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Competing Interests: Competing interests: The authors have no commercial or industry conflicts. IMOA has advisory roles with non-profits such as CEPI, WHO, and Health Data Research-West Africa. MP serves as an advisor to several non-profit organisations including Bill & Melinda Gates Foundation, WHO, Stop TB Partnership, and FIND.

In 2016, WHO designated Lassa fever a priority disease for epidemic preparedness as part of the WHO Blueprint for Action to Prevent Epidemics. One aspect of preparedness is to promote development of effective medical countermeasures (ie, diagnostics, therapeutics, and vaccines) against Lassa fever. Diagnostic testing for Lassa fever has important limitations and key advancements are needed to ensure rapid and accurate diagnosis. Additionally, the only treatment available for Lassa fever is ribavirin, but controversy exists regarding its effectiveness. Finally, no licensed vaccines are available for the prevention and control of Lassa fever. Ongoing epidemiological and behavioural studies are also crucial in providing actionable information for medical countermeasure development, use, and effectiveness in preventing and treating Lassa fever. This Personal View provides current research priorities for development of Lassa fever medical countermeasures based on literature published primarily in the last 5 years and consensus opinion of 20 subject matter experts with broad experience in public health or the development of diagnostics, therapeutics, and vaccines for Lassa fever. These priorities provide an important framework to ensure that Lassa fever medical countermeasures are developed and readily available for use in endemic and at-risk areas by the end of the decade., Competing Interests: Declaration of interests KAM, AJM, NMM, JTO, MTO, and AKU declare receiving financial support for the completion of this Personal View from Wellcome (grant number 226538/Z/22/Z), payments were made to the University of Minnesota. ADTB is a member of the Vaccine Research, Development and Manufacturing Committee of the Coalition for Epidemic Preparedness Innovations (CEPI). DME is employed by FIND. RFG declares grants U01AI151812, U19AI135995, R01AI132223, R01AI132244, and U19AI142790, all awarded from the National Institute of Allergy and Infectious Diseases, LEAP4WA awarded by the European & Developing Countries Clinical Trials Partnership, and ESEP1904 and INTU1901, both awarded by CEPI; stocks in and royalties or licenses from Zalgen Labs; ownership of a monoclonal antibody patent (WO2018106712A1); and travel support from Wellcome to attend the workshop identified in this Personal View. SG declares financial support for this Personal View from WHO and Wellcome; the receipt of drugs for clinical trials from Toyama–Fujifilm; grants (all payments were made to SG's institutions) from the German Research Foundation (grants GU 883/4-2, GU 883/5-1, and GU 883/7-1), the European Commission (project 101103204—INTEGRATE), the German Government, Ministry of Health (projects ZMI1-2521WHO002 and ZMII2-2523GHP006), CEPI (framework agreement for implementing partner services); the Kirmser Foundation (donation of equipment); speaker honoraria for continuing medical education on viral haemorrhagic fevers; and support for attending meetings from WHO, Wellcome, and CEPI, including travel support from Wellcome to attend the workshop identified in this Personal View. LTM declares being a science consultant at FIND, for which she receives grants, contracts, and consulting fees; and travel support from Wellcome to attend the workshop identified in this Personal View. SAO declares a consulting contract with CEPI (payments made to SAO); is a member of the INTEGRATE consortium with grants from the European & Developing Countries Clinical Trials Partnership (payments made to SAO's institution); and support from CEPI and EDCTP funds (payments made to travel agencies and through SAO's institution). CR declares participation on a Data Safety Monitoring Board or Advisory Board (this advisory board was designated after CR's participation in the work leading to this Personal View). WKA is Executive Director of the African Vaccine Manufacturing Initiative, and Cheif Executive of National Vaccine Institute, Ghana. DAA, IMA, WKA, ADTB, DGB, EF-C, IdC, DSG, SBG, MJ, KAM, JTO, MTO, AKU, and CSS declare Wellcome supported for travel to attend the workshop identified in this Personal View. PCF, PJH, and JPG worked at Wellcome during the time that this Personal View was completed. All other authors declare no competing interests. No authors were paid by a pharmaceutical company or any other agency to write this Personal View. The authors alone are responsible for the views expressed in this Personal View and they do not necessarily represent the views, decisions, or policies of the institutions with which they are affiliated. Editorial note: The Lancet Group takes a neutral position with respect to territorial claims in published maps and institutional affiliations., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Introduction: Estimates suggest that one-third of snakebite cases in sub-Saharan Africa affect children. Despite children being at a greater risk of disability and death, there are limited published data. This study has determined the: population-incidence and mortality rate of hospital-attended paediatric snakebite; clinical syndromes of snakebite envenoming; and predictors of severe local tissue damage., Methods: All children presenting to Kilifi County Hospital, Kenya with snakebite were identified through the Kilifi Health and Demographic Surveillance System (KHDSS). Cases were prospectively registered, admitted for at least 24-hours, and managed on a paediatric high dependency unit (HDU). Households within the KHDSS study area have been included in 4-monthly surveillance and verbal autopsy, enabling calculation of population-incidence and mortality. Predictors of severe local tissue damage were identified using a multivariate logistic regression analysis., Results: Between 2003 and 2021, there were 19,606 admissions to the paediatric HDU, of which 584 were due to snakebite. Amongst young children (≤5-years age) the population-incidence of hospital-attended snakebite was 11.3/100,000 person-years; for children aged 6-12 years this was 29.1/100,000 person-years. Incidence remained consistent over the study period despite the population size increasing (98,967 person-years in 2006; and 153,453 person-years in 2021). Most cases had local envenoming alone, but there were five snakebite associated deaths. Low haemoglobin; raised white blood cell count; low serum sodium; high systolic blood pressure; and an upper limb bite-site were independently associated with the development of severe local tissue damage., Conclusion: There is a substantial burden of disease due to paediatric snakebite, and the annual number of cases has increased in-line with population growth. The mortality rate was low, which may reflect the species causing snakebite in this region. The identification of independent predictors of severe local tissue damage can help to inform future research to better understand the pathophysiology of this important complication., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Abouyannis et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Identifying the dissemination patterns and impacts of a virus of economic or health importance during a pandemic is crucial, as it informs the public on policies for containment in order to reduce the spread of the virus. In this study, we integrated genomic and travel data to investigate the emergence and spread of the SARS-CoV-2 B.1.1.318 and B.1.525 (Eta) variants of interest in Nigeria and the wider Africa region. By integrating travel data and phylogeographic reconstructions, we find that these two variants that arose during the second wave in Nigeria emerged from within Africa, with the B.1.525 from Nigeria, and then spread to other parts of the world. Data from this study show how regional connectivity of Nigeria drove the spread of these variants of interest to surrounding countries and those connected by air-traffic. Our findings demonstrate the power of genomic analysis when combined with mobility and epidemiological data to identify the drivers of transmission, as bidirectional transmission within and between African nations are grossly underestimated as seen in our import risk index estimates., (© 2023. The Author(s).)

The COVID-19 global pandemic is being driven by evolving SARS-CoV-2 variants with consequential implications on virus transmissibility, host immunity, and disease severity. Continuous molecular and genomic surveillance of the SARS-CoV-2 variants is therefore necessary for public health interventions toward the management of the pandemic. This study is a retrospective analysis of COVID-19 cases reported in a Nigerian tertiary institution from July to December 2021. In total, 705 suspected COVID-19 cases that comprised 547 students and 158 non-students were investigated by real time PCR (RT-PCR); of which 372 (~52.8%) tested positive for COVID-19. Using a set of selection criteria, 74 (~19.9%) COVID-19 positive samples were selected for next generation sequencing. Data showed that there were two outbreaks of COVID-19 within the university community over the study period, during which more females (56.8%) tested positive than males (47.8%) (p<0.05). Clinical data together with phylogenetic analysis suggested community transmission of SARS-CoV-2 through mostly asymptomatic and/or pre-symptomatic individuals. Confirmed COVID-19 cases were mostly mild, however, SARS-CoV-2 delta (77%) and omicron (4.1%) variants were implicated as major drivers of respective waves of infections during the study period. This study highlights the importance of integrated surveillance of communicable disease during outbreaks., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Adeyemi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Competing Interests: Disclosure of interest: The authors completed the ICMJE Disclosure of Interest Form (available upon request from the corresponding author) and declare no conflicts of interest.

Background: A few studies have assessed the epidemiological impact and the cost-effectiveness of COVID-19 vaccines in settings where most of the population had been exposed to SARS-CoV-2 infection., Methods: We conducted a cost-effectiveness analysis of COVID-19 vaccine in Kenya from a societal perspective over a 1.5-year time frame. An age-structured transmission model assumed at least 80% of the population to have prior natural immunity when an immune escape variant was introduced. We examine the effect of slow (18 months) or rapid (6 months) vaccine roll-out with vaccine coverage of 30%, 50% or 70% of the adult (>18 years) population prioritising roll-out in those over 50-years (80% uptake in all scenarios). Cost data were obtained from primary analyses. We assumed vaccine procurement at US$7 per dose and vaccine delivery costs of US$3.90-US$6.11 per dose. The cost-effectiveness threshold was US$919.11., Findings: Slow roll-out at 30% coverage largely targets those over 50 years and resulted in 54% fewer deaths (8132 (7914-8373)) than no vaccination and was cost saving (incremental cost-effectiveness ratio, ICER=US$-1343 (US$-1345 to US$-1341) per disability-adjusted life-year, DALY averted). Increasing coverage to 50% and 70%, further reduced deaths by 12% (810 (757-872) and 5% (282 (251-317) but was not cost-effective, using Kenya's cost-effectiveness threshold (US$919.11). Rapid roll-out with 30% coverage averted 63% more deaths and was more cost-saving (ICER=US$-1607 (US$-1609 to US$-1604) per DALY averted) compared with slow roll-out at the same coverage level, but 50% and 70% coverage scenarios were not cost-effective., Interpretation: With prior exposure partially protecting much of the Kenyan population, vaccination of young adults may no longer be cost-effective., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Competing Interests: We have read the journal’s policy and the authors of this manuscript have the following competing interests: CI and IMA are past and current Directors-General of the Nigeria Centre for Disease Control. CI is the pioneer Director General of the Nigeria Centre for Disease Control, and led the agency between August 2016 and October 2021. IMA is an Academic Editor for PLOS Global Public Health.

Background: Pneumococcal disease contributes significantly to childhood morbidity and mortality and treatment is costly. Nigeria recently introduced the pneumococcal conjugate vaccine (PCV) to prevent pneumococcal disease. The aim of this study is to estimate health provider and household costs for the treatment of pneumococcal disease in children aged <5 years (U5s), and to assess the impact of these costs on household income., Methods: We recruited U5s with clinical pneumonia, pneumococcal meningitis or pneumococcal septicaemia from a tertiary level hospital and a secondary level hospital in Kano, Nigeria. We obtained resource utilisation data from medical records to estimate costs of treatment to provider, and household expenses and income loss data from caregiver interviews to estimate costs of treatment to households. We defined catastrophic health expenditure (CHE) as household costs exceeding 25% of monthly household income and estimated the proportion of households that experienced it. We compared CHE across tertiles of household income (from the poorest to least poor)., Results: Of 480 participants recruited, 244 had outpatient pneumonia, and 236 were hospitalised with pneumonia (117), septicaemia (66) and meningitis (53). Median (IQR) provider costs were US$17 (US$14-22) for outpatients and US$272 (US$271-360) for inpatients. Median household cost was US$51 (US$40-69). Overall, 33% of households experienced CHE, while 53% and 4% of the poorest and least poor households, experienced CHE, respectively. The odds of CHE increased with admission at the secondary hospital, a diagnosis of meningitis or septicaemia, higher provider costs and caregiver having a non-salaried job., Conclusion: Provider costs are substantial, and households incur treatment expenses that considerably impact on their income and this is particularly so for the poorest households. Sustaining the PCV programme and ensuring high and equitable coverage to lower disease burden will reduce the economic burden of pneumococcal disease to the healthcare provider and households., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Background: Ten-valent pneumococcal conjugate vaccine (PCV10), delivered at 6, 10, and 14 weeks of age was introduced in Kenya in January, 2011, accompanied by a catch-up campaign in Kilifi County for children aged younger than 5 years. Coverage with at least two PCV10 doses in children aged 2-11 months was 80% in 2011 and 84% in 2016; coverage with at least one dose in children aged 12-59 months was 66% in 2011 and 87% in 2016. We aimed to assess PCV10 effect against nasopharyngeal carriage and invasive pneumococcal disease (IPD) in children and adults in Kilifi County., Methods: This study was done at the KEMRI-Wellcome Trust Research Programme among residents of the Kilifi Health and Demographic Surveillance System, a rural community on the Kenyan coast covering an area of 891 km 2 . We linked clinical and microbiological surveillance for IPD among admissions of all ages at Kilifi County Hospital, Kenya, which serves the community, to the Kilifi Health and Demographic Surveillance System from 1999 to 2016. We calculated the incidence rate ratio (IRR) comparing the prevaccine (Jan 1, 1999-Dec 31, 2010) and postvaccine (Jan 1, 2012-Dec 31, 2016) eras, adjusted for confounding, and reported percentage reduction in IPD as 1 minus IRR. Annual cross-sectional surveys of nasopharyngeal carriage were done from 2009 to 2016., Findings: Surveillance identified 667 cases of IPD in 3 211 403 person-years of observation. Yearly IPD incidence in children younger than 5 years reduced sharply in 2011 following vaccine introduction and remained low (PCV10-type IPD: 60·8 cases per 100 000 in the prevaccine era vs 3·2 per 100 000 in the postvaccine era [adjusted IRR 0·08, 95% CI 0·03-0·22]; IPD caused by any serotype: 81·6 per 100 000 vs 15·3 per 100 000 [0·32, 0·17-0·60]). PCV10-type IPD also declined in the post-vaccination era in unvaccinated age groups (<2 months [no cases in the postvaccine era], 5-14 years [adjusted IRR 0·26, 95% CI 0·11-0·59], and ≥15 years [0·19, 0·07-0·51]). Incidence of non-PCV10-type IPD did not differ between eras. In children younger than 5 years, PCV10-type carriage declined between eras (age-standardised adjusted prevalence ratio 0·26, 95% CI 0·19-0·35) and non-PCV10-type carriage increased (1·71, 1·47-1·99)., Interpretation: Introduction of PCV10 in Kenya, accompanied by a catch-up campaign, resulted in a substantial reduction in PCV10-type IPD in children and adults without significant replacement disease. Although the catch-up campaign is likely to have brought forward the benefits by several years, the study suggests that routine infant PCV10 immunisation programmes will provide substantial direct and indirect protection in low-income settings in tropical Africa., Funding: Gavi, The Vaccine Alliance and The Wellcome Trust of Great Britain., (Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Objective: To estimate the population prevalence of active pulmonary tuberculosis in Gambia., Methods: Between December 2011 and January 2013, people aged ≥ 15 years participating in a nationwide, multistage cluster survey were screened for active pulmonary tuberculosis with chest radiography and for tuberculosis symptoms. For diagnostic confirmation, sputum samples were collected from those whose screening were positive and subjected to fluorescence microscopy and liquid tuberculosis cultures. Multiple imputation and inverse probability weighting were used to estimate tuberculosis prevalence., Findings: Of 100 678 people enumerated, 55 832 were eligible to participate and 43 100 (77.2%) of those participated. A majority of participants (42 942; 99.6%) were successfully screened for symptoms and by chest X-ray. Only 5948 (13.8%) were eligible for sputum examination, yielding 43 bacteriologically confirmed, 28 definite smear-positive and six probable smear-positive tuberculosis cases. Chest X-ray identified more tuberculosis cases (58/69) than did symptoms alone (43/71). The estimated prevalence of smear-positive and bacteriologically confirmed pulmonary tuberculosis were 90 (95% confidence interval, CI: 53-127) and 212 (95% CI: 152-272) per 100 000 population, respectively. Tuberculosis prevalence was higher in males (333; 95% CI: 233-433) and in the 35-54 year age group (355; 95% CI: 219-490)., Conclusion: The burden of tuberculosis remains high in Gambia but lower than earlier estimates of 490 per 100 000 population in 2010. Less than half of all cases would have been identified based on smear microscopy results alone. Successful control efforts will require interventions targeting men, increased access to radiography and more accurate, rapid diagnostic tests.

Epidemiological differences exist between Mycobacterium africanum (Maf)- and Mycobacterium tuberculosis (Mtb)-infected patients, but to date, contributing host factors have not been characterised. We analysed clinical outcomes, as well as soluble markers and gene expression profiles in unstimulated, and ESAT6/CFP-10-, whole-Maf- and Mtb-stimulated blood samples of 26 Maf- and 49 Mtb-HIV-negative tuberculosis patients before, and after 2 and 6 months of anti-tuberculosis therapy. Before treatment, both groups had similar clinical parameters, but differed in few cytokines concentration and gene expression profiles. Following treatment the body mass index, skinfold thickness and chest X-ray scores showed greater improvement in the Mtb- compared to Maf-infected patients, after adjusting for age, sex and ethnicity (p = 0.02; 0.04 and 0.007, respectively). In addition, in unstimulated blood, IL-12p70, IL12A and TLR9 were significantly higher in Maf-infected patients, while IL-15, IL-8 and MIP-1α were higher in Mtb-infected patients. Overnight stimulation with ESAT-6/CFP-10 induced significantly higher levels of IFN-γ and TNF-α production, as well as gene expression of CCL4, IL1B and TLR4 in Mtb- compared to Maf-infected patients. Our study confirms differences in clinical features and immune genes expression and concentration of proteins associated with inflammatory processes between Mtb- and Maf-infected patients following anti-tuberculosis treatment These findings have public health implications for treatment regimens, and biomarkers for tuberculosis diagnosis and susceptibility.

Background: A Tuberculin skin test (TST) survey was conducted to assess the prevalence of latent TB Infection (LTBI) and to estimate the annual risk of M. tuberculosis infection (ARTI) in Gambian school children. The results are expected to contribute to understanding of Tuberculosis epidemiology in The Gambia., Methods: This was a nationwide, multi-cluster survey in children aged 6-11 years. Districts, 20 of 37, were selected by probability proportional to size and schools by simple random sampling. All TST were performed using the Mantoux method. Height and weight measurements were obtained for all participants. We calculated prevalence of LTBI using cut-off points of 10mm, the mirror and mixture modelling methods., Results: TST readings were completed 13,386 children with median age of 9 years (interquartile range [IQR] 8-10 years). Mixture analysis yielded a cut-off point of 12 mm, and LTBI prevalence of 6.9% [95%CI 6.47-7.37] and the ARTI was 0.75% [95%CI 0.60-0.91]. LTBI was associated gender and urban residence (p <0.01). Nutritional status was not associated with non-reactive TST or sizes of TST indurations. ARTI did not differ significantly by age, gender, BCG vaccination or residence., Conclusions: This estimates for LTBI prevalence and ARTI were low but this survey provides updated data. Malnutrition did not affect estimates of LTBI and ARTI. Given the low ARTI in this survey and the overlapping distribution of indurations with mixture modelling, further surveys may require complementary tests such as interferon gamma release assays or novel diagnostic tools.

The epidemiology of Mycobacterium tuberculosis (Mtb) and M. africanum (Maf) suggests differences in their virulence, but the host immune profile to better understand the pathogenesis of tuberculosis (TB) have not been studied. We compared the transcriptomic and metabolic profiles between Mtb- and Maf-infected TB cases to identify host biomarkers associated with lineages-specific pathogenesis and response to anti-TB chemotherapy. Venous blood samples from Mtb- and Maf-infected patients obtained before and after anti-TB treatment were analyzed for cell composition, gene expression and metabolic profiles. Prior to treatment, similar transcriptomic profiles were seen in Maf- and Mtb-infected patients. In contrast, post treatment, over 1600 genes related to immune responses and metabolic diseases were differentially expressed between the groups. Notably, the upstream regulator hepatocyte nuclear factor 4-alpha (HNF4α), which regulated 15% of these genes, was markedly enriched. Serum metabolic profiles were similar in both group pre-treatment, but the decline in pro-inflammatory metabolites post treatment were most pronounced in Mtb-infected patients. Together, the differences in both peripheral blood transcriptomic and serum metabolic profiles between Maf- and Mtb-infected patients observed over the treatment period, might be indicative of intrinsic host factors related to susceptibility to TB and/or differential efficacy of the standard anti-TB treatment on the two lineages.

To reach performance levels comparable to human experts, computer-aided detection (CAD) systems are typically optimized following a supervised learning approach that relies on large training databases comprising manually annotated lesions. However, manually outlining those lesions constitutes a difficult and time-consuming process that renders detailedly annotated data difficult to obtain. In this paper, we investigate an alternative approach, namely multiple-instance learning (MIL), that does not require detailed information for optimization. We have applied MIL to a CAD system for tuberculosis detection. Only the case condition (normal or abnormal) was required during training. Based upon the well-known miSVM technique, we propose an improved algorithm that overcomes miSVM's drawbacks related to positive instance underestimation and costly iteration. To show the advantages of our MIL-based approach as compared with a traditional supervised one, experiments with three X-ray databases were conducted. The area under the receiver operating characteristic curve was utilized as a performance measure. With the first database, for which training lesion annotations were available, our MIL-based method was comparable to the supervised system ( 0.86 versus 0.88 ). When evaluating the remaining databases, given their large difference with the previous image set, the most appealing strategy was to retrain the CAD systems. However, since only the case condition was available, only the MIL-based system could be retrained. This scenario, which is common in real-world applications, demonstrates the better adaptation capabilities of the proposed approach. After retraining, our MIL-based system significantly outperformed the supervised one ( 0.86 versus 0.79 and 0.91 versus 0.85 , and p=0.0002 , respectively).

Background: The identification of Mycobacterium-tuberculosis (Mtb) infected individuals remains a challenge due to an insufficient understanding of immune responses detected with the current diagnostic tests for latent tuberculosis i.e. the tuberculin skin test (TST) or IFN-γ release assays (IGRAs) and an inability to distinguish infection stages with current immunologic assays. Further classification based on markers other than IFN-γ may help to define markers of early Mtb infection., Methods: We assessed the TST status of Mtb-exposed household contacts at baseline and at 6 months. Contacts were classified into those with initial positive TST (TST+); those with baseline negative TST but TST conversion at 6 months (TST converters, TSTC) and those with persistently negative TST (PTST-). We assessed their short- and long-term immune responses to PPD and ESAT-6/CFP-10 (EC) via IFN-γ ELISPOT and a multiplex cytokine array in relation to TST status and compared them to those of TB cases to identify immune profiles associated with a spectrum of infection stages., Results: After 1 and 6 days stimulation with EC, 12 cytokines (IFN-γ, IL-2, IP-10, TNF-α, IL-13, IL-17, IL-10, GMCSF, MIP-1β, MCP-3, IL-2RA and IL-1A) were not different in TSTC compared to TST+ suggesting that robust adaptive Mtb-specific immune responses precede TST conversion. Stratifying contacts by baseline IFN-γ ELISPOT to EC in combination with TST results revealed that IP-10 and IL-17 were highest in the group of TST converters with positive baseline ELISPOT, suggesting they might be markers for recent infection., Conclusion: We describe a detailed analysis of Mtb-specific biomarker profiles in exposed household contacts in a TB endemic area that provides insights into the dynamic immune responses to Mtb infection and may help to identify biomarkers for 'at-risk' populations beyond TST and IGRA.

In The Gambia, Mycobacterium tuberculosis (Mtb) and Mycobacterium africanum (Maf) are major causes of tuberculosis (TB). Maf is more likely to cause TB in immune suppressed individuals, implying differences in virulence. Despite this, few studies have assessed the underlying immunity to the two pathogens in human. In this study, we analyzed T-cell responses from 19 Maf- and 29 Mtb-infected HIV-negative patients before and after TB chemotherapy following overnight stimulation of whole blood with TB-specific antigens. Before treatment, percentages of early secreted antigenic target-6(ESAT-6)/culture filtrate protein-10(CFP-10) and purified protein derivative-specific single-TNF-α-producing CD4(+) and CD8(+) T cells were significantly higher while single-IL-2-producing T cells were significantly lower in Maf- compared with Mtb-infected patients. Purified protein derivative-specific polyfunctional CD4(+) T cells frequencies were significantly higher before than after treatment, but there was no difference between the groups at both time points. Furthermore, the proportion of CD3(+) CD11b(+) T cells was similar in both groups pretreatment, but was significantly lower with higher TNF-α, IL-2, and IFN-γ production in Mtb- compared with that of Maf-infected patients posttreatment. Our data provide evidence of differences in T-cell responses to two mycobacterial strains with differing virulence, providing some insight into TB pathogenesis with different Mtb strains that could be prospectively explored as biomarkers for TB protection or susceptibility., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

In West Africa, Mycobacterium tuberculosis strains co-circulate with M. africanum, and both pathogens cause pulmonary tuberculosis in humans. Given recent findings that M. tuberculosis T-cell epitopes are hyperconserved, we hypothesized that more immunogenic strains have increased capacity to spread within the human host population. We investigated the relationship between the composition of the mycobacterial population in The Gambia, as measured by spoligotype analysis, and the immunogenicity of these strains as measured by purified protein derivative-induced interferon-γ release in ELISPOT assays of peripheral blood mononuclear cells. We found a positive correlation between strains with superior spreading capacity and their relative immunogenicity. Although our observation is true for M. tuberculosis and M. africanum strains, the association was especially pronounced in 1 M. africanum sublineage, characterized by spoligotype shared international type 181, which is responsible for 20% of all tuberculosis cases in the region and therefore poses a major public health threat in The Gambia.

Rationale: Biomarkers that can be used to evaluate new interventions against latent tuberculosis infection (LTBI) and predict reactivation TB disease are urgently required., Objectives: To evaluate ESAT-6 and CFP-10 (EC) IFN-γ ELISPOT as a biomarker for treatment efficacy in LTBI., Methods: This was a randomized, blinded, and placebo-controlled trial of INH in EC ELISPOT and Mantoux test positive participants., Measurements and Main Results: Participants received a 6-month course of 900 mg INH twice weekly or a matching placebo. INH acetylator genotypes were determined and urine tested for INH metabolites to confirm adherence. The proportion of positive responders for CFP-10 and ESAT-6 between treatment arms was compared using mixed effects logistic regression models. A Tweedie (compound Poisson) model was fitted to allow for zero inflation and overdispersion of quantitative response. The proportions of EC ELISPOT-positive subjects reduced over time (P < 0.001) but did not differ by study arm (P = 0.36). Median spot-forming units for ESAT-6 and CFP-10 also declined significantly with time (P < 0.001) but did not differ by study arm (P = 0.74 and 0.71, respectively). There was no evidence of an interaction between acetylator status and INH treatment with respect to ELISPOT results over time., Conclusions: In contacts with LTBI, INH therapy plays no role in observed decreases in Mycobacterium tuberculosis antigen-specific T-cell responses over time. IFN-γ ELISPOT is probably not a useful biomarker of treatment efficacy in LTBI. Clinical trial registered with www.clinicaltrials.gov (NCT 00130325).

Background: Introduction of pneumococcal vaccines in Nigeria is a priority as part of the Accelerated Vaccine Introduction Initiative (AVI) of the Global Alliance for Vaccines and Immunisation (GAVI). However, country data on the burden of pneumococcal disease (IPD) is limited and coverage by available conjugate vaccines is unknown. This study was carried out to describe the pre vaccination epidemiology and population biology of pneumococcal carriage in Nigeria., Methods: This was a cross sectional survey. Nasopharyngeal swabs (NPS) were obtained from a population sample in 14 contiguous peri-urban Nigerian communities. Data on demographic characteristics and risk factor for carriage were obtained from all study participants. Pneumococci isolated from NPS were characterised by serotyping, antimicrobial susceptibility and Multi Locus Sequencing Typing (MLST)., Results: The prevalence of pneumococcal carriage was 52.5%. Carriage was higher in children compared to adults (67.4% vs. 26%), highest (≈90%) in infants aged <9 months and reduced significantly with increasing age (P<0.001). Serotypes 19F (18.6%) and 6A (14.4%) were most predominant. Potential vaccine coverage was 43.8%, 45.0% and 62% for PCV-7, PCV-10 and PCV-13 respectively. There were 16 novel alleles, 72 different sequence types (STs) from the isolates and 3 Sequence Types (280, 310 and 5543) were associated with isolates of more than one serotype indicative of serotype switching. Antimicrobial resistance was high for cotrimoxazole (93%) and tetracycline (84%), a third of isolates had intermediate resistance to penicillin. Young age was the only risk factor significantly associated with carriage., Conclusions: Pneumococcal carriage and serotype diversity is highly prevalent in Nigeria especially in infants. Based on the coverage of serotypes in this study, PCV-13 is the obvious choice to reduce disease burden and prevalence of drug resistant pneumococci. However, its use will require careful monitoring. Our findings provide sound baseline data for impact assessment following vaccine introduction in Nigeria.

In 2003, the Institute of Tropical Medicine (ITM) in Antwerp set up an Internet-based decision support service to assist health-care workers in the management of difficult HIV/AIDS cases. This service is available to physicians working in resource-limited settings. Between April 2003 and December 2009, the telemedicine service received 1058 queries, from more than 40 countries, mostly resource-constrained. In the first six years there were 952 queries, of which 459 (49%) were posted on the web-based telemedicine discussion forum and the rest sent by email. All queries were handled by a co-ordinator who forwarded them to a network of specialists, based at the ITM and at other institutions. The average time to provide a first reply was 24 hours. Almost half of the queries received in the first six years (n = 466) were related to the use of antiretroviral medications. The response rate to a user questionnaire was 19% (73 questionnaires returned out of 387 delivered): half of those (n = 37) came from active users and the remainder (n = 36) from clinicians who had never used the system. The user survey showed that telemedicine advice was valuable in the management of specific cases, and significantly influenced the way that clinicians managed other similar cases subsequently. Nonetheless, there was a declining trend in the rate of use of the service.

Determining what constitutes protective immunity to TB is critical for the development of improved diagnostics and vaccines. The comparison of the immune system between contacts of TB patients, who later develop TB disease (progressors), versus contacts who remain healthy (non-progressors), allows for identification of predictive markers of TB disease. This study provides the first comprehensive analysis of the immune system of progressors and non-progressors using a well-characterised TB case-contact (TBCC) platform in The Gambia, West Africa. 22 progressors and 31 non-progressors were analysed at recruitment, 3 months and 18 months (time to progression: median[IQR] of 507[187-714] days). Immunophenotyping of PBMC, plasma cytokine levels and RT-MLPA analysis of whole blood-derived RNA was performed to capture key immune system parameters. At recruitment, progressors had lower PBMC proportions of CD4+ T cells, NKT cells and B cells relative to non-progressors. Analysis of the plasma showed higher levels of IL-18 in progressors compared to non-progressors and analysis of the RNA showed significantly lower gene expression of Bcl2 but higher CCR7 in progressors compared to non-progressors. This study shows several markers that may predict the onset of active TB at a very early stage after infection. Once these markers have been validated in larger studies, they provide avenues to prospectively identify people at risk of developing TB, a key issue in the testing of new TB vaccines.

Background: Qualitative and quantitative changes in IGRA response offer promise as biomarkers to monitor Tuberculosis (TB) drug therapy, and for the comparison of new interventions. We studied the decay kinetics of TB-specific antigen T-cell responses measured with an in-house ELISPOT assay during the course of therapy., Methods: Newly diagnosed sputum smear positive TB cases with typical TB chest radiographs were recruited. All patients were given standard anti-TB treatment. Each subject was followed up for 6 months and treatment outcomes were documented. Blood samples were obtained for the ESAT-6 and CFP-10 (EC) ELISPOT at diagnosis, 1-, 2-, 4- and 6-months. Qualitative and quantitative reversion of the ELISPOT results were assessed with McNemar test, conditional logistic regression and mixed-effects hierarchical Poisson models., Results: A total of 116 cases were recruited and EC ELISPOT was positive for 87% (95 of 109) at recruitment. There was a significant decrease in the proportion of EC ELISPOT positive cases over the treatment period (p<0.001). Most of the reversion occurred between the start and first month of treatment and at completion at 6 months. ESAT-6 had higher median counts compared to CFP-10 at all time points. Counts for each antigen declined significantly with therapy (p<0.001). Reverters had lower median SFUs at the start of treatment compared to non-Reverters for both antigens. Apart from the higher median counts for non-Reverters, no other risk factors for non-reversion were found., Conclusions: TB treatment induces qualitative and quantitative reversion of a positive in-house IGRA in newly diagnosed cases of active TB disease. As this does not occur reliably in the majority of cured individuals, qualitative and quantitative reversion of an IGRA ELISPOT has limited clinical utility as a surrogate marker of treatment efficacy.

Background: Mycobacterium tuberculosis (MTb) infects approximately 2 billion people world-wide resulting in almost 2 million deaths per year. Determining biomarkers that distinguish different stages of tuberculosis (TB) infection and disease will provide tools for more effective diagnosis and ultimately aid in the development of new vaccine candidates. The current diagnostic kits utilising production of IFN-gamma in response to TB antigens can detect MTb infection but are unable to distinguish between infection and disease. The aim of this study was to assess if the use of a longer term assay and the analysis of multiple cytokines would enhance diagnosis of active TB in a TB-endemic population., Methods: We compared production of multiple cytokines (TNF-alpha, IFN-gamma, IL-10, IL-12(p40), IL-13, IL-17 and IL-18) following long-term (7 days) stimulation of whole-blood with TB antigens (ESAT-6/CFP-10 (EC), PPD or TB10.4) from TB cases (n = 36) and their Mycobacterium-infected (TST+; n = 20) or uninfected (TST-; n = 19) household contacts (HHC)., Results and Conclusions: We found that TNF-alpha production following EC stimulation and TNF-alpha and IL-12(p40) following TB10.4 stimulation were significantly higher from TB cases compared to TST+ HHC, while production of IFN-gamma and IL-13 were significantly higher from TST+ compared to TST- HHC following PPD or EC stimulation. Combined analysis of TNF-alpha, IL-12(p40) and IL-17 following TB10.4 stimulation resulted in 85% correct classification into TB cases or TST+ HHC. 74% correct classification into TST+ or TST- HHC was achieved with IFN-gamma alone following TB10.4 stimulation (69% following EC) and little enhancement was seen with additional cytokines. We also saw a tendency for TB cases infected with M. africanum to have increased TNF-alpha and IL-10 production compared to those infected with M. tuberculosis. Our results provide further insight into the pathogenesis of tuberculosis and may enhance the specificity of the currently available diagnostic tests, particularly for diagnosis of active TB.

Background: T cells producing multiple factors have been shown to be required for protection from disease progression in HIV but we have recently shown this not to be the case in TB. Subjects with active disease had a greater proportion of polyfunctional cells responding to ESAT-6/CFP-10 stimulation than their infected but non-diseased household contacts (HHC). We therefore wanted to assess this profile in subjects who had successfully completed standard TB chemotherapy., Methods: We performed a cross-sectional study using PBMC from TB cases (pre- and post-treatment) and HHC. Samples were stimulated overnight with TB antigens (ESAT-6/CFP-10 and PPD) and their CD4+ and CD8+ T cells were assessed for production of CD107a, IFN-gamma, IL-2 and TNF-alpha and the complexity of the responses was determined using SPICE and PESTLE software., Results and Conclusions: We found that an increase in complexity (i.e., production of more than 1 factor simultaneously) of the T cell profile was associated with TB disease and that this was significantly reduced following TB treatment. This implies that T cells are able to respond adequately to TB antigens with active disease (at least initially) but the ability of this response to protect the host from disease progression is hampered, presumably due to immune evasion strategies by the bacteria. These findings have implications for the development of new diagnostics and vaccine strategies.

Objectives: To describe the pattern of tuberculosis (TB) occurrence in Greater Banjul, The Gambia with Geographical Information Systems (GIS) and Spatial Scan Statistics (SaTScan) and to determine whether there is significant TB case clustering., Methods: In Greater Banjul, where 80% of all Gambian TB cases arise, all patients with TB registered at chest clinics between March 2007 and February 2008 were asked to participate. Demographic, clinical characteristics and GPS co-ordinates for the residence of each consenting TB case were recorded. A spatial scan statistic was used to identify purely spatial and space-time clusters of tuberculosis among permanent residents., Results: Of 1145 recruited patients with TB, 84% were permanent residents with 88% living in 37 settlements that had complete maps available down to settlement level. Significant high- and low-rate spatial and space-time clusters were identified in two districts. The most likely cluster of high rate from both the purely spatial analysis and the retrospective space-time analysis were from the same geographical area. A significant secondary cluster was also identified in one of the densely populated areas of the study region., Conclusions: There is evidence of significant clustering of TB cases in Greater Banjul, The Gambia. Systematic use of cluster detection techniques for regular TB surveillance in The Gambia may aid effective deployment of resources. However, passive case detection dictates that community-based active case detection and risk factor surveys would help confirm the presence of true clusters and their causes.

Background: We compared the performance of tuberculin skin test (TST), Quantiferon-TB Gold in-tube (QFT-GIT), and T-SPOT.TB in diagnosing latent tuberculosis (LTBI) among childhood TB contacts in a TB endemic setting with high BCG coverage. We evaluated the performance of interferon gamma release assays (IGRAs) and TST when combined in an algorithm., Methods: Childhood contacts of newly diagnosed TB patients were tested with TST, QFT-GIT, and T-SPOT. The level of exposure in contacts was categorized according to whether they slept in the same room, same house, or a different house as the index case. For the evaluation of combined test performance, prior estimates for prevalence of latent TB were used in Bayesian models that assumed conditional dependence between tests., Results: A total of 285 children were recruited. Overall, 26.5%, 33.0%, and 33.5% were positive for TST, T-SPOT, or QFT-GIT, respectively. All 3 tests responded to the gradient of sleeping proximity to the index case. Neither TST nor IGRA results were confounded by BCG vaccination. There was moderate agreement (kappa = 0.40-0.68) between all 3 tests. Combination of either IGRA with TST increased sensitivity (by 9.3%-9.6%) especially in contacts in the highest exposure category but was associated with loss of specificity (9.9%-11.3%)., Conclusion: IGRAs and TST are similar in their diagnostic performance for LTBI. An approximate 10% sensitivity benefit for using the TST and an IGRA in combination is associated with a slightly greater specificity loss. Testing strategies combining an IGRA and TST with an "or" statement may be useful only in situations where there is a high pretest probability of latent infection.

Population studies showed that there are differences in T-lymphocytes subpopulation of normal children in different regions, and reference values in an area might be different from another. This study compared the values in our population with CDC and WHO reference values. Blood samples from 279 healthy, HIV-negative children <12 years of age were analysed for complete blood count, CD3+, CD4+, CD8+ counts and percentages. Except for CD8%, mean values for all parameters measured significantly decreased with age. CD4+ counts were higher in females than males, P < .05. Using the WHO criteria, 15.9% of subjects had low total lymphocyte count and 20.6% had low CD4 count. Children <3 years had median CD4% lower than WHO normal values. Our median CD4+ counts correlated with CDC values. Values used by WHO in infants are higher than ours. We suggest that our children be assessed using CDC reference values which correlate with ours.

The objective of this study was to establish haematological reference ranges for the West African subregion using a Gambian cohort. We analysed full blood counts from 1279 subjects aged > or =1 year. Anthropometric and body composition measurements were performed. Haematological mean values, medians and 90% reference values were calculated and related to malnutrition in children and thinness and/or obesity in adults. Haemoglobin (Hb) and mean corpuscular volume (MCV) significantly increased with age (P < 0.00001). There were gender-related changes in Hb from 15 years of age (P = 0.001) and for MCV only in adults (P = 0.0002). Hb was significantly reduced in underweight and stunted children (P = 0.0001 and 0.0002, respectively) but was unaffected by thinness or obesity in adults. White blood cell (WBC) and platelet counts were highest under 5 years and declined significantly with age (P < 0.0001 and 0.0001). While, there were no gender-related differences with WBC, there were higher WBC counts in underweight (P = 0.0001) and stunted (P < 0.0001) children. Adult females had significantly higher mean platelet counts compared with males (P = 0.006). The mean and median values of haematological parameters in The Gambia are similar to other standards but the 90% reference range for each parameter encompasses lower values when compared with Western standards.

Most people infected with Mycobacterium tuberculosis, the causative agent of tuberculosis (TB) actually maintain a strong immune response and are able to control bacterial growth (deemed latently infected (LTBI)), while approximately 10% progress to disease resulting in almost 2 million deaths per year. Determining the immune 'footprint' at specific stages of infection and disease will allow for better diagnostics, treatments and ultimately development of new vaccine candidates. In this study we performed multi-factorial flow cytometry on fresh blood from 56 TB cases, 46 Tuberculin Skin Test (TST) positive (LTBI) and 39 TST negative household contacts. We found a highly significant increase in granulocytes and decrease in B cells and invariant (Valpha24+Vbeta11+) NKT cells in TB cases compared to TST+ contacts (p<0.0001, p=0.007 and p=0.01 respectively) which were restored to LTBI levels following 6 months of TB treatment. Using support vector analysis, we found a combination of granulocyte and lymphocyte and/or NKT cell proportions allowed almost 90% correct classification into M. tuberculosis infection or disease. This work has important public health benefits in regards to diagnosis and treatment of TB in sub-Saharan Africa and in furthering our understanding of the requirements for protective immunity to TB.

Numerous studies have reported that HIV-infected pregnant women are at increased risk of delivery of low birth weight (LBW) infants, of preterm deliveries and of intrauterine growth restriction. The objective of the study was to determine the effect of maternal HIV infection on the anthropometric characteristics of the babies at birth. A prospective study was carried out at the Lagos University Teaching Hospital, Nigeria. There were three times more LBW babies in the HIV-positive group than in the uninfected mothers (odds ratio = 3.47, 95% confidence interval = 1.69, 7.27; chi(2) = 12.99, P = 0.0003).The maternal weight (t = 15.85; P = 0.0001), maternal body mass index (BMI) (t = 15.07; P = 0.0003), birth weight of infants (t = 27.17; P = 0.0001) and birth length (t = 31.20; P = 0.001) were significantly less in HIV-positive mothers than in controls. In conclusion, poor maternal bodyweight and low BMI are significant contributors to LBW in HIV-infected women. Nutritional counselling, dietary intake and weight monitoring during pregnancy should be emphasized to improve pregnancy outcome in HIV-infected women.

Tuberculosis (TB) remains a global health problem. The solution involves development of an effective vaccine, but has been limited by incomplete understanding of what constitutes protective immunity during natural infection with Mycobacterium tuberculosis. In this study, M. tuberculosis-specific responses following an overnight whole-blood assay were assessed by intracellular cytokine staining and luminex, and compared between TB cases and exposed household contacts. TB cases had significantly higher levels of IFN-gamma(+)TNF-alpha(+)IL-2(+)CD4(+)T cells compared with contacts. TB cases also had a significantly higher proportion of cells single-positive for TNF-alpha, but lower proportion of cells producing IL-2 alone and these differences were seen for both CD4(+)and CD8(+) T cells. Cytokine profiles from culture supernatants were significantly biased toward a Th1 phenotype (IFN-gamma and IL-12(p40)) together with a complete abrogation of IL-17 secretion in TB cases. Our data indicate that despite a robust response to TB antigens in active TB disease, changes in the pattern of cytokine production between TB infection and disease clearly contribute to disease progression.

Interferon gamma remains a key effector molecule that is still widely used as the most informative biomarker for screening human immune responses against tuberculosis, particularly in ELISPOT assays. We investigated the participation of CD4(+) and CD8(+) T lymphocytes in the PBMC responses to Mycobacterium tuberculosis (Mtb) specific antigens in 33 TB cases and 49 contacts. Responses to ESAT-6 were higher than CFP-10. There was no significant difference in responses to both Mtb antigens between cases and contacts. PBMCs response to ESAT-6 but not CFP-10 in cases was significantly reduced by depletion of CD4(+) cells whereas CD8(+) cell depletion had no impact. In conclusion, ESAT-6 is a more recognized antigen in this population, and CD4(+) lymphocytes are the main participants in IFN-gamma response by ELISPOT. Thus, a decline of CD4(+) T lymphocytes below a critical level might affect the sensitivity of IFN-gamma release assays for detecting Mtb infection.

Background: There is considerable variability in the outcome of Mycobacterium tuberculosis infection. We hypothesized that Mycobacterium africanum was less likely than M. tuberculosis to transmit and progress to tuberculosis disease., Methods: In a cohort study of patients with tuberculosis and their household contacts in The Gambia, we categorized 1808 HIV-negative tuberculosis contacts according to exposure to M. tuberculosis or M. africanum. Positive skin test results indicated transmission, and development of tuberculosis during 2 years of follow-up indicated progression to disease., Results: Transmission rates were similar, but rates of progression to disease were significantly lower in contacts exposed to M. africanum than in those exposed to M. tuberculosis (1.0% vs. 2.9%; hazard ratio [HR], 3.1 [95% confidence interval {CI}, 1.1-8.7]). Within M. tuberculosis sensu stricto, contacts exposed to a Beijing family strain were most likely to progress to disease (5.6%; HR relative to M. africanum, 6.7 [95% CI, 2.0-22])., Conclusions: M. africanum and M. tuberculosis transmit equally well to household contacts, but contacts exposed to M. africanum are less likely to progress to tuberculosis disease than those exposed to M. tuberculosis. The variable rate of progression by lineage suggests that tuberculosis variability matters in clinical settings and should be accounted for in studies evaluating tuberculosis vaccines and treatment regimens for latent tuberculosis infection.

Background: Studies of Tuberculosis (TB) case contacts are increasingly being utilised for understanding the relationship between M. tuberculosis and the human host and for assessing new interventions and diagnostic tests. We aimed to identify the incidence rate of new TB cases among TB contacts and to relate this to their initial Mantoux and ELISPOT test results., Methods and Findings: After initial Mantoux and ELISPOT tests and exclusion of co-prevalent TB cases, we followed 2348 household contacts of sputum smear positive TB cases. We visited them at 3 months, 6 months, 12 months, 18 months and 24 months, and investigated those with symptoms consistent with TB. Those who were diagnosed separately at a government clinic had a chest x-ray. Twenty six contacts were diagnosed with definite TB over 4312 person years of follow-up (Incidence rate 603/100,000 person years; 95% Confidence Interval, 370-830). Nine index and secondary case pairs had cultured isolates available for genotyping. Of these, 6 pairs were concordant and 3 were discordant. 2.5% of non-progressors were HIV positive compared to 12% of progressors (HR 6.2; 95% CI 1.7-22.5; p = 0.010). 25 secondary cases had initial Mantoux results, 14 (56%) were positive ; 21 had initial ELISPOT results, 11 (52%) were positive; 15 (71%) of 21 tested were positive by one or the other test. Of the 6 contacts who had concordant isolates with their respective index case, 4 (67%) were Mantoux positive at recruitment, 3 (50%) were ELISPOT positive; 5 (83%) were positive by one or other of the two tests. ELISPOT positive contacts, and those with discordant results, had a similar rate of progression to those who were Mantoux positive. Those negative on either or both tests had the lowest rate of progression., Conclusions: The incidence rate of TB disease in Gambian TB case contacts, after screening for co-prevalent cases, was 603/100,000 person years. Since initial ELISPOT test and Mantoux tests were each positive in only just over half of cases, but 71% were positive by one or other test, positivity by either might be the best indication for preventive treatment. These data do not support the replacement of the Mantoux test by an ELISPOT test in The Gambia or similar settings.

Background: IFN-gamma Release Assays (IGRAs) have been licensed for the diagnosis of latent Mycobacterium tuberculosis infection (LTBI). Their performance may depend on assay format and may vary across populations and settings. We compared the diagnostic performance of an in-house T -cell and commercial whole blood-based IGRAs for the diagnosis of LTBI and TB disease in The Gambia., Methods: Newly diagnosed sputum smear positive cases and their household contacts were recruited. Cases and contacts were bled for IGRA and contacts had a Mantoux skin test. We assessed agreement and discordance between the tests and categorized a contact's level of M. tuberculosis exposure according to where s/he slept relative to a case: the same room, same house or a different house. We assessed the relationship between exposure and test results by multiple logistic regression., Results: In 80 newly diagnosed TB cases, the sensitivity of ELISPOT was 78.7% and for QFT-GIT was 64.0% (p = 0.047). Of 194 household contacts 57.1% and 58.8% were positive for ELISPOT and QFT-GIT respectively. The overall agreement between both IGRAs for LTBI in contacts was 71.4% and there was no significant discordance (p = 0.29). There was significant discordance between the IGRAs and TST. Neither IGRA nor TST had evidence of false positive results because of Bacille Calmette Guérin (BCG) vaccination. However, agreement between QFT-GIT and TST as well as discordance between both IGRAs and TST were associated with BCG vaccination. Both IGRAs responded to the M. tuberculosis exposure gradient and were positively associated with increasing TST induration (p = 0.003 for ELISPOT and p = 0.001 for QFT-GIT)., Conclusion: The ELISPOT test is more sensitive than the QFT-GIT for diagnosing TB disease. The two tests perform similarly in the diagnosis of LTBI in TB contacts. Significant discordance between the two IGRAs and between each and the TST remain largely unexplained.

Background: Very little longitudinal information is available regarding the performance of T cell-based tests for Mycobacterium tuberculosis infection. To address this deficiency, we conducted a longitudinal assessment of the enzyme-linked immunosorbent spot test (ELISPOT) test in comparison to the standard tuberculin skin test (TST)., Methods and Findings: In tuberculosis (TB) contacts we repeated ELISPOT tests 3 mo (n = 341) and 18 mo (n = 210) after recruitment and TSTs at 18 mo (n = 130). We evaluated factors for association with conversion and reversion and investigated suspected cases of TB. Of 207 ELISPOT-negative contacts, 51 (24.6%) had 3-mo ELISPOT conversion, which was associated with a positive recruitment TST (odds ratio [OR] 2.2, 95% confidence interval [CI] 1.0-5.0, p = 0.048) and negatively associated with bacillus Calmette-Guérin (BCG) vaccination (OR 0.5, 95% CI 0.2-1.0, p = 0.06). Of 134 contacts, 54 (40.2%) underwent 3-mo ELISPOT reversion, which was less likely in those with a positive recruitment TST (OR 0.3, 95% CI 0.1-0.8, p = 0.014). Between 3 and 18 mo, 35/132 (26.5%) contacts underwent ELISPOT conversion and 28/78 (35.9%) underwent ELISPOT reversion. Of the 210 contacts with complete results, 73 (34.8%) were ELISPOT negative at all three time points; 36 (17.1%) were positive at all three time points. Between recruitment and 18 mo, 20 (27%) contacts had ELISPOT conversion; 37 (50%) had TST conversion, which was associated with a positive recruitment ELISPOT (OR 7.2, 95% CI 1.4-37.1, p = 0.019); 18 (32.7%) underwent ELISPOT reversion; and five (8.9%) underwent TST reversion. Results in 13 contacts diagnosed as having TB were mixed, but suggested higher TST sensitivity., Conclusions: Both ELISPOT conversion and reversion occur after M. tuberculosis exposure. Rapid ELISPOT reversion may reflect M. tuberculosis clearance or transition into dormancy and may contribute to the relatively low reported ELISPOT conversion rate. Therefore, a negative ELISPOT test for M. tuberculosis infection should be interpreted with caution.

Background: Low birth weight (LBW) is the most important cause of perinatal mortality and morbidity worldwide and particularly so in developing countries. Maternal HIV (Human Immunodeficiency Virus) infection has been identified as one of the risk factors to the development of low birth weight babies., Objective: To evaluate the effect of maternal HIV infection on the birth weight of the newborn at tertiary hospital in West Africa., Methods: The anthropometry of all HIV seropositive women who delivered in LUTH as well as that of their babies was determined using standard methods. Controls consisted of HIV seronegative women and their babies matched for age and parity with the above subjects., Results: There were a total of 262 subjects of whom 132 (50.4%) were HIV seropositive and 130 (49.6%) were HIV seronegative controls. There were five times more low birth weight (LBW) infants in the HIV seropositive group than in the controls (OR 5.77, CI=2.19-16.80; p=0.000075). The mean maternal body mass index, BMI (p=0.0003), mean maternal weight (p=0.0004) and mean birth weight of newborns (p=0.0002) were significantly lower in the HIV seropositive group than in the controls. Maternal weight and gestational age were significantly associated with low birth weight (OR 15.3, CI=2.6-316.0; p=0.002) and (OR 3.78, CI=1.37-10.9; p=0.007) respectively., Conclusion: Maternal HIV infection is strongly associated with low maternal BMI and low birth weight in their offspring.

The relationship between the T-cell response to mycobacterial antigens and the likelihood of progression to disease has not been defined. We report a rapidly rising ELISPOT count in a 55-year-old man with evidence of Mycobacterium tuberculosis infection prior to the onset of symptoms of disease. This case illustrates the possible utility of quantitative changes in the ELISPOT count in predicting progression from M. tuberculosis infection to disease.

Background: Pediatric HIV/AIDS is increasing in Nigeria through mother-to-child transmission. Lack of diagnostic facility and affordability of therapy are major constraints. These factors were examined in Lagos University Teaching Hospital (LUTH) between 1996 and 2002., Materials and Methods: Case records of pediatric HIV/AIDS patients were examined for age, sex, mode of diagnosis, associated illnesses, treatment outcome and socioeconomic and HIV status of the parents., Results: Out of 124 cases confirmed to have HIV/AIDS, 56.5% were aged <18 months and 89.5% had > or =4 clinical features at presentation. There was an increasing trend in the number of cases from 1996 to 2002. Diagnosis was by WHO clinical criteria as no polymerase chain reaction (PCR), was done and only 12.1% had CD4+ count done. The commonest associated illness was tuberculosis (25.8%). Only 20.2% were placed on antiretroviral drugs during the period. Mothers were significantly younger than fathers (P<0.05) and were more likely to be HIV positive. High rate of discharges against medical advice and default from follow-up occurred., Conclusion: Pediatric HIV/AIDS is on the increase at LUTH, and mothers were more HIV infected than fathers. The prohibitive cost of drugs prevented most patients from receiving therapy.

Definitive diagnosis of HIV infection in infants < 18 months of age who were born to HIV-infected mothers is still posing some difficulty in Nigeria and other developing countries. Within this age definitive diagnosis can only be carried out by antigen based techniques which are indeed not available in these developing countries. This has resulted in the absence of authoritative data on the rate of mother-to-child transmission in these countries. Nigeria inclusive. The present pilot study was therefore carried out to generate some information on the rate of mother to child transmission in Nigeria using the PCR technique. Plasma samples were obtained from 68 children of both sexes less than 18 months of age and who were born to HIV infected mothers. The samples were collected from two pediatric departments. in Lagos and in Benin. The presence of HIV 1 RNA in each of the samples. was determined using the Amplicor Monitor V 1.5 technique (Roche Diagnostics). Data showed that HIV-1 RNA was detected in 15 of the 68 samples tested. This gave an HIV-1 RNA detection rate of 22%. Among women who had some intervention, the rate of transmission of infection was 11% while the rate among those without intervention was 30%. The 22% transmission rate recorded in this study is close to the range of 25 to 35% that has been reported in several developed and a few developing countries. A multicenter nationwide study will still be needed to determine the national mother to child transmission rate in Nigeria.

Introduction: In HIV-1-infected children, haematological disturbances include bone marrow abnormalities and peripheral cytopenias. All three major cell lineages can be depressed., Methods: A cross-sectional study of baseline haematological parameters was undertaken in 68 children with confirmed HIV infection. In all cases, a complete blood count was done and some had CD4+ counts and HIV RNA PCR. The CD4+ count was analysed by the Coulter manual latex particle monoclonal antibody method and HIV RNA PCR by Roche Amplicor Monitor, version 1.5., Results: Anaemia (< 100 g/L) was present in 77.9%, severe (< 60 g/L) in 5.9%, moderate (60-70 g/L) in 32.3% and mild (80-99 g/L) in 39.7%. The mean haemoglobin concentration decreased as disease progressed (p < 0.05); 6% had leucopenia, 17.5% had neutropenia and 2.5% (one case) had thrombocytopenia; also, the four (6%) subjects with leucopenia were in clinical stages B and C. Neutropenia, lymphocytopenia and thrombocytopenia were seen more in clinical stages B and C, though this relationship was not statistically significant., Conclusion: Both the erythroid and other cells lines are affected by HIV/AIDS and other associated factors. Anaemia is the most common haematological abnormality. The severity of peripheral cytopenias is related to the disease burden.

Objective: To compare the enzyme-linked immunospot (ELISPOT) assay with the tuberculin skin test (TST) in children for the diagnosis of Mycobacterium tuberculosis infection in the Gambia., Methods: We divided child contacts of sputum smear-positive tuberculosis cases into 3 age categories (<5, 5-9, and 10-14 years) and assessed agreement between the 2 tests plus their relationship to prior Bacille Calmette-Guerin (BCG) vaccination. We categorized a child's level of M tuberculosis exposure according to where he/she slept relative to a case: the same room, same house, or a different house. The relationship between exposure and test result was assessed by multiple logistic regression., Results: In child contacts of 287 cases, 225 (32.5%) of 693 were positive by TST and 232 (32.3%) of 718 by ELISPOT. The overall agreement between tests was 83% and the discordance was not significant. Both tests responded to the M tuberculosis exposure gradient in each age category. The percentage of those who were TST positive/ELISPOT negative increased with increasing exposure. At the lowest exposure level, the percentage of ELISPOT-positive children who were TST negative was increased compared with the highest exposure level. Neither test had evidence of false positive results because of BCG., Conclusions: In Gambian children, the ELISPOT is slightly less sensitive than the TST in the diagnosis of M tuberculosis infection from recent exposure, and neither test is confounded by prior BCG vaccination. Evidence of reduced TST sensitivity in subjects with the lowest known recent M tuberculosis exposure suggests that, when maximal sensitivity is important, the 2 tests may be best used together.