Abstract Background Microbiological confirmation of paediatric pulmonary tuberculosis is frequently unattainable, rendering chest radiography a critical yet underutilised diagnostic tool. Methods We conducted a retrospective diagnostic accuracy study of the qXR-version 4.2.1 (Qure.ai), a paediatric-optimized computer-aided detection (CAD) algorithm, for pulmonary tuberculosis. Diagnostic performance was assessed against microbiological (MRS) and clinical reference standards (ClRS). Bayesian latent class analysis (LCA) was applied to address the imperfection of both reference standards in children. Performance was quantified using area under the receiver operating characteristic curve (AUROC) and estimates of sensitivity and specificity. Results We included digital chest radiographs of 932 Gambian children (< 15 years) comprising 80 (9%) children with confirmed tuberculosis, 163 (17%) with unconfirmed tuberculosis, and 689 (74%) classified as unlikely tuberculosis. Against MRS, qXR demonstrated AUROC, sensitivity and specificity of 0.68 (95% CI 0.61–0.75), 54% (95% CI 43–64%), and 82% (95% CI 79–84%), respectively. Against ClRS, the AUROC, sensitivity and specificity were 0.73 (95% CI 0.69–0.77), 41% (95% CI 34–49%), and 87% (95% CI 84–89%), respectively. Bayesian LCA, assuming conditional independence, estimated sensitivity of 79% (95% CrI 65–89%) and specificity of 82% (95% CrI 79–84%). Assuming conditional dependence between qXR and expert radiologist, and between culture and Xpert, estimated sensitivity increased to 89% (95% CrI 71–98%), with specificity remaining at 82% (95% CrI 79–84%). Conclusions Paediatric-optimized qXR algorithm provides a valuable complementary tool for diagnosis of paediatric pulmonary tuberculosis. Conventional reference standards likely underestimate the true diagnostic performance of CAD systems in children.

Interactions between human cytomegalovirus (HCMV) and the host immune response to Mycobacterium tuberculosis (M.tb) may influence the risk of tuberculosis (TB) disease progression. Data on an association between HCMV and risk of initial infection with M.tb are lacking. In this correlation analysis, serological measures of HCMV were investigated in two cohorts: a TB case-control study nested within a Ugandan general population epidemiology cohort with serum samples from 25 TB disease cases up to 10 years prior to diagnosis, and a paediatric M.tb infection study with 22 matched pairs of highly-TB-exposed children from The Gambia, where one of each pair was infected with M.tb and the other was not (as determined by a tubeculin skin test (TST)). Among individuals in the Ugandan case-control study, we found a relationship between odds of progression to active TB disease and (i) increased levels of HCMV IgM (odds ratio (OR) 2.5 (99% CI 0.84-7.54) for medium tertile, and OR 3.55 (1.27-9.96) for high tertile), (ii) HCMV IgG avidity (OR 2.82 (0.88-9.01) for medium and OR 3.08 (1.25-11.82) for high), and (iii) C-reactive protein (CRP) levels (OR 1.70 (0.58-5.00) for medium and OR 3.59 (1.20-10.74) for high tertile of response). Among Gambian children, no association was found between TB infection and measures of HCMV exposure. Further evaluation of such associations in larger prospective studies and experimental testing for a causal relationship are needed.This article is part of the discussion meeting issue 'The indirect effects of cytomegalovirus infection: mechanisms and consequences'.

BACKGROUND:Despite the socioeconomic consequences of an increasing burden of chronic respiratory diseases, there is little evidence on the incidence and determinants of catastrophic health expenditure (CHE) in people with chronic respiratory disease symptoms in Kenya. We aimed to generate this evidence by collecting data on medical and non-medical costs, lost income, social protection coverage, and financial coping strategies for such people in Kenya. METHODS:We conducted a cross-sectional survey of consecutively recruited adults seeking care for chronic respiratory disease symptoms at five public health-care facilities in Meru County, Kenya, between Sept 5, 2019, and Oct 1, 2020. Patient costs, National Health Insurance Fund (NHIF) coverage, financial coping strategies, and sociodemographic and clinical data were collected from surveys and medical records. The main study outcomes were the incidence of, and social and health factors associated with, CHE in this cohort. CHE incidence was calculated through the WHO threshold of direct out-of-pocket costs being greater than 10% of a household's monthly total expenditure. Multivariable logistic regression analyses generated adjusted odds ratios (aORs) with 95% CIs of health and social factors associated with CHE, including age, sex, education level, tobacco use, income, being accompanied, poverty level (with the first quintile being the richest to the fifth quintile being the poorest), NHIF usage, coping strategies, final diagnosis, and health system level at which they were seeking care. FINDINGS:Of 319 eligible people invited, 296 (93%) consented to participate and completed surveys. Mean total cost was 1062 Kenyan shillings (KES; 95% CI 896-1228; US$9·1), of which 40·0% was due to direct non-medical costs (KES 425, 95% CI 361-489; $3·7), 36·7% to direct out-of-pocket medical costs (KES 390, 324-456; $3·1), and 23·3% to lost income (KES 247, 153-341, $2·1). 212 (72%) of 296 participants did not have NHIF, 282 (95%) of 296 used coping strategies during care-seeking, and 59 (20%) of 296 were accompanied by a carer during health-care seeking. 76 (26%) of 296 participants had CHE. CHE was associated with being aged 30-44 years old (aOR 2·6, 95% CI 1·3-5·3, p=0·010), being female (1·8, 1·3-2·7, p=0·0021), having higher than secondary school education (1·6, 1·1-2·3, p=0·0083), being accompanied during health-care-seeking visits (3·2, 1·7-5·9, p<0·0001), belonging to the second poverty quintile (2·0, 1·9-2·1, p<0·0001), and seeking care from subcounty hospitals (9·7, 9·6-9·8, p<0·0001) and county hospitals (25·1, 15·7-40·2, p<0·0001). INTERPRETATION:These findings suggest a sizeable burden of CHE in people seeking care for chronic respiratory disease symptoms in Meru County in Kenya, driven by socioeconomic and sex inequalities and impaired access to health care and social protection. FUNDING:UK-Aid, UK National Institute for Health and Care Research, and UK Research and Innovation.

This is the protocol for a Campbell systematic review. The objectives are as follows. The primary objective of this systematic review is to evaluate and synthesise both published and unpublished literature on the effectiveness of sexual and reproductive health blended learning approaches for capacity strengthening of healthcare practitioners in LMICs. Within this context, sexual and reproductive health interventions refer to any of the following four key interventions or services aimed at improving maternal and newborn health (Starrs et al. 2018): (a) antenatal, childbirth and postnatal care, including emergency obstetric and newborn care, (b) safe abortion services and treatment of the complications of unsafe abortion, (c) prevention and treatment of malaria, tuberculosis, HIV and other sexually transmitted infections in pregnant women and d) family planning. In this systematic review, blended learning is defined as any teaching and learning method that combines face-to-face learning with e-learning or online learning. The component of face-to-face and online learning may include any of the components identified by Alammary (2019): (1) face-to-face instructor-led, where students attend a class and an instructor presents teaching and learning materials, with little engagement from students; (2) face-to-face collaboration, where students work together in class, for example, in discussion groups; (3) online instructor-led, where instruction is delivered online and facilitated by an instructor who sets the pace (e.g., virtual classrooms); (4) online collaboration, where students work together online with their peers, for example, online learning communities; and (5) online self-paced, where students study at their own pace and time, and from their chosen location, for example, watching videos, online reading. Specifically, this systematic review will answer the following research questions: (1) What sexual and reproductive health blended learning approaches have been used in LMICs? (2) Does participating in sexual and reproductive health blended learning interventions alone (i.e., compared with no intervention) improve the effective provision of care among healthcare workers in LMICs? (3) Does participating in sexual and reproductive health blended learning interventions compared with non-blended learning approaches (such as conventional face-to-face learning or pure e-learning) facilitate the effective provision of care among healthcare workers in LMICs (measured by, e.g., self-reports of effective maternal and neonatal care)? (4) What is the cost-effectiveness of sexual and reproductive health blended learning compared with non-blended learning approaches (i.e., face-to-face learning or e-learning)? (5) What factors affect the effectiveness of sexual and reproductive health blended learning interventions (e.g., characteristics of participants, type of intervention, course content, setting and mode of delivery)? (6) Do sexual and reproductive health blended learning interventions targeted at healthcare practitioners working in LMICs lead to improvement in patient outcomes (e.g., reduced maternal and neonatal mortality, patient satisfaction reports)?

Background The blended learning (BL) approach to training health care professionals is increasingly adopted in many countries because of high costs and disruption to service delivery in the light of severe human resource shortage in low resource settings. The Covid-19 pandemic increased the urgency to identify alternatives to traditional face-to-face (f2f) education approach. A four-day f2f antenatal care (ANC) and postnatal care (PNC) continuous professional development course (CPD) was repackaged into a 3-part BL course; 1) self-directed learning (16 hours) 2) facilitated virtual sessions (2.5 hours over 3 days) and 3) 2-day f2f sessions.Methods This study assessed the feasibility, change in healthcare providers' knowledge and costs of the BL package in Nigeria, Tanzania, and Kenya. A mixed methods design was used. A total of 89 healthcare professionals, were purposively selected. Quantitative data was collected through an online questionnaire and skills assessments, analyzed using STATA 12 software. Qualitative data was collected through key informant interviews and focus group discussions, analysed using thematic analysis.Results Majority of participants (86%) accessed the online sessions using a mobile phone from home and health facilities. The median (IQR) time of completing the self-directed component was 16 hours, IQR (8, 30). A multi-disciplinary team comprising of 42% nurse-midwives, 28% doctors, 20% clinical officers and 10% other healthcare professionals completed the BL course. Participants liked the BL approach due to its flexibility in learning, highly educative/relevant content, mixing of health worker cadres and CPD points. Aspects that were noted as challenging were related to personal log-in details and network connectivity issues during the self-directed learning and facilitated virtual sessions respectively.Conclusion The blended learning approach to ANC-PNC in-service training was found to be feasible, cost saving compared to the face-to-face approach and acceptable to health care professionals in LMICs.

Computer-aided detection (CAD) systems hold promise for improving tuberculosis (TB) detection on digital chest x-rays (dCXR).However, data on their performance in exclusively paediatric populations are scarce.We conducted a retrospective diagnostic accuracy study evaluating the performance of CAD for TB version 7 (CAD4TBv7 ® ) using dCXR from well-characterised cohorts of Gambian children younger than 15 years with presumed pulmonary TB.The children were consecutively recruited between 2012 and 2022.We measured CAD4TBv7 performance against a microbiological reference standard (MRS) of confirmed TB, and also performed Bayesian latent class analysis (LCA) to address the inherent limitations of MRS in children.Diagnostic performance was assessed using the area under the receiver operating characteristic curve (AUROC) and point estimates of sensitivity and specificity.A total of 724 children were included in the analysis, with confirmed TB in 58 (8%), unconfirmed TB in 145 (20%), and unlikely TB in 521 (72%).Using MRS, CAD4TBv7 showed an AUROC of 0.70 (95% CI 0.60-0.79),and demonstrated sensitivity and specificity of 19.0% (95% CI 11-31%) and 99.0% (95% CI 98.0-100.0%),respectively.Applying Bayesian LCA with assumption of conditional independence between tests, sensitivity and specificity estimates for CAD4TBv7 were 42.7% (95% CrI 29.2-57.5%)and 97.9% (95% CrI 96.6-98.8%),respectively.When allowing for conditional dependence between culture and Xpert assay, CAD4TBv7 demonstrated a sensitivity of 50.3% (95% CrI 32.9-70.0%)and specificity of 98.0% (95% CrI 96.7-98.9%).Although CAD4TBv7 demonstrated high specificity, its suboptimal sensitivity underscores the crucial need for optimisation of the CAD4TBv7 for detecting tuberculosis in children.

Comprehensive assessments of quality of care (QoC) are essential for monitoring progress towards meeting global and national maternal and newborn health (MNH) targets. Liverpool School of Tropical Medicine (LSTM) and the Niger Ministry of Public Health adapted a 2014 WHO QoC tool to cover antenatal care (ANC) and postnatal care (PNC) and include client voices through exit interviews. The objectives of the study were to assess quality of MNH care in Niger and to document lessons learnt from implementing the LSTM QoC tool. Quality of Care (QoC) was assessed using five tools: health facility survey (using register and official record data), partograph reviews, healthcare provider knowledge assessment, exit interviews with clients, and observation of antenatal and postnatal care. A nationally representative sample of 110 public healthcare facilities at three levels (integrated health centres, district hospitals and mother-child hospitals) and 2153 women were included. Descriptive analysis with 95% confidence intervals was presented. The health facility survey showed variable access to electricity (63% [53-72]), water (72% [62-81]), and transportation (40% [31-50]). Tests and treatment for HIV, TB, and malaria were found in more than 90% of relevant facilities. During observation of first ANC visit, 62% [48-74] women were tested for HIV; 13% [5-30] for pre-eclampsia and 22% [12-36] for anaemia. Observation of PNC showed much lower rates of screening (15% [7-27] tested for HIV and 4% [0;11] for malaria). Partographs were used in 86% of deliveries with inconsistent completion. At client interviews, respectful care indicators were variable, with providers not always explaining results to clients (59% [50-67]). Targeted allocation of resources and training could impact on QoC and reduce missed opportunities for prevention, screening and management of diseases among pregnant women and babies. The QoC assessment tool proved capable of offering a comprehensive overview of priorities in MNH, while maintaining feasibility in the Nigerien context.

Background Computer-aided detection (CAD) systems hold promise for improving tuberculosis (TB) detection on digital chest radiographs. However, data on their performance in exclusively paediatric populations are scarce. Methods We conducted a retrospective diagnostic accuracy study evaluating the performance of CAD4TBv7 (Computer-Aided Detection for Tuberculosis version 7) using digital chest radiographs from well-characterised cohorts of Gambian children aged <15 years with presumed pulmonary TB. The children were consecutively recruited between 2012 and 2022. We measured CAD4TBv7 performance against a microbiological reference standard (MRS) of confirmed TB, and also performed Bayesian latent class analysis (LCA) to address the inherent limitations of the MRS in children. Diagnostic performance was assessed using the area under the receiver operating characteristic curve (AUROC) and point estimates of sensitivity and specificity. Results A total of 724 children were included in the analysis, with confirmed TB in 58 (8%), unconfirmed TB in 145 (20%) and unlikely TB in 521 (72%). Using the MRS, CAD4TBv7 showed an AUROC of 0.70 (95% CI 0.60-0.79), and demonstrated sensitivity and specificity of 19.0% (95% CI 11-31%) and 99.0% (95% CI 98.0-100.0%), respectively. Applying Bayesian LCA with the assumption of conditional independence between tests, sensitivity and specificity estimates for CAD4TBv7 were 42.7% (95% CrI 29.2-57.5%) and 97.9% (95% CrI 96.6-98.8%), respectively. When allowing for conditional dependence between culture and Xpert assay, CAD4TBv7 demonstrated a sensitivity of 50.3% (95% CrI 32.9-70.0%) and specificity of 98.0% (95% CrI 96.7-98.9%). Conclusion Although CAD4TBv7 demonstrated high specificity, its suboptimal sensitivity underscores the crucial need for optimisation of CAD4TBv7 for detecting TB in children.

Background Over 500 million people live with chronic respiratory diseases globally and approximately 4 million of these, mostly from the low- and middle-income countries including sub-Saharan Africa, die prematurely every year. Despite high CRD morbidity and mortality, only very few studies describe CRDs and little is known about the economic, social and psychological dimensions of living with CRDs in sub-Saharan Africa. We aimed to gain an in-depth understanding of the social, livelihood and psychological dimensions of living with CRD to inform management of CRDs in Sudan and Tanzania. Method We conducted 12 in-depth interviews in 2019 with people with known or suspected CRD and 14 focus group discussions with community members in Gezira state, Sudan and Dodoma region, Tanzania, to share their understanding and experience with CRD. The data was analysed using thematic framework analysis. Results People with CRD in both contexts reported experiences under two broad themes: impact on economic wellbeing and impact on social and psychological wellbeing. Capacity to do hard physical work was significantly diminished, resulting in direct and indirect economic impacts for them and their families. Direct costs were incurred while seeking healthcare, including expenditures on transportation to health facility and procurement of diagnostic tests and treatments, whilst loss of working hours and jobs resulted in substantial indirect costs. Enacted and internalised stigma leading to withdrawal and social exclusion was described by participants and resulted partly from association of chronic cough with tuberculosis and HIV/AIDS. In Sudan, asthma was described as having negative impact on marital prospects for young women and non-disclosure related to stigma was a particular issue for young people. Impaired community participation and restrictions on social activity led to psychological stress for both people with CRD and their families. Conclusion Chronic respiratory diseases have substantial social and economic impacts among people with CRD and their families in Sudan and Tanzania. Stigma is particularly strong and appears to be driven partly by association of chronic cough with infectiousness. Context-appropriate measures to address economic impacts and chronic cough stigma are urgently needed as part of interventions for chronic respiratory diseases in these sub-Saharan African contexts.

BACKGROUNDAn international multistakeholder participatory workshop was hosted in the Gambia, West Africa, in November 2021.OBJECTIVESTo explore the experiences, challenges and recommendations of workshop participants on health and wellbeing after TB treatment.METHODSAn exploratory, descriptive, qualitative approach was used for data collection through facilitator-guided group discussions. Workshop participants included adolescent and adult TB survivors, and representatives of TB advocacy groups and the policy sector. Discussions were audio-recorded and transcribed verbatim, and the data were analysed using a deductive thematic approach.RESULTSOverall, 38 participants (22 women) from six West African countries participated in the workshop, comprising 33 TB survivors and advocacy group representatives and 5 participants from the policy sector. Although some TB survivors noted improved ability to carry out physical activities, others continued to experience detrimental effects on their family life, social interactions, physical health and ongoing stigma. Policymakers emphasised the lack of data and clear guidelines on post-TB disability.CONCLUSIONSSome TB survivors continue to suffer detrimental effects of the illness even after treatment completion. However, available data on post-TB disability is inadequate to support policy adoption. Therefore, there is an urgent need for increased advocacy, awareness and research to bridge knowledge gaps.

Introduction: An estimated 1.2 million children develop tuberculosis (TB) every year with 240,000 dying because of missed diagnosis. Existing tools suffer from lack of accuracy and are often unavailable. Here, we describe the scientific and clinical methodology applied in RaPaed-TB, a diagnostic accuracy study. Methods: This prospective diagnostic accuracy study evaluating several candidate tests for TB was set out to recruit 1000 children <15 years with presumptive TB in 5 countries (Malawi, Mozambique, South Africa, Tanzania, India). Assessments at baseline included documentation of TB signs and symptoms, TB history, radiography, tuberculin skin test, HIV testing and spirometry. Respiratory samples for reference standard testing (culture, Xpert Ultra) included sputum (induced/spontaneous) or gastric aspirate, and nasopharyngeal aspirate (if <5 years). For novel tests, blood, urine and stool were collected. All participants were followed up at months 1 and 3, and month 6 if on TB treatment or unwell. The primary endpoint followed NIH-consensus statements on categorization of TB disease status for each participant. The study was approved by the sponsor’s and all relevant local ethics committees. Discussion: As a diagnostic accuracy study for a disease with an imperfect reference standard, Rapid and Accurate Diagnosis of Pediatric Tuberculosis Disease (RaPaed-TB) was designed following a rigorous and complex methodology. This allows for the determination of diagnostic accuracy of novel assays and combination of testing strategies for optimal care for children, including high-risk groups (ie, very young, malnourished, children living with HIV). Being one of the largest of its kind, RaPaed-TB will inform the development of improved diagnostic approaches to increase case detection in pediatric TB.

Objectives The co-occurrence of tuberculosis (TB) and multiple chronic communicable and non-communicable diseases is a growing concern in low- and middle-income countries (LMICs). Understanding this ‘complex TB multimorbidity’ (cTBMM) can contribute to improved patient care. We aimed to synthesise the prevalence of clusters of cTBMM and their impact on patient outcomes. Design Systematic review and meta-analysis. Setting LMICs. Papers We searched major databases from inception to 01/10/2020 to identify observational studies reporting primary (prevalence or risk) or secondary (related to disease burden) outcome data for people in LMICs with cTBMM. Titles, abstracts and full text screening, data extraction, and quality assessment were done in duplicate by independent reviewers, and random-effects meta-analyses were performed. Primary and secondary outcome measures Prevalence or risk of cTBMM (primary); any measure of burden of disease (secondary). Results From 21,884 search results, 82 studies representing 773,828 TB patients were included, reporting data on 78 different clusters of cTBMM. In TB patients, the most prevalent co-occurring conditions where depression and anxiety (15.3%, 95% confidence interval [CI] 10.7%-20.5%, 3 studies, 1,473 participants, I2=64%), HIV and anxiety (15.2%, 95%CI 11.3%-19.7%, 4 studies, 1,413 participants, I2=77%), and HIV and post-traumatic stress disorder (14.8%, 95%CI 13.9%-15.8%, 2 studies, 5,400 participants). Sparse evidence indicated lower treatment success and higher risks of death in people with cTBMM. Conclusions Although limited by high heterogeneity, this first systematic review and meta-analysis on cTBMM highlights that multiple conditions co-occurring in TB patients are common and that mental disorders often cluster together or with HIV. Further research assessing the burden of cTBMM and identifying effective health systems responses is required. Registration Prospero CRD42020214021. Strengths and limitations of this study ### Competing Interest Statement EMT declared that he attended the Tuberculosis Modelling and Analytics Consortium meetings (one in-person meeting in the previous 3 years. Istanbul 30/09/2019 - 03/10/2019), for which his travel and expenses were covered (total expenses claimed <150 GBP, reimbursed to him directly). All other authors declare no competing interests. ### Clinical Protocols ### Funding Statement This work was supported by Medical Research Council UK, grant number MC\_PC\_MR/T037806/1. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All the collected data is in the public domain.

Background Tuberculosis (TB) has been repeatedly shown to have socioeconomic impacts in both individual-level and ecological studies; however, much less is known about this effect among children and adolescents and the extent to which being affected by TB during childhood and adolescence can have life-course implications. This paper describes the results of the development of a conceptual framework and scoping review to review the evidence on the short- and long-term socioeconomic impact of tuberculosis on children and adolescents. Objectives To increase knowledge of the socioeconomic impact of TB on children and adolescents. Methods We developed a conceptual framework of the socioeconomic impact of TB on children and adolescents, and used scoping review methods to search for evidence supporting or disproving it. We searched four academic databases from 1 January 1990 to 6 April 2021 and conducted targeted searches of grey literature. We extracted data using a standard form and analysed data thematically. Results Thirty-six studies (29 qualitative, five quantitative and two mixed methods studies) were included in the review. Overall, the evidence supported the conceptual framework, suggesting a severe socioeconomic impact of TB on children and adolescents through all the postulated pathways. Effects ranged from impoverishment, stigma, and family separation, to effects on nutrition and missed education opportunities. TB did not seem to exert a different socioeconomic impact when directly or indirectly affecting children/adolescents, suggesting that TB can affect this group even when they are not affected by the disease. No study provided sufficient follow-up to observe the long-term socioeconomic effect of TB in this age group. Conclusion The evidence gathered in this review reinforces our understanding of the impact of TB on children and adolescents and highlights the importance of considering effects during the entire life course. Both ad-hoc and sustainable social protection measures and strategies are essential to mitigate the socioeconomic consequences of TB among children and adolescents.

Objectives Chronic respiratory diseases (CRD) are among the top four non-communicable diseases globally. They are associated with poor health and approximately 4 million deaths every year. The rising burden of CRD in low/middle-income countries will strain already weak health systems. This study aimed to explore the perspectives of healthcare workers and other health policy stakeholders on the barriers to effective diagnosis and management of CRD in Kenya, Malawi, Sudan, Tanzania and Uganda. Study design Qualitative descriptive study. Settings Primary, secondary and tertiary health facilities, government agencies and civil society organisations in five sub-Saharan African countries. Participants We purposively selected 60 national and district-level policy stakeholders, and 49 healthcare workers, based on their roles in policy decision-making or health provision, and conducted key informant interviews and in-depth interviews, respectively, between 2018 and 2019. Data were analysed through framework approach. Results We identified intersecting vicious cycles of neglect of CRD at strategic policy and healthcare facility levels. Lack of reliable data on burden of disease, due to weak information systems and diagnostic capacity, negatively affected inclusion in policy; this, in turn, was reflected by low budgetary allocations for diagnostic equipment, training and medicines. At the healthcare facility level, inadequate budgetary allocations constrained diagnostic capacity, quality of service delivery and collection of appropriate data, compounding the lack of routine data on burden of disease. Conclusion Health systems in the five countries are ill-equipped to respond to CRD, an issue that has been brought into sharp focus as countries plan for post-COVID-19 lung diseases. CRD are underdiagnosed, under-reported and underfunded, leading to a vicious cycle of invisibility and neglect. Appropriate diagnosis and management require health systems strengthening, particularly at the primary healthcare level.

Key Messages Despite significant morbidity and mortality and socioeconomic consequences, chronic respiratory diseases (CRDs) are underprioritized in public health programs, especially in low-and middle income countries (LMICs) COVID-19 is compounding this lack of prioritization and negatively impacting CRD-related (and other) health-care access, diagnosis, and management Risk factors for exposure to untreated COVID-19, other respiratory infections, and CRDs overlap and could be addressed in concert Prioritization of COVID-19 within the health system is likely to last for years, potentially allowing advocates to reframe the prioritization of CRDs as part of the pandemic preparedness and integration of health care. This includes advocating for approaches that integrate CRDs into existing programs and services systems strengthening.

BACKGROUND:BCG vaccines are given to more than 100 million children every year, but there is considerable debate regarding the effectiveness of BCG vaccination in preventing tuberculosis and death, particularly among older children and adults. We therefore aimed to investigate the age-specific impact of infant BCG vaccination on tuberculosis (pulmonary and extrapulmonary) development and mortality. METHODS:In this systematic review and individual participant data meta-analysis, we searched MEDLINE, Web of Science, BIOSIS, and Embase without language restrictions for case-contact cohort studies of tuberculosis contacts published between Jan 1, 1998, and April 7, 2018. Search terms included "mycobacterium tuberculosis", "TB", "tuberculosis", and "contact". We excluded cohort studies that did not provide information on BCG vaccination or were done in countries that did not recommend BCG vaccination at birth. Individual-level participant data for a prespecified list of variables, including the characteristics of the exposed participant (contact), the index case, and the environment, were requested from authors of all eligible studies. Our primary outcome was a composite of prevalent (diagnosed at or within 90 days of baseline) and incident (diagnosed more than 90 days after baseline) tuberculosis in contacts exposed to tuberculosis. Secondary outcomes were pulmonary tuberculosis, extrapulmonary tuberculosis, and mortality. We derived adjusted odds ratios (aORs) using mixed-effects, binary, multivariable logistic regression analyses with study-level random effects, adjusting for the variable of interest, baseline age, sex, previous tuberculosis, and whether data were collected prospectively or retrospectively. We stratified our results by contact age and Mycobacterium tuberculosis infection status. This study is registered with PROSPERO, CRD42020180512. FINDINGS:We identified 14 927 original records from our database searches. We included participant-level data from 26 cohort studies done in 17 countries in our meta-analysis. Among 68 552 participants, 1782 (2·6%) developed tuberculosis (1309 [2·6%] of 49 686 BCG-vaccinated participants vs 473 [2·5%] of 18 866 unvaccinated participants). The overall effectiveness of BCG vaccination against all tuberculosis was 18% (aOR 0·82, 95% CI 0·74-0·91). When stratified by age, BCG vaccination only significantly protected against all tuberculosis in children younger than 5 years (aOR 0·63, 95% CI 0·49-0·81). Among contacts with a positive tuberculin skin test or IFNγ release assay, BCG vaccination significantly protected against tuberculosis among all participants (aOR 0·81, 95% CI 0·69-0·96), participants younger than 5 years (0·68, 0·47-0·97), and participants aged 5-9 years (0·62, 0·38-0·99). There was no protective effect among those with negative tests, unless they were younger than 5 years (0·54, 0·32-0·90). 14 cohorts reported on whether tuberculosis was pulmonary or extrapulmonary (n=57 421). BCG vaccination significantly protected against pulmonary tuberculosis among all participants (916 [2·2%] in 41 119 vaccinated participants vs 334 [2·1%] in 16 161 unvaccinated participants; aOR 0·81, 0·70-0·94) but not against extrapulmonary tuberculosis (106 [0·3%] in 40 318 vaccinated participants vs 38 [0·2%] in 15 865 unvaccinated participants; 0·96, 0·65-1·41). In the four studies with mortality data, BCG vaccination was significantly protective against death (0·25, 0·13-0·49). INTERPRETATION:Our results suggest that BCG vaccination at birth is effective at preventing tuberculosis in young children but is ineffective in adolescents and adults. Immunoprotection therefore needs to be boosted in older populations. FUNDING:National Institutes of Health.