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.

Cost and operational impact of promoting upfront GeneXpert MTB/RIF test referrals for presumptive pediatric tuberculosis patients in India.

BACKGROUND: Outreach and promotion programs are essential to ensuring uptake of new public health interventions and guidelines. We assessed the costs and operation dynamics of outreach and promotion efforts for up front Xpert MTB/RIF (Xpert) testing for pediatric presumptive tuberculosis (TB) patients in four major Indian cities. METHODS: Xpert test costs were assessed as weighted average per-test costs based on the daily workload dynamics matched by test volume specific Xpert unit cost at each study site. Costs of outreach programs to recruit health providers to refer pediatric patients for Xpert testing were assessed as cost per referral for each quarter based on total program costs and referral data. All costs were assessed in the health service provider's perspective and expressed in 2015 USD. RESULTS: Weighted average per-test costs ranged from $14.71 to $17.81 at the four laboratories assessed. Differences between laboratories were associated with unused testing capacity and/or frequencies of overtime work to cope with increasing demand and same-day testing requirements. Outreach activities generated between 825 and 2,065 Xpert testing referrals on average each quarter across the four study sites, translating into $0.63 to $2.55 per patient referred. Overall outreach costs per referral decreased with time, stabilizing at an average cost of $1.10, and demonstrated a clear association with increased referrals. CONCLUSIONS: Xpert test and outreach program costs within and across study sites were mainly driven by the dynamics of Xpert testing demand resulting from the combined outreach activities. However, these increases in demand required considerable overtime work resulting in additional costs and operational challenges at the study laboratories. Therefore, careful laboratory operational adjustment should be evaluated at target areas in parallel to the anticipated demand from the Xpert referral outreach program scale-up in other Indian regions.

"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.

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.

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.