BCG-induced protection against Mycobacterium tuberculosis infection: Evidence, mechanisms, and implications for next-generation vaccines.

The tuberculosis (TB) vaccine Bacillus Calmette-Guérin (BCG) was introduced 100 years ago, but as it provides insufficient protection against TB disease, especially in adults, new vaccines are being developed and evaluated. The discovery that BCG protects humans from becoming infected with Mycobacterium tuberculosis (Mtb) and not just from progressing to TB disease provides justification for considering Mtb infection as an endpoint in vaccine trials. Such trials would require fewer participants than those with disease as an endpoint. In this review, we first define Mtb infection and disease phenotypes that can be used for mechanistic studies and/or endpoints for vaccine trials. Secondly, we review the evidence for BCG-induced protection against Mtb infection from observational and BCG re-vaccination studies, and discuss limitations and variation of this protection. Thirdly, we review possible underlying mechanisms for BCG efficacy against Mtb infection, including alternative T cell responses, antibody-mediated protection, and innate immune mechanisms, with a specific focus on BCG-induced trained immunity, which involves epigenetic and metabolic reprogramming of innate immune cells. Finally, we discuss the implications for further studies of BCG efficacy against Mtb infection, including for mechanistic research, and their relevance to the design and evaluation of new TB vaccines.

A tuberculosis elimination-focused geospatial approach to optimising access to diagnostic GeneXpert machines in Fiji.

OBJECTIVES: Fiji could be the first country to eliminate tuberculosis. To inform this strategy, we aimed to identify how many GeneXpert® machines are required to enable over 90% of Fijians to be within one-hour easy access. METHODS: We used Geographic Information System (Quantum GIS; QGIS), OpenStreetMap and population data (Kontur) to map possible facilities in relation to QGIS generated 60-min drive-time isochrones, with correction for missing road data. For outer islands, we calculated a distance to nearest hub operation. RESULTS: The solution comprised 24 GeneXpert® machines, allocating 7 GeneXpert® to Viti Levu, 6 GeneXpert® to Vanua Levu and 11 to other islands. This resulted in 827,810 people, 93.6% of Fiji's population, being within 1 h of a machine. Twenty-one thousand four hundred seventy-nine people on outer islands were an average of 43 km by water from the nearest facility. CONCLUSIONS: We conclude that over 90% of Fijians could be within an hour of a GeneXpert® machine with placement of 24 machines.

Selective under-representation of Pacific peoples in population estimates for health indicator measurements in Aotearoa New Zealand misinforms policy making.

BACKGROUND: The Census of Populations and Dwellings' is the five yearly population count of Aotearoa New Zealand. Best available populations (BAP) are subnational projections based on census data and demographic assumptions developed for healthcare planning and funding allocation but are also used as the denominator for health indicator monitoring. Pacific people are systematically undercounted, but the impact on health statistics is not well studied. For COVID-19 vaccination coverage, health service user (HSU) data were considered a more reliable denominator than BAP but introduced new biases. We aimed to understand how the choice of denominator population impacts estimates of population size and health system performance for Pacific people at a local level. METHODS: We described how declining census response rates affected population data quality. We compared BAP and HSU data at district level. For the indicators 'access to primary care' and 'cervical cancer screening uptake' we replaced currently used BAP denominators with HSU and examined the impact for different ethnic groups in different geographic districts. RESULTS: Overall Census 2018 response declined by 10%, but for Maori and Pacific people by 21% and 23%, respectively. This inequitably affected BAP accuracy. Census undercount was highest in the district with the largest Pacific populations, where HSU exceeded BAP most. Notably, 'access to primary care' for Pacific people in this district consistently exceeds 100%. Using BAP, both health indicators are currently estimated as highest for Pacific people compared to other ethnic groups, but when based on HSU, they dropped to lowest. Similar, but less pronounced trends occurred in other districts. Changes in trends over time for both indicators coincided mostly with adjustments in BAP, rather than changes in the numerators. CONCLUSIONS: The current use of BAP denominators for health statistics does not enable reliable monitoring of key health indicators for Pacific people. HSU denominators are also unsuitable for monitoring health. Exploring the feasibility of a real-time population register is strongly recommended as a new, transparent, way of obtaining more reliable, timely population data to guide policymaking and underpin a more equitable health system under the health reforms. Meanwhile, reporting of ethnic specific outcomes need to include a clear assessment of the potential for bias due to inaccurate population estimates.

An Aspiration to Radically Shorten Phase 3 Tuberculosis Vaccine Trials.

A new tuberculosis vaccine is a high priority. However, the classical development pathway is a major deterrent. Most tuberculosis cases arise within 2 years after Mycobacterium tuberculosis exposure, suggesting a 3-year trial period should be possible if sample size is large to maximize the number of early exposures. Increased sample size could be facilitated by working alongside optimized routine services for case ascertainment, with strategies for enhanced case detection and safety monitoring. Shortening enrolment could be achieved by simplifying screening criteria and procedures and strengthening site capacity. Together, these measures could enable radically shortened phase 3 tuberculosis vaccine trials.

Pneumonia, Meningitis, and Septicemia in Adults and Older Children in Rural Gambia: 8 Years of Population-Based Surveillance.

BACKGROUND: Representative data describing serious infections in children aged ≥5 years and adults in Africa are limited. METHODS: We conducted population-based surveillance for pneumonia, meningitis, and septicemia in a demographic surveillance area in The Gambia between 12 May 2008 and 31 December 2015. We used standardized criteria to identify, diagnose, and investigate patients aged ≥5 years using conventional microbiology and radiology. RESULTS: We enrolled 1638 of 1657 eligible patients and investigated 1618. Suspected pneumonia, septicemia, or meningitis was diagnosed in 1392, 135, and 111 patients, respectively. Bacterial pathogens from sterile sites were isolated from 105 (7.5%) patients with suspected pneumonia, 11 (8.1%) with suspected septicemia, and 28 (25.2%) with suspected meningitis. Streptococcus pneumoniae (n = 84), Neisseria meningitidis (n = 16), and Staphylococcus aureus (n = 15) were the most common pathogens. Twenty-eight (1.7%) patients died in hospital and 40 (4.1%) died during the 4 months after discharge. Thirty postdischarge deaths occurred in patients aged ≥10 years with suspected pneumonia. The minimum annual incidence was 133 cases per 100 000 person-years for suspected pneumonia, 13 for meningitis, 11 for septicemia, 14 for culture-positive disease, and 46 for radiological pneumonia. At least 2.7% of all deaths in the surveillance area were due to suspected pneumonia, meningitis, or septicemia. CONCLUSIONS: Pneumonia, meningitis, and septicemia in children aged ≥5 years and adults in The Gambia are responsible for significant morbidity and mortality. Many deaths occur after hospital discharge and most cases are culture negative. Improvements in prevention, diagnosis, inpatient, and follow-up management are urgently needed.

Rapid SARS-CoV-2 Seroprevalence Survey in Central and Western Divisions of Fiji, 2021.

During November-December 2021, we performed a SARS-CoV-2 seroprevalence survey in Central and Western Divisions of Fiji. A total of 539 participants 8-70 years of age were 95.5% (95% CI 93.4%-97.1%) seropositive, indicating high community levels of immunity. Seroprevalence studies can inform public health responses to emerging SARS-CoV-2 variants.

BCG Vaccine Protection Against Mycobacterium tuberculosis Infection by Level of Exposure in The Gambia.

In Indonesia, BCG vaccine protection against Mycobacterium tuberculosis infection decreased with increasing exposure to the pathogen. We aimed to validate these findings in Africa. Poisson regression was used to estimate BCG protection, stratified by pathogen exposure using an exposure score, against enzyme-linked immunospot assay conversion at 3 months in 220 Gambian case contacts. Although the interaction between BCG and exposure was not significant (P = .13), BCG protection was strongest in the lowest-exposure tertile (relative risk, 0.35 [95% confidence interval, .15-.82; P = .02] vs 0.50 [.30-.83; P = .008] and 0.71 (.45-1.13; P = .1] for the middle and highest-exposure tertiles, respectively. These results are consistent with those from Indonesia.

Persistent and Emerging Pneumococcal Carriage Serotypes in a Rural Gambian Community After 10 Years of Pneumococcal Conjugate Vaccine Pressure.

BACKGROUND: The continuing impact of pneumococcal conjugate vaccines (PCVs) in regions with high pneumococcal transmission is threatened by the persistence of vaccine serotypes (VTs) and the emergence of nonvaccine serotypes (NVTs). METHODS: In 2016, we conducted a cross-sectional carriage survey (CSS5) in a community where PCV7 was first introduced in 2006 during a cluster-randomized trial conducted before nationwide introduction of PCV7 (2009) and PCV13 (2011). We estimated prevalence of PCV13 VT and NVT by age and compared these with earlier surveys before (CSS0), during (CSS1-3), and after the trial but before PCV13 (CSS4). Genomic analysis was conducted for the nontypeable pneumococci. RESULTS: Prevalence of PCV13 VT carriage decreased during the 10 years between CSS0 and CSS5 across all age groups (67.6% to 13.5%, P < .001; 59.8% to 14.4%, P < .001; 43.1% to 17.9%, P < .001; and 24.0% to 5.1%, P < .001, in <2, 2-4, 5-14, and ≥15 years, respectively). However, there was no difference between CSS4 and CSS5 in children ≥2 years and adults (children <2 years, no data). The prevalence of PCV13 NVT increased between CSS0 and CSS5 for children <2 years but decreased in older children and adults. In CSS5, serotypes 3, 6A, and 19F were the most common VT and nontypeable isolates were the most common NVT. Among nontypeable isolates, 73.0% lost the ability to express a capsule. Of these, 70.8% were from a VT background. CONCLUSIONS: The decrease in PCV13 VT that has occurred since the introduction of PCV13 appears to have plateaued. Significant carriage of these serotypes remains in all age groups.

Genomic Profiling of Mycobacterium tuberculosis Strains, Myanmar.

Multidrug resistance is a major threat to global elimination of tuberculosis (TB). We performed phenotypic drug-susceptibility testing and whole-genome sequencing for 309 isolates from 342 consecutive patients who were given a diagnosis of TB in Yangon, Myanmar, during July 2016‒June 2018. We identified isolates by using the GeneXpert platform to evaluate drug-resistance profiles. A total of 191 (62%) of 309 isolates had rifampin resistance; 168 (88%) of these rifampin-resistant isolates were not genomically related, indicating the repeated emergence of resistance in the population, rather than extensive local transmission. We did not detect resistance mutations to new oral drugs, including bedaquiline and pretomanid. The current GeneXpert MTB/RIF system needs to be modified by using the newly launched Xpert MTB/XDR cartridge or line-probe assay. Introducing new oral drugs to replace those currently used in treatment regimens for multidrug-resistant TB will also be useful for treating TB in Myanmar.

Safety and Side Effects of Rifampin versus Isoniazid in Children.

BACKGROUND: The treatment of latent infection with Mycobacterium tuberculosis is important in children because of their vulnerability to life-threatening forms of tuberculosis disease. The current standard treatment - 9 months of isoniazid - has been associated with poor adherence and toxic effects, which have hampered the effectiveness of the drug. In adults, treatment with 4 months of rifampin has been shown to be safer and to have higher completion rates than 9 months of isoniazid. METHODS: In this multicenter, open-label trial, we randomly assigned 844 children (<18 years of age) with latent M. tuberculosis infection to receive either 4 months of rifampin or 9 months of isoniazid. The primary outcome was adverse events of grade 1 to 5 that resulted in the permanent discontinuation of a trial drug. Secondary outcomes were treatment adherence, side-effect profile, and efficacy. Independent review panels whose members were unaware of trial-group assignments adjudicated all adverse events and progression to active tuberculosis. RESULTS: Of the children who underwent randomization, 829 were eligible for inclusion in the modified intention-to-treat analysis. A total of 360 of 422 children (85.3%) in the rifampin group completed per-protocol therapy, as compared with 311 of 407 (76.4%) in the isoniazid group (adjusted difference in the rates of treatment completion, 13.4 percentage points; 95% confidence interval [CI], 7.5 to 19.3). There were no significant between-group differences in the rates of adverse events, with fewer than 5% of the children in the combined groups with grade 1 or 2 adverse events that were deemed to be possibly related to a trial drug. Active tuberculosis, including 1 case with resistance to isoniazid, was diagnosed in 2 children in the isoniazid group during 542 person-years of follow-up, as compared with no cases in the rifampin group during 562 person-years (rate difference, -0.37 cases per 100 person-years; 95% CI, -0.88 to 0.14). CONCLUSIONS: Among children under the age of 18 years, treatment with 4 months of rifampin had similar rates of safety and efficacy but a better rate of adherence than 9 months of treatment with isoniazid. (Funded by the Canadian Institutes of Health Research and Conselho Nacional de Pesquisa; ClinicalTrials.gov number, NCT00170209 .).

Four Months of Rifampin or Nine Months of Isoniazid for Latent Tuberculosis in Adults.

BACKGROUND: A 9-month regimen of isoniazid can prevent active tuberculosis in persons with latent tuberculosis infection. However, the regimen has been associated with poor adherence rates and with toxic effects. METHODS: In an open-label trial conducted in nine countries, we randomly assigned adults with latent tuberculosis infection to receive treatment with a 4-month regimen of rifampin or a 9-month regimen of isoniazid for the prevention of confirmed active tuberculosis within 28 months after randomization. Noninferiority and potential superiority were assessed. Secondary outcomes included clinically diagnosed active tuberculosis, adverse events of grades 3 to 5, and completion of the treatment regimen. Outcomes were adjudicated by independent review panels. RESULTS: Among the 3443 patients in the rifampin group, confirmed active tuberculosis developed in 4 and clinically diagnosed active tuberculosis developed in 4 during 7732 person-years of follow-up, as compared with 4 and 5 patients, respectively, among 3416 patients in the isoniazid group during 7652 person-years of follow-up. The rate differences (rifampin minus isoniazid) were less than 0.01 cases per 100 person-years (95% confidence interval [CI], -0.14 to 0.16) for confirmed active tuberculosis and less than 0.01 cases per 100 person-years (95% CI, -0.23 to 0.22) for confirmed or clinically diagnosed tuberculosis. The upper boundaries of the 95% confidence interval for the rate differences of the confirmed cases and for the confirmed or clinically diagnosed cases of tuberculosis were less than the prespecified noninferiority margin of 0.75 percentage points in cumulative incidence; the rifampin regimen was not superior to the isoniazid regimen. The difference in the treatment-completion rates was 15.1 percentage points (95% CI, 12.7 to 17.4). The rate differences for adverse events of grade 3 to 5 occurring within 146 days (120% of the 4-month planned duration of the rifampin regimen) were -1.1 percentage points (95% CI, -1.9 to -0.4) for all events and -1.2 percentage points (95% CI, -1.7 to -0.7) for hepatotoxic events. CONCLUSIONS: The 4-month regimen of rifampin was not inferior to the 9-month regimen of isoniazid for the prevention of active tuberculosis and was associated with a higher rate of treatment completion and better safety. (Funded by the Canadian Institutes of Health Research and the Australian National Health and Medical Research Council; ClinicalTrials.gov number, NCT00931736 .).

Cost analysis and critical success factors of the use of oxygen concentrators versus cylinders in sub-divisional hospitals in Fiji.

BACKGROUND: Oxygen is vital in the treatment of illnesses in children and adults, yet is lacking in many low and middle-income countries health care settings. Oxygen concentrators (OCs) can increase access to oxygen, compared to conventional oxygen cylinders. We investigated the costs and critical success factors of OCs in three hospitals in Fiji, and extrapolated these to estimate the oxygen delivery cost to all Sub-Divisional hospitals (SDH) nationwide. METHODS: Data sources included key personnel interviews, and data from SDH records, Ministry of Health and Medical Services, and a non-governmental organisation. We used Investment Logic Mapping (ILM) to define key issues. An economic case was developed to identify the investment option that optimised value while incorporating critical success factors identified through ILM. A fit-for-purpose analysis was conducted using cost analysis of four short-listed options. Sensitivity analyses were performed by altering variables to show the best or worst case scenario. All costs are presented in Fijian dollars. RESULTS: Critical success factors identifed included oxygen availability, safety, ease of use, feasibility, and affordability. Compared to the status quo of having only oxygen cylinders, an option of having a minimum number of concentrators with cylinder backup would cost $434,032 (range: $327,940 to $506,920) over 5 years which would be 55% (range: 41 to 64%) of the status quo cost. CONCLUSION: Introducing OCs into all SDHs in Fiji would reduce overall costs, while ensuring identified critical success factors are maintained. This study provides evidence for the benefits of OCs in this and similar settings.

Early Clearance of Mycobacterium tuberculosis: The INFECT Case Contact Cohort Study in Indonesia.

BACKGROUND: Early clearance of Mycobacterium tuberculosis is the eradication of infection before an adaptive immune response develops. We aimed to identify host factors associated with early clearance. METHODS: Indonesian household contacts patients with smear-positive tuberculosis (TB) had an interferon-γ release assay (IGRA) at baseline and 14 weeks later. Early clearance was defined as a persistently negative IGRA. Contact characteristics, exposure, and disease phenotype were assessed for association with a positive IGRA at each time point. RESULTS: Of 1347 contacts of 462 TB cases, 780 (57.9%) were IGRA positive and 490 (36.3%) were IGRA negative. After 14 weeks, 116 of 445 (26.1%) initially negative contacts were IGRA converters; 317 (71.2%) remained persistently negative. BCG vaccination reduced the risk of a positive baseline IGRA (relative risk [RR], 0.89 [95% confidence interval {CI} .83-.97]; P = .01), and strongly reduced the risk of IGRA conversion (RR, 0.56 [95% CI, .40-.77]; P < .001). BCG protection decreased with increasing exposure (P = .05) and increasing age (P = .004). Risk of IGRA conversion was positively associated with hemoglobin concentration (P = .04). CONCLUSIONS: A quarter of household TB case contacts were early clearers. Protection against M. tuberculosis infection was strongly associated with BCG vaccination. Lower protection from BCG with increasing M. tuberculosis exposure and age can inform vaccine development.

Early Clearance of Mycobacterium tuberculosis Is Associated With Increased Innate Immune Responses.

BACKGROUND: A proportion of tuberculosis (TB) case contacts do not become infected, even when heavily exposed. We studied the innate immune responses of TB case contacts to understand their role in protection against infection with Mycobacterium tuberculosis, termed "early clearance." METHODS: Indonesian household contacts of TB cases were tested for interferon-γ release assay (IGRA) conversion between baseline and 14 weeks post recruitment. Blood cell populations and ex vivo innate whole blood cytokine responses were measured at baseline and, in a subgroup, flow cytometry was performed at weeks 2 and 14. Immunological characteristics were measured for early clearers, defined as a persistently negative IGRA at 3 months, and converters, whose IGRA converted from negative to positive. RESULTS: Among 1347 case contacts, 317 were early clearers and 116 were converters. Flow cytometry showed a resolving innate cellular response from 2 to 14 weeks in persistently IGRA-negative contacts but not converters. There were no differences in cytokine responses to mycobacterial stimuli, but compared to converters, persistently IGRA-negative contacts produced more proinflammatory cytokines following heterologous stimulation with Escherichia coli and Streptococcus pneumoniae. CONCLUSIONS: Early clearance of M. tuberculosis is associated with enhanced heterologous innate immune responses similar to those activated during induction of trained immunity.

Changes in Transcript, Metabolite, and Antibody Reactivity During the Early Protective Immune Response in Humans to Mycobacterium tuberculosis Infection.

BACKGROUND: Strategies to prevent Mycobacterium tuberculosis (Mtb) infection are urgently required. In this study, we aimed to identify correlates of protection against Mtb infection. METHODS: Two groups of Mtb-exposed contacts of tuberculosis (TB) patients were recruited and classified according to their Mtb infection status using the tuberculin skin test (TST; cohort 1) or QuantiFERON (QFT; cohort 2). A negative reading at baseline with a positive reading at follow-up classified TST or QFT converters and a negative reading at both time points classified TST or QFT nonconverters. Ribonucleic acid sequencing, Mtb proteome arrays, and metabolic profiling were performed. RESULTS: Several genes were found to be differentially expressed at baseline between converters and nonconverters. Gene set enrichment analysis revealed a distinct B-cell gene signature in TST nonconverters compared to converters. When infection status was defined by QFT, enrichment of type I interferon was observed. A remarkable area under the curve (AUC) of 1.0 was observed for IgA reactivity to Rv0134 and an AUC of 0.98 for IgA reactivity to both Rv0629c and Rv2188c. IgG reactivity to Rv3223c resulted in an AUC of 0.96 and was markedly higher compared to TST nonconverters. We also identified several differences in metabolite profiles, including changes in biomarkers of inflammation, fatty acid metabolism, and bile acids. Pantothenate (vitamin B5) was significantly increased in TST nonconverters compared to converters at baseline (q = 0.0060). CONCLUSIONS: These data provide new insights into the early protective response to Mtb infection and possible avenues to interfere with Mtb infection, including vitamin B5 supplementation.Analysis of blood from highly exposed household contacts from The Gambia who never develop latent Mycobacterium tuberculosis infection shows distinct transcriptomic, antibody, and metabolomic profiles compared to those who develop latent tuberculosis infection but prior to any signs of infection.

Diabetes Mellitus Among Pulmonary Tuberculosis Patients From 4 Tuberculosis-endemic Countries: The TANDEM Study.

BACKGROUND: Diabetes mellitus (DM) increases active tuberculosis (TB) risk and worsens TB outcomes, jeopardizing TB control especially in TB-endemic countries with rising DM prevalence rates. We assessed DM status and clinical correlates in TB patients across settings in Indonesia, Peru, Romania, and South Africa. METHODS: Age-adjusted DM prevalence was estimated using laboratory glycated hemoglobin (HbA1c) or fasting plasma glucose in TB patients. Detailed and standardized sociodemographic, anthropometric, and clinical measurements were made. Characteristics of TB patients with or without DM were compared using multilevel mixed-effect regression models with robust standard errors. RESULTS: Of 2185 TB patients (median age 36.6 years, 61.2% male, 3.8% human immunodeficiency virus-infected), 12.5% (267/2128) had DM, one third of whom were newly diagnosed. Age-standardized DM prevalence ranged from 10.9% (South Africa) to 19.7% (Indonesia). Median HbA1c in TB-DM patients ranged from 7.4% (Romania) to 11.3% (Indonesia). Compared to those without DM, TB-DM patients were older and had a higher body mass index (BMI) (P value < .05). Compared to those with newly diagnosed DM, TB patients with diagnosed DM had higher BMI and HbA1c, less severe TB, and more frequent comorbidities, DM complications, and hypertension (P value < .05). CONCLUSIONS: We show that DM prevalence and clinical characteristics of TB-DM vary across settings. Diabetes is primarily known but untreated, hyperglycemia is often severe, and many patients with TB-DM have significant cardiovascular disease risk and severe TB. This underlines the need to improve strategies for better clinical management of combined TB and DM.

Persistence of Nasopharyngeal Pneumococcal Vaccine Serotypes and Increase of Nonvaccine Serotypes Among Vaccinated Infants and Their Mothers 5 Years After Introduction of Pneumococcal Conjugate Vaccine 13 in The Gambia.

BACKGROUND: The widespread use of pneumococcal conjugate vaccine (PCV) has brought about a dramatic decrease in pneumococci of vaccine serotypes (VTs) but nonvaccine serotypes (NVTs) have emerged. METHODS: We conducted a cross-sectional survey (CSS) among infants who received 3 doses of 13-valent PCV (PCV13) and their mothers 5 years (CSS3) after PCV13 introduction. Nasopharyngeal swab samples were collected and cultured for isolation of Streptococcus pneumoniae. Whole-genome sequencing of the nontypeable strains was performed. Data were compared with those from 2 previous surveys conducted before PCV13 introduction (CSS1) and 1 year later (CSS2). RESULTS: Among infants, VT carriage decreased from 33.3% (113/339) in CSS1 to 11.4% (40/351) in CSS3 (P = .001) while NVTs increased from 53.1% (180/339) in CSS1 to 74.4% (261/351) in CSS3 (P < .001). Among mothers, there was a significant decrease in VTs between CSS2 8.4% (29/347) and CSS3 5.6% (19/342) (P = .006). NVTs increased from 16.6% (55/331) in CSS1 to 32.2% (110/342) in CSS3 (P < .001). In CSS3, the most prevalent VTs were 7F in infants and 3 in mothers, and the most prevalent NVTs were serogroup 16 and nontypeables, respectively. Genomic analysis showed that VTs were more likely than NVTs to lose their ability to express the capsule. CONCLUSIONS: Five years after PCV13 introduction, we show both direct (infants) and indirect effects (mothers) of the vaccine, while NVT replacement has occurred in both groups. Ongoing circulation of VTs warrants further study of their relevance in any consideration of a reduced dose schedule.

Staphylococcus aureus Bacteremia in Children of Rural Areas of The Gambia, 2008-2015.

Staphylococcus aureus bacteremia is a substantial cause of childhood disease and death, but few studies have described its epidemiology in developing countries. Using a population-based surveillance system for pneumonia, sepsis, and meningitis, we estimated S. aureus bacteremia incidence and the case-fatality ratio in children <5 years of age in 2 regions in the eastern part of The Gambia during 2008-2015. Among 33,060 children with suspected pneumonia, sepsis, or meningitis, we performed blood culture for 27,851; of 1,130 patients with bacteremia, 198 (17.5%) were positive for S. aureus. S. aureus bacteremia incidence was 78 (95% CI 67-91) cases/100,000 person-years in children <5 years of age and 2,080 (95% CI 1,621-2,627) cases/100,000 person-years in neonates. Incidence did not change after introduction of the pneumococcal conjugate vaccine. The case-fatality ratio was 14.1% (95% CI 9.6%-19.8%). Interventions are needed to reduce the S. aureus bacteremia burden in The Gambia, particularly among neonates.

Latent tuberculosis infection in healthcare workers in low- and middle-income countries: an updated systematic review.

Healthcare workers (HCWs) are at increased risk of latent tuberculosis (TB) infection (LTBI) and TB disease.We conducted an updated systematic review of the prevalence and incidence of LTBI in HCWs in low- and middle-income countries (LMICs), associated factors, and infection control practices. We searched MEDLINE, Embase and Web of Science (January 1, 2005-June 20, 2017) for studies published in any language. We obtained pooled estimates using random effects methods and investigated heterogeneity using meta-regression.85 studies (32 630 subjects) were included from 26 LMICs. Prevalence of a positive tuberculin skin test (TST) was 14-98% (mean 49%); prevalence of a positive interferon-γ release assay (IGRA) was 9-86% (mean 39%). Countries with TB incidence ≥300 per 100 000 had the highest prevalence (TST: pooled estimate 55%, 95% CI 41-69%; IGRA: pooled estimate 56%, 95% CI 39-73%). Annual incidence estimated from the TST was 1-38% (mean 17%); annual incidence estimated from the IGRA was 10-30% (mean 18%). The prevalence and incidence of a positive test was associated with years of work, work location, TB contact and job category. Only 15 studies reported on infection control measures in healthcare facilities, with limited implementation.HCWs in LMICs in high TB incidence settings remain at increased risk of acquiring LTBI. There is an urgent need for robust implementation of infection control measures.