Treatment of lymph node tuberculosis a randomized clinical trial of two 6-month regimens

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1 Tropical Medicine and International Health doi: /j x volume 10 no 11 pp november 2005 Treatment of lymph node tuberculosis a randomized clinical trial of two 6-month regimens M. S. Jawahar 1, K. Rajaram 2, S. Sivasubramanian 1, C. N. Paramasivan 1, K. Chandrasekar 2, M. N. Kamaludeen 3, A. J. Thirithuvathas 3, V. Ananthalakshmi 3 and R. Prabhakar 1 1 Tuberculosis Research Centre, Chennai, India 2 Tuberculosis Research Centre Unit, Government Rajaji Hospital, Madurai, India 3 Madurai Medical College & Government Rajaji Hospital, Madurai, India Summary objective The currently recommended treatment for lymph node tuberculosis is 6 months of rifampicin and isoniazid plus pyrazinamide for the first 2 months, given either daily or thrice weekly. The objective of this study was to assess the efficacy of a 6-month twice-weekly regimen and a daily twodrug regimen. methods Patients with biopsy confirmed superficial lymph node tuberculosis were randomly allocated to receive either a daily self-administered 6-month regimen of rifampicin and isoniazid, or a twiceweekly, directly observed, 6-month regimen of rifampicin and isoniazid plus pyrazinamide for the first 2 months, in Madurai, South India, Patients were followed up for 36 months after completing treatment. results Of 277 enrolled patients, data was available for analysis in 268. At the end of treatment, 116 of 134 [87%; 95% confidence interval (CI) 81 93%] patients in each treatment group had a favourable clinical response; 14 (11%; 95% CI 6 16%) and 17 (13%; 95% CI 7 19%) patients had a doubtful response, and 4 (3%; 95% CI 0 6%) and 1 (1%; 95% CI 0 2%) patients had an unfavourable response among those treated with the daily and twice-weekly regimen, respectively. During 36 months after completion of treatment, five patients [2 (2%; 95% CI 1 3%) and 3 (2%; 95% CI 1 3%) patients treated with the daily and twice-weekly regimen, respectively] had relapse of lymph node tuberculosis, of 260 assessed. Adverse reactions probably attributable to the treatment regimens occurred in 1% of the patients treated daily and in 11% of those treated twice-weekly (P < 0.001). At the end of 36 months after treatment, 126 of 134 (94%; 95% CI 90 98%) and 129 of 134 (96%; 95% CI 94 98%) of the patients treated with the daily and twice-weekly regimen, respectively, had a successful outcome. conclusion Both the self-administered daily regimen and the fully observed twice-weekly regimen were highly efficacious for treating patients with lymph node tuberculosis and may be considered as alternative options to the recommended regimens. keywords tuberculous lymphadenitis, lymphadenitis, clinical trial, treatment Introduction Lymphadenitis is the commonest extra-pulmonary manifestation of tuberculosis. In a series of randomized clinical trials, the British Thoracic Society (BTS) showed that the duration of treatment for this disease could be shortened from 18 months to 9 months initially and later to 6 months (Campbell & Dyson 1977,1979; British Thoracic Society Research Committee 1985,1988,1992; Campbell et al. 1993). A clinical trial by the Tuberculosis Research Centre, Chennai had previously shown that childhood tuberculous lymphadenitis could be successfully treated with a 6-month regimen that included streptomycin (Jawahar et al. 1990). The World Health Organisation (WHO) currently recommends a 6-month regimen consisting of rifampicin and isoniazid, plus pyrazinamide for the first 2 months, given daily or thrice-weekly for the treatment of patients with category-iii tuberculosis which includes lymph node tuberculosis (World Health Organization 1997). Twice-weekly 6-month regimens are effective for treating pulmonary tuberculosis (Rani 1991). A randomized clinical trial has demonstrated the efficacy of a daily 6-month regimen of rifampicin and isoniazid for treating spinal tuberculosis (Indian Council of Medical Research/ British Medical Research Council Working Party in South 1090 ª 2005 Blackwell Publishing Ltd

2 India 1989). We hypothesized that similar regimens, i.e., a three-drug twice-weekly regimen or a two-drug daily regimen may be equally effective in lymph node tuberculosis since it is a paucibacillary disease. Such regimens will offer a great practical advantage, both for patients and health care providers. Aim of study We conducted a randomized clinical trial to study the efficacy of two 6-month regimens for treating patients with biopsy-confirmed, superficial lymph node tuberculosis: one a twice-weekly regimen of rifampicin and isoniazid, supplemented by pyrazinamide for the first 2 months, given under direct observation, and the other a daily selfadministered regimen of rifampicin and isoniazid with once-weekly clinic attendance. Materials and methods Patients Patients attending the paediatric and adult surgical outpatient departments of a large tertiary care hospital in Madurai, South India, with superficial lymphadenitis, were assessed for the trial. A lymph node was surgically excised from each patient and divided into two parts, one for histological examination and the other for mycobacterial culture using multiple culture media (Mitchison et al. 1983; Vanajakumar et al. 1997). Positive cultures were tested to identify the species of the mycobacteria by standard procedures (Kubica 1973) and susceptibility to isoniazid, streptomycin and rifampicin (Canetti et al. 1969). Patients with either histological or bacteriological evidence of tuberculosis were included in the trial if they (or their parent or guardian, in case of children), gave informed consent, were willing to attend the clinic for observed treatment and permitted home visits by the clinic staff. Patients with smear-positive pulmonary tuberculosis, or those who had received previous treatment for tuberculosis for longer than a month and those with evidence of renal or hepatic disease were not admitted to the study. On enrollment, each participant had a full clinical examination, tuberculin test with 1 TU PPD RT23 and an X-ray of the chest (PA view). Two sputum specimens were examined by smear and culture for tubercle bacilli if patients had an abnormal chest X-ray. Clinical examination was repeated every month up to 12 months, every 3 months from then until 24 months, and every 6 months thereafter till 36 months. Chest X-rays were taken at 1 month after starting treatment, at end of treatment, and at 12, 24 and 36 months, for those with initial abnormal films. Interventions Using sealed envelopes containing numbered slips generated by random numbers, a statistician randomly assigned participants to the two study arms. Participants who received isoniazid and rifampicin daily for 6 months (6RH) collected the drugs once weekly for self-administration. The other group received isoniazid and rifampicin for 6 months plus pyrazinamide for the first 2 months, twiceweekly (2RHZ 2 /4RH 2 ) under direct observation. Adult patients ( 13 years of age) received isoniazid 300 mg (daily) or 600 mg (twice-weekly); rifampicin 450 mg (daily or twice-weekly) and pyrazinamide 1500 mg twice-weekly. Children (1 12 years of age) received a weight-adjusted dose, based on 5 mg/kg for i- soniazid (daily) or 10 mg/kg (twice-weekly); 10 mg/kg for rifampicin (daily or twice-weekly) and 30 mg/kg for pyrazinamide (twice-weekly). Patients who defaulted for treatment were visited by a clinic staff or a letter was posted. Adherence to treatment among patients receiving the daily regimen was monitored by surprise home visits and pill counts. Outcome measures An independent assessor, who was blinded to the regimen to which the patient had been allocated, examined all patients at the end of treatment, or earlier if considered necessary. He classified the clinical response to treatment as favourable, if there was disappearance or regression of lymph nodes to 10 mm diameter, and healing of sinuses and abscesses, if any; as unfavourable if there was clinical deterioration or lack of clinical response after 4 months of treatment, or development of tuberculosis at other sites; or as doubtful when lymph nodes regressed in size but were still palpable and exceeding 10 mm diameter with no other symptoms. Patients with doubtful response were advised repeat lymph node biopsies and were reviewed with the results of the biopsies. If culture of the node yielded Mycobacterium tuberculosis, the clinical response was revised as unfavourable and the patient was re-treated for tuberculosis. Patients whose lymph node histology was suggestive of tuberculosis but whose culture was negative, were kept under observation. In patients with a favourable or doubtful response at end of treatment, relapse was defined as recurrence of lymph node enlargement, either with biopsy-confirmed tuberculosis with histological or bacteriological proof of diagnosis, or in association with clinical deterioration. ª 2005 Blackwell Publishing Ltd 1091

3 Adverse reactions to treatment were those symptoms possibly attributable to the drugs used in the treatment regimens. Sample size calculation Sample size was calculated in consultation with the statistician. Assuming a favourable outcome in previous studies of lymph node TB in 95%, and expecting the cure rate of the test regimens to be 90% (since these are less intensive regimens), with a confidence limit factor of 95%, and applying the formula n ¼ z 2 pq/l 2, the number of patients required for each regimen was estimated to be 138. For a two-regimen study the required sample size was thus 278. Statistical analysis The proportions of patients with different outcome measures in the two regimens were compared using the chisquare test of significance with Yate s correction. Fisher s exact test was used whenever an expected value was less than five. A P-value 0.05 was considered statistically significant. An approximate 95% confidence interval (CI) was calculated using the formula P ± 1.96 p pq/n. Ethical approval The study protocol was approved by the institutional Scientific Advisory and Ethics Committees. Informed consent was obtained from all patients or their parents/ guardians in the case of children. Results Between June 1988 and September 1993, 831 patients who had lymph node biopsy suggestive of tuberculosis at the Madurai Rajaji Hospital were assessed for eligibility for the trial. Of these, 351 were unwilling to participate in the trial and 160 were from locations beyond the study site. Forty-three patients were found ineligible for reasons such as previous TB treatment, poor clinical condition, concomitant TB at other sites etc. Of 277 patients enrolled to the study, nine were excluded (lost for treatment, seven; wrong diagnosis, one; non-tb death, one) and 268 were available for analysis of results at the end of treatment. During the 36 months after completion of treatment, two patients died from non-tb causes and one was lost for follow-up (Figure 1). Baseline patient characteristics are shown in Table 1. The median age was 10 years (range 1 55) for males and 20 years (range 1 65) for females. Sixty-three (72%) children and 171 (95%) adults had involvement of the cervical nodes, either alone or in association with other nodes (P < 0.001). Involvement of the cervical nodes alone was seen in 26 (30%) children and 136 (75%) adults (P < 0.001). Multiple sites ( 3 groups) were involved in 12 (14%) children and 11 (6%) adults. Lymph node abscesses or sinuses were present in 17 (20%) children and 14 (8%) adults (P < 0.01). Fourteen patients, whose lymph node culture yielded non-tuberculous mycobacteria (NTM), were included in the analysis because the lymph node histology was suggestive of tuberculosis, and the culture of NTM was considered to be due to contamination. Lymph node histology was suggestive of tuberculosis for 259 of the 268 patients. For six patients the histology was not suggestive of tuberculosis, and for three, no histology report was available. In these nine patients the lymph node culture yielded M. tuberculosis. Fifteen (17%) children and 26 (14%) adults had abnormal radiological features not suggestive of active pulmonary tuberculosis. Response to treatment Results at the end of treatment for 268 patients are shown in Figure 2. One hundred and sixteen (87%; CI 81 93%) of 134 patients in each treatment arm had a favourable response at the end of treatment. Four patients (3%; CI 0 6%) had an unfavourable response with the daily regimen; all were female, years of age; in two, lymph node cultures for M. tuberculosis were initially positive, one of which was resistant to isoniazid. All four patients received between 90% and 100% of the prescribed treatment. One patient (1%; CI 0 2%) had an unfavourable response with the twice-weekly regimen; a male aged 13 years whose initial lymph node culture grew NTM. He received only 71% of the prescribed treatment. All five patients were re-treated for tuberculosis and responded well to treatment. Fourteen patients (11%; CI 6 16%) in the daily regimen arm and 17 patients (13%; CI 7 19%) in the twice-weekly regimen arm were classified as having a doubtful response. Of the 21 patients with initial lymph node culture resistant to isoniazid, or streptomycin or both (Table 1), all eight treated with the twice-weekly regimen had a favourable response; of the 13 patients treated with the daily regimen, nine (69%; CI 44 94%) had a favourable response, three (23%; CI 12 34%) had a doubtful response and one (8%; CI 0 16%) had an unfavourable response. All three patients with resistance to rifampicin (twice-weekly regimen), rifampicin and isoniazid (daily regimen) and rifampicin, isoniazid and streptomycin (twice-weekly regimen) had a favourable response ª 2005 Blackwell Publishing Ltd

4 Assessed for eligibility 831 Ineligible 554 (Unwilling 351, out of study area 160, other reasons 43) Allocated to Treatment 277 Daily Twice-weekly Lost to treatment 1 6 Error in initial diagnosis - 1 Non-TB death 1 - Analysed for efficacy Unfavourable at end of treatment 4 1 Lost to follow-up/ non-tb death 2 1 Followed up for 36 months after treatment Relapse of lymphnode 2 (2%) 3 (2%) tuberculosis Favourable at end of follow-up Unfavourable at end of treatment clinical deterioration, or, lack of clinical response after 4 months of treatment, or development of pulmonary tuberculosis, or tuberculosis at other sites Relapse recurrence of lymphnode enlargement, either with biopsy-confirmed tuberculosis with histological or bacteriological proof of diagnosis, or in association with clinical deterioration, during follow-up in patients with a favourable or doubtful clinical response at the end of treatment. Figure 1 Profile of a randomized clinical trial to assess the efficacy of two 6-month regimens for the treatment of patients with lymph node tuberculosis in Madurai, South India. Relapse of lymph node tuberculosis In the 36 months following treatment, of the 232 patients who had a favourable response at the end of treatment (116 each treated with the daily and twice-weekly regimen, respectively), two died due to non-tb causes and one was lost to follow-up (Table 2). Three patients had relapses with lymph node tuberculosis: one treated with the daily regimen, at 21 months, and two treated with the twiceweekly regimen; at 10 and 20 months, respectively. Of the 31 patients (14 plus 17 treated with the daily and twice-weekly regimen, respectively) for whom the clinical response was classified as doubtful at the end of treatment, 10 had repeat lymph node biopsies subsequently. Of these 10 patients, one in the daily regimen group had a lymph node histology suggestive of tuberculosis and a culture that yielded M. tuberculosis; this patient was treated as a relapse at 18 months. Six patients had a positive histology but negative cultures; one of these relapsed at 8 months (twice-weekly regimen). Three patients had negative ª 2005 Blackwell Publishing Ltd 1093

5 Table 1 Baseline characteristics of 268 patients with lymph node tuberculosis admitted to a randomized clinical trial in Madurai, South India Regimen Baseline characteristics Daily n ¼ 134 Twice-weekly n ¼ 134 Total patients n ¼ 268 Age and sex Children (n ¼ 87) Male (62%) Female (38%) Adults years (n ¼ 144) Male (15%) Female (85%) years (n ¼ 35) Male (20%) Female (80%) 50 years (n ¼ 4) Male (50%) Female (50%) Tuberculin reaction to 1 TU PPD 0 9 mm (19%) mm (22%) 20 mm (59%) Lymph node culture for mycobacteriaà Positive for M. tuberculosis (67%) Negative (28%) Non-tuberculous mycobacteria (5%) Drug susceptibility profile of M. tuberculosis cultures (n ¼ 178) Susceptible to isoniazid, streptomycin and rifampicin (87%) Resistant to Isoniazid (5%) Streptomycin (4%) Isoniazid and streptomycin (3%) Rifampicin 0 1 1o Isoniazid and rifampicin (2%) Isoniazid and streptomycin and rifampicin Tuberculin reaction results were not available for nine patients. à Lymph node culture results were not available for three patients. histology and culture results. Apart from the two patients with relapses in this group of 31, the other 29 patients were doing well at 36 months after treatment. Thus, in all five patients relapsed, two (2%; CI 1 3%) in the daily regimen arm and three (2%; CI 1 3%) in the twice-weekly regimen arm. Overall, 126 of 134 (94%; CI 90 98%) and 129 of 134 (96%; CI 94 98%) patients treated with the daily and twice-weekly regimen, respectively, had a favourable outcome at 36 months after completing treatment. Fresh lymph node events during treatment and follow-up Both during treatment and follow-up, new nodes appeared, or existing nodes increased in size in some patients in both regimens (Table 2). There were no statistically significant differences between the regimens. These nodes regressed in size spontaneously when treatment was continued and did not require change of treatment. Adverse reactions attributable to anti-tuberculosis drugs Adverse reactions possibly attributable to the anti-tb drugs were assessed in 276 patients admitted to the study excluding one for whom the initial diagnosis was incorrect (Table 2). Gastrointestinal symptoms such as nausea and vomiting were the commonest reported events. One patient treated with the twice-weekly regimen developed jaundice in the last month of treatment. Isoniazid and rifampicin were withheld and the jaundice subsided. All the other 1094 ª 2005 Blackwell Publishing Ltd

6 No. of patients adverse reactions recorded were in adult patients and none in children. They ranged from mild to moderate and were managed with symptomatic measures. Discussion Efficacy of test regimens Daily 4 Regimen Both regimens tested in this study were successful both when assessed at the end of treatment and after 36 months of follow-up. The clinical response was favourable in 116 of the 134 (87%) patients in each treatment arm, at the end of treatment. Even though the response was classified as doubtful for 31 patients (i.e., they had palpable residual nodes that measured >10 mm in the maximum diameter), only two had a relapse of lymph node tuberculosis and the other 29 continued to remain well and free of symptom at 36 months after completing treatment. It has to be conceded that the measurement of the lymph node diameter was subject to assessment bias. In all, only five patients (2%), two and three, respectively, in the two treatment arms had relapse of lymph node tuberculosis in the 36 months after treatment. Overall, 126 of 134 (94%) and 129 of 134 (96%) patients treated with the daily and twice-weekly regimen, respectively, had a successful outcome at 36 months after completing treatment. These results compare favourably with the experience of the BTS Research Committee, which found a 17 1 Twice-weekly Favourable Doubtful Unfavourable Figure 2 Results at the end of treatment in 268 patients with lymph node tuberculosis treated with 6-month daily or twiceweekly regimens in Madurai, South India. Daily regimen: Isoniazid and rifampicin daily for 6 months; Twice-weekly regimen: Isoniazid and rifampicin twice-weekly for 6 months plus pyrazinamide for first 2 months. 6-month daily regimen of rifampicin and isoniazid plus pyrazinamide for the first 2 months to be as effective as two 9-month regimens (British Thoracic Society Research Committee 1992; Campbell et al. 1993). Although the same drugs were used in our study, they were administered only twice a week, an important consideration in observed treatment. Intermittent regimens for tuberculosis are known to be as effective as daily regimens while being less toxic (Girling 1978). Further, intermittent therapy is cheaper and easier to observe. Thus, our regimen while using the same drugs as the BTS study, offers these additional advantages. A study from Hong Kong showed no difference in efficacy among patients treated with 6 or 9-month fully intermittent regimens (Yuen et al. 1997). The intensive phase in this study was 4 months of four drugs that included streptomycin. Our results show that a less intensive regimen (three oral drugs in a 2 months, intensive phase) given only twice-weekly, produced comparable, if not superior results. An encouraging feature of the 6-month daily regimen of rifampicin and isoniazid was that even patients with lymph node cultures resistant to one or more drugs fared well. Of 14 such patients, including one who was resistant to rifampicin and isoniazid, only one failed to respond to treatment while three had a doubtful response. Concerns have been expressed as to whether, in the scenario of increasing drug resistance, a two-drug regimen of isoniazid and rifampicin could be effective for the treatment of tuberculosis. While these concerns are justified, our study shows that at least for lymph node tuberculosis, where the bacillary load is small, satisfactory results may be obtained with the rifampicin isoniazid regimen. Moreover, a similar regimen has been shown to be highly successful in treating patients for spinal tuberculosis (Indian Council of Medical Research/British Medical Research Council Working Party in South India 1989). However, in populations with significant isoniazid or multidrug resistance or where HIV seroprevalence is high this two-drug regimen may not be adequate. We did not test our patients for HIV infection. Preliminary results of a randomized clinical trial at the Tuberculosis Research Centre suggests that HIV positive pulmonary tuberculosis patients respond equally well to the standard 4-drug or 3-drug 6-month regimen compared to immunocompetent pulmonary tuberculosis patients, though the relapse rates may be higher. Adverse drug reactions Both the regimens were well tolerated. Adverse reactions attributable to anti-tuberculosis drugs were observed in only 17 of 276 (6%) of patients, almost all of them treated ª 2005 Blackwell Publishing Ltd 1095

7 Relapse/events during treatment and follow-up Regimen Daily n (%) Twice-weekly n (%) P value At 36 months after completing treatment Number assessed ( Favourable plus Doubtful at end of treatment) Non-TB death/lost to follow-up 2 1 Relapse of lymph node TB 2* (2%) 3 (2%) 0.511à Favourable 126 (94%) 129 (96%) Lymph node events (new nodes/enlargement of nodes) During treatment Number assessed Events 4 (3%) 9 (7%) During follow-up Number assessed Events 8 (6%) 6 (5%) Adverse reactions to treatment regimens Number assessed Patients with any reaction 1 (1%) 16 (11%) Gastrointestinal symptoms 0 8 (6%) 0.004à Arthralgia 0 4 (3%) 0.065à Giddiness 0 2 (1%) 0.256à Pruritis 1 (1%) 1 (<1%) 0.744à Jaundice 0 1 (<1%) 0.507à Table 2 Response to treatment and events during treatment and follow-up among 268 patients with lymph node tuberculosis admitted to a randomized clinical trial in Madurai, South India *One each from Favourable and Doubtful groups. Two from Favourable and one from Doubtful group. à Fisher s exact test. Chi-square test with Yates correction. 126/134 ¼ 94% and 129/134 ¼ 96%. with the twice-weekly regimen. This is much lower than those reported among pulmonary tuberculosis patients treated with short-course chemotherapy, where usually four drugs are used in the intensive phase (Tuberculosis Research Centre 1983, 1986, 1997). Of patients treated with the daily regimen, only one had an adverse reaction, and probably reflects the fact that only two drugs were used in this regimen. Paradoxical reactions Physicians treating patients for lymph node tuberculosis often observe nodes enlarge in size or appear at new sites after treatment begins. This is often a source of concern, for both the patient and the treating physician. They have been widely reported and are thought to reflect immune reactions to the release of mycobacterial proteins caused by the bactericidal action of the treatment regimens (Campbell & Dyson 1977; British Thoracic Society Research Committee 1985; Anonymous 1987; Jawahar et al ). We also observed similar events among some of our patients and no statistically significant differences were seen between the two regimens. Gender differences Two striking observations from this study are the high ratio of females to males among the adult patients and the strongly positive tuberculin reactions. Although it is well known that lymph node tuberculosis, unlike pulmonary tuberculosis, is more common among females (Pamra & Mathur 1974; Farer et al. 1979; Research Committee of the Tuberculosis Association of India 1987), the female to male ratio of 5:1 that we observed in the year age group was remarkable. Most patients had a very strong tuberculin reaction. This is unusual and we have not observed this type of strong reaction in other forms of extra-pulmonary tuberculosis (Rani & Rajeswari 2000). Lymph node culture Contrary to the common belief that mycobacterial culture from extra-pulmonary specimens is often not rewarding, 1096 ª 2005 Blackwell Publishing Ltd

8 lymph node specimens yielded positive cultures of M. tuberculosis in 178 of 265 (67%) patients, despite the fact that the specimens were transported from Madurai to Chennai, to the central laboratory 300 miles away. This involved a mean delay of 3 4 days between the time of the biopsy and the time of testing. Preservation of the specimens was facilitated by the use of multiple culture media and the use of a transport medium (Michison et al. 1983; Vanajakumar et al. 1997). Strengths and limitations of the study One of the strengths of this study is that we were able to follow-up all but three of the 268 patients who completed treatment, for 36 months to monitor for relapse. The limitation of our study, as in all clinical trials, is that the results may not be replicated under different conditions, unless adherence to treatment is meticulously ensured. This patient-management issue remains the biggest challenge in the fight against tuberculosis. A solution may lie in shortening the duration of treatment. The success of ofloxacin-containing 4- and 5-month regimens for treating patients with pulmonary tuberculosis, reported recently, is promising (Tuberculosis Research Centre 2002). A 3- or 4-month fluoroquinolone-containing regimen for the treatment of lymph node tuberculosis may be a realistic option in the near future. Implications for TB control The success of the two regimens reported on here has important implications for the tuberculosis control programmes. The WHO in its global efforts to control tuberculosis is promoting the widespread use of the directly observed treatment, short course (DOTS) strategy, in which lymph node tuberculosis is classified as category III, for which the recommended treatment is rifampicin and isoniazid for 6 months, plus pyrazinamide for the first 2 months, either daily or thrice-weekly (World Health Organization 1997). The intermittent regimen used in our study is the same regimen advocated by WHO, except that the drugs are given twice-weekly instead of thrice-weekly or daily. Our study shows that even this less-intensive (and less expensive) regimen can be highly effective. However good the regimens are, unless they are acceptable for the patients they are unlikely to succeed. We feel that a twice-weekly regimen instead of a thrice-weekly one, and a two-drug regimen instead of a three-drug one are easier options that may appeal to patients. In conclusion, the findings from our study show that lymph node tuberculosis can be successfully treated with a 6-month, twice-weekly regimen with three drugs in the intensive phase, or with a daily regimen of rifampicin and isoniazid. Both regimens were highly successful and well tolerated. With DOTS being expanded rapidly to cover almost 150 countries worldwide (WHO Report 2002), these regimens offer cost-effective and patient-friendly treatment options for countries planning to implement tuberculosis control programmes. Acknowledgements The successful conduct of this study owes much to the contributions of many people apart from the authors. We acknowledge the contributions of the following staff of the Tuberculosis Research Centre at Madurai: Dr. Palani Murugan and Dr. Paul Kumaran, Research Officers, Mr. Victor Mohan, Technical Officer, Mr. Subramanian K and Mr. Shripad Bhatt, Research Assistants (Statistics), Mr. Raja Sakthivel, Mr. Thiruvalluvan and Ms. Chandra S, Medical Social Workers, Ms. Arumaikannu Anbalagan, Public Health Nurse, Ms. Mary Eunice Chellammal and Ms. Chellam S, Clinic Nurses, Ms. Revathi V, Ms. Valarmathi R, Ms. Indirani V, Ms. Angel Nirmala, Ms. Pandeeswari, Ms. Rathinam M and Ms. Mohana, Health Visitors. We acknowledge with gratitude the contributions of Dr. Renu Garg, WHO Consultant, Dr. Bandana Malhotra, and Dr. P R Narayanan, Director, Tuberculosis Research Centre, in the preparation of this manuscript in its various stages. The study was funded entirely by the Indian Council of Medical Research. No pharmaceutical company was associated with the study. Finally this trial would not have been possible but for the willing participation of the patients who constituted the subjects for this study. We acknowledge their contribution with humility and gratitude. References Anonymous (1987) Paradoxical responses during the chemotherapy of tuberculosis [Editorial]. Journal of Infecitous 15, 13. British Thoracic Society Research Committee (1985) Short course chemotherapy for tuberculosis of lymph nodes: a controlled trial. BMJ 290, British Thoracic Society Research Committee (1988) Short course chemotherapy for lymph node tuberculosis Final report at 5 years. British Journal of Disease Chest 82, British Thoracic Society Research Committee (1992) Six-month versus nine-month chemotherapy for tuberculosis of lymph nodes: Preliminary results. Respiratory Medicine 86, Campbell IA & Dyson DJ (1977) Lymph node tuberculosis: a comparison of various methods of treatment. Tubercle 58, ª 2005 Blackwell Publishing Ltd 1097

9 Campbell IA & Dyson DJ (1979) Lymph node tuberculosis: a comparison of treatment 18 months after completion of chemotherapy. Tubercle 60, Campbell IA, Ormerod LP & Friend JAR (1993) Six-month versus nine-month chemotherapy for tuberculosis of lymph nodes: final results. Respiratory Medicine 87, Canetti G, Fox W, Khomenko A et al. (1969) Advances in techniques of testing mycobacterial drug sensitivity and the use of sensitivity tests in tuberculosis control programme. Bulletin of the World Health Organization 41, Farer LS, Lowell AM & Meador MP (1979) Extra pulmonary tuberculosis in the United States. American Jounal of Epidemiology 109, Girling DJ (1978) The hepatic toxicity of antituberculosis regimens containing isoniazid, rifampicin and pyrazinamide. Tubercle 59, Indian Council of Medical Research/British Medical Research Council Working Party in South India (1989) Controlled clinical trial of short course regimens of chemotherapy in patients receiving ambulatory treatment or undergoing radical surgery for tuberculosis of the spine. Indian Journal of Tuberculosis 36 (Suppl.), Jawahar MS, Sivasubramanian S, Vijayan VK et al. (1990) Short course chemotherapy for tuberculous lymphadenitis in children. BMJ 301, Kubica SP (1973) Differential identification of mycobacteria. Key features for identification of clinically significant mycobacteria. American Review of Respiratory Disease 107, Mitchison DA, Allen BW & Devi M (1983) Selective Kirchner medium in the culture of specimens other than sputum for mycobacteria. Journal of Clinical Pathology 36, Pamra SP & Mathur GP (1974) A co-operative study of tuberculous cervical lymphadenitis. Indian Journal of Medical Research 62, Rani B (1991) Fully intermittent six-month regimens for pulmonary tuberculosis in South India. Indian Journal of Tuberculosis 38, Rani B & Rajeswari R (2000) Management of non-pulmonary forms of tuberculosis: review of TRC studies over two decades. Indian Journal of Pediatrics 67 (Suppl. 2), Research Committee of the Tuberculosis Association of India (1987) Cervical lymphadenitis. Indian Journal of Tuberculosis 34, Tuberculosis Research Centre, Madras (1983) Study of chemotherapy regimens of 5 and 7 months duration and the role of corticosteroids in the treatment of sputum-positive patients with pulmonary tuberculosis in South India. Tubercle 64, Tuberculosis Research Centre (1997) A controlled clinical trial of oral short course regimens in the treatment of sputum positive pulmonary tuberculosis. International Journal of Tuberculosis and Lung Disease 1, Tuberculosis Research Centre (2002) Shortening short course chemotherapy a randomized clinical trial for the treatment of smear positive pulmonary tuberculosis with regimens containing ofloxacin. Indian Journal of Tuberculosis 49, Tuberculosis Research Centre, Madras, & National Tuberculosis Institute, Bangalore (1986) A controlled clinical trial of 3- and 5-month regimens in the treatment of sputum-positive pulmonary tuberculosis in South India. American Review of Respiratory Disease 134, Vanajakumar, Selvakumar N, Jawahar MS, Rajaram K & Paramasivan CN (1997) Transportation of lymph node biopsy specimens in selective Kirchner s liquid medium for culture of tubercle bacilli. Journal of Medical Microbiology 46, World Health Organization (1997) Treatment of Tuberculosis. Guidelines for National Programmes (second edition). WHO/ TB/ WHO Report (2002) WHO/CDS/TB/ Yuen AP, Wong SH, Tam CM, Chan SL, Wei WI & Lau SK (1997) Prospective randomized study of thrice weekly six-month and nine-month chemotherapy for cervical tuberculous lymphadenopathy [Abstr]. Otolaryngology Head Neck Surgery 116, Authors M. S. Jawahar (corresponding author), K. Rajaram, C. N. Paramasivan and K. Chandrasekar, Tuberculosis Research Centre, Mayor V R Ramanathan Road, Chetput, Chennai , India. Tel.: ; shaheedjawahar@rediffmail.com, shaheedjawahar@gmail.com, cnparamasivan@gmail.com, chandru_pmpi@yahoo.com S. Sivasubramanian, 123 Kamarajar Salai, Ramakrishna Nagar, Alwarthirunagar, Chennai , India. Tel.: ; sivaa1938@yahoo.com M. N. Kamaludeen, Department of Surgery, Government Rajaji Hospital, Madurai , India. Tel.: ; mnkasisec@yahoo.co.in A. J. Thirithuvathas, 23 Pattimedu Road, Visalakshipuram, Madurai , India. Tel.: ; thirithuvathas@eth.net V. Ananthalakshmi, 16 Bharathi Park Road II, Avinashalingam University Post, Coimbatore , India. Tel.: R. Prabhakar, K III, 16th Street, Block K3, L2 Apartments, Bogainvilla, Annanagar, Chennai , India. Tel.: ª 2005 Blackwell Publishing Ltd