Pathways to diagnosis of pediatric TB patients: A mixed methods study from India.

BACKGROUND: A significant proportion of pediatric tuberculosis (TB) patients go unnotified due to the challenges in diagnosis of TB among children. The experiences of this vulnerable group while going through the TB care cascade remain largely undocumented. The aim of this study was to explore the experiences of pediatric TB patients and families along the pathway to TB diagnosis and appropriate treatment in four cities of India. METHODS: The study used a mixed methods, single phased, embedded design. The primary qualitative and secondary quantitative data were collected simultaneously by interviewing families of 100 randomly selected Xpert MTB/RIF positive pediatric TB patients, under the pediatric TB project, in 4 Indian cities using a semi-structured questionnaire. The qualitative component was analyzed to deduce patterns and themes on the patient and family experiences. Descriptive statistics were used to quantify various events along the TB care pathway including various delays (patient, diagnosis and total) and number of providers visited by patients during the diagnostic process. RESULTS: The median patient, diagnostic and total delays were 3 (IQR: 2,5), 39 (IQR: 23, 91) and 43 days (IQR: 28.5, 98.5), respectively. Patients visited a median of 3 (IQR: 2,4) providers before accessing Xpert MTB/RIF testing. On an average, 68.4% of physicians ordered any test most of them being irrelevant for TB diagnosis. Qualitative data showed considerable suffering for children and their families before and after TB diagnosis including serious concerns of stigma, disruption in education and social life and recurrence of the disease. CONCLUSION: Our study highlights the significant physical and social distress that the children with TB and their families undergo along the TB care pathway. It also shows diagnostic delay in excess of a month during which multiple providers were met and the patients underwent several diagnostic tests, most of them being inappropriate. Efforts to make Xpert MTB/RIF testing more accessible and part of physicians' toolkit will be of considerable value to ease the complexity of TB diagnosis in children. In addition, communication strategy needs to be developed and implemented to generate awareness among general population around pediatric TB and its management.

Upfront Xpert MTB/RIF for diagnosis of pediatric TB-Does it work? Experience from India.

BACKGROUND: Diagnosis of TB in pediatric population poses several challenges. A novel initiative was implemented in several major cities of India aimed at providing upfront access to free-of-cost Xpert MTB/RIF to presumptive pediatric TB cases. This paper aims to describe the experience of implementing this large initiative and assess feasibility of the intervention in high TB burden settings. METHODS: Data were drawn from the pediatric TB project implemented in 10 major cities of India between April 2014 and March 2018. In each city, providers, both public and private, were engaged and linked with a high throughput Xpert MTB/RIF lab (established in that city) through rapid specimen transportation and electronic reporting system. Rates and proportions were estimated to describe the characteristics of this cohort. RESULTS: Of the total 94,415 presumptive pediatric TB cases tested in the project, 6,270 were diagnosed positive for MTB (6.6%) on Xpert MTB/RIF (vs 2% on smear microscopy). Among MTB positives, 545 cases were rifampicin resistant (8.7%). The median duration between collection of specimens and reporting of results was 0 days (same day) and >89% cases were initiated on treatment. Approximately 50% of the specimens tested were non-sputum. The number of providers/facilities engaged under the project increased >10-fold (from 124 in Q2'14 to 1416 in Q1'18). CONCLUSION: This project, which was one of the largest initiatives globally among pediatric population, demonstrated the feasibility of sustaining rapid and upfront access to free-of-cost Xpert MTB/RIF testing. The project underscores the efficiency of this rapid diagnostic assay in tackling several challenges in pediatric TB diagnosis, identifies opportunities for further interventions as well as brings to light scope for effective engagement with healthcare providers. The findings have facilitated a policy decision by National TB Programme mandating the use of Xpert MTB/RIF as a primary diagnostic tool for TB diagnosis in children, which is being scaled-up.

Modelling the impact of effective private provider engagement on tuberculosis control in urban India.

In India, the country with the world's largest burden of tuberculosis (TB), most patients first seek care in the private healthcare sector, which is fragmented and unregulated. Ongoing initiatives are demonstrating effective approaches for engaging with this sector, and form a central part of India's recent National Strategic Plan: here we aimed to address their potential impact on TB transmission in urban settings, when taken to scale. We developed a mathematical model of TB transmission dynamics, calibrated to urban populations in Mumbai and Patna, two major cities in India where pilot interventions are currently ongoing. We found that, when taken to sufficient scale to capture 75% of patient-provider interactions, the intervention could reduce incidence by upto 21.3% (95% Bayesian credible interval (CrI) 13.0-32.5%) and 15.8% (95% CrI 7.8-28.2%) in Mumbai and Patna respectively, between 2018 and 2025. There is a stronger impact on TB mortality, with a reduction of up to 38.1% (95% CrI 20.0-55.1%) in the example of Mumbai. The incidence impact of this intervention alone may be limited by the amount of transmission that has already occurred by the time a patient first presents for care: model estimates suggest an initial patient delay of 4-5 months before first seeking care, followed by a diagnostic delay of 1-2 months before ultimately initiating TB treatment. Our results suggest that the transmission impact of such interventions could be maximised by additional measures to encourage early uptake of TB services.

Upfront Xpert MTB/RIF testing on various specimen types for presumptive infant TB cases for early and appropriate treatment initiation.

BACKGROUND: Diagnosis of tuberculosis (TB) in infants is challenging due to non-specific clinical presentations of the disease in this age-group and low sensitivity of widely available TB diagnostic tools, which in turn delays prompt access to TB treatment. Upfront access to Xpert/MTB RIF (Xpert) testing, a highly sensitive and specific rapid diagnostic tool, could potentially address some of these challenges. Under the current project, we assessed the utility and feasibility of applying upfront Xpert for diagnosis of tuberculosis in infants, including for testing of non-sputum specimens. METHODS: A high throughput lab was established in each of the four project cities, and linked to various health care providers across the city, through rapid specimen transportation and electronic reporting linkages. Free Xpert testing was offered to all infant (<2 years of age) presumptive TB cases (both pulmonary and extra-pulmonary) seeking care at public and private health facilities. RESULTS: A total of 7,994 presumptive infant TB cases were enrolled in the project from April 2014 to October 2016, detecting 465 (5.8%, CI: 5.3-6.4) TB cases. The majority (93.9%; CI: 93.4-94.4) of patient specimens were non-sputum and TB positivity was higher amongst non-sputum specimens. Further, a high proportion (5.6% CI 3.8-8.1) of infant TB cases were found to be rifampicin resistant. Covering large cities with a single lab per city over more than two years, the project demonstrated the feasibility of same-day diagnosis with upfront Xpert testing. This in turn led to prompt treatment initiation, with a two-day median turnaround time to treatment initiation. Case mortality observed in the project cohort of diagnosed TB cases was 11.0% (CI 8.4-14.1), the majority of which was pre- or early treatment mortality, in spite of prompt access to treatment for most diagnosed cases. CONCLUSION: The current project demonstrated the feasibility of applying rapid and upfront Xpert testing for presumptive infant TB cases. Rapid TB diagnosis in turn facilitates prompt and appropriate treatment initiation. Further, levels of rifampicin resistance observed in infants TB cases highlight the additional benefit of upfront resistance testing. However, high rates of early case mortality, in spite of prompt diagnosis and treatment initiation, highlight the need for further research in infant patient pathways for overall improvement in TB care for infant populations.

Catalysing progressive uptake of newer diagnostics by health care providers through outreach and education in four major cities of India.

BACKGROUND: Unlike in adults, diagnosis of TB can be challenging in children, as signs and symptoms of paediatric TB can be very non-specific and similar to other common childhood chest infections, which may lead to under or delayed diagnosis of TB disease. In spite of the increasing availability of rapid high-sensitivity diagnostics in public and private sectors, majority of paediatric TB cases are empirically diagnosed, without laboratory confirmation. To address these diagnostic challenges, World Health Organization (WHO) has recommended upfront Xpert MTB/RIF (Xpert) testing for the diagnosis of TB in paediatric presumptive pulmonary and extra-pulmonary TB (EPTB) cases. However, in spite of the increasing availability of rapid high-sensitivity diagnostics, a significant gap exists in its application with Xpert being rarely used as an upfront diagnostic among patients presumed to have TB. Under an ongoing paediatric project since April 2014, which provided free-of-cost upfront Xpert testing, several low-cost outreach and education interventions were undertaken to increase the diagnostic uptake by different providers catering to the paediatric population, thereby increasing adherence to global guidance. METHODS: Providers catering to paediatric population in the project cities were systematically mapped and contacted using different outreach strategies. The focus of outreach efforts was to increase provider literacy and increase their awareness of the availability of free rapid diagnostic services with the goal of changing their diagnostic approaches. RESULTS: From April 2014 to June 2016, more than 5,700 providers/facilities were mapped and 3,670 of them were approached. The number of providers/facilities engaged under the project increased more than 10-fold (43 in April, 2014 to 466 in June, 2016), with significant increase in project uptake, both from public and private sector. Overall 42,238 paediatric presumptive TB cases were enrolled in the project, across the four cities. Over the project period, quarterly diagnostic uptake and paediatric TB cases detection rates increased more than two-fold. TB detection rates were similar in patients from public and private sectors. CONCLUSIONS: Ongoing efforts in scaling up new rapid diagnostics involves significant investments. These efforts need to be complemented with proactive provider engagement to ensure provider-literacy and awareness, for maximizing impact of this scale-up. The current project demonstrated the usefulness of outreach and education interventions for the effective uptake of newer diagnostics.

"Before Xpert I only had my expertise": A qualitative study on the utilization and effects of Xpert technology among pediatricians in 4 Indian cities.

BACKGROUND: Diagnosing tuberculosis (TB) in children presents considerable challenges. Upfront testing on Xpert® MTB/RIF ('Xpert')-a rapid molecular assay with high sensitivity and specificity-for pediatric presumptive TB patients, as recommended by India's Revised National Tuberculosis Control Program (RNTCP), can pave the way for early TB diagnosis. As part of an ongoing project implemented by Foundation for Innovative New Diagnostics (FIND) dedicated to providing upfront free-of-cost (FOC) Xpert testing to children seeking care in the public and private sectors, a qualitative assessment was designed to understand how national guidelines on TB diagnosis and Xpert technology have been integrated into the pediatric TB care practices of different health providers. METHODS: We conducted semi-structured interviews with a sample of health providers from public and private sectors engaged in the ongoing pediatric project in 4 major cities of India. Providers were sampled from intervention data based on sector of practice, number of Xpert referrals, and TB detection rates amongst referrals. A total of 55 providers were interviewed with different levels of FOC Xpert testing uptake. Data were transcribed and analyzed inductively by a medical anthropologist using thematic content analysis and narrative analysis. RESULTS: It was observed that despite guidance from RNTCP on the use of Xpert and significant efforts by FIND and state authorities to disseminate these guidelines, there was notable diversity in their implementation by different health care providers. Xpert, apart from being utilized as intended, i.e. as a first diagnostic test for children, was utilized variably-as an initial screening test (to rule out TB), confirmatory test (once TB diagnosis is established based on antibiotic trial or clinically) and/or only for drug susceptibility testing after TB diagnosis was confirmed. Most providers who used Xpert frequently reported that Xpert was an important tool for managing pediatric TB cases, by reducing the proportion of cases diagnosed only on clinical suspicion and by providing upfront information on drug resistance, which is seldom suspected in children. Despite non-standard use, these results showed that Xpert access helped raise awareness, aided in antibiotic stewardship, and reduced dependence on clinical diagnosis among those who diagnose and treat TB in children. CONCLUSION: Access to free and rapid Xpert testing for all presumptive pediatric TB patients has had multiple positive effects on pediatricians' diagnosis and treatment of TB. It has important effects on speed of diagnosis, empirical treatment, and awareness of drug resistance among TB treatment naive children. In addition, our study shows that access to public sector Xpert machines may be an important way to encourage Public-Private integration and facilitate the movement of patients from the private to public sector for anti-TB treatment. Despite availability of rapid and free Xpert testing, our study showed an alarming diversity of Xpert utilization strategies across different providers who may be moving toward suggested practice over time. The degree of diversity in TB diagnostic approaches in children reported here highlights the urgent need for concerted efforts to place Xpert early in diagnostic algorithms to positively impact the pediatric TB care pathway. A positive change in diagnostic algorithms may be possible with continued advocacy, time, and increased access.

Accelerating access to quality TB care for pediatric TB cases through better diagnostic strategy in four major cities of India.

BACKGROUND: Diagnosis of TB in children is challenging, and is largely based on positive history of contact with a TB case, clinical and radiological findings, often without microbiological confirmation. Diagnostic efforts are also undermined by challenges in specimen collection and the limited availability of high sensitivity, rapid diagnostic tests that can be applied with a quick turnaround time. The current project was undertaken in four major cities of India to address TB diagnostic challenges in pediatric population, by offering free of cost Xpert testing to pediatric presumptive TB cases, thereby paving the way for better TB care. METHODS: A high throughput lab was established in each of the four project cities, and linked to various health care providers across the city through rapid specimen transportation and electronic reporting linkages. Free Xpert testing was offered to all pediatric (0-14 years) presumptive TB cases (both pulmonary and extra-pulmonary) seeking care at public and private health facilities. RESULTS: The current project enrolled 42,238 pediatric presumptive TB cases from April, 2014 to June, 2016. A total of 3,340 (7.91%, CI 7.65-8.17) bacteriologically confirmed TB cases were detected, of which 295 (8.83%, CI 7.9-9.86) were rifampicin-resistant. The level of rifampicin resistance in the project cohort was high. Overall Xpert yielded a high proportion of valid results and TB detection rates were more than three-fold higher than smear microscopy. The project provided same-day testing and early availability of results led to rapid treatment initiation and success rates and very low rates of treatment failure and loss to follow-up. CONCLUSION: The current project demonstrated the feasibility of rolling out rapid and upfront Xpert testing for pediatric presumptive TB cases through a single Xpert lab per city in an efficient manner. Rapid turnaround testing time facilitated prompt and appropriate treatment initiation. These results suggest that the upfront Xpert assay is a promising solution to address TB diagnosis in children. The high levels of rifampicin resistance detected in presumptive pediatric TB patients tested under the project are a major cause of concern from a public health perspective which underscores the need to further prioritize upfront Xpert access to this vulnerable population.

Scaling-up the Xpert MTB/RIF assay for the detection of tuberculosis and rifampicin resistance in India: An economic analysis.

BACKGROUND: India is considering the scale-up of the Xpert MTB/RIF assay for detection of tuberculosis (TB) and rifampicin resistance. We conducted an economic analysis to estimate the costs of different strategies of Xpert implementation in India. METHODS: Using a decision analytical model, we compared four diagnostic strategies for TB patients: (i) sputum smear microscopy (SSM) only; (ii) Xpert as a replacement for the rapid diagnostic test currently used for SSM-positive patients at risk of drug resistance (i.e. line probe assay (LPA)); (iii) Upfront Xpert testing for patients at risk of drug resistance; and (iv) Xpert as a replacement for SSM for all patients. RESULTS: The total costs associated with diagnosis for 100,000 presumptive TB cases were: (i) US$ 619,042 for SSM-only; (ii) US$ 575,377 in the LPA replacement scenario; (iii) US$ 720,523 in the SSM replacement scenario; and (iv) US$ 1,639,643 in the Xpert-for-all scenario. Total cohort costs, including treatment costs, increased by 46% from the SSM-only to the Xpert-for-all strategy, largely due to the costs associated with second-line treatment of a higher number of rifampicin-resistant patients due to increased drug-resistant TB (DR-TB) case detection. The diagnostic costs for an estimated 7.64 million presumptive TB patients would comprise (i) 19%, (ii) 17%, (iii) 22% and (iv) 50% of the annual TB control budget. Mean total costs, expressed per DR-TB case initiated on treatment, were lowest in the Xpert-for-all scenario (US$ 11,099). CONCLUSIONS: The Xpert-for-all strategy would result in the greatest increase of TB and DR-TB case detection, but would also have the highest associated costs. The strategy of using Xpert only for patients at risk for DR-TB would be more affordable, but would miss DR-TB cases and the cost per true DR-TB case detected would be higher compared to the Xpert-for-all strategy. As such expanded Xpert strategy would require significant increased TB control budget to ensure that increased case detection is followed by appropriate care.

Factors Associated with Tuberculosis and Rifampicin-Resistant Tuberculosis amongst Symptomatic Patients in India: A Retrospective Analysis.

BACKGROUND: Tuberculosis remains a major public health challenge for India. Various studies have documented different levels of TB and multi-drug resistant (MDR) TB among diverse groups of the population. In view of renewed targets set under the End TB strategy by 2035, there is an urgent need for TB diagnosis to be strengthened. Drawing on data from a recent, multisite study, we address key questions for TB diagnosis amongst symptomatics presenting for care: are there subgroups of patients that are more likely than others, to be positive for TB? In turn, amongst these positive cases, are there factors-apart from treatment history-that may be predictive for multi-drug resistance? METHODS: We used data from a multi-centric prospective demonstration study, conducted from March 2012 to December 2013 in 18 sub-district level TB programme units (TUs) in India and covering a population of 8.8 million. In place of standard diagnostic tests, upfront Xpert MTB/RIF testing was offered to all presumptive TB symptomatics. Here, using data from this study, we used logistic regression to identify association between risk factors and TB and Rifampicin-Resistant TB among symptomatics enrolled in the study. RESULTS: We find that male gender; history of TB treatment; and adult age compared with either children or the elderly are risk factors associated with high TB detection amongst symptomatics, across the TUs. While treatment history is found be a significant risk factor for rifampicin-resistant TB, elderly (65+ yrs) people have significantly lower risk than other age groups. However, pediatric TB cases have no less risk of rifampicin resistance as compared with adults (OR 1.23 (95% C.I. 0.85-1.76)). Similarly, risk of rifampicin resistance among both the genders was the same. These patterns applied across the study sites involved. Notably in Mumbai, amongst those patients with microbiological confirmation of TB, female patients showed a higher risk of having MDR-TB than male patients. CONCLUSION: Our results cast fresh light on the characteristics of symptomatics presenting for care who are most likely to be microbiologically positive for TB, and for rifampicin resistance. The challenges posed by TB control are complex and multifactorial: evidence from diverse sources, including retrospective studies such as that addressed here, can be invaluable in informing future strategies to accelerate declines in TB burden.

Piloting Upfront Xpert MTB/RIF Testing on Various Specimens under Programmatic Conditions for Diagnosis of TB & DR-TB in Paediatric Population.

BACKGROUND: India accounts for one-fifth of the global TB incidence. While the exact burden of childhood TB is not known, TB remains one of the leading causes of childhood mortality in India. Bacteriological confirmation of TB in children is challenging due to difficulty in obtaining quality specimens, in the absence of which diagnosis is largely based on clinical judgement. While testing multiple specimens can potentially contribute to higher proportion of laboratory confirmed paediatric TB cases, lack of high sensitivity tests adds to the diagnostic challenge. We describe here our experiences in piloting upfront Xpert MTB/RIF testing, for diagnosis of TB in paediatric population in respiratory and extra pulmonary specimens, as recently recommended by WHO. METHOD: Xpert MTB/RIF testing was offered to all paediatric (0-14 years) presumptive TB cases (both pulmonary and extra-pulmonary) seeking care at public and private health facilities in the project areas covering 4 cities of India. RESULTS: Under this pilot project, 8,370 paediatric presumptive TB & presumptive DR-TB cases were tested between April and-November 2014. Overall, 9,149 specimens were tested, of which 4,445 (48.6%) were non-sputum specimens. Xpert MTB/RIF gave 9,083 (99.2%, CI 99.0-99.4) valid results. Of the 8,143 presumptive TB cases enrolled, 517 (6.3%, CI 5.8-6.9) were bacteriologically confirmed. TB detection rates were two fold higher with Xpert MTB/RIF as compared to smear microscopy. Further, a total of 60 rifampicin resistant TB cases were detected, of which 38 were detected among 512 presumptive TB cases while 22 were detected amongst 227 presumptive DR-TB cases tested under the project. CONCLUSION: Xpert MTB/RIF with advantages of quick turnaround testing-time, high proportion of interpretable results and feasibility of rapid rollout, substantially improved the diagnosis of bacteriologically confirmed TB in children, while simultaneously detecting rifampicin resistance.

The Potential Impact of Up-Front Drug Sensitivity Testing on India's Epidemic of Multi-Drug Resistant Tuberculosis.

BACKGROUND: In India as elsewhere, multi-drug resistance (MDR) poses a serious challenge in the control of tuberculosis (TB). The End TB strategy, recently approved by the world health assembly, aims to reduce TB deaths by 95% and new cases by 90% between 2015 and 2035. A key pillar of this approach is early diagnosis of tuberculosis, including use of higher-sensitivity diagnostic testing and universal rapid drug susceptibility testing (DST). Despite limitations of current laboratory assays, universal access to rapid DST could become more feasible with the advent of new and emerging technologies. Here we use a mathematical model of TB transmission, calibrated to the TB epidemic in India, to explore the potential impact of a major national scale-up of rapid DST. To inform key parameters in a clinical setting, we take GeneXpert as an example of a technology that could enable such scale-up. We draw from a recent multi-centric demonstration study conducted in India that involved upfront Xpert MTB/RIF testing of all TB suspects. RESULTS: We find that widespread, public-sector deployment of high-sensitivity diagnostic testing and universal DST appropriately linked with treatment could substantially impact MDR-TB in India. Achieving 75% access over 3 years amongst all cases being diagnosed for TB in the public sector alone could avert over 180,000 cases of MDR-TB (95% CI 44187 - 317077 cases) between 2015 and 2025. Sufficiently wide deployment of Xpert could, moreover, turn an increasing MDR epidemic into a diminishing one. Synergistic effects were observed with assumptions of simultaneously improving MDR-TB treatment outcomes. Our results illustrate the potential impact of new and emerging technologies that enable widespread, timely DST, and the important effect that universal rapid DST in the public sector can have on the MDR-TB epidemic in India.

Has introduction of rapid drug susceptibility testing at diagnosis impacted treatment outcomes among previously treated tuberculosis patients in Gujarat, India?

BACKGROUND: Revised National TB Control Programme (RNTCP) in India recommends that all previously-treated TB (PT) patients are offered drug susceptibility testing (DST) at diagnosis, using rapid diagnostics and screened out for rifampicin resistance before being treated with standardized, eight-month, retreatment regimen. This is intended to improve the early diagnosis of rifampicin resistance and its appropriate management and improve the treatment outcomes among the rest of the patients. In this state-wide study from Gujarat, India, we assess proportion of PT patients underwent rapid DST at diagnosis and the impact of this intervention on their treatment outcomes. METHODS: This is a retrospective cohort study involving review of electronic patient-records maintained routinely under RNTCP. All PT patients registered for treatment in Gujarat during January-June 2013 were included. Information on DST and treatment outcomes were extracted from 'presumptive DR-TB patient register' and TB treatment register respectively. We performed a multivariate analysis to assess if getting tested is independently associated with unfavourable outcomes (death, loss-to-follow-up, failure, transfer out). RESULTS: Of 5,829 PT patients, 5306(91%) were tested for drug susceptibility with rapid diagnostics. Overall, 71% (4,113) TB patients were successfully treated - 72% among tested versus 60% among non-tested. Patients who did not get tested at diagnosis had a 34% higher risk of unsuccessful outcomes as compared to those who got tested (aRR - 1.34; 95% CI 1.20-1.50) after adjusting for age, sex, HIV status and type of TB. Unfavourable outcomes (particularly failure and switched to category IV) were higher among INH-resistant patients (39%) as compared to INH-sensitive (29%). CONCLUSION: Offering DST at diagnosis improved the treatment outcomes among PT patients. However, even among tested, treatment outcomes remained suboptimal and were related to INH resistance and high loss-to-follow-up. These need to be addressed urgently for further progress.

Standards for TB care in India: A tool for universal access to TB care.

In 2014, Government of India in collaboration with World Health Organization Country Office for India released the policy document on Standards for tuberculosis (TB) care in India after in-depth deliberation with national and international experts. The standards for TB care represent what is expected for quality TB care from the Indian healthcare system including both public and private systems. The details of each standard have been compiled in this review article. It is envisioned that the standards detailed in the manuscript are adapted by all TB care providers across the country.

Public-private mix for TB care in India: Concept, evolution, progress.

To achieve "Universal access to TB care and treatment for all", Revised National Tuberculosis Control Programme (RNTCP) has taken steps to reach the unreached by synergizing the efforts of all partners and stakeholders. RNTCP is engaging with private sector partners in major cities of India with primary focus on notification through innovative partnership mechanisms. The manuscript details the concept behind the public-private mix for TB Care in RNTCP, its evolution and progress over the decades in India.

Enhancing TB case detection: experience in offering upfront Xpert MTB/RIF testing to pediatric presumptive TB and DR TB cases for early rapid diagnosis of drug sensitive and drug resistant TB.

BACKGROUND: Diagnosis of pulmonary tuberculosis (PTB) in children is challenging due to difficulties in obtaining good quality sputum specimens as well as the paucibacillary nature of disease. Globally a large proportion of pediatric tuberculosis (TB) cases are diagnosed based only on clinical findings. Xpert MTB/RIF, a highly sensitive and specific rapid tool, offers a promising solution in addressing these challenges. This study presents the results from pediatric groups taking part in a large demonstration study wherein Xpert MTB/RIF testing replaced smear microscopy for all presumptive PTB cases in public health facilities across India. METHODS: The study covered a population of 8.8 million across 18 programmatic sub-district level tuberculosis units (TU), with one Xpert MTB/RIF platform established at each study TU. Pediatric presumptive PTB cases (both TB and Drug Resistant TB (DR-TB)) accessing any public health facilities in study area were prospectively enrolled and tested on Xpert MTB/RIF following a standardized diagnostic algorithm. RESULTS: 4,600 pediatric presumptive pulmonary TB cases were enrolled. 590 (12.8%, CI 11.8-13.8) pediatric PTB were diagnosed. Overall 10.4% (CI 9.5-11.2) of presumptive PTB cases had positive results by Xpert MTB/RIF, compared with 4.8% (CI 4.2-5.4) who had smear-positive results. Upfront Xpert MTB/RIF testing of presumptive PTB and presumptive DR-TB cases resulted in diagnosis of 79 and 12 rifampicin resistance cases, respectively. Positive predictive value (PPV) for rifampicin resistance detection was high (98%, CI 90.1-99.9), with no statistically significant variation with respect to past history of treatment. CONCLUSION: Upfront access to Xpert MTB/RIF testing in pediatric presumptive PTB cases was associated with a two-fold increase in bacteriologically-confirmed PTB, and increased detection of rifampicin-resistant TB cases under routine operational conditions across India. These results suggest that routine Xpert MTB/RIF testing is a promising solution to present-day challenges in the diagnosis of PTB in pediatric patients.

Does Alcohol consumption during multidrug-resistant tuberculosis treatment affect outcome?. A population-based study in Kerala, India.

RATIONALE: India reports the largest number of multidrug-resistant tuberculosis cases in the world; yet, no longitudinal study has assessed factors related to treatment outcomes under programmatic conditions in the public sector. OBJECTIVES: To describe demographic, clinical, and risk characteristics associated with treatment outcomes for all patients with multidrug-resistant tuberculosis registered in the Revised National Tuberculosis Control Programme, Kerala State, India from January 1, 2009 to June 30, 2010. METHODS: Cox regression methods were used to calculate adjusted hazard ratios with 95% confidence intervals (CIs) to assess factors associated with an unsuccessful treatment outcome. MEASUREMENTS AND MAIN RESULTS: Of 179 patients with multidrug-resistant tuberculosis registered, 112 (63%) had successful treatment outcomes (77 bacteriologically cured, 35 treatment completed) and 67 (37%) had unsuccessful treatment outcomes (30 died, 26 defaulted, 9 failed treatment, 1 stopped treatment because of drug-related adverse events, and 1 developed extensively drug-resistant tuberculosis). The hazard for unsuccessful outcome was significantly higher among patients who consumed alcohol during treatment (adjusted hazard ratio, 4.3; 95% CI, 1.1-17.6) than those who did not. Persons who consumed alcohol during treatment, on average, missed 18 more intensive-phase doses (95% CI, 13-22) than those who did not. Although many patients had diabetes (33%), were ever smokers (39%), or had low body mass index (47%), these factors were not associated with outcome. CONCLUSION: Overall treatment success was greater than global and national averages; however, outcomes among patients consuming alcohol remained poor. Integration of care for multidrug-resistant tuberculosis and alcoholism should be considered to improve treatment adherence and outcomes.

Comparing same day sputum microscopy with conventional sputum microscopy for the diagnosis of tuberculosis--Chhattisgarh, India.

BACKGROUND: The World Health Organization (WHO) recommends same day sputum microscopy (spot-spot) in preference to conventional strategy (spot-morning) for the diagnosis of smear positive tuberculosis with the view that completing diagnosis on a single day may be more convenient to the patients and reduce pre-treatment losses to follow-up. METHODS: We conducted a cross-sectional study in seven selected district level hospitals of Chhattisgarh State, India. During October 2012 - March 2013, two sputum specimens (spot-early morning) were collected from consecutively enrolled adult (≥ 18 years) presumptive TB patients as per current national guidelines. In addition, a second sample was collected (one hour after the collection of first spot sample) from the same patients. All the samples were examined by ziehl-Neelsen (ZN) microscopy. McNemar's test was used to compare statistical differences in the proportion smear positive between the two approaches (spot-spot versus spot-morning). RESULTS: Of 2551 presumptive TB patients, 69% were male. All patients provided the first spot specimen, 2361 (93%) provided the second spot specimen, and 2435 (96%) provided an early morning specimen. 72% of specimens were mucopurulent in conventional strategy as compared to 60% in same day strategy. The proportion of smear-positive patients diagnosed by same day microscopy was 14%, as compared to 17% by the conventional method (p<0.001). A total of 73 (16.9%) potential cases were missed by the same day method compared to only 2 (0.5%) by the conventional method. CONCLUSION: Same-day microscopy method missed 17% of smear-positive cases and contrary to prior perception, did not increase the proportion of suspects providing the second sample. These findings call for an urgent need to revisit the WHO recommendation of switching to same-day diagnosis over the current policy.

High diabetes prevalence among tuberculosis cases in Kerala, India.

BACKGROUND: While diabetes mellitus (DM) is a known risk factor for tuberculosis, the prevalence among TB patients in India is unknown. Routine screening of TB patients for DM may be an opportunity for its early diagnosis and improved management and might improve TB treatment outcomes. We conducted a cross-sectional survey of TB patients registered from June-July 2011 in the state of Kerala, India, to determine the prevalence of DM. METHODOLOGY/PRINCIPAL FINDINGS: A state-wide representative sample of TB patients in Kerala was interviewed and screened for DM using glycosylated hemoglobin (HbA1c); patients self-reporting a history of DM or those with HbA1c ≥6.5% were defined as diabetic. Among 552 TB patients screened, 243(44%) had DM - 128(23%) had previously known DM and 115(21%) were newly diagnosed - with higher prevalence among males and those aged >50 years. The number needed to screen(NNS) to find one newly diagnosed case of DM was just four. Of 128 TB patients with previously known DM, 107(84%) had HbA1c ≥7% indicating poor glycemic control. CONCLUSIONS/SIGNIFICANCE: Nearly half of TB patients in Kerala have DM, and approximately half of these patients were newly-diagnosed during this survey. Routine screening of TB patients for DM using HbA1c yielded a large number of DM cases and offered earlier management opportunities which may improve TB and DM outcomes. However, the most cost-effective ways of DM screening need to be established by futher operational research.

Sputum smear microscopy at two months into continuation-phase: should it be done in all patients with sputum smear-positive tuberculosis?

BACKGROUND: The Revised National Tuberculosis Control Program (RNTCP) of India recommends follow-up sputum smear examination at two months into the continuation phase of treatment. The main intent of this (mid-CP) follow-up is to detect patients not responding to treatment around two-three months earlier than at the end of the treatment. However, the utility of mid-CP follow-up under programmatic conditions has been questioned. We undertook a multi-district study to determine if mid-CP follow-up is able to detect cases of treatment failures early among all types of patients with sputum smear-positive TB. METHODOLOGY: We reviewed existing records of patients with sputum smear-positive TB registered under the RNTCP in 43 districts across three states of India during a three month period in 2009. We estimated proportions of patients that could be detected as a case of treatment failure early, and assessed the impact of various policy options on laboratory workload and number needed to test to detect one case of treatment failure early. RESULTS: Of 10055 cases, mid-CP follow-up was done in 6944 (69%) cases. Mid-CP follow-up could benefit 117/8015 (1.5%) new and 206/2040 (10%) previously-treated sputum smear-positive cases by detecting their treatment failure early. Under the current policy, 31 patients had to be tested to detect one case of treatment failure early. All cases of treatment failure would still be detected early if mid-CP follow-up were discontinued for new sputum smear-positive cases who become sputum smear-negative after the intensive-phase of treatment. This would reduce the related laboratory workload by 69% and only 10 patients would need to be tested to detect one case of treatment failure early. CONCLUSION: Discontinuation of mid-CP follow-up among new sputum smear-positive cases who become sputum smear-negative after completing the intensive-phase of treatment will reduce the laboratory workload without impacting overall early detection of cases of treatment failure.

Source of previous treatment for re-treatment TB cases registered under the National TB control Programme, India, 2010.

BACKGROUND: In 2009, nearly half (289,756) of global re-treatment TB notifications are from India; no nationally-representative data on the source of previous treatment was available to inform strategies for improvement of initial TB treatment outcome. OBJECTIVES: To assess the source of previous treatment for re-treatment TB patients registered under India's Revised National TB control Programme (RNTCP). METHODOLOGY: A nationally-representative cross sectional study was conducted in a sample of 36 randomly-selected districts. All consecutively registered retreatment TB patients during a defined 15-day period in these 36 districts were contacted and the information on the source of previous treatment sought. RESULTS: Data was collected from all 1712 retreatment TB patients registered in the identified districts during the study period. The data includes information on 595 'relapse' cases, 105 'failure' cases, 437 'treatment after default (TAD)' cases and 575 're-treatment others' cases. The source of most recent previous anti-tuberculosis therapy for 754 [44% (95% CI, 38.2%-49.9%)] of the re-treatment TB patients was from providers outside the TB control programme. A higher proportion of patients registered as TAD (64%) and 'retreatment others' (59%) were likely to be treated outside the National Programme, when compared to the proportion among 'relapse' (22%) or 'failure' (6%). Extrapolated to national registration, of the 292,972 re-treatment registrations in 2010, 128,907 patients would have been most recently treated outside the national programme. CONCLUSIONS: Nearly half of the re-treatment cases registered with the national programme were most recently treated outside the programme setting. Enhanced efforts towards extending treatment support and supervision to patients treated by private sector treatment providers are urgently required to improve the quality of treatment and reduce the numbers of patients with recurrent disease. In addition, reasons for the large number of recurrent TB cases from those already treated by the national programme require urgent detailed investigation.