Determining the Best Immunization Strategy for Protecting African Children Against Invasive Salmonella Disease.

BACKGROUND: The World Health Organization recently prequalified a typhoid conjugate vaccine (TCV), recommending its use in persons ≥6 months to 45 years residing in typhoid fever (TF)-endemic areas. We now need to consider how TCVs can have the greatest impact in the most vulnerable populations. METHODS: The Typhoid Fever Surveillance in Africa Program (TSAP) was a blood culture-based surveillance of febrile patients from defined populations presenting at healthcare facilities in 10 African countries. TF and invasive non-typhoidal Salmonella (iNTS) disease incidences were estimated for 0-10 year-olds in one-year age increments. RESULTS: Salmonella Typhi and iNTS were the most frequently isolated pathogens; 135 and 94 cases were identified, respectively. Analysis from three countries was excluded (incomplete person-years of observation (PYO) data). Thirty-seven of 123 TF cases (30.1%) and 71/90 iNTS disease cases (78.9%) occurred in children aged <5 years. No TF and 8/90 iNTS infections (8.9%) were observed in infants aged <9 months. The TF incidences (/100 000 PYO) for children aged <1 year and 1 to <2 years were 5 and 39, respectively; the highest incidence was 304 per 100 000 PYO in 4 to <5 year-olds. The iNTS disease incidence in the defined age groups ranged between 81 and 233 per 100 000 PYO, highest in 1 to <2 year-olds. TF and iNTS disease incidences were higher in West Africa. CONCLUSIONS: High burden of TF detected in young children strengthens the need for TCV introduction. Given the concurrent iNTS disease burden, development of a trivalent vaccine against S. Typhi, S. Typhimurium, and S. Enteritidis may be timely in this region

The Severe Typhoid Fever in Africa Program: Study Design and Methodology to Assess Disease Severity, Host Immunity, and Carriage Associated With Invasive Salmonellosis

Background. Invasive salmonellosis is a common community-acquired bacteremia in persons residing in sub-Saharan Africa. However, there is a paucity of data on severe typhoid fever and its associated acute and chronic host immune response and carriage. The Severe Typhoid Fever in Africa (SETA) program, a multicountry surveillance study, aimed to address these research gaps and contribute to the control and prevention of invasive salmonellosis. Methods. A prospective healthcare facility-based surveillance with active screening of enteric fever and clinically suspected severe typhoid fever with complications was performed using a standardized protocol across the study sites in Burkina Faso, the Democratic Republic of Congo (DRC), Ethiopia, Ghana, Madagascar, and Nigeria. Defined inclusion criteria were used for screening of eligible patients for enrollment into the study. Enrolled patients with confirmed invasive salmonellosis by blood culture or patients with clinically suspected severe typhoid fever with perforation were eligible for clinical follow-up. Asymptomatic neighborhood controls and immediate household contacts of each case were enrolled as a comparison group to assess the level of Salmonella-specific antibodies and shedding patterns. Healthcare utilization surveys were performed to permit adjustment of incidence estimations. Postmortem questionnaires were conducted in medically underserved areas to assess death attributed to invasive Salmonella infections in selected sites. Results. Research data generated through SETA aimed to address scientific knowledge gaps concerning the severe typhoid fever and mortality, long-term host immune responses, and bacterial shedding and carriage associated with natural infection by invasive salmonellae. Conclusions. SETA supports public health policy on typhoid immunization strategy in Africa

Multicountry Distribution and Characterization of Extended-spectrum β-Lactamase-associated Gram-negative Bacteria From Bloodstream Infections in Sub-Saharan Africa.

BACKGROUND: Antimicrobial resistance (AMR) is a major global health concern, yet, there are noticeable gaps in AMR surveillance data in regions such as sub-Saharan Africa. We aimed to measure the prevalence of extended-spectrum β-lactamase (ESBL) producing Gram-negative bacteria in bloodstream infections from 12 sentinel sites in sub-Saharan Africa. METHODS: Data were generated during the Typhoid Fever Surveillance in Africa Program (TSAP), in which standardized blood cultures were performed on febrile patients attending 12 health facilities in 9 sub-Saharan African countries between 2010 and 2014. Pathogenic bloodstream isolates were identified at the sites and then subsequently confirmed at a central reference laboratory. Antimicrobial susceptibility testing, detection of ESBL production, and conventional multiplex polymerase chain reaction (PCR) testing for genes encoding for β-lactamase were performed on all pathogens. RESULTS: Five hundred and five pathogenic Gram-negative bloodstream isolates were isolated during the study period and available for further characterization. This included 423 Enterobacteriaceae. Phenotypically, 61 (12.1%) isolates exhibited ESBL activity, and genotypically, 47 (9.3%) yielded a PCR amplicon for at least one of the screened ESBL genes. Among specific Gram-negative isolates, 40 (45.5%) of 88 Klebsiella spp., 7 (5.7%) of 122 Escherichia coli, 6 (16.2%) of 37 Acinetobacter spp., and 2 (1.3%) of 159 of nontyphoidal Salmonella (NTS) showed phenotypic ESBL activity. CONCLUSIONS: Our findings confirm the presence of ESBL production among pathogens causing bloodstream infections in sub-Saharan Africa. With few alternatives for managing ESBL-producing pathogens in the African setting, measures to control the development and proliferation of AMR organisms are urgently needed

The genomic epidemiology of multi-drug resistant invasive non-typhoidal Salmonella in selected sub-Saharan African countries

Funder: Swedish International Development Cooperation Agency (SIDA)Funder: Government of Republic of KoreaFunder: US Centers for Disease Control and PreventionBackground: Invasive non-typhoidal Salmonella (iNTS) is one of the leading causes of bacteraemia in sub-Saharan Africa. We aimed to provide a better understanding of the genetic characteristics and transmission patterns associated with multi-drug resistant (MDR) iNTS serovars across the continent. Methods: A total of 166 iNTS isolates collected from a multi-centre surveillance in 10 African countries (2010–2014) and a fever study in Ghana (2007–2009) were genome sequenced to investigate the geographical distribution, antimicrobial genetic determinants and population structure of iNTS serotypes–genotypes. Phylogenetic analyses were conducted in the context of the existing genomic frameworks for various iNTS serovars. Population-based incidence of MDR-iNTS disease was estimated in each study site. Results: Salmonella Typhimurium sequence-type (ST) 313 and Salmonella Enteritidis ST11 were predominant, and both exhibited high frequencies of MDR; Salmonella Dublin ST10 was identified in West Africa only. Mutations in the gyrA gene (fluoroquinolone resistance) were identified in S. Enteritidis and S. Typhimurium in Ghana; an ST313 isolate carrying blaCTX-M-15 was found in Kenya. International transmission of MDR ST313 (lineage II) and MDR ST11 (West African clade) was observed between Ghana and neighbouring West African countries. The incidence of MDR-iNTS disease exceeded 100/100 000 person-years-of-observation in children aged <5 years in several West African countries. Conclusions: We identified the circulation of multiple MDR iNTS serovar STs in the sampled sub-Saharan African countries. Investment in the development and deployment of iNTS vaccines coupled with intensified antimicrobial resistance surveillance are essential to limit the impact of these pathogens in Africa

Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie

Inactivation of \u3ci\u3eAscaris suum\u3c/i\u3e by Ammonia in Feces Simulating the Physical-Chemical Parameters of the Solar Toilet Under Laboratory Conditions

Access to sustainable sanitation systems is a determining factor in human health and economic development. However, more than a third of the world’s population lives without access to improved sanitation facilities. To meet the sanitation United Nations Millennium Development target, halve, by 2015, the proportion of people without sustainable access to safe drinking water and basic sanitation , a wide range of non conventional sanitation technologies have been implemented in developing countries, including waterless systems. These systems function by diverting urine away from feces and collecting, storing, and dehydrating the fecal material in watertight dehydration vaults. From a public health perspective, adequate inactivation of fecal pathogens in a sanitation system is essential before any use or disposal of fecal material. In rural areas of El Salvador, the solar toilet is capable of inactivating fecal pathogens and reducing the prevalence of parasitic infections in its users when compared to other waterless systems. Nevertheless, not all solar toilets are able to inactivate completely Ascaris spp. ova after the recommended storage period. Un-ionized ammonia (NH3) has the potential to inactivate pathogens in solutions and sludge, including Ascaris spp. ova. This study hypothesized that adding ammonia to the solar toilet will improve the technology since pathogen inactivation with ammonia could be potentiated by the alkaline medium and high temperatures achieved inside the toilet vaults. To evaluate this approach, a series of experiments in solution and biosolid were performed in a laboratory environment using physical and chemical parameters similar to those achieved by the solar toilet. Eggs of the swine Ascaris species, Ascaris suum, were used as model in all experiments. In ammonia solution, the parasite ova were stored for a period of three days and; in biosolid, the parasite ova were stored for two months. Urea was used as the source of ammonia in biosolid. In addition to the experiments with ammonia, normal viability and morphological changes within the parasite ova during incubation in vitro at 28 C° were investigated and described to complement current literature published. Results from the experiments in ammonia solution indicated that addition of ammonia (1% and 2%) could improve the system since the critical parameters that significantly reduced A. suum ova viability to zero in three days could be achieved by the solar toilet: temperature of 35°C or higher and pH value of 9.3. Results from the experiments in biosolid further showed that inactivation of A. suum ova was faster in samples exposed to urea and to temperatures higher than 28°C. All samples exposed to urea achieved 100% inactivation after 14 days (28°C), 3 days (35°C) and 24 hours (40°C and 45°C). Survival analysis of the data showed that there was a significant difference (p value \u3c.0001) between the inactivation achieved in the samples exposed to urea (1% and 2%) and the samples not exposed to urea. A logistic regression analysis estimated the effect of Urea (Treatment, OR: 25.9), Temperature (OR: 1.8), and Storage (OR: 1.17) on inactivation. Results from the experiment with A. suum ova in normal incubation solution showed that the ova went through clearly identified morphological changes at different speed of development. Two new additional stages of development were identified (Pre-larva 1 and Pre-larva 2) and no significant statistical difference was observed among the viability reported early in incubation and the one reported after three weeks of in vitro incubation, indicating that early stages of development may be use as an alternative to reduce the time to report viability. The results of this study suggest that inactivation of Ascaris spp ova by ammonia is possible in fecal material stored in the solar toilet or any other dry toilet, if the following physical and chemical conditions are met: a closed vault with a minimum temperature of 28°C; an initial pH of 8.3, minimum moisture of 27.5%, and addition of 1% urea to the biosolid. At 28°C longer storage time would be required for 100% inactivation while at higher temperatures less time of storage would be necessary. A community intervention is recommended to include field conditions and human behavior as other predictors for Ascaris spp. inactivation by ammonia

Inactivation of Ascaris suum by Ammonia in Feces Simulating the Physical-Chemical Parameters of the Solar Toilet Under Laboratory Conditions

Access to sustainable sanitation systems is a determining factor in human health and economic development. However, more than a third of the world’s population lives without access to improved sanitation facilities. To meet the sanitation United Nations Millennium Development target, halve, by 2015, the proportion of people without sustainable access to safe drinking water and basic sanitation , a wide range of non conventional sanitation technologies have been implemented in developing countries, including waterless systems. These systems function by diverting urine away from feces and collecting, storing, and dehydrating the fecal material in watertight dehydration vaults. From a public health perspective, adequate inactivation of fecal pathogens in a sanitation system is essential before any use or disposal of fecal material. In rural areas of El Salvador, the solar toilet is capable of inactivating fecal pathogens and reducing the prevalence of parasitic infections in its users when compared to other waterless systems. Nevertheless, not all solar toilets are able to inactivate completely Ascaris spp. ova after the recommended storage period. Un-ionized ammonia (NH3) has the potential to inactivate pathogens in solutions and sludge, including Ascaris spp. ova. This study hypothesized that adding ammonia to the solar toilet will improve the technology since pathogen inactivation with ammonia could be potentiated by the alkaline medium and high temperatures achieved inside the toilet vaults. To evaluate this approach, a series of experiments in solution and biosolid were performed in a laboratory environment using physical and chemical parameters similar to those achieved by the solar toilet. Eggs of the swine Ascaris species, Ascaris suum, were used as model in all experiments. In ammonia solution, the parasite ova were stored for a period of three days and; in biosolid, the parasite ova were stored for two months. Urea was used as the source of ammonia in biosolid. In addition to the experiments with ammonia, normal viability and morphological changes within the parasite ova during incubation in vitro at 28 C° were investigated and described to complement current literature published. Results from the experiments in ammonia solution indicated that addition of ammonia (1% and 2%) could improve the system since the critical parameters that significantly reduced A. suum ova viability to zero in three days could be achieved by the solar toilet: temperature of 35°C or higher and pH value of 9.3. Results from the experiments in biosolid further showed that inactivation of A. suum ova was faster in samples exposed to urea and to temperatures higher than 28°C. All samples exposed to urea achieved 100% inactivation after 14 days (28°C), 3 days (35°C) and 24 hours (40°C and 45°C). Survival analysis of the data showed that there was a significant difference (p value Results from the experiment with A. suum ova in normal incubation solution showed that the ova went through clearly identified morphological changes at different speed of development. Two new additional stages of development were identified (Pre-larva 1 and Pre-larva 2) and no significant statistical difference was observed among the viability reported early in incubation and the one reported after three weeks of in vitro incubation, indicating that early stages of development may be use as an alternative to reduce the time to report viability. The results of this study suggest that inactivation of Ascaris spp ova by ammonia is possible in fecal material stored in the solar toilet or any other dry toilet, if the following physical and chemical conditions are met: a closed vault with a minimum temperature of 28°C; an initial pH of 8.3, minimum moisture of 27.5%, and addition of 1% urea to the biosolid. At 28°C longer storage time would be required for 100% inactivation while at higher temperatures less time of storage would be necessary. A community intervention is recommended to include field conditions and human behavior as other predictors for Ascaris spp. inactivation by ammonia

Table_4_Madagascar's EPI vaccine programs: A systematic review uncovering the role of a child's sex and other barriers to vaccination.DOCX

BackgroundImmunizations are one of the most effective tools a community can use to increase overall health and decrease the burden of vaccine-preventable diseases. Nevertheless, socioeconomic status, geographical location, education, and a child's sex have been identified as contributing to inequities in vaccine uptake in low- and middle-income countries (LMICs). Madagascar follows the World Health Organization's Extended Programme on Immunization (EPI) schedule, yet vaccine distribution remains highly inequitable throughout the country. This systematic review sought to understand the differences in EPI vaccine uptake between boys and girls in Madagascar.MethodsA systematic literature search was conducted in August 2021 through MEDLINE, the Cochrane Library, Global Index Medicus, and Google Scholar to identify articles reporting sex-disaggregated vaccination rates in Malagasy children. Gray literature was also searched for relevant data. All peer-reviewed articles reporting sex-disaggregated data on childhood immunizations in Madagascar were eligible for inclusion. Risk of bias was assessed using a tool designed for use in systematic reviews. Data extraction was conducted with a pre-defined data extraction tool. Sex-disaggregated data were synthesized to understand the impact of a child's sex on vaccination status.FindingsThe systematic search identified 585 articles of which a total of three studies were included in the final data synthesis. One additional publication was included from the gray literature search. Data from included articles were heterogeneous and, overall, indicated similar vaccination rates in boys and girls. Three of the four articles reported slightly higher vaccination rates in girls than in boys. A meta-analysis was not conducted due to the heterogeneity of included data. Six additional barriers to immunization were identified: socioeconomic status, mother's education, geographic location, supply chain issues, father's education, number of children in the household, and media access.InterpretationThe systematic review revealed the scarcity of available sex-stratified immunization data for Malagasy children. The evidence available was limited and heterogeneous, preventing researchers from conclusively confirming or denying differences in vaccine uptake based on sex. The low vaccination rates and additional barriers identified here indicate a need for increased focus on addressing the specific obstacles to vaccination in Madagascar. A more comprehensive assessment of sex-disaggregated vaccination status of Malagasy children and its relationship with such additional obstacles is recommended. Further investigation of potential differences in vaccination status will allow for the effective implementation of strategies to expand vaccine coverage in Madagascar equitably.Funding and registrationAH, BT, FM, GN, and RR are supported by a grant from the Bill and Melinda Gates Foundation (grant number: OPP1205877). The review protocol is registered in the Prospective Register of Systematic Reviews (PROSPERO ID: CRD42021265000).</p

Table_3_Madagascar's EPI vaccine programs: A systematic review uncovering the role of a child's sex and other barriers to vaccination.DOCX

BackgroundImmunizations are one of the most effective tools a community can use to increase overall health and decrease the burden of vaccine-preventable diseases. Nevertheless, socioeconomic status, geographical location, education, and a child's sex have been identified as contributing to inequities in vaccine uptake in low- and middle-income countries (LMICs). Madagascar follows the World Health Organization's Extended Programme on Immunization (EPI) schedule, yet vaccine distribution remains highly inequitable throughout the country. This systematic review sought to understand the differences in EPI vaccine uptake between boys and girls in Madagascar.MethodsA systematic literature search was conducted in August 2021 through MEDLINE, the Cochrane Library, Global Index Medicus, and Google Scholar to identify articles reporting sex-disaggregated vaccination rates in Malagasy children. Gray literature was also searched for relevant data. All peer-reviewed articles reporting sex-disaggregated data on childhood immunizations in Madagascar were eligible for inclusion. Risk of bias was assessed using a tool designed for use in systematic reviews. Data extraction was conducted with a pre-defined data extraction tool. Sex-disaggregated data were synthesized to understand the impact of a child's sex on vaccination status.FindingsThe systematic search identified 585 articles of which a total of three studies were included in the final data synthesis. One additional publication was included from the gray literature search. Data from included articles were heterogeneous and, overall, indicated similar vaccination rates in boys and girls. Three of the four articles reported slightly higher vaccination rates in girls than in boys. A meta-analysis was not conducted due to the heterogeneity of included data. Six additional barriers to immunization were identified: socioeconomic status, mother's education, geographic location, supply chain issues, father's education, number of children in the household, and media access.InterpretationThe systematic review revealed the scarcity of available sex-stratified immunization data for Malagasy children. The evidence available was limited and heterogeneous, preventing researchers from conclusively confirming or denying differences in vaccine uptake based on sex. The low vaccination rates and additional barriers identified here indicate a need for increased focus on addressing the specific obstacles to vaccination in Madagascar. A more comprehensive assessment of sex-disaggregated vaccination status of Malagasy children and its relationship with such additional obstacles is recommended. Further investigation of potential differences in vaccination status will allow for the effective implementation of strategies to expand vaccine coverage in Madagascar equitably.Funding and registrationAH, BT, FM, GN, and RR are supported by a grant from the Bill and Melinda Gates Foundation (grant number: OPP1205877). The review protocol is registered in the Prospective Register of Systematic Reviews (PROSPERO ID: CRD42021265000).</p

The Burden of Typhoid Fever in Sub-Saharan Africa: A Perspective.

While typhoid fever has largely been eliminated in high-income regions which have developed modern water, sanitation, and hygiene facilities, it remains a significant public health burden resulting in morbidity and mortality among millions of individuals in resource-constrained settings. Prevention and control efforts are needed that integrate several high-impact interventions targeting facilities and infrastructure, including those addressing improvements in sanitation, access to safe water, and planned urbanization, together with parallel efforts directed at effective strategies for use of typhoid conjugate vaccines (TCV). The use of TCVs is a critical tool with the potential of having a rapid impact on typhoid fever disease burden; their introduction will also serve as an important strategy to combat evolving antimicrobial resistance to currently available typhoid fever treatments. Well-designed epidemiological surveillance studies play a critical role in establishing the need for, and monitoring the impact of, typhoid fever control and prevention strategies implemented by public health authorities. Here, we present a perspective based on a narrative review of the impact of typhoid fever on morbidity and mortality in sub-Saharan Africa and discuss ongoing surveillance activities and the role of vaccination in prevention and control efforts