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Using a matched case control design conducted at MRC Gambia in 2015, we measured vitamin D levels in pairs of asymptomatic children with discordant tuberculin skin test status despite the same sleeping proximity to the same adult TB index case. Median ages of groups (infected; 10.0 years, uninfected 8.8 years) were not significantly different (p = 0.13). Mean vitamin D levels were 2.05 ng/mL (95% CI − 0.288 to 4.38) higher in 24 highly TB-exposed uninfected children compared with 24 matched highly TB-exposed infected children (p = 0.08). The findings warrant further investigation in larger studies to understand the implications and significance. Conclusion: Vitamin D levels were higher in TB-uninfected children compared with TB-infected despite equal high exposure to a TB case. What is Known:• Paediatrics TB represents one of the leading causes of child death globally.• Current literature shows an inconsistent relationship between vitamin D deficiency and increased risk of TB disease however a large Phase 3 trial of vitamin D supplementation in (largely vitamin D deficient) Mongolian children did not find any association with TB infection rates. What is New:• This study adds to the literature in a vitamin D sufficient paediatric population whereby children with equal exposure to a household TB case with no evidence of TB infection have higher levels of vitamin D compared with matched children with TB infection.

BackgroundPost-tuberculosis (post-TB) lung disease is an under-recognised consequence of pulmonary tuberculosis (pTB). We aimed to estimate the prevalence of residual lung function impairment and reduced health-related quality of life (HRQoL) in children after pTB treatment completion.MethodsWe conducted a cross-sectional comparative study of children aged less than 15 years at TB diagnosis who had completed treatment for pTB at least 6 months previously with a comparator group of age-matched children without a history of pTB. Symptoms, spirometry and HRQoL measured with PedsQL scale were collected. Variables associated with lung function impairment were identified through logistic regression models.ResultsWe enrolled 68 post-TB cases (median age 8.9 (IQR 7.2–11.2) years) and 91 children in the comparison group (11.5 (8.0–13.7) years). Spirometry from 52 (76.5%) post-TB cases and 89 (94.5%) of the comparison group met the quality criteria for acceptability and repeatability. Lung function impairment was present in 20/52 (38.5%) post-TB cases and 15/86 (17.4%) in the comparison group, p=0.009. Previous pTB and a history of chronic cough were significantly associated with the presence of lung function impairment (p=0.047 and 0.006 respectively). Forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVCz-scores were significantly lower in the post-TB cases compared with the comparison group (p= ConclusionsPrevious TB in children is associated with significantly impaired lung function and HRQoL.

BackgroundThe COVID-19 pandemic has caused major disruption to healthcare services globally and has impacted on tuberculosis (TB) patients and TB diagnosis and treatment services both in low- and high-income countries. We therefore explored the perspectives of members of regional and international TB control and research networks to further understand TB service disruptions and compared the experiences of members from West African and European countries.MethodsThis cross-sectional, explorative descriptive study was conducted from May to July 2020 using an open online survey with target respondents from both West African and European countries. The survey comprised discrete questions exploring challenges faced with TB screening, diagnosis, treatment, prevention, and changes implemented. Additionally, respondents were asked to provide recommendations for remedial actions.ResultsWe analysed responses from 124 respondents based in 29 countries located in Europe and West Africa. About half of the respondents reported challenges in delivering routine TB services during the COVID-19 pandemic, with over one third reporting having some form of guidance issued regarding maintaining delivery of routine TB services. Respondents emphasised the need for strengthening TB services especially in light of COVID-19 pandemic. Considerable similarities were found between the challenges experienced by TB professionals in both West African and European settings. Responses also highlighted the hidden challenges faced in some countries prior to the COVID-19 pandemic, especially in some West African settings where staff shortages and laboratory issues predated COVID-19.ConclusionsTB control and research professionals in West African and European settings experienced similar challenges to the delivery of TB diagnosis and treatment services due to the COVID-19 pandemic, and highlighted the need for clear communication of guidelines, prioritisation of routine TB service delivery, ongoing health education, and possible integration of TB and COVID-19 services to ensure that TB services are more resilient against the impact of the pandemic.

Using a matched case-control design we measured vitamin D levels in pairs of Gambian children with discordant infection status despite the same sleeping proximity to the same adult TB index case. Vitamin D levels were 2.05ng/mL higher in 24 highly TB-exposed uninfected children compared with 24 matched highly TB-Exposed infected children (p=0.08). The findings warrant further investigation in larger studies to understand the implications and significance. Conclusion: Vitamin D levels were higher in TB-uninfected children compared with TB-infected despite equal high exposure to a TB case.

Using a matched case control design conducted at MRC Gambia in 2015, we measured vitamin D levels in pairs of asymptomatic children with discordant tuberculin skin test status despite the same sleeping proximity to the same adult TB index case. Median ages of groups (infected; 10.0 years, uninfected 8.8 years) were not significantly different (p = 0.13). Mean vitamin D levels were 2.05 ng/mL (95% CI - 0.288 to 4.38) higher in 24 highly TB-exposed uninfected children compared with 24 matched highly TB-exposed infected children (p = 0.08). The findings warrant further investigation in larger studies to understand the implications and significance. Conclusion: Vitamin D levels were higher in TB-uninfected children compared with TB-infected despite equal high exposure to a TB case.

The WHO developed a generic ‘TB patient cost survey’ tool and a standardized approach to assess the direct and indirect costs of TB incurred by patients and their households, estimate the proportion of patients experiencing catastrophic costs, and measure the impact of interventions to reduce patient costs. While the generic tool is a facility-based cross-sectional survey, this standardized approach needs to be adapted for longitudinal studies. A longitudinal approach may overcome some of the limitations of a cross-sectional design and estimate the economic burden of TB more precisely. We describe the process of creating a longitudinal instrument and its application to the TB Sequel study, an ongoing multi-country, multi-center observational cohort study. We adapted the cross-sectional WHO generic TB patient cost survey instrument for the longitudinal study design of TB Sequel and the local context in each study country (South Africa, Mozambique, Tanzania, and The Gambia). The generic instrument was adapted for use at enrollment (start of TB treatment; Day 0) and at 2, 6, 12 and 24 months after enrollment, time points intended to capture costs incurred for diagnosis, during treatment, at the end of treatment, and during long-term follow-up once treatment has been completed. These time points make the adapted version suitable for use in patients with either drug-sensitive or drug-resistant TB. Using the adapted tool provides the opportunity to repeat measures and make comparisons over time, describe changes that extend beyond treatment completion, and link cost survey data to treatment outcomes and post-TB sequelae. Trial registration: ClinicalTrials.gov: NCT032516 August 1196, 2017. Abbreviations: DOTS: Directly observed treatment, short-course; DR-TB: Drug-resistant tuberculosis; MDR-TB: Multi-drug resistant tuberculosis; NTP: National Tuberculosis Programme; TB: Tuberculosis; USD: United States Dollar; WHO: World Health Organization.

Background\ud Our study aimed to identify a host cytokine biosignature that could distinguish childhood tuberculosis (TB) from other respiratory diseases (OD).\ud \ud Methods\ud Cytokine responses in prospectively recruited children with symptoms suggestive of TB were measured in whole blood assay supernatants, harvested after overnight incubation, using a Luminex platform. We used logistic regression models with Least Absolute Shrinkage and Selection Operator (LASSO) penalty to identify the optimal biosignature associated with confirmed TB disease in the training set. We subsequently assessed its performance in the test set.\ud \ud Findings\ud Of the 431 children included in the study, 44 had bacteriologically confirmed TB, 60 had clinically diagnosed TB while 327 had OD. All children were HIV-negative. Application of LASSO regression models to the training set (n = 260) resulted in the combination of IL-1ra, IL-7 and IP-10 from unstimulated samples as the optimally discriminant cytokine biosignature associated with bacteriologically confirmed TB. In the test set (n = 171), this biosignature distinguished children diagnosed with TB disease, irrespective of microbiological confirmation, from OD with area under the receiver operator characteristic curve (AUC) of 0•74 (95% CI: 0•67, 0•81), and demonstrated sensitivity and specificity of 72•2% (95% CI: 60•4, 82•1%) and 75•0% (95% CI: 64•9, 83•4%) respectively, with its performance independent of their age group and their age- and sex-adjusted nutritional status.\ud \ud Interpretation\ud This novel biosignature of childhood TB derived from unstimulated supernatants is promising. Independent validation with further optimisation will improve its performance and translational potential.\ud \ud Funding\ud Steinberg Fellowship (McGill University); Grand Challenges Canada; MRC Program Grant.

Background Children are particularly susceptible to tuberculosis. However, most children exposed to Mycobacterium tuberculosis are able to control the pathogen without evidence of infection. Correlates of human protective immunity against tuberculosis infection are lacking, and their identification would aid vaccine design. Methods We recruited pairs of asymptomatic children with discordant tuberculin skin test status but the same sleeping proximity to the same adult with sputum smear-positive tuberculosis in a matched case-control study in The Gambia. Participants were classified as either Highly TB-Exposed Uninfected or Highly TB-Exposed Infected children. Serial luminescence measurements using an in vitro functional auto-luminescent Bacillus Calmette–Guerin (BCG) whole blood assay quantified the dynamics of host control of mycobacterial growth. Assay supernatants were analysed with a multiplex cytokine assay to measure associated inflammatory responses. Findings 29 pairs of matched Highly TB-Exposed Uninfected and Highly TB-Exposed Infected children aged 5 to 15 years old were enroled. Samples from Highly TB-Exposed Uninfected children had higher levels of mycobacterial luminescence at 96 hours than Highly TB-Exposed Infected children. Highly TB-Exposed Uninfected children also produced less BCG-specific interferon-γ than Highly TB-Exposed Infected children at 24 hours and at 96 hours. Interpretation Highly TB-Exposed Uninfected children showed less control of mycobacterial growth compared to Highly TB-Exposed Infected children in a functional assay, whilst cytokine responses mirrored infection status. Funding Clinical Research Training Fellowship funded under UK Medical Research Council/Department for International Development Concordat agreement and part of EDCTP2 programme supported by European Union (MR/K023446/1). Also MRC Program Grants (MR/K007602/1, MR/K011944/1, MC_UP_A900/1122).

We applied a metabonomic strategy to identify host biomarkers in serum to diagnose paediatric tuberculosis (TB) disease. 112 symptomatic children with presumptive TB were recruited in The Gambia and classified as bacteriologically-confirmed TB, clinically diagnosed TB, or other diseases. Sera were analysed using 1H nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS). Multivariate data analysis was used to distinguish patients with TB from other diseases. Diagnostic accuracy was evaluated using Receiver Operating Characteristic (ROC) curves. Model performance was tested in a validation cohort of 36 children from the UK. Data acquired using 1H NMR demonstrated a sensitivity, specificity and Area Under the Curve (AUC) of 69% (95% confidence interval [CI], 56–73%), 83% (95% CI, 73–93%), and 0.78 respectively, and correctly classified 20% of the validation cohort from the UK. The most discriminatory MS data showed a sensitivity of 67% (95% CI, 60–71%), specificity of 86% (95% CI, 75–93%) and an AUC of 0.78, correctly classifying 83% of the validation cohort. Amongst children with presumptive TB, metabolic profiling of sera distinguished bacteriologically-confirmed and clinical TB from other diseases. This novel approach yielded a diagnostic performance for paediatric TB comparable to that of Xpert MTB/RIF and interferon gamma release assays.

Electronic Health (eHealth) is the use of information and communication technologies for health and plays a significant role in improving public health. The rapid expansion and development of eHealth initiatives allow researchers and healthcare providers to connect more effectively with patients. The aim of the CIHLMU Symposium 2020 was to discuss the current challenges facing the field, opportunities in eHealth implementation, to share the experiences from different healthcare systems, and to discuss future trends addressing the use of digital platforms in health. The symposium on eHealth explored how the health and technology sector must increase efforts to reduce the obstacles facing public and private investment, the efficacy in preventing diseases and improving patient quality of life, and the ethical and legal frameworks that influence the proper development of the different platforms and initiatives related to the field. This symposium furthered the sharing of knowledge, networking, and patient/user and practitioner experiences in low- and middle-income countries (LMIC) in both public and private sectors.

Background: Children are particularly susceptible to tuberculosis. However, most children exposed to Mycobacterium tuberculosis are able to control the pathogen without evidence of infection. Correlates of human protective immunity against tuberculosis infection are lacking, and their identification would aid vaccine design. Methods: We recruited pairs of asymptomatic children with discordant tuberculin skin test status but the same sleeping proximity to the same adult with sputum smear-positive tuberculosis in a matched case-control study in The Gambia. Participants were classified as either Highly Exposed Uninfected [HEU] or Highly Exposed Infected [HEI] children. Serial luminescence measurements using an in vitro functional auto-luminescent Bacillus Calmette–Guerin (BCG) whole blood assay quantified the dynamics of host control of mycobacterial growth. Assay supernatants were analysed with a multiplex cytokine assay to measure associated inflammatory responses. Findings: 29 pairs of matched HEI and HEU children aged 5 to 15 years old were enrolled. Samples from HEU children had higher levels of mycobacterial luminescence at 96H than HEI children. HEU children also produced less BCG-specific interferon-γ than HEI children at 24 hours and at 96 hours. Interpretation: HEI children showed superior control of mycobacterial growth compared to HEU children in a functional assay whilst cytokine responses mirrored infection status. Funding: Clinical Research Training Fellowship jointly funded by UK Medical Research Council (MRC) and UK Department for International Development (DFID) under MRC/DFID Concordat agreement and part of the EDCTP2 programme supported by the European Union (MR/K023446/1). Also enabled by MRC Program Grants (MR/K007602/1, MR/K011944/1, MC_UP_A900/1122). Declaration of Interests: BK holds a patent for a paediatric TB diagnostic biosignature. The authors do not have any other commercial or other association that might pose a conflict of interest. The data presented here form part of RB’s PhD thesis “Protection from Mycobacterium tuberculosis infection: Learning from exposed but uninfected children” awarded March 2018 by Imperial College London. Ethics Approval Statement: The study was approved by The Gambia Government/MRC Joint Ethics Committee (SCC1405 and SCC1273) and the Imperial College Healthcare Tissue Bank (R13071).

Greater Banjul Area of the Gambia.To identify co-prevalent tuberculosis (TB) among child contacts of adults with smear-positive TB.Child contacts aged

Summary Background Vitamin D is essential in the host defence against tuberculosis (TB) as an immune modulator. The aim of this study was to determine the level of 25-hydroxyvitamin D (25 (OH) D) from adult TB index cases before and after treatment and their exposed household contacts (HHC) in The Gambia. Methods Serum from adult index TB cases and their TB-exposed household contacts (HHC) was analysed for 25(OH) D and Vitamin D binding protein (VDBP) concentrations. Tuberculin skin test (TST) status was used as a measure of Mycobacterium tuberculosis (Mtb) infectivity in the HHC. In addition, HHC who later progressed to active TB (incident cases) were assessed alongside non-progressors to determine the influence of 25 (OH) D levels on TB risk. Results Eighty-three TB cases, 46 TST+ and 52 TST− HHC were analysed. Generally levels of 25(OH) D were considered insufficient in all subjects. However, median levels of 25(OH) D and VDBP were significantly higher in TB cases compared to both TST+ and TST− HHC at recruitment and were significantly reduced after TB therapy (p

SETTING Greater Banjul Area, The Gambia. OBJECTIVE To conduct a pragmatic evaluation of the Xpert(®) MTB/RIF assay in the diagnosis of tuberculosis (TB) among child contacts. DESIGN In this prospective study, one induced sputum sample was obtained from TB contacts aged

To the Editor: Tuberculosis continues to be a major public health problem in developing countries [1]. One of the roadblocks in reducing tuberculosis transmission is the lack of accurate laboratory-free diagnostic tests for use at the point of care. If tuberculosis is to be eliminated, we need a robust, low-cost and safe point-of-care diagnostic test, which in turn requires identification of appropriate biomarkers [2]. Rapid tests based on microfluidics (lateral flow tests) hold great promise for tuberculosis diagnostics. They are easy to use, cheap, provide an answer within minutes, do not require specialised equipment and are stable at room temperature, making them ideal for use in high tuberculosis burden, resource-poor settings. To date, however, no such test has been developed for tuberculosis due to lack of sensitivity related to the markers and/or sample type. Development of tests based on host biomarkers requires evaluation of different sample types [3]–[5] and markers other than interferon (IFN)-γ [5] to provide differential diagnosis of active tuberculosis, latent infection and other respiratory disorders. We have previously shown that a combination of three host factors in pleural fluid resulted in 96% correct classification of tuberculosis among other respiratory diseases (ORD) (including bacterial pneumonia) regardless of HIV status [6]. However, this sample type is not easy to obtain and we therefore wanted to determine if we could use ex vivo sputum, which is noninvasive and easy to obtain in adult pulmonary tuberculosis patients. Subjects were consecutively recruited from the outpatient clinic and ward at the Medical Research Council Unit, Fajara, the Gambia. All subjects were adults (≥18 years of age) with symptoms suggestive of tuberculosis. Subjects were subsequently classified into two groups: those with culture-confirmed tuberculosis and those with ORD. 75% of the tuberculosis and …

BackgroundRoutine laboratory diagnostic methods for M. Tuberculosis complex (MTBC) in induced sputum samples such as smear microscopy, GeneXpert and liquid Mycobacteria growth indicator tube (MGIT) culture are often negative due to the paucibacillary nature of childhood tuberculosis. We hypothesise that prolonged incubation beyond routine culture time could potentially improve MTBC detection in specimens.MethodsOut of over 1000 induced sputum samples collected during our childhood TB contact tracing research programme, we randomly selected 102 MTBC-negative MGIT cultures that had either been reported as contaminated (n=35) or negative (n=67) and further incubated these at 37°C for the duration of one month. Ziehl-Neelsen microscopy, MPT64 Antigen secretion and GeneXpert tests were repeated on all samples to detect MTBC. Bacterial DNA was extracted by CTAB method and genotyped using spoligotyping analysis.ResultsOf the 1160 routinely collected induced-sputum samples 12 (1%) were smear-positives; 41 (3.5%) Xpert-positives and 51 (4.4%) MGIT culture MTBC-positives. The remaining MGIT cultures were flagged as contaminated 393 (33.9%) or MTBC-negative 644 (55.5%). After prolonged incubation and retesting of the randomly selected ones, 26/102 (25.5%) were now microscopy-positive, 2/55 (3.63%) were GeneXpert-positive, 8/102 (7.8%) MPT64-Antigen-positive, and 38/102 (37.2%) had readable spoligotyping patterns. The predominant lineages were Mtb-Euro-American 16 (42.1%), Mtb-Indo-Oceanic 11 (28.9%) and M. africanum West African type-2 8 (21%).ConclusionProlonged incubation of routinely MTBC-negative induced-sputum cultures yielded positive results upon retest, highlighting the low sensitivity of routine diagnosis tools on pauci-bacillary paediatric samples. Spoligotyping was more sensitive to detect MTBC compared to GeneXpert. However, prolonged incubation will cause diagnostic delays and thus better strategies are needed to improve timely childhood TB diagnosis.

Setting: Greater Banjul area of The Gambia. Objectives: To evaluate uptake, adherence and completion of treatment among tuberculosis (TB) exposed children in The Gambia when isoniazid preventive treatment (IPT) is delivered at home Design: Child (age

The predictive value of a combination of clinical and radiological features with interferon-γ release assay (IGRA) for diagnosis of active tuberculosis (TB) disease among TB-exposed children is unknown.150 symptomatic HIV-negative children (aged 3 months to 14 years), prospectively recruited through active contact tracing, were included. Backward stepwise logistic regression and bootstrapping techniques were used for the development and internal validation of a clinical prediction model for active TB disease. Model discrimination and incremental value of a positive IGRA test were assessed by area under the receiver operating characteristic curve (AUC).35 (23%) children were diagnosed with active TB disease and started on treatment and 115 (77%) had other respiratory tract infections. A final parsimonious clinical model, comprising age versus 0.70; p=0.644).A clinical algorithm, including age