The authors have declared that no competing interests exist.
Conceived and designed the experiments: SM SZ SS ADH. Performed the experiments: SM SS SC RPV. Analyzed the data: SM SZ SS SC RZ ADH. Contributed reagents/materials/analysis tools: SM SZ SS SC RZ ADH. Wrote the paper: SM SZ SS SC RZ ADH.
The Indian guidelines on following up sputum smear-negative Pulmonary tuberculosis (PTB) patients differ from the current World Health Organization (WHO) guidelines in that the former recommends two follow up sputum examinations (once at the end of intensive phase and the other at the end of treatment) while the latter recommends only one follow up sputum smear microscopy examination, which is done at the end of the intensive phase. This study was conducted to examine if there was any added value in performing an additional sputum smear examination at the end of treatment within the context of a national TB program.
This study was a descriptive record based review conducted in nine tuberculosis (TB) units in Delhi, India. All consecutive new sputum smear-negative PTB patients registered in these nine TB units from 1st January 2009 to 31st December 2009 were included in the study.
Of 2567 new sputum smear-negative TB patients, 1973 (90%) had sputum specimens examined at the end of the intensive phase, of whom 36 (2%) were smear-positive: the majority (n = 28) successfully completed treatment with either the same or a re-treatment regimen. At treatment completion, 1766 (85%) patients had sputum specimens examined, of whom 16 (0.9%) were smear-positive: all these were changed to a re-treatment regimen. Amongst the sputum-positive patients identified as a result of follow up (n = 52), four were diagnosed with multi-drug resistant TB (MDR-TB), three of whom were detected after smear examination at the end of treatment.
Given the high burden of TB in India, a 0.9% additional yield of smear-positive sputum smears at the end of treatment translates to 3,297 cases of smear-positive PTB. End-of-treatment smear is a low-yield strategy for detection of smear-positive TB cases, although further studies are needed to determine its population-level impact and cost, particularly in relation to other TB control interventions.
India is the highest tuberculosis (TB) burden country in the world accounting for one fifth of global incidence
According to current Indian guidelines, a patient is labelled as sputum smear-negative pulmonary tuberculosis (PTB) when he/she has clinical features of PTB, has two consecutive sputum smear examinations negative for acid-fast bacilli (AFB) and has radiographic abnormalities consistent with active PTB, as determined by a medical officer
The Indian guidelines on following up sputum smear-negative PTB patients differ from the current World Health Organization (WHO) guidelines in that the latter recommends only one follow up sputum microscopy examination, which is done at the end of the intensive phase
In a cohort of newly registered sputum smear-negative PTB patients, we determined i) the proportion of patients who had sputum smear examinations done at the end of the intensive phase and at the end of treatment, ii) the number and percentage of patients with positive sputum smears at these time points and iii) the treatment outcomes of those patients who were found to be sputum smear-positive.
This was a descriptive study using routine programme data.
The study was conducted in the state of Delhi, the National Capital of India. Delhi has an area of 1483 sq km, with a total population of 17 million and population density of 11,000/sq km, with 40% of the population living in slums or similar contexts. The Revised National TB Control Programme (RNTCP) has been implemented in all districts of Delhi since 1997. For the management of RNTCP, the state has been divided into 24 Chest Clinics
Patients were registered in the programme in one of three treatment categories: details of these categories and the treatment regimens are presented in
Treatment category | Type of patients | Treatment regimens |
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Intensive Phase | Continuation phase | ||
Category 1 | New sputum smear-positive PTB | 2(H3R3Z3E3) | 4(H3R3) |
New sputum smear-negative PTB, seriously ill |
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New extra-PTB, seriously ill |
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Category 2 | Sputum smear-positive relapse | 2(H3R3Z3E3S3)+1(H3R3Z3E3) | 5(H3R3E3) |
Sputum smear-positive treatment failure | |||
Sputum smear-positive treatment after default | |||
Category 3 | New sputum smear-negative, not seriously ill |
2(H3R3Z3) | 4(H3R3) |
New extra-PTB, not seriously ill |
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Category 4 | Multi Drug Resistant –TB (MDR-TB) |
6 (9) Km Lvx Eto Cs Z E (daily) | 18 Lvx Eto Cs E (daily) |
PTB = Pulmonary Tuberculosis; EPTB = Extrapulmonary Tuberculosis; H = Isoniazid; R = Rifampicin; Z = Pyrazinamide; E = Ethambutol; Km = Kanamicin; Lvx = Levofloxacin; Eto = Ethionamide; Cs = Cycloserine.
The number before the letters indicates number of months of treatment; numbers in subscript indicate the number of days per week of doses.
Seriously ill includes patients that have military TB, extensive parenchymal infiltration, co-infection with HIV, cavitary disease. In children, seriously ill sputum smear-negative PTB includes all forms of sputum smear-negative PTB other than primary complex. Seriously ill EP-TB includes TB meningitis (TBM), disseminated TB, TB pericarditis, TB peritonitis and intestinal TB, bilateral extensive pleurisy, spinal TB with or without neurological complications, genitourinary TB, and bone and joint TB.
Not seriously ill sputum smear-negative PTB includes primary complex. Not seriously ill EP-TB includes lymph node TB and unilateral pleural effusion.
The dosage strengths are as follows: H : Isoniazid (600 mg), R:Rifampicin (450 mg), Z: Pyrazinamide (1500 mg); E: Ethambutol (1200 mg); S: Streptomycin (750 mg).
MDR-TB diagnosis is done through culture and drug sensitivity testing from a quality-assured laboratory. Treatment of MDR-TB uses a standardized regimen, comprising of 6 drugs – Km (Kanamycin), Lvx (levofloxacin), Eto (Ethionamide), Z (pyrazinamide), E (Ethambutol) and Cs (Cycloserine) during 6–9 months of intensive phase and 4 drugs (Lvx, Eto, E and Cs) during the 18 months of continuation phase. Dosages of drugs are based on three weight bands (16–25 kg, 26–45 Kg, and >45 Kg).
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Or: A sputum smear-negative TB patient who has received a full course of treatment and has not become smear-positive during or at the end of treatment. |
Or: An extra-pulmonary TB patient who has received a full course of treatment and has not become smear-positive during or at the end of treatment. |
From each of the nine revenue districts of Delhi, if there were more than one tuberculosis units, the TB unit that registered the maximum number of patients during the study period was selected for inclusion in the study. All consecutive new sputum smear-negative pulmonary TB patients registered in these nine TB units from 1st January 2009 to 31st December 2009 were included in the study.
Data were obtained from the TB registers. A data extraction sheet was used by the study investigators to capture details on sputum smear examination and treatment outcome status at the end of the intensive phase and on treatment completion. Cross validation of the records was undertaken for 10% of smear-negative Pulmonary TB patients by examining patient treatment cards and TB Laboratory registers. Data were entered and analyzed using a Microsoft Excel spreadsheet Version 2007.
Ethical approval was obtained from the Institutional Ethics Committee of Public Health Foundation of India, New Delhi and the Union Ethics Advisory Group, Paris. The study was a retrospective review of routine programme records and reports, and permission was obtained from the programme managers at the state and national levels to access these data. Individual patient consent was deemed un-necessary by both the ethics committees. Electronic databases created for the analysis were stripped of personal health identifiers and maintained securely.
A total of 2,567 new sputum smear negative PTB patients were registered in the 9 TB units in Delhi. The management of these patients and the numbers who were eligible for and had sputum smear examination performed from diagnosis until the end of treatment is shown in
Of all newly registered patients, 367 (14%) were not eligible for sputum smear examination at end of the intensive phase due to various reasons shown in
During the continuation phase of treatment, 111 (5%) patients were not eligible for sputum smear examination at the end of treatment (6 months) due to various reasons shown in
Amongst these smear-positive patients, 6 were receiving category 1 and 10 were receiving category 3 treatment regimens. Of the 16 smear-positive patients, 12 were changed to a category 2 retreatment regimen. Two other patients from each category were lost to follow up after their treatment was completed and their outcome was registered as treatment completed. The outcomes of the 12 patients who were changed to a retreatment regimens shown in
A sensitivity analysis was performed to check what the estimate would have been if all of the patients who did not get their last follow up sputum smear examination turned out to be smear-positive or smear-negative. If all the missing patients had been smear-positive, the smear-positivity rate at the end of treatment would have been 16%. Conversely, if all these patients had been smear-negative, then the estimate would have been 0.8%. Even with the low estimate of 0.8%, from a public health perspective, the absolute number in terms of cases of potentially resistant TB cases identified is still significant.
The cost of undertaking a single sputum smear examination in our setting is US $ 0.90
This is one of the first studies evaluating the added value of sputum smear examinations at the end of the intensive as well as the end of treatment in new sputum smear negative PTB patients. The majority of patients who were eligible to submit sputum specimens at the end of the intensive phase of treatment and at the end of treatment had their sputum smears examined. Smear-positivity was 2% for the smear examination at the end of the intensive phase and 0.9% at the end of treatment. These percentages may seem low, but in India with an estimated 366,381 annual new smear negative PTB patients registered in 2009, this translates to over 7000 cases with positive smears at 2 months and 3297 cases of smear positive PTB at the end of treatment. For patients on the category 3 regimen, all of those with smear-positive sputum at 2 months were changed to a retreatment regimen with a generally successful treatment outcome, so action was taken on the result. Action was not so clear for those found to be smear-positive at the end of treatment. A quarter of patients were incorrectly registered as treatment completed. The remainder was changed to a re-treatment regimen with mixed results, but three patients were identified with MDR-TB and changed to the appropriate treatment, an action which would not have occurred if the smear examination had not been performed.
There are important public health implications from these findings. First, persistent smear positivity at the end of treatment completion might herald misdiagnosis, failure on current drug regimens or primary or acquired drug resistance. In particular, the possibility of persistent smear positivity heralding MDR-TB is of major concern as this form of drug resistance needs early identification in order to limit its spread to households and the community at large. Such cases will add to the “difficult to manage” TB cases and the already high background burden of disease. Second, from a patient perspective, this failure of treatment is likely to impact on individual survival. It is not known what happened to the patients with smear-positive sputum at the end of treatment who were incorrectly declared successfully treated or what happens in general to these patients if the smear examination is not performed. However, it is likely that outcomes are compromised.
One consideration is that our study group included patients in category 3 with a three-drug treatment regimen in the intensive phase in addition to patients in category 1 who were treated with a four-drug treatment regimen in the intensive phase. The category 3 regimen is considered a relatively inferior regimen and no longer exists in the country. It is possible that the country-wide shift to a category 1 regimen for all smear-negative PTB patients might affect our study estimate of 1%. It is thus urgent that RNTCP audits current data under the revised national guidelines to fully validate these findings.
The strengths of this study are that a large number of patients were studied, and we used routine programme data. The findings are therefore likely to reflect the operational reality on the ground. We have also adhered to the STROBE guidelines on reporting
The study has a number of limitations. First, the use of record reviews does mean that sometimes the data are inaccurately recorded. Second, our estimate of the added value of 0.9% positive sputum smears at the end of treatment might be affected by the 15% of patients who for various reasons did not undergo the last follow up smear examination at the end of treatment completion. A large number of patients not undergoing follow-up sputum smear examination is not unique to this study and/or region and has also been highlighted in another study from a different region in the country
This is the first report of its kind coming from a high TB burden country like India, but like many studies it raises additional questions. First, the RNTCP has stopped giving category 3 treatment, and therefore a similar study with the same research question should be conducted for another cohort of patients receiving the changed treatment regimens. Second, a prospective study should be done for a similar cohort of patients as this would obviate a number of the limitations inherent in this retrospective record review study. A prospective study could also include sputum culture and drug sensitivity testing on all specimens as well as a detailed cost-analysis on all aspects. The decision to continue sputum smear examination at end of continuation phase will also be dependent on CBR of the additional sputum smear examination. Given the political commitment by the Government of India to support the RNTCP with the aim of improving its performance over several years, the current costs of performing the additional end-of-treatment smear as presented in the results section, do not seem to impose an economic challenge to the programme. The end of smear examination in patients with smear-negative pulmonary TB must be assessed in relation to other strategies for improving case detection as part of the country's TB control efforts; for example, comparisons made with contact investigation of index patients where the yield may be in the region of 2–5%
In light of above and the evidence generated through this study, there is need for further evaluation on this research question. End-of-treatment smear is a low-yield strategy for detection of smear-positive TB cases, although further studies are needed to determine its population-level impact and cost, particularly in relation to other TB control interventions.