Impact of systematic early tuberculosis detection using Xpert MTB/RIF Ultra in children with severe pneumonia in high tuberculosis burden countries (TB-Speed pneumonia): a stepped wedge cluster randomized trial.

BACKGROUND: In high tuberculosis (TB) burden settings, there is growing evidence that TB is common in children with pneumonia, the leading cause of death in children under 5 years worldwide. The current WHO standard of care (SOC) for young children with pneumonia considers a diagnosis of TB only if the child has a history of prolonged symptoms or fails to respond to antibiotic treatments. As a result, many children with TB-associated severe pneumonia are currently missed or diagnosed too late. We therefore propose a diagnostic trial to assess the impact on mortality of adding the systematic early detection of TB using Xpert MTB/RIF Ultra (Ultra) performed on nasopharyngeal aspirates (NPA) and stool samples to the WHO SOC for children with severe pneumonia, followed by immediate initiation of anti-TB treatment in children testing positive on any of the samples. METHODS: TB-Speed Pneumonia is a pragmatic stepped-wedge cluster randomized controlled trial conducted in six countries with high TB incidence rate (Côte d'Ivoire, Cameroon, Uganda, Mozambique, Zambia and Cambodia). We will enrol 3780 children under 5 years presenting with WHO-defined severe pneumonia across 15 hospitals over 18 months. All hospitals will start managing children using the WHO SOC for severe pneumonia; one hospital will be randomly selected to switch to the intervention every 5 weeks. The intervention consists of the WHO SOC plus rapid TB detection on the day of admission using Ultra performed on 1 nasopharyngeal aspirate and 1 stool sample. All children will be followed for 3 months, with systematic trial visits at day 3, discharge, 2 weeks post-discharge, and week 12. The primary endpoint is all-cause mortality 12 weeks after inclusion. Qualitative and health economic evaluations are embedded in the trial. DISCUSSION: In addition to testing the main hypothesis that molecular detection and early treatment will reduce TB mortality in children, the strength of such pragmatic research is that it provides some evidence regarding the feasibility of the intervention as part of routine care. Should this intervention be successful, safe and well tolerated, it could be systematically implemented at district hospital level where children with severe pneumonia are referred. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03831906 . Registered 6 February 2019.

Early detection of tuberculosis through community-based active case finding in Cambodia.

BACKGROUND: Since 2005, Cambodia's national tuberculosis programme has been conducting active case finding (ACF) with mobile radiography units, targeting household contacts of TB patients in poor and vulnerable communities in addition to routine passive case finding (PCF). This paper examines the differences in the demographic characteristics, smear grades, and treatment outcomes of pulmonary TB cases detected through both active and passive case finding to determine if ACF could contribute to early case finding, considering associated project costs for ACF. METHODS: Demographic characteristics, smear grades, and treatment outcomes were compared between actively (n = 405) and passively (n = 602) detected patients by reviewing the existing programme records (including TB registers) of 2009 and 2010. Additional analyses were performed for PCF cases detected after the ACF sessions (n = 91). RESULTS: The overall cost per case detected through ACF was US$ 108. The ACF approach detected patients from older populations (median age of 55 years) compared to PCF (median age of 48 years; p < 0.001). The percentage of smear-negative TB cases detected through ACF was significantly higher (71.4%) than that of PCF (40.5%). Among smear-positive patients, lower smear grades were observed in the ACF group compared to the PCF group (p = 0.002). A fairly low initial defaulter rate (21 patients, 5.2%) was observed in the ACF group. Once treatment was initiated, high treatment success rates were achieved with 96.4% in ACF and with 95.2% in PCF. After the ACF session, the smear grade of TB patients detected through routine PCF continued to be low, suggesting increased awareness and early case detection. CONCLUSIONS: The community-based ACF in Cambodia was found to be a cost-effective activity that is likely to have additional benefits such as contribution to early case finding and detection of patients from a vulnerable age group, possibly with an extended benefit for reducing secondary cases in the community. Further investigations are required to clarify the primary benefits of ACF in early and increased case detection and to assess its secondary impact on reducing on-going transmission.

The multi-step process of building TB/HIV collaboration in Cambodia.

Tuberculosis and HIV/AIDS have synergistic health impacts in terms of disease development and progression. Therefore, collaborative TB and HIV/AIDS activities are a logical health systems response. However, the establishment of these activities presents a challenge for countries that have strong vertical disease programs that differ in their implementation philosophies. Here, we review the process by which TB/HIV collaboration was established in Cambodia. A cycle of overlapping and mutually reinforcing initiatives - local research; piloted implementation with multiple options; and several rounds of policy formulation guided by a cross-functional Technical Working Group - was used to drive nationwide introduction of a full set of TB/HIV collaborative activities. Senior Ministry of Health officials and partner organizations brought early attention to TB/HIV. Both national programs implemented initial screening and testing interventions, even in the absence of a detailed, overarching framework. The use of multiple options for HIV testing identified which programmatic options worked best, and early implementation and pilots determined what unanswered questions required further research. Local conduct of this research - on co-treatment timing and TB symptom screening - speeded adoption of the results into policy guidance, and clarified the relative roles of the two programs. Roll-out is continuing, and results for a variety of key indicators, including screening PLHIV for TB, and testing TB patients for HIV, are at 70-80% and climbing. This experience in Cambodia illustrates the influence of health research on policy, and demonstrates that clear policy guidance, the pursuit of incremental advances, and the use of different approaches to generate evidence can overcome structural barriers to change and bring direct benefits to patients.

Health-system strengthening and tuberculosis control.

Weak health systems are hindering global efforts for tuberculosis care and control, but little evidence is available on effective interventions to address system bottlenecks. This report examines published evidence, programme reviews, and case studies to identify innovations in system design and tuberculosis control to resolve these bottlenecks. We outline system bottlenecks in relation to governance, financing, supply chain management, human resources, health-information systems, and service delivery; and adverse effects from rapid introduction of suboptimum system designs. This report also documents innovative solutions for disease control and system design. Solutions pursued in individual countries are specific to the nature of the tuberculosis epidemic, the underlying national health system, and the contributors engaged: no one size fits all. Findings from countries, including Bangladesh, Cambodia, India, Tanzania, Thailand, and Vietnam, suggest that advances in disease control and system strengthening are complementary. Tuberculosis care and control are essential elements of health systems, and simultaneous efforts to innovate systems and disease response are mutually reinforcing. Highly varied and context-specific responses to tuberculosis show that solutions need to be documented and compared to develop evidence-based policies and practice.

Results from a roving, active case finding initiative to improve tuberculosis detection among older people in rural cambodia using the Xpert MTB/RIF assay and chest X-ray.

BACKGROUND: Cambodia has one of the highest tuberculosis (TB) prevalence rates in the world. People aged 55 years and over account for an estimated 50% of the country's TB burden, yet this group has a low notification rate owing to specific barriers in accessing health services. One-off active case finding (ACF) days with mobile GeneXpert and X-ray systems were organized at 75 government health facilities in four operational districts. Symptomatic community members with an abnormal chest X-ray were tested using the Xpert MTB/RIF assay. People with TB were then treated at health facilities after screening services moved onto the next site. METHODS: De-identified project data were analysed to produce descriptive statistics about the people tested on Xpert and those diagnosed with TB. A linear regression was fit through the 12 quarters of National TB Program (NTP) TB case notification data immediately prior to ACF. The regression was used to calculate trend-expected notifications during and after the ACF quarters. Notifications from the ACF quarters were then compared to actual notifications from the previous year and to the trend-expected notifications during the ACF quarter by age group and type of TB. Finally, NTP TB treatment outcomes for the patients started on treatment during the ACF quarter were compared to those from a year prior. RESULTS: 2068 individuals submitted sputum for Xpert MTB/RIF testing, resulting in the identification of 319 (15.4%) bacteriologically-positive TB patients and an additional 574 people who were clinically diagnosed with TB. In the ACF quarters, new bacteriologically-positive notifications increased +119.2% for all ages and +262.7% for people aged 55 and over compared with trend-expected notifications. Treatment initiation figures remained above trend-expected notifications for three full quarters after ACF. The treatment success rate across all operational districts was significantly higher for patients detected in the ACF quarters (88.8% vs 94.5%, p = 0.012). CONCLUSION: A series of roving, one-off ACF days at government health facilities were able to increase TB diagnosis, treatment initiation and treatment outcomes in a key population with high TB prevalence. Targeted ACF interventions such as this could be used to reduce a backlog of untreated, prevalent TB.

A strong TB programme embedded in a developing primary healthcare system is a lose-lose situation: insights from patient and community perspectives in Cambodia.

As exemplified by the situation in Cambodia, disease specific (vertical) health programmes are often favoured when the health system is fragile. The potential of such an approach to impede strengthening of primary healthcare services has been studied from a health systems perspective in terms of access and quality of care. In this bottom-up, qualitative study we investigate patient and community member experiences of health services when a strong tuberculosis (TB) programme is embedded into a relatively underutilized primary healthcare system. We conducted six gender-stratified community focus group discussions (n = 49) and seven mixed-gender focus group discussions with TB patients (n = 45) in three provinces located in urban, peri-urban and rural areas of Cambodia. Our analysis of health-seeking behaviour and experiences for TB and TB-like illness indicates that building a strong vertical TB control programme has had numerous benefits, including awareness of typical symptoms and need to seek care early; confidence in free TB services at public facilities; and willingness to complete treatment. However, there was a clear dichotomy in experiences and behaviour with respect to care-seeking for less severe illness at primary health services, which were generally avoided owing to access barriers and perceived poor quality. The tendency to delay seeking health care until the development of severe symptoms clearly indicative of TB is a major barrier to early diagnosis and treatment of TB. Our study indicates that an imbalance in the strength of vertical and primary health services could be a lose-lose situation as this impedes improvements in health system functioning and constrains progress of vertical disease control programmes.

Increased Case Notification through Active Case Finding of Tuberculosis among Household and Neighbourhood Contacts in Cambodia.

BACKGROUND: Globally, there has been growing evidence that suggests the effectiveness of active case finding (ACF) for tuberculosis (TB) in high-risk populations. However, the evidence is still insufficient as to whether ACF increases case notification beyond what is reported in the routine passive case finding (PCF). In Cambodia, National TB Control Programme has conducted nationwide ACF with Xpert MTB/RIF that retrospectively targeted household and neighbourhood contacts alongside routine PCF. This study aims to investigate the impact of ACF on case notifications during and after the intervention period. METHODS: Using a quasi-experimental cluster randomized design with intervention and control arms, we compared TB case notification during the one-year intervention period with historical baseline cases and trend-adjusted expected cases, and estimated additional cases notified during the intervention period (separately for Year 1 and Year 2 implementation). The proportion of change in case notification was compared between intervention and control districts for Year 1. The quarterly case notification data from all intervention districts were consolidated, aligning different implementation quarters, and separately analysed to explore the additionality. The effect of the intervention on the subsequent case notification during the post-intervention period was also assessed. RESULTS: In Year 1, as compared to expected cases, 1467 cases of all forms (18.5%) and 330 bacteriologically-confirmed cases (9.6%) were additionally notified in intervention districts, whereas case notification in control districts decreased by 2.4% and 2.3%, respectively. In Year 2, 2737 cases of all forms (44.3%) and 793 bacteriologically-confirmed cases (38%) were additionally notified as compared to expected cases. The proportions of increase in case notifications from baseline cases and expected cases to intervention period cases were consistently higher in intervention group than in control group. The consolidated quarterly data showed sharp rises in all forms and bacteriologically-confirmed cases notified during the intervention quarter, with 64.6% and 68.4% increases (compared to baseline cases), and 46% and 52.9% increases (compared to expected cases), respectively. A cumulative reduction of case notification for five quarters after ACF reached more than -200% of additional cases. CONCLUSIONS: The Cambodia's ACF with Xpert MTB/RIF that retrospectively targeted household and neighbourhood contacts resulted in the substantial increase in case notification during the intervention period and reduced subsequent case notification during the post-intervention period. The applicability of retrospective contact investigation in other high-burden settings should be explored.

Mitigating Financial Burden of Tuberculosis through Active Case Finding Targeting Household and Neighbourhood Contacts in Cambodia.

BACKGROUND: Despite free TB services available in public health facilities, TB patients often face severe financial burden due to TB. WHO set a new global target that no TB-affected families experience catastrophic costs due to TB. To monitor the progress and strategize the optimal approach to achieve the target, there is a great need to assess baseline cost data, explore potential proxy indicators for catastrophic costs, and understand what intervention mitigates financial burden. In Cambodia, nationwide active case finding (ACF) targeting household and neighbourhood contacts was implemented alongside routine passive case finding (PCF). We analyzed household cost data from ACF and PCF to determine the financial benefit of ACF, update the baseline cost data, and explore whether any dissaving patterns can be a proxy for catastrophic costs in Cambodia. METHODS: In this cross-sectional comparative study, structured interviews were carried out with 108 ACF patients and 100 PCF patients. Direct and indirect costs, costs before and during treatment, costs as percentage of annual household income and dissaving patterns were compared between the two groups. RESULTS: The median total costs were lower by 17% in ACF than in PCF ($240.7 [IQR 65.5-594.6] vs $290.5 [IQR 113.6-813.4], p = 0.104). The median costs before treatment were significantly lower in ACF than in PCF ($5.1 [IQR 1.5-25.8] vs $22.4 [IQR 4.4-70.8], p<0.001). Indirect costs constituted the largest portion of total costs (72.3% in ACF and 61.5% in PCF). Total costs were equivalent to 11.3% and 18.6% of annual household income in ACF and PCF, respectively. ACF patients were less likely to dissave to afford TB-related expenses. Costs as percentage of annual household income were significantly associated with an occurrence of selling property (p = 0.02 for ACF, p = 0.005 for PCF). CONCLUSIONS: TB-affected households face severe financial hardship in Cambodia. ACF has the great potential to mitigate the costs incurred particularly before treatment. Social protection schemes that can replace lost income are critically needed to compensate for the most devastating costs in TB. An occurrence of selling household property can be a useful proxy for catastrophic cost in Cambodia.

Responding to cough presentations: an interview study with Cambodian pharmacies participating in a National Tuberculosis Referral Program.

RATIONALE, AIMS AND OBJECTIVES: Asia-Pacific carries a high burden of respiratory-related mortality. Timely referral and detection of tuberculosis cases optimizes patient and public health outcomes. Registered private pharmacies in Cambodia participate in a National Tuberculosis Referral Program to refer clients with cough suggestive of tuberculosis to public sector clinics for diagnosis and care. The objective of this study was to investigate clinical intentions of pharmacy staff when presented with a hypothetical case of a client with prolonged cough suggestive of tuberculosis. METHOD: A random sample of 180 pharmacies was selected. Trained interviewers administered a hypothetical case scenario to trained pharmacy staff. Participants provided 'yes'/'no' responses to five clinical actions presented in the scenario. Actions were not mutually exclusive. Data were tabulated and compared using chi-square tests or Fisher's exact tests. RESULTS: Overall, 156 (92%) participants would have referred the symptomatic client in the case scenario. Participants who would have referred the client were less likely to sell a cough medicine (42% vs. 100%, P < 0.001) and less likely to sell an antibiotic (19% vs. 79%, P < 0.001) than those who would not have referred the client. CONCLUSION: Involving pharmacies in a Referral Program may have introduced concepts of appropriate clinical care when responding to clients presenting with cough suggestive of tuberculosis. However, results showed enhancing clinical competence among all referral programme participants particularly among non-referring pharmacies and those making concurrent sales of cough-related products would optimize pharmacy-initiated referral. Further research into actual clinical practices at Referral Program pharmacies would be justified.

Tuberculosis case-finding in Cambodia: analysis of case notification data, 2000 to 2013.

The routine tuberculosis (TB) surveillance system in Cambodia has been strengthened under the National TB Programme (NTP). This paper provides an overview of the TB surveillance data for Cambodia at the national level for the period 2000 to 2013 and at the subnational level for 2013. The proportion of the total population that were screened for TB rose from 0.4% in 2001 to 1.1% in 2013, while the smear-positivity rate decreased from 28.9% to 8.1% in the same period. The total number of notified TB cases increased steadily from 2000; this has stabilized in recent years with 39 055 cases notified in 2013. The proportion of all TB cases that were smear-positive decreased from 78% in 2000 to 36% in 2013. Case notification rates (CNRs) for all forms of TB and new smear-positive TB in 2013 were 261 and 94 per 100 000 population, respectively. Higher CNRs were found in the north-western and south-eastern parts of the country and were higher for males especially in older age groups. The increase in TB screening, decline in the smear-positive rate and decline in notified smear-positive TB cases likely reflect a long-term positive impact of the NTP. A negative correlation between the proportion of the population screened and the smear-positivity rate at the subnational level helped identify where to find undiagnosed cases. Subnational differences in case notification of the elderly and in children provide more specific targets for case-finding and further encourage strategic resource allocation.

The association between household poverty rates and tuberculosis case notification rates in Cambodia, 2010.

INTRODUCTION: Poverty is a risk factor for tuberculosis (TB); it increases the risk of infection and active disease but limits diagnostic opportunities. The role of poverty in the stagnant case detection in Cambodia is unclear. This study aims to assess the relationship between district household poverty rates and sputum-positive TB case notification rates (CNRs) in Cambodia in 2010. METHODS: Poisson regression models were used to calculate the relative risk of new sputum-positive TB CNR for Operational Districts (ODs) with different poverty rates using data from the National Centre for Tuberculosis and Leprosy Control and the National Committee for SubNational Democratic Development. Models were adjusted for other major covariates and a geographical information system was used to examine the spatial distribution of these covariates in the country. RESULTS: The univariate model showed a positive association between household poverty rates and sputum-positive TB CNRs. However, in multivariate models, after adjusting for major covariates, household poverty rates showed a significantly negative association with sputum-positive TB CNRs (relative risk [RR] = 0.95 per 5% increase in poverty rate). The negative association was stronger among males than females (RR = 0.93 versus 0.96 per 5% increase in poverty rate). Similar spatial patterns were observed between household poverty rates and other covariates, particularly OD population density. CONCLUSION: Household poverty rate is associated with a decrease in sputum-positive TB CNR in Cambodia, particularly in men. The potential of combining surveillance data and socioeconomic variables should be explored further to provide more insights for TB control programme planning.