Accuracy of line probe assays for the diagnosis of pulmonary and multidrug-resistant tuberculosis: a systematic review and meta-analysis.

Only 25% of multidrug-resistant tuberculosis (MDR-TB) cases are currently diagnosed. Line probe assays (LPAs) enable rapid drug-susceptibility testing for rifampicin (RIF) and isoniazid (INH) resistance and Mycobacterium tuberculosis detection. Genotype MTBDRplusV1 was WHO-endorsed in 2008 but newer LPAs have since been developed. This systematic review evaluated three LPAs: Hain Genotype MTBDRplusV1, MTBDRplusV2 and Nipro NTM+MDRTB. Study quality was assessed with QUADAS-2. Bivariate random-effects meta-analyses were performed for direct and indirect testing. Results for RIF and INH resistance were compared to phenotypic and composite (incorporating sequencing) reference standards. M. tuberculosis detection results were compared to culture. 74 unique studies were included. For RIF resistance (21 225 samples), pooled sensitivity and specificity (with 95% confidence intervals) were 96.7% (95.6–97.5%) and 98.8% (98.2–99.2%). For INH resistance (20 954 samples), pooled sensitivity and specificity were 90.2% (88.2–91.9%) and 99.2% (98.7–99.5%). Results were similar for direct and indirect testing and across LPAs. Using a composite reference standard, specificity increased marginally. For M. tuberculosis detection (3451 samples), pooled sensitivity was 94% (89.4–99.4%) for smear-positive specimens and 44% (20.2–71.7%) for smear-negative specimens. In patients with pulmonary TB, LPAs have high sensitivity and specificity for RIF resistance and high specificity and good sensitivity for INH resistance. This meta-analysis provides evidence for policy and practice

Multidrug-resistant tuberculosis and migration to Europe.

Multidrug-resistant tuberculosis (MDR-TB) in low-incidence countries in Europe is more prevalent among migrants than the native population. The impact of the recent increase in migration to EU and EEA countries with a low incidence of TB (<20 cases per 100 000) on MDR-TB epidemiology is unclear. This narrative review synthesizes evidence on MDR-TB and migration identified through an expert panel and database search. A significant proportion of MDR-TB cases in migrants result from reactivation of latent infection. Refugees and asylum seekers may have a heightened risk of MDR-TB infection and worse outcomes. Although concerns have been raised around 'health tourists' migrating for MDR-TB treatment, numbers are probably small and data are lacking. Migrants experience significant barriers to testing and treatment for MDR-TB, exacerbated by increasingly restrictive health systems. Screening for latent MDR-TB is highly problematic because current tests cannot distinguish drug-resistant latent infection, and evidence-based guidance for treatment of latent infection in contacts of MDR patients is lacking. Although there is evidence that transmission of TB from migrants to the general population is low-it predominantly occurs within migrant communities-there is a human rights obligation to improve the diagnosis, treatment and prevention of MDR-TB in migrants. Further research is needed into MDR-TB and migration, the impact of screening on detection or prevention, and the potential consequences of failing to treat and prevent MDR-TB among migrants in Europe. An evidence-base is urgently needed to inform guidelines for effective approaches for MDR-TB management in migrant populations in Europe

Parallel use of low-complexity automated nucleic acid amplification tests on respiratory samples and stool with or without lateral flow lipoarabinomannan assays to detect pulmonary tuberculosis disease in children

Objectives: This is a protocol for a Cochrane Review (diagnostic). The objectives are as follows:. To compare the diagnostic accuracy of the parallel use of low-complexity automated nucleic acid amplification tests on respiratory and stool specimens in children and lateral flow urine lipoarabinomannan amongst children with HIV versus each assay alone for detecting pulmonary tuberculosis. Secondary objectives To compare the diagnostic accuracy of low-complexity automated nucleic acid amplification tests on respiratory and stool specimens in combination versus each sample type alone. To investigate the following sources of heterogeneity: clinical setting, signs and symptoms of pulmonary tuberculosis disease, screening positivity by chest X-ray abnormalities, age group, specimen type; and also amongst children with HIV: CD4 cell-count or percent category, advanced HIV disease, and serious illness.</p

Parallel Use of Low-Complexity Automated Nucleic Acid Amplification Tests and Lateral Flow Urine Lipoarabinomannan Assays to Detect Tuberculosis Disease in Adults and Adolescents Living with HIV

This is a protocol for a Cochrane Review (diagnostic). The objectives are as follows: To compare the diagnostic accuracy of parallel use of lateral flow urine lipoarabinomannan on urine and low-complexity automated nucleic acid amplification tests on respiratory samples versus each test alone for detection of tuberculosis disease in adults and adolescents living with HIV who present with presumptive tuberculosis. Secondary objectives To investigate the following sources of heterogeneity: clinical setting; signs and symptoms of tuberculosis; screening positivity for tuberculosis disease by chest x-ray, C-reactive protein elevation, and molecular World Health Organization-recommended rapid diagnostics; seriously ill; advanced HIV; and CD4 cell count

The role of counselling in tuberculosis diagnostic evaluation and contact tracing: scoping review and stakeholder consultation of knowledge and research gaps

Background Tuberculosis (TB) care cascade analyses show large gaps at early stages, including care-seeking and diagnostic evaluation, where promising interventions to decrease attrition are urgently needed. Person-centered care is prioritized in the World Health Organization’s End TB strategy; yet little is known about how it is delivered and can be optimized. Recommendations for counselling, a core component of person-centered care, are largely limited to its role in improving TB treatment adherence. The role of counselling to close key diagnostic gaps in the care cascade is poorly understood. Methods We conducted a scoping review to identify evidence on the use of counselling at TB diagnosis, for both people with presumptive TB and index patients to promote patient retention and contact tracing. Using search terms for TB, diagnosis and counselling, we systematically searched PubMed, EMBASE and Web of Science. Two independent reviewers screened all abstracts, full-texts, extracted data and conducted a quality assessment. We used thematic analysis to identify key themes. Results After screening 1785 articles, we extracted data from 15 studies and determined that the major themes best corresponded to the following gaps in the TB care cascade: care-seeking, pre-diagnosis, and pre-treatment. Studies were conducted across varied settings including pharmacies, primary health centres, and clinics, primarily in high TB incidence countries. No study directly evaluated the impact of counselling on outcomes such as treatment initiation or retention in care. Included studies suggested counselling may play an important role in improving the uptake of diagnostic testing and contact tracing. Barriers to counselling included time and personnel requirements. Stakeholder consultation emphasized the importance of high-quality counselling as a core tenet of TB care. Conclusion Data on the impact of counselling to improve TB case detection are absent from the literature. The shift towards person-centred care for TB presents an opportunity to incorporate counselling during earlier stages of the TB care cascade; however, evidence-based approaches are needed. Implementation research is needed to operationalize and evaluate counselling to strengthen high-quality TB care delivery

Strengthening accountability for tuberculosis policy implementation in South Africa: perspectives from policymakers, civil society, and communities

Background: Translating health policy into effective implementation is a core priority for responding effectively to the tuberculosis (TB) crisis. The national TB Recovery Plan was developed in response to the negative impact that the COVID-19 pandemic had on TB care in South Africa. We aimed to explore the implementation of the TB Recovery Plan and develop recommendations for strengthening accountability for policy implementation for this and future TB policies. Methods: We interviewed 24 participants working on or impacted by TB policy implementation in South Africa. This included perspectives from national, provincial, and local health department representatives, civil society, and community representatives. In-depth interviews were conducted in English and isiXhosa and we drew on reflexive thematic methods for analysis. Results: Participants felt that there was potential for COVID-19 innovations and urgency to influence TB policy development and implementation, including the use of data dashboards. Implementation of the TB Recovery Plan predominantly used a top-down approach to implementation (cascading from national policy to local implementers) but experienced bottlenecks at provincial level. Recommendations for closing the TB policy-implementation gap included using phased implementation and enhancing provincial-level accountability. Civil society organisations were concerned about the lack of provincial implementation data which impeded advocacy for improved accountability and inadequate resourcing for implementation. Community health workers were viewed as key to implementation but were not engaged in the policy development process and were often not aware of new TB policies. At local level, there were also opportunities to strengthen community engagement in policy implementation including through community-led monitoring. Participants recommended broader multi-stakeholder engagement that includes community and community health worker representatives in the development and implementation phases of new TB policies. Conclusions: Communities affected by TB, with the support of civil society organisations, could play a bigger role in monitoring policy implementation at local level and need to be capacitated to do this. This bottom-up approach could complement existing top-down strategies and contribute to greater accountability for TB policy implementation

Solar Disinfection of MODS Mycobacterial Cultures in Resource-Poor Settings

INTRODUCTION: Safe disposal of TB culture material in which the infectious burden of clinical samples has been greatly amplified is an important challenge in resource-limited settings. The bactericidal capacity of solar cookers has been demonstrated previously for conventional bacteria and contaminated clinical waste. We investigated the use of a simple solar cooker for the sterilization of mycobacterial broth cultures from the microscopic observation drug susceptibility assay (MODS). METHODS: Simulated TB culture materials were prepared by inoculating 24-well MODS plates with 500 microL of a known concentration of Mycobacterium bovis BCG. In a series of experiments, samples were simultaneously placed inside a box-type solar cooker and control box and removed at timepoints between 15 minutes and 6 hours. Quantitative cultures were performed using retrieved samples to determine sterilization effect. RESULTS: All cultures from the control box were positive at or within 1-4 logs of inoculation concentration. Simulated culture plates at concentrations from 10(3) colony-forming-units (CFU)/ml to 10(7) CFU/ml were completely sterilized after only one hour of cooker exposure, at temperatures between 50-102 degrees C. At 10(9) CFU/ml (far in excess of diagnostic cultures), it was only possible to recover mycobacterial growth in plates removed after 15 minutes. By 30 minutes all plates were effectively sterilized. DISCUSSION: Solar disinfection provides a very effective, safe and low-cost alternative to conventional equipment used for disposal of mycobacterial culture material. Effect of climatic conditions and optimal operating procedure remain to be defined

Analysing interventions designed to reduce tuberculosis-related stigma: a scoping review

Stigma is a critical barrier for TB care delivery; yet data on stigma reduction interventions is limited. This review maps the available literature on TB stigma reduction interventions, using the Health Stigma and Discrimination framework and an implementation analysis to identify research gaps and inform intervention design. Using search terms for TB and stigma, we systematically searched PubMed, EMBASE and Web of Science. Two independent reviewers screened all abstracts, full-texts, extracted data, conducted a quality assessment, and assessed implementation. Results were categorized by socio-ecological level, then sub-categorized by the stigma driver or manifestation targeted. After screening 1865 articles, we extracted data from nine. Three studies were implemented at the individual and interpersonal level using a combination of TB clubs and interpersonal support to target internal and anticipated stigma among persons with TB. Two studies were implemented at the interpersonal level using counselling or a video based informational tool delivered to households to reduce stigma drivers and manifestations. Three studies were implemented at the organizational level, targeting drivers of stigma among healthcare workers (HW) and enacted stigma among HWs. One study was implemented at the community level using an educational campaign for community members. Stakeholder consultation emphasized the importance of policy level interventions and education on the universality of risk to destigmatize TB. Review findings suggest that internal and anticipated TB stigma may be addressed effectively with interventions targeted towards individuals using counselling or support groups. In contrast, enacted TB stigma may be better addressed with information-based interventions implemented at the organizational or community level. Policy level interventions were absent but identified as critical by stakeholders. Implementation barriers included the lack of high-quality training and integration with mental health services. Three key gaps must be addressed in future research: consistent stigma definitions, standardized stigma measurement, and measurement of implementation outcomes

Implementation strategies to increase the uptake and impact of molecular WHO-recommended rapid diagnostic tests: evidence from a mixed-methods systematic review

IntroductionFewer than 50% of people with tuberculosis receive a molecular WHO-recommended rapid diagnostic test (mWRD). We performed a mixed-methods systematic review to categorise barriers and enablers that affect mWRD use and impact and evaluate mWRD implementation strategies. Parts of this review informed the WHO standard: Universal Access to Tuberculosis Diagnostics.MethodsWe searched multiple databases without language restrictions until 29 July 2022. We included studies that used qualitative, quantitative or mixed methods study designs. Four reviewers independently screened studies and extracted data. We categorised studies as thick or thin depending on whether authors analysed findings beyond a descriptive list of barriers or enablers and demonstrated insights into participants' perspectives. We appraised study quality by adapting the Standards for Reporting Implementation Studies statement. We synthesised data using a thematic approach and used GRADE-CERQual to assess confidence in the findings.ResultsWe identified 54 high-thickness studies from 18 countries, including public and private healthcare settings. Implementation strategies included engaging patients, training and supporting clinicians, building infrastructure and interactive assistance. Examples included remote outreach programmes, community testing, longitudinal clinician engagement, auxiliary workers, multicomponent strategies, performance feedback, improving health information management to strengthen care linkage and diagnostic network improvement. We had high or moderate confidence in our findings.ConclusionInnovative and contextually relevant implementation strategies are needed for tuberculosis programmes to realise the benefits of improved accuracy and diagnostic expediency that mWRDs offer. Multicomponent strategies that centre equity and longitudinal health worker training across the diagnostic cascade must be prioritised

Trajectories of interferon-gamma release assay results over two years in independent cohorts from China, South Africa, Tanzania, and the United States

Background: There is an ongoing debate about whether clearance of Mycobacterium tuberculosis infection occurs and at what magnitude. Recent studies quantifying ‘uncertainty zones’ of interferon-gamma release assays (IGRA) provide a more stringent estimate of reversion, potentially indicating clearance. Research Question: When accounting for ‘uncertainty zones’ through stringent cutoffs, what are the trajectories of interferon-gamma release assays in cases of Mycobacterium tuberculosis infection? Study Design and Methods: We followed five cohorts from South Africa, China, Tanzania, and the United States tested with an IGRA test three or more times for stringent conversion and reversion. The annual risk of IGRA reversion was assessed after an IGRA conversion and among those with baseline positivity. Results: 26,596 IGRA measurements were taken over 13,593 years of follow-up (Nparticipants=7,683). Stringent reversion at year 2 after stringent conversion at year 1 varied between cohorts, occurring in 48% (43/90) for WANTAI, 37% (22/59) for QuantiFERON, and 17% (2/12) for T-SPOT.TB, respectively. In the U.S. cohorts, stringent reversion at year 1 after stringent conversion at 6 months was 58% (15/26) for QuantiFERON and 18% (12/60) for T-SPOT.TB. Stringent reversion at 1 year after baseline positivity occurred in 12% (47/404) for WANTAI, 21% (10/48) for QuantiFERON and 44% for T-SPOT.TB (45/102). In one cohort from (N=399; age range, 59 years [IQR, 48–67]), IGRA reversion was more common in younger participants (Adjusted Odds Ratio [aOR], 0.95; 95% CI, 0.93–0.97) and those without recent close tuberculosis exposure (aOR, 0.35; 95%CI, 0.11–1.03 in South Africa; 0.10; 95%CI, 0.01–0.61 in China). Interpretation: These results suggest high annual rates of IGRA reversion, even with the use of ‘uncertainty zones’; reversion rates decreased with time from exposure and at older ages