien de la positivite bacteriologique a ete le manque de cooperation conduisant a I’interruption de la chimiotherapie. L’auteur conclut qu’une organisation efficiente permet aux services de traitement de routine d’obtenir des resultats hautement satisfaisants et I’observation prolongde des malades qui ont recu un traitement correct n’est pas necessaire. Resumen En la Republica de Singapur se instituyo una Encuesta National de Tratamiento de Tuberculosis en 1969 con el objetivo de evaluar 10s Servicios de Tratamiento de la Tuberculosis de Singapur. El seguimiento durante 5 adios de la encuesta de 1969 se basd en la evolution de 10s primeros 1 .OOOpacientes registrados para su tratamiento durante el aiio. Se excluyeron 246 case por diversas razones, y quedaron 754 para analizar. Al cabo de 10s 5 aAos solo 2 (0,3 %) tenian cultivos positivos, 677 (89,8 %) tenian cultivos negativos, 48 cases (6,4 %) habian muerto por tuberculosis y 27
36
132
Chew cases (3,6 %) se perdieron. El factor m&s importante que influyo en la bacteriologia positiva fue la falta de cooperacidn que llevo a la interruption de la quimioterapia. Se concluye que con una organization eficiente pueden alcanzarse resultados muy satisfactorios con 10s tratamientos de rutina, y que la observation prolongada de 10s pacientes bien tratados no es necesaria. Introduction
Singapore is an island republic situated at the southern tip of the Malay peninsula, about 137 km north of the equator. It has a land area of approximately 586 km2 and its population in 1969 was approximately 2 million. This relatively high population density is particularly suitable for mass control health and treatment programmes. Resources for treatment are good and the estimated prevalence of active tuberculosis is approximately 0.5 %. In 1969, a prospective National Tuberculosis Treatment Survey was instituted with the aim of evaluating the country’s tuberculosis treatment services. Thus from 1 January to 31 December 1969, a common system of documentation and a standardized procedure for bacteriological and radiological examinations were introduced. The number of patients registered for treatment for the year approximated very closely to the number of patients notified (Tuberculosis Control Unit, Ministry of Health, Singapore, 1969). The findings of the one-year and two-year follow-up of this national treatment evaluation have been reported (Chew, 1972; 1974) and it was shown that highly satisfactory results could be achieved by the routine treatment services. The purpose of this paper is to ascertain : whether the good results obtained at the end of one year and two years from registration could be maintained at the end of five years; whether prolonged follow-up of adequately treated patients was necessary; and to identify factors which might have influenced bacteriological failures, deaths due to tuberculosis and losses from the treatment services by studying the case records of the first 1000 consecutive patients registered for treatment in 1969. Material and Methods These have been dealt with in detail in previous communications (Chew, 1972; 1974). Briefly, identification details, extent of disease and any history of prior antituberculosis chemotherapy were recorded. Two sputum specimens were collected in consecutive clinic days before commencement of treatment, at one year and at two years after registration. For this study two specimens were collected five years after registration. These specimens were subjected to smear and culture examinations, and if tubercle bacilli were isolated, susceptibility to streptomycin, PAS and isoniazid was assessed. Niacin test was also carried out. The initial PA chest radiographs were assessed for extent of disease (National Tuberculosis 8 Respiratory Diseases Association, 1969) and for extent of cavitation (Veterans Administration, 1958). A procedure for retrieving defaulting patients was also formalized : all defaulting patients who did not respond to letters were home visited approximately one week after a missed attendance. Details of all deaths were obtained from the Registrar of Deaths. In all other respects the treatment services operated in the routine way. Chemotherapy The vast majority of patients ‘standard’ in 1969 : 1 Daily isoniazid
received the following
(300 mg) plus PAS (10 g) ;
regimens which
were considered
as
Tuberculosis 2 streptomycin (1 g) plus high dosage of isoniazid supervision twice a week.
Treatment in Singapore
(15 mg/kg)
administered
133
under full
Both these regimens followed an initial intensive phase of 12 weeks of daily streptomycin (1 g). PAS (10 g) and isoniazid (300 mg). The total duration of chemotherapy was between 18 months to 2 years. Treatment was administered mostly on an ambulatory basis. Thiacetazone-containing regimens were not used, as it has been found that this drug was unduly toxic for Singaporeans of all races (Singapore Tuberculosis Services/Brompton Hospital/ British Medical Research Council Investigation, 1971). For failure patients with drug resistant cultures to primary drugs, ‘reserve’ drugs which included ethambutol and rifampicin among others were used in combination and the regimens were left to the discretion of the patients’ physicians. This small group of patients received chemotherapy for at least two years. Initial population
Details of the entire initial population of the survey are shown in Table I. A total of 3422 patients were registered for anti-tuberculosis treatment during the year. The population is sub-divided according to results of smear examinations, culture examinations, the niacin test and history of prior treatment. Thus, 1176 of those assessed were smear positive (34.6 %), 1713 had a positive culture (51 %) and excluding those yielding only niacin-negative strains and those with no niacin test results, there remained 1631 culture-positive cases including 121 with a history of prior treatment exceeding one month’s duration and 1510 with no such history. Table I. ----__
Initial population
(Chew, 1972; 1974)
Smear examination
Culture examination
Niacin test result
History of prior treatment
Total assessed Negative Positive Not assessed Total -~--
3399 2223 1176 23 3422
3356 1643 1713 43 3399
1677 46 1631 36 1713
1631 1510 121 0 1631
Culture-positive
cases
Results
Although the number of culture-positive cases corresponded to a case rate of 85 per 100 000 of the estimated mid-year population of 1969, the overall rate observed in males (121) was over twice that of females (47) and the highest rate of all was in males over the age of 40 (Table rl). Table II. -.__
Culture-positive
Age group (in years)
cases by sex and age (Chew, 1972; 1974)
Culture-positive cases
Culture-positive
cases /
100,000popolation
Total
Male
Female
Total
Male
Female
1713 175 536 1002
1256 103 355 798
457 72 181 204
85 16 100 237
121 19 128 356
47 14 69 103
--Total Less than 20 20 to 39 40 or more
134
Chew
Method of assessment at five years The assessment of the five-year status was principally made in bacteriological terms consisting of culture examinations of patients who were available for the examination from the first 1000 consecutive cases registered for treatment in 1969 (29 % of the initial population). In the analysis, particular attention was also given to prognostic factors which might have influenced bacteriological failures and deaths due to tuberculosis such as extent of disease, presence or absence of cavitation, irregularity and interruption of chemotherapy, diabetes mellitus, corticosteroid therapy or alcoholism. Reasons for non-attendance of patients for their 5 year examination were analysed. Results Two hundred and forty-six patients were excluded from the five-year assessment: 116 died from non-tuberculous causes (14 from bronchial carcinoma), 67 migrated (42 after completing treatment), 37 failed to yield the requisite sputum specimens and 26 were transferred to other treatment agencies ; thus leaving 754 cases for assessment. The results of this treatment survey five years after registration were as follows. Of the 754 cases available for assessment, it is gratifying to note that only 2 cases (0.3 %) were culture positive and 677 (89.8 %) were culture negative. Forty-eight (6.4 %) died from tuberculosis, although the great majority of deaths occurred shortly after the detection of the disease, and only 4 (0.5 %) died after the second year of registration. Twenty-seven (3.6 %) were considered as lost. Of the two culture-positive cases, one patient with initial moderately advanced disease with cavitation admitted to stopping regular oral chemotherapy (PAS and isoniazid) after 8 months and he relapsed with drug-sensitive cultures to streptomycin and isoniazid. He has since been commenced on fully supervised chemotherapy and has converted. The second patient admitted to repeated interruptions of chemotherapy as his occupation required his frequent visits to other countries. His cultures were resistant to streptomycin, PAS and isoniazid and he is being persuaded to go on a reserve regimen. Both were not diabetics and were not on corticosteroid therapy. With regard to the 4 who died after the second year of registration, all were males over the age of 45, all had far advanced disease with multiple cavitation and death occurred between the 25th and 37th month of registration. Three were unto-operative and had frequent interruptions of treatment as a result of irregularity of attendance. One had a history of prior unsatisfactory treatment for several months before registration and the cultures were resistant to isoniazid, streptomycin and PAS. This patient also had diabetes mellitus, which was complicated by nephropathy and hypertensive heart disease. None were on corticosteroid therapy. With regard to losses from the treatment services, 9 could not be located because they had left no forwarding addresses and 18 refused to attend further follow-up examinations despite repeated home visits as they felt quite well and had no symptoms. A further analysis of their records showed that they had negative sputum examinations and had radiologically inactive disease on their last attendances. Discussion Too little is known about the results of treatment in ordinary clinical practice as opposed to controlled trials (Leading Article, 1971). The most significant and gratifying finding of this tuberculosis treatment survey under routine conditions 5 years after the registration of patients is the bacteriological culture status of the cases that were analysed; only 2 of 754 patients
Tuberculosis
Treatment in Singapore
135
(0.3 %) were found to have positive cultures and the great majority were culture-negative (89.8 %). By comparison, at the end of one year and two years, 3 % and 2 % were culture positive and 88 % and 82 % were culture negative respectively (Chew, 1972 ; 1974). Of the two bacteriological failures one had sensitive cultures and the other resistant. Both had had major interruption of chemotherapy. Neither were diabetics, alcoholics or had received corticosteroid therapy. The percentages of deaths due to tuberculosis were 4 % and 6 % at one year and two years respectively (Chew, 1972; 1974). Throughout the 5 years of follow-up, 48 cases (6.4%) died from tuberculosis and only 4 died after the second year (0.5 %), thus emphasizing the fact that the majority of deaths due to the disease occurred during the first year of follow-up; indeed, most of them shortly after the detection of the disease. It is well known that desperately ill patients may die before even the best chemotherapeutic regimens can have an effect; thus underlining the importance for earlier detection of such cases (Chew, 1974; Fox and Mitchson, 1975). Of the four cases who died, all were over the age of 45 and had multiple cavitation. In addition three were unto-operative while the other had diabetic nephropathy and hypertensive heart disease. All had electrocardiographic evidence of right ventricular hypertrophy and indeed it was surprising that death had not occurred earlier in these cases. It is interesting to note, in passing, that of the 116 non-tuberculous deaths, 14 (12 %) were due to bronchogenie carcinoma. The high incidence of bronchogenic carcinoma in tuberculosis has been noted previously (Springett, 1971 ; Pearce & Horne, 1974; Ong and others, 1975). Twenty-seven patients (3.6 %) were considered as lost at the end of 5 years of registration. Two-thirds of this group refused further follow-up in spite of repeated home visits; they were in good health and were attending their own general practitioners or their firms’ medical services for follow-up. The others had moved without informing the registry of their change of address. It has been shown that if cases were precisely documented, such losses should be rare (Chew, 1972). A review of the records of all these cases showed that they had radiologically inactive disease when last seen and had negative sputum examinations. It is unlikely that any in this small group of patients has relapsed without the knowledge of the tuberculosis services if they remained in Singapore. Tuberculosis is a disease which is well known for its relapsing nature and prolonged follow-up of treated patients, sometimes even for life, has in the past been commonly advocated in some countries. However, the results of this prospective survey clearly show that prolonged follow-up of adequately treated patients is not necessary. Further, in agreement with Pearce and Horne (1974) who studied 825 patients in Edinburgh, it is considered that each patient requiring continued observation should be assessed individually. As has been found in this study, the only important factor which justifies continued supervision is lack of co-operation of the patient. This policy would lessen the demands on the health services (Edsall and Collins, 1973), which is of outstanding importance for developing countries with poor economic resources (Ramakrishnan and others, 1969). It can thus be concluded that the results of this prospective survey not only confirm the observations in previous reports (Chew, 1972, 1974) but more importantly support the findings of other prospective and retrospective studies (Ramakrishnan and others, 1969; Stead and Jurgens, 1973; Pearce and Horne, 1974; British Thoracic and Tuberculosis Association Joint Tuberculosis Report, 1975; Poh and Chew, 1975) that, with an efficient treatment organization, good and inexpensive regimens and good patient co-operation, gratifying results can be achieved by routine treatment services, even in developing countries, the number of relapses is negligible and prolonged observation of adequately treated patients is not necessary.
136
Chew
Acknowledgements This survey is a project of the Tuberculosis Research Committee of the Ministry of Health, Singapore. I wish to thank my colleagues in the Committee and the staff of Tan Tack Seng Hospital for their assistance in the preparation of this report. I am particularly grateful to Dr D. M. Macfadyen and Dr W. Chan for their help in analyzing the one-year and the twoyear results respectively. References British Thoracic and Tuberculosis Association Joint Tuberculosis Committee Report (1975). An assessment of the need for follow-up of patients with pulmonary tuberculosis adequately treated by chemotherapy. British Medica/Joorna/, 2,28. Chew, C. H. (1972). A national treatment survey in Singapore. Bulletin of the International Union Against Tuberculosis, 47,94. Chew, C. H. (1974). A national treatment survey in Singapore-A two year follow-up. Bulletin of the lnternationai Union Against Tuberculosis, 46, Supplement 1,236. Edsall, J., 8 Collins, G. (1973). Routine follow-up of inactive tuberculosis, a practice to be abandoned. American Review of Respiratory Disease, 107,851. Fox, W., & Mitchison, D. A. (1975). Short course-chemotherapy for pulmonary tuberculosis. American Review of Respiratory Disease, 111,326. Leading Article (1971). The Twenty-first International Tuberculosis Conference. Tubercle, 52, 242. National Tuberculosis and Respiratory Disease Association (1969). Diagnostic Standard and Classification of Tuberculosis, New York. Ong, Y. Y., Nadarajah, K. 8 Chew, C. H. (1975). A study of primary lung cancer in Singapore. Anna/s of the Academy of Medicine, Singapore, 4. 386. Pearce, S. J., 8 Horne, N. W. (1974). Follow-up of patients with pulmonary tuberculosis adequately treated by chemotherapy: is this really necessary? Lancer, 2,641. Singapore Medical Poh, S. C., Et Chew, S. E. (1975). Routine follow-up of patients with treated pulmonary tuberculosis. Journal, 16,200. Ramakrishnan, C. V., Devadatta, S., Evans, C., Fox, W., Menon, N. K., Nazareth, 0.. Radakrishna, S., Sambamoorthy, S., Stott, H., Tripathy, S. P., & Velu, S. (1969). A four-year follow-up of patients with quiescent pulmonary tuberculosis at the end of a year of chemotherapy with twice-weekly isoniazid plus streptomycin or daily isoniazid plus PAS. Tubercfe, 60,115. Singapore Tuberculosis Services/Brompton Hospital/British Medical Research Council Investigation (1971). A controlled clinical trial of the role of thiacetazone-containing regimens in the treatment of pulmonary tuberculosis in Singapore. Tobercfe, 52,88. Springett, V. H. (1971). Ten-year results during the introduction of chemotherapy for tuberculosis. Tubercle, 62,73. Stead, W. W. Et Jurgens, G. H. (1973). Productivity of prolonged follow-up after chemotherapy for tuberculosis, American Review of Respiratory Disease, 106.314. Tuberculosis Control Unit, Ministry of Health, Singapore (1969). Annual Report. Veterans Administration (1958). Protocols for the chemotherapy of tuberculosis, p. 481, Transactions of the 17th Conference on the Chemotherapy of Tuberculosis, Washington.
