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ARTICLE
Year : 2013  |  Volume : 2  |  Issue : 4  |  Page : 199-205

Sputum smear positivity at two months in previously untreated pulmonary tuberculosis patients


1 Department of Tuberculosis and Chest Diseases, Lala Ram Sarup Institute of Tuberculosis and Respiratory Diseases, New Delhi 110030, India
2 Department of Epidemiology, Lala Ram Sarup Institute of Tuberculosis and Respiratory Diseases, New Delhi 110030, India
3 Department of Microbiology, Lala Ram Sarup Institute of Tuberculosis and Respiratory Diseases, New Delhi 110030, India
4 Department of Respiratory & Critical Care Medicine, Post Graduate Institute of Medical Education & Research, Chandigarh, India

Date of Web Publication28-Feb-2017

Correspondence Address:
Rupak Singla
Department of Tuberculosis & Respiratory Diseases, Lala Ram Sarup Institute of Tuberculosis and Respiratory Diseases, Sri Aurobindo Marg, New Delhi 110030
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.1016/j.ijmyco.2013.08.002

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  Abstract 


Background and Objectives: In pulmonary tuberculosis, bacteriological status at two months affects subsequent treatment and prognosis. The effect on treatment outcome and risk factors for sputum conversion at two months treatment in previously untreated pulmonary tuberculosis (PTB) patients was studied in the following report.
Methods: A 1:1 case-control study was performed from June 2006 to February 2008 on patients in the Revised National Tuberculosis Control Program in a tertiary level institute in Delhi, India. Patients with previously untreated PTB with sputum smear positive at 2 months of treatment (cases) were compared with those who achieved conversion (controls).
Results: In 74 cases and 74 controls, independent risk factors for sputum smear positive at two months were: illness for >2 months, presence of cavity or extensive disease on chest X-ray, and interruption in intensive phase of treatment. Patients with smear positive at 2 or 3 months of treatment were more likely to fail or default from treatment. Aforesaid factors were also associated with sputum culture positive status at 2 months in univariate analysis. Patients who interrupted treatment ≥3 times in the first two months were more likely to be culture positive at two months and had a higher rate of default and failure.
Conclusions: Illness for more than 2 months, presence of cavity or extensive disease on chest X-ray, and interruption in intensive phase of treatment are independent risk factors for sputum smear positivity at two months, which in turn is associated with poor treatment outcomes. Patients with these factors merit special attention under the national program.

Keywords: Risk-factors, Sputum-smear, Tuberculosis


How to cite this article:
Singla R, Bharty SK, Gupta UA, Khayyam KU, Vohra V, Singla N, Myneedu VP, Behera D. Sputum smear positivity at two months in previously untreated pulmonary tuberculosis patients. Int J Mycobacteriol 2013;2:199-205

How to cite this URL:
Singla R, Bharty SK, Gupta UA, Khayyam KU, Vohra V, Singla N, Myneedu VP, Behera D. Sputum smear positivity at two months in previously untreated pulmonary tuberculosis patients. Int J Mycobacteriol [serial online] 2013 [cited 2019 Oct 22];2:199-205. Available from: http://www.ijmyco.org/text.asp?2013/2/4/199/201117




  Introduction Top


In the Revised National Tuberculosis Control Program (RNTCP) of India [Central Tuberculosis Division 2005], new sputum smear-positive patients with pulmonary tuberculosis (PTB) are treated with a regimen consisting of an initial intensive phase (IP) of 2 months of thrice-weekly isoniazid (H), rifampicin (R), pyrazinamide (Z) and ethambutol (E) followed by 4 months of thrice-weekly H and R (2[HRZE]3/4[HR]3) under the Directly Observed Treatment Short Course Strategy (DOTS). At the end of 2, 4 and 6 months of treatment, two direct sputum smears for acid-fast bacilli (AFB) are performed. In patients who remain smear positive at two months, the intensive phase is extended for one more month after which they are put on continuation phase irrespective of the smear status [1].

The bacteriological status at 2 months is an important milestone in the management of PTB patients. It influences subsequent treatment to be given to the patient [1],[2],[3]. Persistent sputum smear positivity at 2 months presages poor outcome, higher rates of treatment failure, and relapse [1],[4],[5]. Further, patients who harbor multi drug-resistant strains may be more likely to be positive at two months of treatment under DOTS [6].

In intermittent therapy, missing the dose on its due date can challenge the efficacy of the regimen since the increased gap may not be sufficient to sustain the lag period [7]. This interruption in treatment may ultimately lead to failure of a given anti-tuberculosis (ATT) regimen [6],[8]. The effect of missing single or multiple ATT doses in the first two months on bacteriological status at two months of treatment was not previously known.

The primary aim of the present study is to study clinical, radiological and bacteriological factors that may be associated with sputum smear positivity at the end of two months of treatment under RNTCP. The influence of interruption of treatment on sputum positivity at two months and on treatment outcome was also analyzed.


  Materials and methods Top


A 1:1, case-control study was performed from June 2006 to February 2008 on patients enrolled in the RNTCP in Lala Ram Sarup Institute of Tuberculosis and Respiratory Diseases, a tertiary level national TB institute in South Delhi, India. The study was reviewed and approved by the ethics and research committee of the Institute. The study group consisted of new sputum AFB smear-positive PTB patients started on treatment under RNTCP. The patients were enrolled in the study at the end of the initial two months of treatment.

The ”cases' were comprised of patients whose sputum direct smear was positive for AFB after 2 months of treatment. Sputum was examined and graded per RNTCP guidelines as: scanty, 1+, 2+, 3+ or negative [1]. The ”controls' were comprised of patients whose sputum direct smear was negative after two months of treatment. The control group was matched by age and sex. As far as possible, the controls were selected from the same DOTS center and within a month of the date of registration of the cases. The cases and controls were followed-up until treatment completion, and treatment outcome was recorded. Informed consent was obtained and a standardized Performa was filled out.

The data regarding the duration of illness prior to starting treatment; tobacco smoking, alcohol intake, socioeconomic status [9], associated diabetes mellitus (DM), body mass index (BMI), human immune-deficiency virus (HIV) status and radiological extent of disease at enrollment were collected. If any dose of ATT was missed in the intensive phase, it was counted as ”treatment interrupted'. In RNTCP, these doses are subsequently given and the total number of doses in the regimen is completed. The patients were advised to provide two sputa (spot and early morning), which were stained by Ziehl Nelson method for AFB and also cultured for Mycobacterium tuberculosis on Lowenstein-Jensen medium. Positive cultures were subjected to drug susceptibility testing (DST) by using the absolute concentration method. The minimum inhibitory concentration (MIC) of the drugs used was as follows: SM 16 μg/ml, INH 0.4 μg/ml, RMP 128 μg/ml and EMB 8 μg/ml.

The data for radiological extent of disease was collected in the categories mentioned by NTA [10], but for data analysis, the category ”far advanced' was compared with the aggregation of ”less advanced' and ”minimal' category, termed as ”less advanced' in this study. Similarly, data for initial sputum grade was collected as per RNTCP definitions [1], but, for analysis, sputum grade 3+ was compared with the aggregate of ”2+, 1+ and scanty' termed as ”non-3+'.

Data was analyzed in SPSS version 12.0 (SPSS Inc., Chicago, IL). For parametric data – t test for independent samples and Analysis of Variance; for nominal data – Pearson's chi square test or fisher's exact test was used. For hypothesis testing, a probability of 0.05 was considered significant. Those variables which were significant on univariate analysis were tested for independent association using binary logistic regression.


  Results Top


In the study period, data from 74 cases and 74 controls was obtained. [Table 1] shows the clinical, bacteriological and radiological profile of cases and controls. On univariate analysis ([Table 1]), it was found that patients who were smear positive at two months did not differ significantly with respect to age, sex, associated DM or HIV, smoking and alcohol use from those who were smear negative at two months. The patients who were smear positive at two months were significantly more likely to have been ill for more than 2 months, to have lower BMI, to have cavity and far-advanced disease on chest X-ray, to have initial sputum smear grade 3+, and to be an interrupter than the controls.
Table 1: Univariate analysis of profile of cases and controls at 2 months of treatment.

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On binary logistic regression ([Table 2]), it was found that more than 2 months' duration of illness, cavity on chest X-ray, far advanced disease radiologically, and occasional and frequent interruption were the risk factors independently associated with being smear positive at 2 months of treatment. However, low body mass index and initial sputum grade were not independent risk factors (not shown in [Table 2]).
Table 2: Binary logistic regression analysis of variables found significant on univariate analysis that are known at the start of category I.

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The culture and DST results of 74 smear positive cases at two months are shown in [Figure 1]. Among them, culture was positive in 30 (40.5%) patients; 7 had MDR-TB; 9 were pan-sensitive; and 9 had non-MDR-TB. In two patients the culture was contaminated. In five culture positive patients the DST was contaminated.
Figure 1: Culture and DST of smear positive sputa collected at two months of treatment.

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The culture positivity among smear positive patients represents the presence of live bacilli. On univariate analysis of a total of 148 cases and controls, it was observed that all the factors associated with smear positivity at two months were also associated with culture positivity at 2 months ([Table 3]). Multivariate analysis was not done owing to paucity of numbers in the culture positive subgroup.
Table 3: Factors associated with a 2 month positive culture result.

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All the patients were followed up, and the outcome of treatment of patients with smear positive results at two months was compared with patients with smear negative results at two months ([Table 4]). Out of the 74 patients with smear positive results at two months, 27 (36.5%) patients remained smear positive at three months; 47 (63.5%) patients were cured; and 20 (27%) patients failed treatment. Comparison of treatment outcome of patients whose sputa were positive at two or three months with those who achieved sputum conversion at two or three months showed that the former group had lower cure rates and more defaults, failures and deaths (P <0.001, Fisher's exact test).
Table 4: Outcome of patients remaining smear positive at 2 monthsa.

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[Table 5] shows analysis of treatment interrupters in the intensive phase. Out of a total of 148 patients under study, 84 (56.8%) did not interrupt treatment. There was progressively less patients with a rising number of interruptions (P for linear trend<0.001). The interrupters had higher chances of being smear positive at two months (P < 0.038) compared with non-interrupters. Patients who interrupted treatment once or twice were counted together as ”occasional interrupters' and patients who interrupted treatment thrice or more were counted together as ”frequent interrupters'. There were 45 (30.4%) occasional interrupters and 19 (12.8%) frequent interrupters (P for linear trend<0.014).
Table 5: Interruptions in treatment in cases and controls.

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[Table 6] shows the culture, DST and treatment outcomes for patients who interrupted treatment. Frequent interrupters had significantly higher rates of being culture positive at 2 months, higher default and failure rates, and lower cure rates than the occasional interrupters.
Table 6: Effect of treatment interruptions on sputum culture at 2 months, DST at 2months and treatment outcome.

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Out of the total 148 patients, the sensitivity, specificity, positive predictive value and negative predictive value of smear status at two months to predict failure of treatment was 100%, 58%, 27% and 100%, respectively.


  Discussion Top


Persistent sputum smear positivity at 2 months may predict poor treatment outcome, higher rates of treatment failure and relapse [4],[5]. It influences subsequent treatment to be given to the patient [1],[2],[3]. In this study an attempt was made to identify clinical, radiological and bacteriological risk factors for sputum smear positivity at two months under field conditions under the national program in Delhi, India. The patients with persistent sputum positive at two months did not differ with respect to their diabetes mellitus or HIV status, smoking, alcohol intake and body mass index ([Table 1]) with those who achieved sputum smear conversion. Earlier, Singla et al. also reported that the presence of diabetes mellitus did not affect smear positivity at two months [6]. Banu Rekha et al. (2007) found that in new sputum smear positive patients with tuberculosis, the presence of diabetes mellitus, HIV seropositivity and weight did not affect smear or culture positivity at two months [11]. In a retrospective analysis of 851 patients, mostly with pulmonary tuberculosis, in Hong Kong, ever smokers were as likely as never smokers to have smear or culture positive results at the end of two months of treatment [12].

Malnutrition or lower body mass index is known to lead to reactivation of tuberculosis and poorer outcomes to treatment [2],[12],[13],[14]. In this study, lower BMI was associated with being smear positive at two months in univariate analysis, but not in multivariate analysis ([Table 2] and [Table 3]).

Patients whose initial sputum smear grade was 3+ were more likely to be smear positive at 2 months as compared with patients with lesser grades of sputum. However, this difference was not an independent predictor of smear positivity at two months. Other larger retrospective studies done earlier have shown that a higher initial sputum smear grade is associated with being smear positive at two or three months [5, 6, 15–17].

In this study, radiologically far advanced disease and cavity were independently associated with smear positivity at 2 months of treatment ([Table 2] and [Table 3]). Cavity and extensive disease harbor a higher bacterial load [18]. Singla et al. (2003) have reported earlier that the presence of multiple cavities on X-ray was associated with persistent smear positivity at two months [6]. Cavities on chest X-ray have also been associated with less patients' culture converting by two months [19].

The influence of interruption in treatment during the intensive phase on sputum positivity at 2 months and on treatment outcome under a national program has not been analyzed before. This study ([Table 5] and [Table 6]) showed that frequent interrupters (those who interrupted treatment thrice or more) had significantly higher chances of being smear and culture positive at 2 months; had higher default and failure rates; and lower cure rates than the occasional interrupters (who interrupted treatment only once or twice). The occasional interrupters should be identified early lest they become frequent interrupters, with adverse treatment outcomes. This study demonstrated that there exists an operationally useful differentiation of ”occasional' and ”frequent' interrupters'. In future studies, the precise cut-off and influence of the number of interruptions should be better elucidated.

The factors predicting sputum AFB smear positivity at 2 months of treatment among new TB patients also predicted sputum AFB culture positivity at 2 months of treatment. This shows the association of these factors with the presence of live bacilli at 2 months, further strengthening the association of these risk factors to delayed killing of bacilli.

In India, among new TB patients, MDR-TB is estimated to be low: up to 3% [20]. Patients remaining sputum positive at 2 months also showed to be harboring higher levels of drug resistant bacilli, including multidrug-resistant bacilli to the level of 9.5% (see Figure). The interruptions during treatment among patients remaining sputum positive at 2 months may have led to amplification of drug resistance and could be the reason for observed higher levels of MDR-TB at 2 months among these patients.

Among patients who remain sputum positive at 2 months, the intensive phase of treatment is extended for one more month. Comparison of treatment outcome of patients whose sputa were positive at two or three months with those who achieved sputum conversion at two to three months ([Table 4]) showed that the former group had lower cure rates and more defaults, failures and deaths (P < 0.001, Fisher's exact test). These observations reaffirm earlier observations that sputum positivity at two to three months of treatment is a predictor of poor treatment outcome [4],[5],[6].

The sensitivity and specificity of smear positive status at two months to predict failure of treatment was 100% and 58%, respectively, as compared with smear negative patients. In a meta-analysis, Horne et al. (2010) found that there was substantial heterogeneity in sputum status at 2 months predicting failure for sensitivity across 7 studies (χ2 = 22.31, 6df, p = 0.001; I2 = 73.1%), making meaningful interpretation difficult. They concluded that although the sputum status at two months may not be a good enough surrogate marker for a poor outcome of treatment, these patients are more likely to have a failure [21]. This study suggests that the patients remaining sputum positive at 2 months of treatment, who are at a higher risk to fail treatment, form a focus group that merits more attention under the national TB control program.

This study was limited by its small sample size. There were no patients who were smear negative at two months and who had a culture positive or smear positive at three months or poor outcome of treatment, making meaningful comparison difficult.

To conclude, this study showed that under field conditions duration of illness for more than 2 months, the presence of cavity or extensive disease on chest X-ray, and interruptions in intensive phase of treatment were significant independent predictors of being smear/culture positive at two months. Sputum positivity at two months is also associated with poor treatment outcomes. An early identification of patients with these risk factors may aid in care of individual patients, achieving greater efficiency in resource utilization under the program conditions, as well as in the evaluation of new tuberculosis therapeutics. The study also highlighted the plausible influence of frequency of interruptions on adverse treatment outcome, suggesting that regularity of treatment must be ensured.


  Conflict of interest Top


None declared.



 
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    Figures

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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]


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