Non-conversion of sputum culture among patients with smear positive pulmonary tuberculosis in Cameroon: a prospective cohort study

Tuberculosis (TB), despite the existing prevention and control strategies remains a major public health problem. In the year 2011 alone for example, 8.7 million new cases of the disease were declared around the world, with a large proportion of these occurring in developing countries [1]. In developing countries, insufficient resources are a deterrent to routine testing of the susceptibility of Mycobacterium tuberculosis (M. tuberculosis) to antituberculosis drugs prior to the treatment. In this context, direct sputum examination for the presence of acid-fast bacilli (AFB) is routinely used both to assess the contagiosity and to predict the outcome of care during the treatment of patients with smear positive pulmonary tuberculosis (SPPTB) [2, 3]. A negative sputum smear on direct sputum examination at the end of the intensive phase of treatment is equally used as criteria for the transition to the continuation phase [2, 3]. About 5 to 30% of patients with a first episode of SPPTB according to some reports remain positive after two months of treatment. A variable proportion of these patients still have viable M. tuberculosis and as such continue to contribute to the spread of the disease [4]. It also appears that the course of the disease in such patients is less favourable with high rates of treatment failure and treatment discontinuation [5, 6].

The relationship of positive smear with culture conversion for M. tuberculosis at the completion of the intensive phase of antituberculosis treatment as well as its impact if any, on the outcome of care have in general have been less investigated. In a study by Su et al. [7] the non-use of directly observed treatment (DOT) and resistance to rifampicin were reported to be the main factors associated with non-conversion of sputum culture at the end of intensive phase of antituberculosis treatment in Taiwan. The aim of this study was to determine the frequency and identify factors associated with non-conversion of sputum culture for M. tuberculosis as well as assess its impact on the outcome of patients treated for a first episode of SPPTB with persistent sputum smear positivity at the end of the two month intensive phase of antituberculosis treatment.

Four main findings emerge from this study conducted in a country with medium endemicity for tuberculosis among patients with positive smear after the intensive phase of treatment for a first episode of SPPTB: 1) over half of the patients with positive smears after the intensive phase of treatment have positive cultures for M. tuberculosis (culture non-conversion); 2) current active smoking and absence of haemoptysis are the main determinants of culture non-conversion; 3) about 4% of patients with culture non-conversion have multidrug resistant TB; and 4) treatment failure is very high among patients with positive cultures compared to those with negative cultures.

Our findings suggest that over half of the patients with persistent positive smears on direct examination after the intensive phase of anti-TB treatment also have positive cultures, and therefore remain contagious. In a cohort followed by Su and co-workers [7], Involving 113 patients with positive smears after receiving intensive treatment, 56% also had positive cultures for M. tuberculosis. Our findings are also similar to those reported by Ramarokoto et al. in Madagascar [10]. WHO guidelines are currently against extending the intensive phase of treatment among patients who remain smear positive after two months of an intensive treatment with a regimen containing rifampicin [3]. This recommendation essentially is based on the fact that positive sputum smears on direct examination following the intensive phase of anti-TB treatment is not a good indicator of the treatment outcome. It is instead recommended that sputum culture and drug susceptibility tests be conducted in all patients with positive smears at the completion of the intensive treatment and at the end of the 3^rd month of treatment. In resource limited countries however, the high incidence of tuberculosis and insufficient equipment remain deterrents to systematic sputum culture and susceptibility tests.

In Cameroon where about 6-13% of patients with smear positive tuberculosis are still positive after completing the intensive phase of treatment [6, 11], our findings suggest that per year, about 1200 patients with tuberculosis in the country remain contagious after completing this phase of treatment. The current approach of the National Tuberculosis Control Program(NTCP), which consists in extending this phase by an additional month [2] needs to be clarified by further studies, since despite the extension of the intensive phase, the failure rate is fairly high especially in the subgroup of patients with positive culture. Such a strategy could aid in reducing the spread of the disease by a number of these patients. It is however known that the median time from treatment start to achieving negative smear is about 17.5 days [8]. Therefore, patients with persistent positive smears after two months of intensive treatment are likely a subgroup of patients for whom specific actions are needed to optimise the treatment and care. The adoption therefore in developing countries of modern rapid methods for identifying and testing the susceptibility of M. tuberculosis to at least rifampicin should be considered and encouraged. These will help considerably in improving clinical decision making. Even in the absence of multiple drugs resistant tuberculosis, treatment failure was high in group C + patients. These were essentially clinical failure, likely due to poor adherence; suggesting the need for an ongoing supervision of these patients throughout the entire course of their treatment.

None of the baseline radiographic or bacteriologic features was associated with culture non-conversion after intensive treatment among our patients. A study in Taiwan reported the presence of cavitation or condensation on chest X-ray, as well as non-use of Direct Observed Treatment strategy, to be associated with culture non-conversion [7]. Elsewhere, high baseline bacillary load (≥2+) has been associated with delayed culture conversion [4]. In this study, haemoptysis was observed to be significantly associated with patients having culture conversions (C+). The exact reason for this association is not known. In agreement with the results of our study, current smoking at baseline has also been observed to be associated with culture non-conversion in similar studies from Brazil [12] and Spain [13]. It could be speculated that the impairment of local pulmonary defences caused by the persistent irritation of tobacco smoke may play a role. Screening for these factors in settings where culture of mycobacterium are not available, could aid the identification of a subgroup of patients who require more intensive monitoring.

In this study, the prevalence of multidrug resistant M. tuberculosis strains in patients with positive cultures was 4.3%. This prevalence is relatively high as compared to rates (0 to 2.7%) reported for patients with a first episode of SPPTB in the same region [14]. This suggests that patients with persistent culture positivity at the end of the 2 month intensive phase of anti-tuberculosis treatment constitute a high risk group for multidrug resistant tuberculosis MDR-TB. As such this group of patients should like retreatment cases be included in the high risk group of patients for MDR-TB so that they could benefit from sputum cultures for identification and drug susceptibility testing of their M. tuberculosis strains. This will allow for a timely adjustment of their treatment as opposed to waiting until 3 months as recommended presently by WHO [3]. Cost-effectiveness studies are needed to guide the choice of the appropriate strategies particularly in resources-limited settings.

The present study has some limitations. No sputum smear control examination was done at the end of the extended intensive phase. This would have allowed us to assess the effects of non-conversion after 3 months of intensive treatment on the outcomes of care. Furthermore, no culture was performed at the end of the entire treatment cycle, and the outcome of care was essentially guided by the WHO recommendations, based on smear examination at five or six months of treatment [2, 3]. The study also has some major advantages including its prospective nature, the enrolment of both HIV + and HIV- patients, and the relatively large number of patients with persistent positive smears after receiving intensive phase treatment.

Over half of the patients with a first episode of SPPTB presenting persistent positive smears after an intensive phase of anti-TB treatment have positive cultures for Mycobacterium tuberculosis in Yaounde. Treatment failure is more frequent among these patients, even in the absence of MDR-TB. Our findings support the need for a monitoring of the entire treatment cycle in these patients, and the adoption of rapid drug susceptibility tests for patients with persistent positive smears after intensive phase treatment. This will allow timely adjustment of the treatment as opposed to waiting until the end of the third month of treatment as currently done.