Search

Background: Typhoid Fever remains a major cause of morbidity and mortality in low-income settings. The Severe Typhoid in Africa programme was designed to address regional gaps in typhoid burden data and identify populations eligible for interventions using novel typhoid conjugate vaccines., Methods: A hybrid design, hospital-based prospective surveillance with population-based health-care utilisation surveys, was implemented in six countries in sub-Saharan Africa. Patients presenting with fever (≥37·5°C axillary or ≥38·0°C tympanic) or reporting fever for three consecutive days within the previous 7 days were invited to participate. Typhoid fever was ascertained by culture of blood collected upon enrolment. Disease incidence at the population level was estimated using a Bayesian mixture model., Findings: 27 866 (33·8%) of 82 491 participants who met inclusion criteria were recruited. Blood cultures were performed for 27 544 (98·8%) of enrolled participants. Clinically significant organisms were detected in 2136 (7·7%) of these cultures, and 346 (16·2%) Salmonella enterica serovar Typhi were isolated. The overall adjusted incidence per 100 000 person-years of observation was highest in Kavuaya and Nkandu 1, Democratic Republic of the Congo (315, 95% credible interval 254-390). Overall, 46 (16·4%) of 280 tested isolates showed ciprofloxacin non-susceptibility., Interpretation: High disease incidence (ie, >100 per 100 000 person-years of observation) recorded in four countries, the prevalence of typhoid hospitalisations and complicated disease, and the threat of resistant typhoid strains strengthen the need for rapid dispatch and implementation of effective typhoid conjugate vaccines along with measures designed to improve clean water, sanitation, and hygiene practices., Funding: The Bill & Melinda Gates Foundation., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 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.)

Background: With more than 1.2 million illnesses and 29,000 deaths in sub-Saharan Africa in 2017, typhoid fever continues to be a major public health problem. Effective control of the disease would benefit from an understanding of the subnational geospatial distribution of the disease incidence., Method: We collated records of the incidence rate of typhoid fever confirmed by culture of blood in Africa from 2000 to 2022. We estimated the typhoid incidence rate for sub-Saharan Africa on 20 km × 20 km grids by exploring the association with geospatial covariates representing access to improved water and sanitation, health conditions of the population, and environmental conditions., Results: We identified six published articles and one pre-print representing incidence rate estimates in 22 sites in 2000-2022. Estimated incidence rates showed geospatial variation at sub-national, national, and regional levels. The incidence rate was high in Western and Eastern African subregions followed by Southern and Middle African subregions. By age, the incidence rate was highest among 5-14 yo followed by 2-4 yo, > 14 yo, and 0-1 yo. When aggregated across all age classes and grids that comprise each country, predicted incidence rates ranged from 43.7 (95% confidence interval: 0.6 to 591.2) in Zimbabwe to 2,957.8 (95% CI: 20.8 to 4,245.2) in South Sudan per 100,000 person-years. Sub-national heterogeneity was evident with the coefficient of variation at the 20 km × 20 km grid-level ranging from 0.7 to 3.3 and was generally lower in high-incidence countries and widely varying in low-incidence countries., Conclusion: Our study provides estimates of 20 km × 20 km incidence rate of typhoid fever across sub-Saharan Africa based on data collected from 2000 through 2020. Increased understanding of the subnational geospatial variation of typhoid fever in Africa may inform more effective intervention programs by better targeting resources to heterogeneously disturbed disease risk., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Kim 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.)

Typhoid fever is an invasive bacterial disease associated with bloodstream infection that causes a high burden of disease in Africa and Asia. Typhoid primarily affects individuals ranging from infants through to young adults. The causative organism, Salmonella enterica subsp. enterica serovar Typhi is transmitted via the faecal-oral route, crossing the intestinal epithelium and disseminating to systemic and intracellular sites, causing an undifferentiated febrile illness. Blood culture remains the practical reference standard for diagnosis of typhoid fever, where culture testing is available, but novel diagnostic modalities are an important priority under investigation. Since 2017, remarkable progress has been made in defining the global burden of both typhoid fever and antimicrobial resistance; in understanding disease pathogenesis and immunological protection through the use of controlled human infection; and in advancing effective vaccination programmes through strategic multipartner collaboration and targeted clinical trials in multiple high-incidence priority settings. This Primer thus offers a timely update of progress and perspective on future priorities for the global scientific community., (© 2023. Springer Nature Limited.)

Background: The Global Typhoid Genomics Consortium was established to bring together the typhoid research community to aggregate and analyse Salmonella enterica serovar Typhi (Typhi) genomic data to inform public health action. This analysis, which marks 22 years since the publication of the first Typhi genome, represents the largest Typhi genome sequence collection to date (n=13,000)., Methods: This is a meta-analysis of global genotype and antimicrobial resistance (AMR) determinants extracted from previously sequenced genome data and analysed using consistent methods implemented in open analysis platforms GenoTyphi and Pathogenwatch., Results: Compared with previous global snapshots, the data highlight that genotype 4.3.1 (H58) has not spread beyond Asia and Eastern/Southern Africa; in other regions, distinct genotypes dominate and have independently evolved AMR. Data gaps remain in many parts of the world, and we show the potential of travel-associated sequences to provide informal 'sentinel' surveillance for such locations. The data indicate that ciprofloxacin non-susceptibility (>1 resistance determinant) is widespread across geographies and genotypes, with high-level ciprofloxacin resistance (≥3 determinants) reaching 20% prevalence in South Asia. Extensively drug-resistant (XDR) typhoid has become dominant in Pakistan (70% in 2020) but has not yet become established elsewhere. Ceftriaxone resistance has emerged in eight non-XDR genotypes, including a ciprofloxacin-resistant lineage (4.3.1.2.1) in India. Azithromycin resistance mutations were detected at low prevalence in South Asia, including in two common ciprofloxacin-resistant genotypes., Conclusions: The consortium's aim is to encourage continued data sharing and collaboration to monitor the emergence and global spread of AMR Typhi, and to inform decision-making around the introduction of typhoid conjugate vaccines (TCVs) and other prevention and control strategies., Funding: No specific funding was awarded for this meta-analysis. Coordinators were supported by fellowships from the European Union (ZAD received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 845681), the Wellcome Trust (SB, Wellcome Trust Senior Fellowship), and the National Health and Medical Research Council (DJI is supported by an NHMRC Investigator Grant [GNT1195210])., Competing Interests: MC, ZD, DI, AA, MA, MC, KC, JC, BH, KK, MM, CP, SV, HW, AA, AA, SA, JA, PA, BB, AB, JC, Kd, AD, Jd, PD, CD, SD, ME, LF, DG, GG, MG, AG, CG, MG, RH, RH, YH, JH, OI, JI, JJ, CJ, DJ, JJ, GK, AK, AK, AK, SK, RK, RK, AL, ML, RL, SL, GM, TM, CM, AM, GN, SN, SN, TN, SN, EN, IO, SP, AP, FQ, FQ, SR, SR, DR, PR, RR, TR, JR, SS, SS, KS, MS, JS, JS, VS, JS, RS, SS, MS, AS, AS, KT, DT, AT, MT, MT, RT, NT, ST, KV, MV, BV, FW, JW, GD, SA, JK, DA, SB, KH No competing interests declared, NF NAF chairs the Wellcome Surveillance and Epidemiology of Drug Resistant Infections (SEDRIC) group, which has a focus on antimicrobial resistance. This could be perceived as relevant although not a direct conflict, IB IB has consulted to BlueDot and the NHL Players' Association, AP AJP is chair of the UK Department of Health and Social Care's (DHSC) Joint Committee on Vaccination and Immunisation (JCVI) but does not take part in the JCVI COVID-19 committee. He was a member of WHO SAGE until 2022. AJPs employer, Oxford University has entered into a partnership with AstraZeneca for development of a COVID-19 vaccine. AJP has provided advice to Shionogi & Co., Ltd on development of a COVID19 vaccine, (© 2023, Carey et al.)

Growing evidence suggests considerable variation in endemic typhoid fever incidence at some locations over time, yet few settings have multi-year incidence estimates to inform typhoid control measures. We sought to describe a decade of typhoid fever incidence in the Kilimanjaro Region of Tanzania. Cases of blood culture confirmed typhoid were identified among febrile patients at two sentinel hospitals during three study periods: 2007-08, 2011-14, and 2016-18. To account for under-ascertainment at sentinel facilities, we derived adjustment multipliers from healthcare utilization surveys done in the hospital catchment area. Incidence estimates and credible intervals (CrI) were derived using a Bayesian hierarchical incidence model that incorporated uncertainty of our observed typhoid fever prevalence, of healthcare seeking adjustment multipliers, and of blood culture diagnostic sensitivity. Among 3,556 total participants, 50 typhoid fever cases were identified. Of typhoid cases, 26 (52%) were male and the median (range) age was 22 (<1-60) years; 4 (8%) were aged <5 years and 10 (20%) were aged 5 to 14 years. Annual typhoid fever incidence was estimated as 61.5 (95% CrI 14.9-181.9), 6.5 (95% CrI 1.4-20.4), and 4.0 (95% CrI 0.6-13.9) per 100,000 persons in 2007-08, 2011-14, and 2016-18, respectively. There were no deaths among typhoid cases. We estimated moderate typhoid incidence (≥10 per 100 000) in 2007-08 and low (<10 per 100 000) incidence during later surveillance periods, but with overlapping credible intervals across study periods. Although consistent with falling typhoid incidence, we interpret this as showing substantial variation over the study periods. Given potential variation, multi-year surveillance may be warranted in locations making decisions about typhoid conjugate vaccine introduction and other control measures., Competing Interests: The authors have declared that no competing interests exist.

Objectives: To examine the world's population, development, and health by condensed Coordinated Universal Time (UTC) offset to support a normative position on how to most defensibly schedule global health teleconferences with the primary goal of advancing equitable regard for participants by health condition., Design: Spatial exploration examined through the lens of equitable regard for participants., Setting: The Earth., Participants: The global population., Main Outcome Measures: Global population, countries, Human Development Index (HDI), and health measured in total and disease-specific disability-adjusted life years (DALYs) per 100 000 per year by UTC offset. Strengths and weaknesses of scheduling teleconferences accordingly to alternative approaches., Results: The UTC offset with the largest population of approximately 1 724 million persons occurred in UTC+5, largest country count of approximately 40 countries in UTC+1, and the lowest median HDI of 0.527 occurred in UTC0. The highest median total DALYs per 100 000 per year of 41 873 occurred in UTC+11, highest median HIV/AIDS DALYs per 100 000 per year of 941 in UTC0, and highest median typhoid and paratyphoid fevers DALYs per 100 000 per year of 279 occurred in UTC+5. Hypothetical teleconference scheduling scenarios generated temporal distances of up to 11 hours to UTC offsets representing the most countries and greatest number of DALYs per 100 000 per year. Teleconference scheduling based on egoism was considered to be problematic, and contractualism as unrealistically demanding. Utilitarianism resulted in the risk of systematically disadvantaging small, temporally remote groups. Egalitarianism offered equality, but prioritarianism offered the possibility of addressing health inequities., Conclusions: Global health teleconferences may generate great temporal distances between participants compromising representative participation, as well as the well-being of attendees. Our spatial exploration of the world's population and health by UTC offset may be used to support a normative position on scheduling global health teleconferences that enhance progress towards health equity., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Typhoid is an endemic in Fiji with increases observed since the early 2000s and frequent outbreaks reported. We assessed the diagnostic accuracy of currently available typhoid rapid diagnostic tests (RDTs) (TUBEX, Typhidot Rapid, and Test-It assay) to establish their performance against blood culture in Fiji and to examine their suitability for rapid typhoid outbreak identification. The performance of RDTs was assessed in the public health reference laboratory in Suva, Fiji, according to the manufacturers' instructions. A simulation was used to examine the potential use of RDTs for attribution of a febrile illness outbreak to typhoid. For the diagnostic evaluation, 179 patients were included; 49 had blood culture-confirmed typhoid, 76 had fever as a result of non-typhoid etiologies, and 54 were age-matched community controls. The median (interquartile range) age was 29 (20-46) years. Of the participants, 92 (51.4%) were male and 131 (73.2%) were indigenous Fijians. The sensitivities of the tests were 77.6% for TUBEX, 75.5% for Typhidot Rapid, and 57.1% for Test-It assay. The Test-It assay had the highest specificity of 93.4%, followed by Typhidot Rapid 85.5% and TUBEX 60.5%. Typhidot Rapid had the best performance in the simulation for attribution of a febrile illness outbreak to typhoid. Typhoid RDTs performed suboptimally for individual patient diagnosis due to low sensitivity and variable specificity. We demonstrate that RDTs could be useful in the field for rapid attribution of febrile illness outbreaks to typhoid. Typhidot Rapid had the best combination of sensitivity, specificity, positive and negative predictive values, cost, and ease of use for this purpose.

Objectives: Updated estimates of the prevalence of complications and case fatality ratio (CFR) among typhoid fever patients are needed to understand disease burden., Methods: Articles published in PubMed and Web of Science from 1 January 1980 through 29 January 2020 were systematically reviewed for hospital or community-based non-surgical studies that used cultures of normally sterile sites, and hospital surgical studies of typhoid intestinal perforation (TIP) with intra- or post-operative findings suggestive of typhoid. Prevalence of 21 pre-selected recognized complications of typhoid fever, crude and median (interquartile range) CFR, and pooled CFR estimates using a random effects meta-analysis were calculated., Results: Of 113 study sites, 106 (93.8%) were located in Asia and Africa, and 84 (74.3%) were non-surgical. Among non-surgical studies, 70 (83.3%) were hospital-based. Of 10,355 confirmed typhoid patients, 2,719 (26.3%) had complications. The pooled CFR estimate among non-surgical patients was 0.9% for the Asia region and 5.4% for the Africa region. Delay in care was significantly correlated with increased CFR in Asia (r = 0.84; p<0.01). Among surgical studies, the median CFR of TIP was 15.5% (6.7-24.1%) per study., Conclusions: Our findings identify considerable typhoid-associated illness and death that could be averted with prevention measures, including typhoid conjugate vaccine introduction., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

In 1993, the International Task Force on Disease Eradication classified the political will for typhoid eradication as "none." Here we revisit the Task Force's assessment in light of developments in typhoid vaccines and increasing antimicrobial resistance in Salmonella Typhi that have served to increase interest in typhoid elimination. Considering the requisite biological and technical factors for elimination, effective interventions exist for typhoid, and humans are the organism's only known reservoir. Improvements in water supply, sanitation, hygiene, and food safety are critical for robust long-term typhoid control, and the recent Strategic Advisory Group of Experts on Immunization recommendation and World Health Organization prequalification should make typhoid conjugate vaccine more accessible and affordable in low-income countries, which will allow the vaccine to offer a critical bridge to quickly reduce burden. While these developments are encouraging, all current typhoid diagnostics are inadequate, having either poor performance characteristics, limited scalability, or both. No clear solution exists, and this should be viewed as a critical challenge to any elimination effort. Moreover, asymptomatic carriers and limited data and surveillance remain major challenges, and countries considering elimination campaigns will need to develop strategies to identify high-risk populations and to monitor progress over time. Finally, policymakers must be realistic in planning, learn from the planning failures of previous elimination and eradication efforts, and expect unforeseeable shocks and setbacks. In the end, if we assume neither unanticipated breakthroughs in typhoid control nor any chaotic shocks, history suggests that we should expect typhoid elimination to take decades., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: Typhoid fever has been endemic on the island nation of Samoa (2016 population, 195 979) since the 1960s and has persisted through 2019, despite economic development and improvements in water supply and sanitation., Methods: Salmonella enterica serovar Typhi isolates from the 2 hospitals with blood culture capability and matched patient demographic and clinical data from January 2008 through December 2019 were analyzed. Denominators to calculate incidence by island, region, and district came from 2011 and 2016 censuses and from 2017-2019 projections from Samoa's Bureau of Statistics. Data were analyzed to describe typhoid case burden and incidence from 2008 to 2019 by time, place, and person., Results: In sum, 53-193 blood culture-confirmed typhoid cases occurred annually from 2008 to 2019, without apparent seasonality. Typhoid incidence was low among children age < 48 months (17.6-27.8/105), rose progressively in ages 5-9 years (54.0/105), 10-19 years (60.7-63.4/105), and 20-34 years (61.0-79.3/105), and then tapered off; 93.6% of cases occurred among Samoans < 50 years of age. Most typhoid cases and the highest incidence occurred in Northwest Upolu, but Apia Urban Area (served by treated water supplies) also exhibited moderate incidence. The proportion of cases from short-cycle versus long-cycle transmission is unknown. Samoan S. Typhi are pansusceptible to traditional first-line antibiotics. Nevertheless, enhanced surveillance in 2019 detected 4 (2.9%) deaths among 140 cases., Conclusions: Typhoid has been endemic in Samoa in the period 2008-2019. Interventions, including mass vaccination with a Vi-conjugate vaccine coadministered with measles vaccine are planned., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.)

Typhoid fever remains an important public health problem in low- and middle-income countries, with large outbreaks reported from Africa and Asia. Although the WHO recommends typhoid vaccination for control of confirmed outbreaks, there are limited data on the epidemiologic characteristics of outbreaks to inform vaccine use in outbreak settings. We conducted a literature review for typhoid outbreaks published since 1990. We found 47 publications describing 45,215 cases in outbreaks occurring in 25 countries from 1989 through 2018. Outbreak characteristics varied considerably by WHO region, with median outbreak size ranging from 12 to 1,101 cases, median duration from 23 to 140 days, and median case fatality ratio from 0% to 1%. The largest number of outbreaks occurred in WHO Southeast Asia, 13 (28%), and African regions, 12 (26%). Among 43 outbreaks reporting a mode of disease transmission, 24 (56%) were waterborne, 17 (40%) were foodborne, and two (5%) were by direct contact transmission. Among the 34 outbreaks with antimicrobial resistance data, 11 (32%) reported Typhi non-susceptible to ciprofloxacin, 16 (47%) reported multidrug-resistant (MDR) strains, and one reported extensively drug-resistant strains. Our review showed a longer median duration of outbreaks caused by MDR strains (148 days versus 34 days for susceptible strains), although this difference was not statistically significant. Control strategies focused on water, sanitation, and food safety, with vaccine use described in only six (13%) outbreaks. As typhoid conjugate vaccines become more widely used, their potential role and impact in outbreak control warrant further evaluation.

Typhoid conjugate vaccines represent a new tool for typhoid control. However, incidence data are needed to inform decisions about introduction. We sought to estimate typhoid and paratyphoid fever incidence in Vientiane, the capital and largest city of the Lao People's Democratic Republic (Lao PDR). We did a representative cluster survey of health-seeking behavior for fever in Vientiane from January 15, 2019 through January 26, 2019. Multipliers derived from the survey were applied to data from Salmonella Typhi and Salmonella Paratyphi A bloodstream infection surveillance from Mahosot Hospital, Vientiane, for the period of January 1, 2015 through December 31, 2017, to estimate enteric fever incidence. A total of 336 households representing 1,740 persons were enrolled in the healthcare utilization survey, and multipliers were derived based on responses to questions about healthcare seeking in the event of febrile illness. Of 7,997 Vientiane residents receiving blood cultures over the 2-year surveillance period at Mahosot Hospital, we identified 16 (0.2%) with Salmonella Typhi and six (< 0.1%) with Salmonella Paratyphi A bloodstream infection. After applying multipliers, we estimated that the annual incidence of typhoid was 4.7 per 100,000 persons and paratyphoid was 0.5 per 100,000 persons. During the study period, the incidence of typhoid and paratyphoid fever was low in Vientiane. Ongoing surveillance is warranted to identify increases in future years. Similar studies elsewhere in the Lao PDR would be useful to understand the wider enteric fever situation in the country.

Objectives: Hospital-based studies of community-onset bloodstream infections (CO-BSI) are less resource-intensive to carry out than population-based incidence studies. We examined several metrics capturing the potential role of Salmonella Typhi as a cause of CO-BSI for making inferences about incidence., Methods: We systematically reviewed three databases for hospital-based studies of CO-BSI. We determined, by study, the prevalence and rank order of Salmonella among pathogenic bloodstream isolates, and the prevalence ratio of Salmonella Typhi to Escherichia coli (S:E ratio). We then describe these hospital-based study metrics in relation to population-based typhoid fever incidence data from a separate systematic review., Results: Forty-four studies met the inclusion criteria, of which 23 (52.3%) isolated Salmonella Typhi at least once. Among studies isolating Salmonella Typhi, the median (interquartile range) prevalence and rank order of Salmonella Typhi compared to other pathogens isolated in BSI was 8.3% (3.2-37.9%) and 3 (1-6), respectively. The median (interquartile range) S:E ratio was 1.0 (0.4-3.0). With respect to incidence, in Pemba Island, Tanzania, prevalence, rank order, S:E ratio, and incidence was 64.8%, 1, 9.2 and 110 cases per 100 000, respectively, and in Boulkiemdé, Burkina Faso, was 13.3%, 3, 2.3 and 249 cases per 100 000., Conclusions: We describe considerable variation in place and time for Salmonella Typhi prevalence, rank order, and S:E ratio among hospital-based studies of CO-BSI. Data from simultaneous typhoid prevalence and incidence studies are limited. We propose that hospital-based study metrics warrant evaluation for making inference about typhoid incidence and as covariates in typhoid incidence models., (© 2019 The Authors. Tropical Medicine & International Health Published by John Wiley & Sons Ltd.)

Background: Typhoid fever is endemic in Fiji. We sought to describe the epidemiology, clinical features and case fatality risk of blood culture-confirmed typhoid fever from January 2014 through December 2015., Methods: Blood culture-positive patients were identified from a typhoid surveillance line list. A standardised case investigation form was used to record data from patients' medical records., Results: Of 542 patients, 518 (95.6%) were indigenous Fijians (iTaukei) and 285 (52.6%) were male. The median (IQR) age was 25 (16-38) y. Mean (SD) time from the onset of illness to admission was 11.1 (6.9) d. Of 365 patients with clinical information, 346 (96.9%) had fever, 239 (66.9%) diarrhoea, 113 (33.5%) vomiting, and 72 (30.2%) abdominal pain. There were 40 (11.0%) patients with complications, including 17 (4.7%) with shock, and 11 (3.0%) with hepatitis. Nine patients died for a case fatality risk of 1.7%. Of the 544 Salmonella Typhi isolates tested, none were resistant to first line antimicrobials; 3(0.8%) were resistant to ciprofloxacin and 5(1.4%) to nalidixic acid., Conclusions: In Fiji, most blood culture-confirmed typhoid fever cases were in young adults. Common clinical manifestations were fever and gastrointestinal symptoms. Further studies are required to elucidate the factors associated with complications and death., (© The Author(s) 2019. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.)

Proximal characteristics and conditions in the residential setting deserve greater attention for their potential to influence typhoid transmission. Using a case-control design in Central Division, Republic of Fiji, we examined bacterial (coliform and Escherichia coli ) contamination and chemical composition of water and soil as potential vehicles of exposure to Salmonella Typhi, combining observational analysis of residential living conditions, geospatial analysis of household locations, and factor analysis to explore multivariate associations with the risk of developing typhoid fever. Factors positively associated with typhoid infection related to drainage [phosphate (OR 4.235, p = 0.042) and E. coli concentrations (OR 2.248, p = 0.029) in toilet drainage soil, housing [external condition (OR 3.712, p < 0.001)], drinking water contamination (OR 2.732, p = 0.003) and sanitary condition (OR 1.973, p = 0.031). These five factors explained 42.5% of the cumulative variance and were significant in predicting typhoid infection. Our results support the hypothesis that a combination of spatial and biophysical attributes of the residential setting influence the probability of typhoid transmission; in this study, factors associated with poor drainage, flooding, and sanitary condition increase local exposure to contaminated water and soil, and thereby infection. These findings extend testing of causal assumptions beyond the immediate domestic domain, enhance the scope of traditional case control epidemiology and allow greater specificity of interventions at the scale of the residential setting., Competing Interests: The authors declare no conflict of interest.

Background: Accurate estimates of typhoid disease burden are needed to guide policy decisions, including on vaccine use. Data on the incidence of enteric fever in Myanmar are scarce. We estimated typhoid and paratyphoid fever incidence among adolescents and adults in Yangon, Myanmar, by combining sentinel hospital surveillance with a healthcare utilization survey., Methods: We conducted a population-based household health care utilization survey in the Yangon Region 12 March through 5 April 2018. Multipliers derived from this survey were then applied to hospital-based surveillance of Salmonella Typhi and Paratyphi A bloodstream infections from 5 October 2015 through 4 October 2016 at Yangon General Hospital (YGH) to estimate the incidence of typhoid and paratyphoid fevers among person ≥12 years of age., Results: A total of 336 households representing 1598 persons were enrolled in the health care utilization survey, and multipliers were derived based on responses to questions about healthcare seeking in the event of febrile illness. Of 671 Yangon residents enrolled over a 1-year period at YGH, we identified 33 (4.9%) with Salmonella Typhi and 9 (1.3%) with Salmonella Paratyphi A bloodstream infection. After applying multipliers, we estimated that the annual incidence of typhoid was 391 per 100 000 persons and paratyphoid was 107 per 100 000 persons., Conclusions: Enteric fever incidence is high in Yangon, Myanmar, warranting increased attention on prevention and control, including consideration of typhoid conjugate vaccine use as well as nonvaccine control measures. Research on incidence among infants and children, as well as sources and modes of transmission is needed., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: Contemporary incidence estimates of typhoid fever are needed to guide policy decisions and control measures and to improve future epidemiological studies., Methods: We systematically reviewed 3 databases (Ovid Medline, PubMed, and Scopus) without restriction on age, country, language, or time for studies reporting the incidence of blood culture-confirmed typhoid fever. Outbreak, travel-associated, and passive government surveillance reports were excluded. We performed a meta-analysis using a random-effects model to calculate estimates of pooled incidence, stratifying by studies that reported the incidence of typhoid fever and those that estimated incidence by using multipliers., Results: Thirty-three studies were included in the analysis. There were 26 study sites from 16 countries reporting typhoid cases from population-based incidence studies, and 17 sites in 9 countries used multipliers to account for underascertainment in sentinel surveillance data. We identified Africa and Asia as regions with studies showing high typhoid incidence while noting considerable variation of typhoid incidence in time and place, including in consecutive years at the same location. Overall, more recent studies reported lower typhoid incidence compared to years prior to 2000. We identified variation in the criteria for collecting a blood culture, and among multiplier studies we identified a lack of a standardization for the types of multipliers being used to estimate incidence., Conclusions: Typhoid fever incidence remains high at many sites. Additional and more accurate typhoid incidence studies are needed to support country decisions about typhoid conjugate vaccine adoption. Standardization of multiplier types applied in multiplier studies is recommended., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.)

Salmonella enterica subspecies enterica serovar Typhi (Salmonella Typhi) is the cause of typhoid fever and a human host-restricted organism. Our understanding of the global burden of typhoid fever has improved in recent decades, with both an increase in the number and geographic representation of high-quality typhoid fever incidence studies, and greater sophistication of modeling approaches. The 2017 World Health Organization Strategic Advisory Group of Experts on Immunization recommendation for the introduction of typhoid conjugate vaccines for infants and children aged >6 months in typhoid-endemic countries is likely to require further improvements in our understanding of typhoid burden at the global and national levels. Furthermore, the recognition of the critical and synergistic role of water and sanitation improvements in concert with vaccine introduction emphasize the importance of improving our understanding of the sources, patterns, and modes of transmission of Salmonella Typhi in diverse settings., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.)

This article is the introduction to a 12-paper supplement on global trends in typhoid fever. The Tackling Typhoid (T2) project was initiated in 2015 to synthesize the existing body of literature on typhoidal salmonellae and study national and regional typhoid fever trends. In addition to a global systematic review, eight case studies were undertaken to examine typhoid and paratyphoid fever trends in endemic countries alongside changes in relevant contextual factors. Incidence variations exist both within and between regions with large subnational differences as well, suggesting that public health changes impacting typhoid and paratyphoid fevers in one setting may not have similar impacts in another. This supplement also brings to light the lack of national typhoid fever surveillance systems, inconsistencies in diagnostics, and the lack of typhoid fever associated morbidity and mortality data in many countries, making it difficult to accurately quantify and track burden of disease. To better understand typhoid fever there is a need for more high-quality data from resource-poor settings. The implementation of typhoid surveillance systems alongside the transition to blood-culture confirmation of cases, where possible, would aid in the improvement of data quality in low-income settings. The following supplement includes the results of our global systematic review, eight-country case study articles, a qualitative article informed by semistructured interviews, and a conclusion article on potential ways forward for typhoid control.

The Tackling Typhoid supplement shows that typhoid fever continues to be a problem globally despite socioeconomic gains in certain settings. Morbidity remains high in many endemic countries, notably in sub-Saharan Africa and South Asia. In addition, antimicrobial resistance is a growing issue that poses a challenge for clinical management. The findings from this supplement revealed that outside of high-income countries, there were few reliable population-based estimates of typhoid and paratyphoid fever derived from surveillance systems. This indicates the need for monitoring systems that can also characterize the effectiveness of interventions, particularly in low- and middle-income settings. The country case studies indicated that gains in economic conditions, education, and environmental health may be associated with reductions in typhoid fever burden. Over the study period, the effect is mainly notable in countries with higher baseline levels of economic development, female literacy, and investments in public sanitation. High burden countries must continue to invest in strategies at the local level to address environmental factors such as access to safe drinking water and improved public sanitation that are known to interrupt transmission or diminish the risk of acquiring typhoid. Developing more effective vaccines and incorporating appropriate immunization strategies that target populations with the greatest risk could potentially alleviate disease burden.

Background: Typhoid fever is endemic in Fiji, with high reported annual incidence. We sought to identify the sources and modes of transmission of typhoid fever in Fiji with the aim to inform disease control., Methodology/principal Findings: We identified and surveyed patients with blood culture-confirmed typhoid fever from January 2014 through January 2017. For each typhoid fever case we matched two controls by age interval, gender, ethnicity, and residential area. Univariable and multivariable analysis were used to evaluate associations between exposures and risk for typhoid fever. We enrolled 175 patients with typhoid fever and 349 controls. Of the cases, the median (range) age was 29 (2-67) years, 86 (49%) were male, and 84 (48%) lived in a rural area. On multivariable analysis, interrupted water availability (odds ratio [OR] = 2.17; 95% confidence interval [CI] 1.18-4.00), drinking surface water in the last 2 weeks (OR = 3.61; 95% CI 1.44-9.06), eating unwashed produce (OR = 2.69; 95% CI 1.48-4.91), and having an unimproved or damaged sanitation facility (OR = 4.30; 95% CI 1.14-16.21) were significantly associated with typhoid fever. Frequent handwashing after defecating (OR = 0.57; 95% CI 0.35-0.93) and using soap for handwashing (OR = 0.61; 95% CI 0.37-0.95) were independently associated with a lower odds of typhoid fever., Conclusions: Poor sanitation facilities appear to be a major source of Salmonella Typhi in Fiji, with transmission by drinking contaminated surface water and consuming unwashed produce. Improved sanitation facilities and protection of surface water sources and produce from contamination by human feces are likely to contribute to typhoid control in Fiji., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: DS at present is a full time employee of GlaxoSmithKline vaccine.

Typhoid and paratyphoid fever may follow a seasonal pattern, but this pattern is not well characterized. Moreover, the environmental drivers that influence seasonal dynamics are not fully understood, although increasing evidence suggests that rainfall and temperature may play an important role. We compiled a database of typhoid, paratyphoid, or enteric fever and their potential environmental drivers. We assessed the seasonal dynamics by region and latitude, quantifying the mean timing of peak prevalence and seasonal variability. Moreover, we investigated the potential drivers of the seasonal dynamics and compared the seasonal dynamics for typhoid and paratyphoid fever. We observed a distinct seasonal pattern for enteric and typhoid fever by latitude, with seasonal variability more pronounced further from the equator. We also found evidence of a positive association between preceding rainfall and enteric fever among settings 35°-11°N and a more consistent positive association between temperature and enteric fever incidence across most regions of the world. In conclusion, we identified varying seasonal dynamics for enteric or typhoid fever in association with environmental factors. The underlying mechanisms that drive the seasonality of enteric fever are likely dependent on the local context and should be taken into account in future control efforts.

Background: Available incidence data for invasive salmonella disease in sub-Saharan Africa are scarce. Standardised, multicountry data are required to better understand the nature and burden of disease in Africa. We aimed to measure the adjusted incidence estimates of typhoid fever and invasive non-typhoidal salmonella (iNTS) disease in sub-Saharan Africa, and the antimicrobial susceptibility profiles of the causative agents., Methods: We established a systematic, standardised surveillance of blood culture-based febrile illness in 13 African sentinel sites with previous reports of typhoid fever: Burkina Faso (two sites), Ethiopia, Ghana, Guinea-Bissau, Kenya, Madagascar (two sites), Senegal, South Africa, Sudan, and Tanzania (two sites). We used census data and health-care records to define study catchment areas and populations. Eligible participants were either inpatients or outpatients who resided within the catchment area and presented with tympanic (≥38·0°C) or axillary temperature (≥37·5°C). Inpatients with a reported history of fever for 72 h or longer were excluded. We also implemented a health-care utilisation survey in a sample of households randomly selected from each study area to investigate health-seeking behaviour in cases of self-reported fever lasting less than 3 days. Typhoid fever and iNTS disease incidences were corrected for health-care-seeking behaviour and recruitment., Findings: Between March 1, 2010, and Jan 31, 2014, 135 Salmonella enterica serotype Typhi (S Typhi) and 94 iNTS isolates were cultured from the blood of 13 431 febrile patients. Salmonella spp accounted for 33% or more of all bacterial pathogens at nine sites. The adjusted incidence rate (AIR) of S Typhi per 100 000 person-years of observation ranged from 0 (95% CI 0-0) in Sudan to 383 (274-535) at one site in Burkina Faso; the AIR of iNTS ranged from 0 in Sudan, Ethiopia, Madagascar (Isotry site), and South Africa to 237 (178-316) at the second site in Burkina Faso. The AIR of iNTS and typhoid fever in individuals younger than 15 years old was typically higher than in those aged 15 years or older. Multidrug-resistant S Typhi was isolated in Ghana, Kenya, and Tanzania (both sites combined), and multidrug-resistant iNTS was isolated in Burkina Faso (both sites combined), Ghana, Kenya, and Guinea-Bissau., Interpretation: Typhoid fever and iNTS disease are major causes of invasive bacterial febrile illness in the sampled locations, most commonly affecting children in both low and high population density settings. The development of iNTS vaccines and the introduction of S Typhi conjugate vaccines should be considered for high-incidence settings, such as those identified in this study., Funding: Bill & Melinda Gates Foundation., (Copyright © 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY license. Published by Elsevier Ltd.. All rights reserved.)

Background: New immunization programs are dependent on data from surveillance networks and disease burden estimates to prioritize target areas and risk groups. Data regarding invasive Salmonella disease in sub-Saharan Africa are currently limited, thus hindering the implementation of preventive measures. The Typhoid Fever Surveillance in Africa Program (TSAP) was established by the International Vaccine Institute to obtain comparable incidence data on typhoid fever and invasive nontyphoidal Salmonella (iNTS) disease in sub-Saharan Africa through standardized surveillance in multiple countries., Methods: Standardized procedures were developed and deployed across sites for study site selection, patient enrolment, laboratory procedures, quality control and quality assurance, assessment of healthcare utilization and incidence calculations., Results: Passive surveillance for bloodstream infections among febrile patients was initiated at thirteen sentinel sites in ten countries (Burkina Faso, Ethiopia, Ghana, Guinea-Bissau, Kenya, Madagascar, Senegal, South Africa, Sudan, and Tanzania). Each TSAP site conducted case detection using these standardized methods to isolate and identify aerobic bacteria from the bloodstream of febrile patients. Healthcare utilization surveys were conducted to adjust population denominators in incidence calculations for differing healthcare utilization patterns and improve comparability of incidence rates across sites., Conclusions: By providing standardized data on the incidence of typhoid fever and iNTS disease in sub-Saharan Africa, TSAP will provide vital input for targeted typhoid fever prevention programs., (© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.)

Background: Salmonella enterica serovar Typhi is a predominant cause of bloodstream infections in sub-Saharan Africa (SSA). Increasing numbers of S. Typhi with resistance to ciprofloxacin have been reported from different parts of the world. However, data from SSA are limited. In this study, we aimed to measure the ciprofloxacin susceptibility of S. Typhi isolated from patients with febrile illness in SSA., Methods: Febrile patients from 9 sites within 6 countries in SSA with a body temperature of ≥38.0°C were enrolled in this study. Blood samples were obtained for bacterial culture, and Salmonella isolates were identified biochemically and confirmed by multiplex polymerase chain reaction (PCR). Antimicrobial susceptibility of all Salmonella isolates was performed by disk diffusion test, and minimum inhibitory concentrations (MICs) against ciprofloxacin were measured by Etest. All Salmonella isolates with reduced susceptibility to ciprofloxacin (MIC > 0.06 µg/mL) were screened for mutations in quinolone resistance-determining regions in target genes, and the presence of plasmid-mediated quinolone resistance (PMQR) genes was assessed by PCR., Results: A total of 8161 blood cultures were performed, and 100 (1.2%) S. Typhi, 2 (<0.1%) Salmonella enterica serovar Paratyphi A, and 27 (0.3%) nontyphoid Salmonella (NTS) were isolated. Multidrug-resistant S. Typhi were isolated in Kenya (79% [n = 38]) and Tanzania (89% [n = 8]) only. Reduced ciprofloxacin-susceptible (22% [n = 11]) S. Typhi were isolated only in Kenya. Among those 11 isolates, all had a Glu133Gly mutation in the gyrA gene combined with either a gyrA (Ser83Phe) or gyrB mutation (Ser464Phe). One Salmonella Paratyphi A isolate with reduced susceptibility to ciprofloxacin was found in Senegal, with 1 mutation in gyrA (Ser83Phe) and a second mutation in parC (Ser57Phe). Mutations in the parE gene and PMQR genes were not detected in any isolate., Conclusions: Salmonella Typhi with reduced susceptibility to ciprofloxacin was not distributed homogenously throughout SSA. Its prevalence was very high in Kenya, and was not observed in other study countries. Continuous monitoring of antimicrobial susceptibility is required to follow the potential spread of antimicrobial-resistant isolates throughout SSA., (© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.)

Background: Assessing healthcare utilization is important to identify weaknesses of healthcare systems, to outline action points for preventive measures and interventions, and to more accurately estimate the disease burden in a population., Methods: A healthcare utilization survey was developed for the Typhoid Fever Surveillance in Africa Program (TSAP) to adjust incidences of salmonellosis determined through passive, healthcare facility-based surveillance. This cross-sectional survey was conducted at 11 sites in 9 sub-Saharan African countries. Demographic data and healthcare-seeking behavior were assessed at selected households. Overall and age-stratified percentages of each study population that sought healthcare at a TSAP healthcare facility and elsewhere were determined., Results: Overall, 88% (1007/1145) and 81% (1811/2238) of the population in Polesgo and Nioko 2, Burkina Faso, respectively, and 63% (1636/2590) in Butajira, Ethiopia, sought healthcare for fever at any TSAP healthcare facility. A far smaller proportion-namely, 20%-45% of the population in Bissau, Guinea-Bissau (1743/3885), Pikine, Senegal (1473/4659), Wad-Medani, Sudan (861/3169), and Pietermaritzburg, South Africa (667/2819); 18% (483/2622) and 9% (197/2293) in Imerintsiatosika and Isotry, Madagascar, respectively; and 4% (127/3089) in Moshi, Tanzania-sought healthcare at a TSAP healthcare facility. Patients with fever preferred to visit pharmacies in Imerintsiatosika and Isotry, and favored self-management of fever in Moshi. Age-dependent differences in healthcare utilization were also observed within and across sites., Conclusions: Healthcare utilization for fever varied greatly across sites, and revealed that not all studied populations were under optimal surveillance. This demonstrates the importance of assessing healthcare utilization. Survey data were pivotal for the adjustment of the program's estimates of salmonellosis and other conditions associated with fever., (© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.)

Salmonella enterica serovar Typhi expresses a capsule of Vi polysaccharide, while most Salmonella serovars, including S. Enteritidis and S. Typhimurium, do not. Both S. Typhi and S. Enteritidis express the lipopolysaccharide O:9 antigen, yet there is little evidence of cross-protection from anti-O:9 antibodies. Vaccines based on Vi polysaccharide have efficacy against typhoid fever, indicating that antibodies against Vi confer protection. Here we investigate the role of Vi capsule and antibodies against Vi and O:9 in antibody-dependent complement- and phagocyte-mediated killing of Salmonella. Using isogenic Vi-expressing and non-Vi-expressing derivatives of S. Typhi and S. Typhimurium, we show that S. Typhi is inherently more sensitive to serum and blood than S. Typhimurium. Vi expression confers increased resistance to both complement- and phagocyte-mediated modalities of antibody-dependent killing in human blood. The Vi capsule is associated with reduced C3 and C5b-9 deposition, and decreased overall antibody binding to S. Typhi. However, purified human anti-Vi antibodies in the presence of complement are able to kill Vi-expressing Salmonella, while killing by anti-O:9 antibodies is inversely related to Vi expression. Human serum depleted of antibodies to antigens other than Vi retains the ability to kill Vi-expressing bacteria. Our findings support a protective role for Vi capsule in preventing complement and phagocyte killing of Salmonella that can be overcome by specific anti-Vi antibodies, but only to a limited extent by anti-O:9 antibodies.

Background: The clinical diagnosis of bacterial bloodstream infections (BSIs) in sub-Saharan Africa is routinely confused with malaria due to overlapping symptoms. The Typhoid Surveillance in Africa Program (TSAP) recruited febrile inpatients and outpatients of all ages using identical study procedures and enrollment criteria, thus providing an opportunity to assess disease etiology and pretreatment patterns among children and adults., Methods: Inpatients and outpatients of all ages with tympanic or axillary temperatures of ≥38.0 or ≥37.5°C, respectively, and inpatients only reporting fever within the previous 72 hours were eligible for recruitment. All recruited patients had one blood sample drawn and cultured for microorganisms. Data from 11 TSAP surveillance sites in nine different countries were used in the analysis. Bivariate analysis was used to compare frequencies of pretreatment and BSIs in febrile children (<15 years old) and adults (≥15 years old) in each country. Pooled Cochran Mantel-Haenszel odds ratios (ORs) were calculated for overall trends., Results: There was no significant difference in the odds of a culture-proven BSI between children and adults among inpatients or outpatients. Among both inpatients and outpatients, children had significantly higher odds of having a contaminated blood culture compared with adults. Using country-pooled data, child outpatients had 66% higher odds of having Salmonella Typhi in their bloodstream than adults (OR, 1.66; 95% confidence interval [CI], 1.01-2.73). Overall, inpatient children had 59% higher odds of pretreatment with analgesics in comparison to inpatient adults (OR, 1.59; 95% CI, 1.28-1.97)., Conclusions: The proportion of patients with culture-proven BSIs in children compared with adults was similar across the TSAP study population; however, outpatient children were more likely to have Salmonella Typhi infections than outpatient adults. This finding points to the importance of including outpatient facilities in surveillance efforts, particularly for the surveillance of typhoid fever. Strategies to reduce contamination among pediatric blood cultures are needed across the continent to prevent the misdiagnosis of BSI cases in children., (© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

The emergence of multidrug-resistant (MDR) typhoid is a major global health threat affecting many countries where the disease is endemic. Here whole-genome sequence analysis of 1,832 Salmonella enterica serovar Typhi (S. Typhi) identifies a single dominant MDR lineage, H58, that has emerged and spread throughout Asia and Africa over the last 30 years. Our analysis identifies numerous transmissions of H58, including multiple transfers from Asia to Africa and an ongoing, unrecognized MDR epidemic within Africa itself. Notably, our analysis indicates that H58 lineages are displacing antibiotic-sensitive isolates, transforming the global population structure of this pathogen. H58 isolates can harbor a complex MDR element residing either on transmissible IncHI1 plasmids or within multiple chromosomal integration sites. We also identify new mutations that define the H58 lineage. This phylogeographical analysis provides a framework to facilitate global management of MDR typhoid and is applicable to similar MDR lineages emerging in other bacterial species.

The country of Fiji, with a population of approximately 870 000 people, faces a growing burden of several communicable diseases including the bacterial infection typhoid fever. Surveillance data suggest that typhoid has become increasingly common in rural areas of Fiji and is more frequent amongst young adults. Transmission of the organisms that cause typhoid is facilitated by faecal contamination of food or water and may be influenced by local behavioural practices in Fiji. The Fijian Ministry of Health, with support from Australian Aid, hosted a meeting in August 2012 to develop comprehensive control and prevention strategies for typhoid fever in Fiji. International and local specialists were invited to share relevant data and discuss typhoid control options. The resultant recommendations focused on generating a clearer sense of the epidemiology of typhoid in Fiji and exploring the contribution of potential transmission pathways. Additionally, the panel suggested steps such as ensuring that recommended ciprofloxacin doses are appropriate to reduce the potential for relapse and reinfection in clinical cases, encouraging proper hand hygiene of food and drink handlers, working with water and sanitation agencies to review current sanitation practices and considering a vaccination policy targeting epidemiologically relevant populations., (© 2014 The Authors. Tropical Medicine & International Health published by John Wiley & Sons Ltd.)

Objective: To evaluate three commercial typhoid rapid antibody tests for Salmonella Typhi antibodies in patients suspected of having typhoid fever in Mpumalanga, South Africa, and Moshi, United Republic of Tanzania., Methods: The diagnostic accuracy of Cromotest(®) (semiquantitative slide agglutination and single tube Widal test), TUBEX(®) and Typhidot(®) was assessed against that of blood culture. Performance was modelled for scenarios with pretest probabilities of 5% and 50%., Findings: In total 92 patients enrolled: 53 (57.6%) from South Africa and 39 (42.4%) from the United Republic of Tanzania. Salmonella Typhi was isolated from the blood of 28 (30.4%) patients. The semiquantitative slide agglutination and single-tube Widal tests had positive predictive values (PPVs) of 25.0% (95% confidence interval, CI: 0.6-80.6) and 20.0% (95% CI: 2.5-55.6), respectively. The newer typhoid rapid antibody tests had comparable PPVs: TUBEX(®), 54.1% (95% CI: 36.9-70.5); Typhidot(®) IgM, 56.7% (95% CI: 37.4-74.5); and Typhidot(®) IgG, 54.3% (95% CI: 36.6-71.2). For a pretest probability of 5%, PPVs were: TUBEX(®), 11.0% (95% CI: 6.6-17.9); Typhidot(®) IgM, 9.1% (95% CI: 5.8-14.0); and Typhidot(®) IgG, 11.0% (6.3-18.4). For a pretest probability of 50%, PPVs were: TUBEX(®), 70.2% (95% CI: 57.3-80.5); Typhidot(®) IgM, 65.6% (95% CI: 54.0-75.6); and Typhidot(®) IgG, 70.0% (95% CI: 56.0-81.1)., Conclusion: Semiquantitative slide agglutination and single-tube Widal tests performed poorly. TUBEX(®) and Typhidot(®) may be suitable when pretest probability is high and blood cultures are unavailable, but their performance does not justify deployment in routine care settings in sub-Saharan Africa.

Typhoid and paratyphoid fever continue to be important causes of illness and death, particularly among children and adolescents in south-central and Southeast Asia, where enteric fever is associated with poor sanitation and unsafe food and water. High-quality incidence data from Asia are underpinning efforts to expand access to typhoid vaccines. Efforts are underway to develop vaccines that are immunogenic in infants after a single dose and that can be produced locally in countries of endemicity. The growing importance of Salmonella enterica serotype Paratyphi A in Asia is concerning. Antimicrobial resistance has sequentially emerged to traditional first-line drugs, fluoroquinolones, and third-generation cephalosporins, posing patient treatment challenges. Azithromycin has proven to be an effective alternative for treatment of uncomplicated typhoid fever. The availability of full genome sequences for S. enterica serotype Typhi and S. enterica serotype Paratyphi A confirms their place as monomorphic, human-adapted pathogens vulnerable to control measures if international efforts can be redoubled.

Patients with typhoid fever due to Salmonella enterica serotype Typhi strains for which fluoroquinolones MICs are elevated yet that are classified as susceptible by the current interpretive criteria of the Clinical and Laboratory Standards Institute may not respond adequately to fluoroquinolone therapy. Patients from seven U.S. states with invasive Salmonella serotype Typhi infection between 1999 and 2002 were enrolled in a multicenter retrospective cohort study. Patients infected with Salmonella serotype Typhi isolates with ciprofloxacin MICs of 0.12 to 1 microg/ml (decreased ciprofloxacin susceptibility but not resistant to ciprofloxacin [DCS]) were compared with patients infected with isolates with ciprofloxacin MICs <0.12 microg/ml for fever clearance time and treatment failure. Of 71 patients, 30 (43%) were female and 24 (34%) were infected with Salmonella serotype Typhi with DCS; the median age was 14 years (range, 1 to 51 years). Twenty-one (88%) of 24 isolates with DCS were resistant to nalidixic acid. The median antimicrobial-related fever clearance times in the DCS and non-DCS groups were 92 h (range, 21 to 373 h) and 72 h (range, 19 to 264 h) (P = 0.010), respectively, and the fluoroquinolone-related fever clearance times in the DCS and non-DCS groups were 90 h (range, 9 to 373 h) and 64 h (range, 34 to 204 h) (P = 0.153), respectively. Four (17%) of 24 patients in the DCS group and 2 (4%) of 46 patients in the non-DCS group (relative risk, 2.5; 95% confidence interval, 1.2 to 5.1) experienced treatment failure. Associations persisted after adjustment for potential confounders. We demonstrate that patients infected with Salmonella serotype Typhi isolates with DCS show evidence of a longer time to fever clearance and more frequent treatment failure. Nalidixic acid screening does not detect all isolates with DCS.

There are only 10 contemporary, population-based studies of typhoid fever that evaluate disease incidence using blood culture for confirmation of cases. Reported incidence ranged from 13 to 976/100 000 persons per year. These studies are likely to have been done preferentially in high- incidence sites which makes generalization of data difficult. Only five of these studies reported mortality. Of these the median (range) mortality was 0% (0-1.8%). Since study conditions usually involved enhanced clinical management of patients and the studies were not designed to evaluate mortality as an outcome, their usefulness for generalizing case-fatality rates is uncertain. No contemporary population-based studies reported rates of complications. Hospital-based typhoid fever studies reported median (range) complication rates of 2.8% (0.6-4.9%) for intestinal perforation and case-fatality rates of 2.0% (0-14.8%). Rates of complications other than intestinal perforation were not reported in contemporary hospital-based studies. Hospital-based studies capture information on the most severe illnesses among persons who have access to health-care services limiting their generalizability. Only two studies have informed the current understanding of typhoid fever age distribution curves. Extrapolation from population-based studies suggests that most typhoid fever occurs among young children in Asia. To reduce gaps in the current understanding of typhoid fever incidence, complications, and case-fatality rate, large population-based studies using blood culture confirmation of cases are needed in representative sites, especially in low and medium human development index countries outside Asia.

Background: To investigate the risk factors for infection with endemic typhoid fever in the Samarkand region of Uzbekistan., Methods: Case-control study of culture-confirmed bloodstream infection with Salmonella Typhi. Patients were compared to age-matched community controls. Salmonella Typhi isolates were tested for antimicrobial susceptibility., Results: We enrolled 97 patients and 192 controls. The median age of patients was 19 years. In a conditional regression model, consumption of unboiled surface water outside the home [adjusted odds ratio (aOR)=3.0, 95% confidence interval (CI)=1.1-8.2], use of antimicrobials in the 2 weeks preceding onset of symptoms (aOR=12.2, 95% CI 4.0-37.0), and being a student (aOR=4.0, 95% CI 1.4-11.3) were independently associated with typhoid fever. Routinely washing vegetables (aOR 0.06, 95% CI 0.02-0.2) and dining at a tea-house (aOR 0.4, 95% CI 0.2-1.0) were associated with protection against illness. Salmonella Typhi resistant to ampicillin, chloramphenicol, and trimethoprim-sulfamethoxazole was identified in 6 (15%) of 41 isolates tested., Conclusions: Endemic typhoid fever in Uzbekistan is transmitted by contaminated water. Recent use of antimicrobials also increased risk of infection. Targeted efforts at improving drinking water quality, especially for students and young adults, are likely to decrease transmission of typhoid fever. Measures to decrease the unnecessary use of antimicrobials would be expected to reduce the risk of typhoid fever and decrease the spread of multiple drug-resistant Salmonella Typhi.

Credible measures of disease incidence are necessary to guide typhoid fever control efforts. In Egypt, incidence estimates have been derived from hospital-based syndromic surveillance, which may not represent the population with typhoid fever. To determine the population-based incidence of typhoid fever in Fayoum Governorate (pop. 2,240,000), we established laboratory-based surveillance at five tiers of health care. Incidence estimates were adjusted for sampling and test sensitivity. Of 1,815 patients evaluated, cultures yielded 90 (5%) Salmonella Typhi isolates. The estimated incidence of typhoid fever was 59/100,000 persons/year. We estimate 71% of typhoid fever patients are managed by primary care providers. Multidrug-resistant (MDR) Salmonella Typhi (resistant to chloramphenicol, ampicillin, and trimethoprim-sulfamethoxazole) was isolated from 26 (29%) patients. Population-based surveillance indicates moderate typhoid fever incidence in Fayoum, and a concerning prevalence of MDR typhoid. The majority of patients are evaluated at the primary care level and would not have been detected by hospital-based surveillance.

Objective: To use new data to make a revised estimate of the global burden of typhoid fever, an accurate understanding of which is necessary to guide public health decisions for disease control and prevention efforts., Methods: Population-based studies using confirmation by blood culture of typhoid fever cases were sought by computer search of the multilingual scientific literature. Where there were no eligible studies, data were extrapolated from neighbouring countries and regions. Age-incidence curves were used to model rates measured among narrow age cohorts to the general population. One-way sensitivity analysis was performed to explore the sensitivity of the estimate to the assumptions. The burden of paratyphoid fever was derived by a proportional method., Findings: A total of 22 eligible studies were identified. Regions with high incidence of typhoid fever (>100/100,000 cases/year) include south-central Asia and south-eastAsia. Regions of medium incidence (10-100/100,000 cases/year) include the rest of Asia, Africa, Latin America and the Caribbean, and Oceania, except for Australia and New Zealand. Europe, North America, and the rest of the developed world have low incidence of typhoid fever (<10/100,000 cases/year). We estimate that typhoid fever caused 21,650,974 illnesses and 216,510 deaths during 2000 and that paratyphoid fever caused 5,412,744 illnesses., Conclusion: New data and improved understanding of typhoid fever epidemiology enabled us to refine the global typhoid burden estimate, which remains considerable. More detailed incidence studies in selected countries and regions, particularly Africa, are needed to further improve the estimate.

We developed and evaluated an enzyme-linked immunosorbent assay (ELISA) using monoclonal antibodies to capture somatic antigen 9 (O9), flagellar antigen d (Hd), and the Vi capsular polysaccharide antigen (Vi) from the urine of persons with and without typhoid fever. Sequential urine samples were collected from 44 patients with blood culture-confirmed typhoid fever and from two control groups. The first control group included patients with brucellosis (n = 12) and those with clinically diagnosed, non-typhoid, acute, febrile illness (n = 27). The second control group was a sample of healthy volunteer laboratory workers (n = 11). When assessed relative to date of fever onset, sensitivity was highest during the first week for all three antigens: Vi was detected in the urine of nine (100%) patients, O9 in 4 (44%) patients, and Hd in 4 (44%) patients. Sequential testing of two urine samples from the same patient improved test sensitivity. Combined testing for Vi with O9 and Hd produced a trend towards increased sensitivity without compromising specificity. The specificity for Vi exceeded 90% when assessed among both febrile and healthy control subjects, but was only 25% when assessed among patients with brucellosis. Detection of urinary Vi antigen with this ELISA shows promise for the diagnosis of typhoid fever, particularly when used within the first week after fever onset. However, positive reactions for Vi antigen in patients with brucellosis must be understood before urinary Vi antigen detection can be developed further as a useful rapid diagnostic test.

To measure the incidence of typhoid fever and other febrile illnesses in Bilbeis District, Egypt, we conducted a household survey to determine patterns of health seeking among persons with fever. Then we established surveillance for 4 months among a representative sample of health providers who saw febrile patients. Health providers collected epidemiologic information and blood (for culture and serologic testing) from eligible patients. After adjusting for the provider sampling scheme, test sensitivity, and seasonality, we estimated that the incidence of typhoid fever was 13/100,000 persons per year, and the incidence of brucellosis was 18/100,000 persons per year in the district. This surveillance tool could have wide applications for surveillance for febrile illness in developing countries.