Enteric Fever-Associated Hemophagocytic Lymphohistiocytosis: A Systematic Review of Clinical Characteristics and Outcomes.

Enteric fever is a major contributor to rising health care costs in developing countries. Associated disease-related complications and drug resistance further compound this problem. Hemophagocytic lymphohistiocytosis (HLH) is an uncommon complication of enteric fever with high morbidity and mortality. This systematic review aimed to evaluate the clinical characteristics and treatment outcomes in enteric fever-associated HLH syndrome. We searched major electronic databases (PubMed, Google Scholar, and Scopus) to identify the cases of enteric fever associated with HLH from inception until June 2023. Prespecified data regarding clinical presentation, outcomes, and HLH therapy were collected. A total of 53 cases of enteric fever with HLH were included in the final analysis. The mean age of patients was 20 years, and the proportions of female and pediatric patients were 52.8% and 45.3%, respectively. The mean duration of illness was 10.4 days. A total of 39.6% of patients had enteric fever-associated complications; coagulopathy and encephalopathy were the most common (23.1% and 13.5%). The overall mortality rate was 9.4% in HLH. A total of 51% of patients received HLH-specific therapy (corticosteroids in 41.5% and intravenous immunoglobulin in 20.8% of patients). On multivariate analysis, high ferritin levels (≥5,000 ng/mL) were significantly associated with mortality (hazard ratio, 3.01; 95% CI = 0.62-14.12, P = 0.041). Enteric fever with secondary HLH is associated with high mortality. This review reveals the potential role of ferritin in disease prognosis. In cases with significantly elevated ferritin levels, the role of immunosuppressants or combination antibiotics should be explored.

Changes in historical typhoid transmission across 16 U.S. cities, 1889-1931: Quantifying the impact of investments in water and sewer infrastructures.

Investments in water and sanitation systems are believed to have led to the decline in typhoid fever in developed countries, such that most cases now occur in regions lacking adequate clean water and sanitation. Exploring seasonal and long-term patterns in historical typhoid mortality in the United States can offer deeper understanding of disease drivers. We fit modified Time-series Susceptible-Infectious-Recovered models to city-level weekly mortality counts to estimate seasonal and long-term typhoid transmission. We examined seasonal transmission separately by city and aggregated by water source. Typhoid transmission peaked in late summer/early fall. Seasonality varied by water source, with the greatest variation occurring in cities with reservoirs. We then fit hierarchical regression models to measure associations between long-term transmission and annual financial investments in water and sewer systems. Overall historical $1 per capita ($16.13 in 2017) investments in the water supply were associated with approximately 5% (95% confidence interval: 3-6%) decreases in typhoid transmission, while $1 increases in the overall sewer system investments were associated with estimated 6% (95% confidence interval: 4-9%) decreases. Our findings aid in the understanding of typhoid transmission dynamics and potential impacts of water and sanitation improvements, and can inform cost-effectiveness analyses of interventions to reduce the typhoid burden.

Prophylactic potential of cytolethal distending toxin B (CdtB) subunit of typhoid toxin against Typhoid fever.

Typhoid fever caused by Salmonella enterica serovar Typhi (S.Typhi) continues to be a major problem, especially in developing countries. Due to the rapid emergence of multi-drug-resistant (MDR) strains, which limits the efficacy of conventional antibiotics as well as problems associated with the existing vaccines, efforts are being made to develop effective prophylactic agents. CdtB subunit of typhoid toxin was selected for assessing its vaccine potential due to its high conservation throughout the Typhi strains. In-vitro assessment of DNase activity of cloned and purified CdtB protein showed a significant decrease in the band intensity of DNA. The measure of metabolic activity and morphological alterations assessed using different cell lines in the presence of CdtB protein showed no significant signs of toxicity. These observations were further strengthened by cell cycle analysis, assessed by flow cytometry. Keeping these observations in mind, the immunoprotective potential of CdtB was assessed using S.Typhi induced mouse peritonitis model. A significant titer of IgG antibodies (>128000) against CdtB protein was recorded in the immunized mice by enzyme-linked immunosorbent assay (ELISA), which was also validated by immunoblotting. Active immunization with the protein protected 75% mice against a lethal dose of S.Typhi Ty2. The data indicated a significant (up to 5 log) reduction in the bacterial load in the spleen and liver of immunized-infected mice compared to control (unimmunized-infected) mice which might have resulted in the modulation of histoarchitecture of spleen and liver and the levels of cytokines (IL-6, TNF-α and IL-10) production; thereby indicating the effectiveness of the subunit. The observations deduced from the study give the proof of concept of immunogenic potential of protein. However, further studies involving the immunoreactivity of CdtB with the statistically significant number of sera samples obtained from the human patients would be helpful in establishing the relevance of CdtB protein in humans and for making the strategies to develop it as an effective vaccine candidate.

Water and Filth: Reevaluating the First Era of Sanitary Typhoid Intervention (1840-1940).

While typhoid fever remains an important cause of illness in many low- and middle-income countries, important insights can be learned by exploring the historical experience with typhoid fever in industrialized countries. We used archival research to examine British and American attempts to control typhoid via sanitary interventions from the 1840s to 1940s. First, we assess how varying perceptions of typhoid and conflicts of interest led to a nonlinear evolution of control attempts in Oxford, United Kingdom. Our qualitative analysis shows how professional rivalries and tensions between Oxford's university and citizens ("gown and town"), as well as competing theories of typhoid proliferation stalled sanitary reform until the provision of cheap external credit created cross-party alliances at the municipal level. Second, we use historical mortality data to evaluate and quantify the impact of individual sanitary measures on typhoid transmission in major US cities. Together a historiographic and epidemiological study of past interventions provides insights for the planning of future sanitary programs.

A retrospective study of patients with blood culture-confirmed typhoid fever in Fiji during 2014-2015: epidemiology, clinical features, treatment and outcome.

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.

Small alarmones (p)ppGpp regulate virulence associated traits and pathogenesis of Salmonella enterica serovar Typhi.

How Salmonella enterica serovar Typhi (S. Typhi), an important human pathogen, survives the stressful microenvironments inside the gastrointestinal tract and within macrophages remains poorly understood. We report here that S. Typhi has a bonafide stringent response (SR) system, which is mediated by (p)ppGpp and regulates multiple virulence-associated traits and the pathogenicity of the S. Typhi Ty2 strain. In an iron overload mouse model of S. Typhi infection, the (p)ppGpp0 (Ty2ΔRelAΔSpoT) strain showed minimal systemic spread and no mortality, as opposed to 100% death of the mice challenged with the isogenic wild-type strain. Ty2ΔRelAΔSpoT had markedly elongated morphology with incomplete septa formation and demonstrated severely attenuated motility and chemotaxis due to the loss of flagella. Absence of the Vi-polysaccharide capsule rendered the mutant strain highly susceptible to complement-mediated lysis. The phenotypes of Ty2ΔRelAΔSpoT was contributed by transcriptional repression of several genes, including fliC, tviA, and ftsZ, as found by reverse transcriptase quantitative polymerase chain reaction and gene complementation studies. Finally, Ty2ΔRelAΔSpoT had markedly reduced invasion into intestinal epithelial cells and significantly attenuated survival within macrophages. To the best of our knowledge, this was the first study that addressed SR in S. Typhi and showed that (p)ppGpp was essential for optimal pathogenic fitness of the organism.

The global burden of typhoid and paratyphoid fevers: a systematic analysis for the Global Burden of Disease Study 2017.

BACKGROUND: Efforts to quantify the global burden of enteric fever are valuable for understanding the health lost and the large-scale spatial distribution of the disease. We present the estimates of typhoid and paratyphoid fever burden from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017, and the approach taken to produce them. METHODS: For this systematic analysis we broke down the relative contributions of typhoid and paratyphoid fevers by country, year, and age, and analysed trends in incidence and mortality. We modelled the combined incidence of typhoid and paratyphoid fevers and split these total cases proportionally between typhoid and paratyphoid fevers using aetiological proportion models. We estimated deaths using vital registration data for countries with sufficiently high data completeness and using a natural history approach for other locations. We also estimated disability-adjusted life-years (DALYs) for typhoid and paratyphoid fevers. FINDINGS: Globally, 14·3 million (95% uncertainty interval [UI] 12·5-16·3) cases of typhoid and paratyphoid fevers occurred in 2017, a 44·6% (42·2-47·0) decline from 25·9 million (22·0-29·9) in 1990. Age-standardised incidence rates declined by 54·9% (53·4-56·5), from 439·2 (376·7-507·7) per 100 000 person-years in 1990, to 197·8 (172·0-226·2) per 100 000 person-years in 2017. In 2017, Salmonella enterica serotype Typhi caused 76·3% (71·8-80·5) of cases of enteric fever. We estimated a global case fatality of 0·95% (0·54-1·53) in 2017, with higher case fatality estimates among children and older adults, and among those living in lower-income countries. We therefore estimated 135·9 thousand (76·9-218·9) deaths from typhoid and paratyphoid fever globally in 2017, a 41·0% (33·6-48·3) decline from 230·5 thousand (131·2-372·6) in 1990. Overall, typhoid and paratyphoid fevers were responsible for 9·8 million (5·6-15·8) DALYs in 2017, down 43·0% (35·5-50·6) from 17·2 million (9·9-27·8) DALYs in 1990. INTERPRETATION: Despite notable progress, typhoid and paratyphoid fevers remain major causes of disability and death, with billions of people likely to be exposed to the pathogens. Although improvements in water and sanitation remain essential, increased vaccine use (including with typhoid conjugate vaccines that are effective in infants and young children and protective for longer periods) and improved data and surveillance to inform vaccine rollout are likely to drive the greatest improvements in the global burden of the disease. FUNDING: Bill & Melinda Gates Foundation.

Spatial and temporal heterogeneities of district-level typhoid morbidities in Ghana: A requisite insight for informed public health response.

Typhoid fever is estimated to cause between 9.9-24.2 million cases and 75,000-208,000 deaths per year globally. Low-income and middle-income countries report the majority of cases, especially those in sub-Saharan Africa. The epidemiology of typhoid fever is poorly understood, particularly in Ghana where there has been no study of the within-country variation. Our objective was to explore and analyze the spatial and temporal patterns of typhoid fever morbidities in Ghana. We used the global and local Moran's indices to uncover the existence of global and local spatial patterns, respectively. Generalized linear autoregressive moving average (glarma) models were developed to explore the overall and regional level temporal patterns of morbidities. The overall index of spatial association was 0.19 (p < 0.001). The global Moran's monthly indices of clustering ranged from ≈ 0 - 0.28, with few non-significant (p > 0.05) estimates. The yearly estimates were all significant (p < 0.001) and ranged from 0.1-0.19, suggesting spatial clustering of typhoid. The local Moran's maps indicated isolated high contributions of clustering within the Upper West and Western regions. The overall and regional level glarma models indicated significant first and second-order serial correlation as well as quarterly trends. These findings can provide relevant epidemiological insight into the spatial and temporal patterns of typhoid epidemiology and useful to complement the development of control strategies by public health managers.

Case-Fatality Ratio of Blood Culture-Confirmed Typhoid Fever in Dhaka, Bangladesh.

With impending rollout of new conjugate typhoid vaccines, better estimates of typhoid case-fatality ratio are needed for countries to set priorities for public health programs. We enrolled 1425 patients of all ages with blood culture-confirmed Salmonella Typhi from laboratory networks serving inpatients and outpatients in Dhaka, Bangladesh. Participants were asked about symptoms and complications including death experienced over a median 3-month period following blood culture diagnosis. Four fatal cases were identified (case-fatality ratio of 0.3% [95% confidence interval, .05%-.55%]). Applying this case-fatality ratio to global typhoid burden estimates would reduce deaths by 70%.

Typhoid Fever: Tracking the Trend in Nigeria.

Typhoid fever continues to pose a serious health challenge in developing countries. A reliable database on positive blood cultures is essential for prompt interventions. To generate reliable data on Salmonella enterica serovar Typhi (S. Typhi)-positive blood culture trends in typhoidal Salmonella in Nigeria alongside changing contextual factors and antimicrobial resistance patterns, a retrospective cohort study was conducted in two hospitals in Lagos between 1993 and 2015. Medical records of typhoid patients were reviewed for positive culture and antibiogram, using standard procedures and analyzed. Additional data were retrieved from a previous study in seven facilities in Abuja and three hospitals in Kano from 2008 to 2017 and 2013 to 2017, respectively. A declining trend in percent positivity of S. Typhi was observed in Abuja with more erratic trends in Lagos and Kano. In Lagos, more than 80% of the isolates from the entire study period exhibited multiple drug resistance with a generally increasing trend. Of the chosen contextual factors, improvements were recorded in female literacy, access to improved water supply, diarrheal mortality in children younger than 5 years, gross domestic product, and poverty while access to improved sanitation facilities decreased over time nationally. Typhoid fever still poses a serious health challenge in Nigeria and in antibiotic resistance, and is a major health security issue. A combined approach that includes the use of typhoid vaccines, improvements in sanitation, and safe water supply is essential.

Introductory Article on Global Burden and Epidemiology of Typhoid Fever.

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.

Case Fatality Rate of Enteric Fever in Endemic Countries: A Systematic Review and Meta-analysis.

Enteric fever is a febrile illness, occurring mostly in Asia and Africa, which can present as a severe and possibly fatal disease. Currently, a case fatality rate (CFR) of 1% is assumed when evaluating the global burden of enteric fever. Until now, no meta-analysis has been conducted to summarize mortality from enteric fever. Therefore, we conducted a systematic review and meta-analysis to aggregate all available evidence. We estimated an overall CFR of 2.49% (95% confidence interval, 1.65%-3.75%; n = 44), and a CFR in hospitalized patients of 4.45% (2.85%-6.88%; n = 21 of 44). There was considerably heterogeneity in estimates of the CFR from individual studies. Neither age nor antimicrobial resistance were significant prognostic factors, but limited data were available for these analyses. The combined estimate of the CFR for enteric fever is higher than previously estimated, and the evaluation of prognostic factors, including antimicrobial resistance, urgently requires more data.

Typhoid Fever in South Africa in an Endemic HIV Setting.

BACKGROUND: Typhoid fever remains an important disease in Africa, associated with outbreaks and the emerging multidrug resistant Salmonella enterica serotype Typhi (Salmonella Typhi) haplotype, H58. This study describes the incidence of, and factors associated with mortality due to, typhoid fever in South Africa, where HIV prevalence is high. METHODS AND FINDINGS: Nationwide active laboratory-based surveillance for culture-confirmed typhoid fever was undertaken from 2003-2013. At selected institutions, additional clinical data from patients were collected including age, sex, HIV status, disease severity and outcome. HIV prevalence among typhoid fever patients was compared to national HIV seroprevalence estimates. The national reference laboratory tested Salmonella Typhi isolates for antimicrobial susceptibility and haplotype. Unadjusted and adjusted logistic regression analyses were conducted determining factors associated with typhoid fever mortality. We identified 855 typhoid fever cases: annual incidence ranged from 0.11 to 0.39 per 100,000 population. Additional clinical data were available for 369 (46.8%) cases presenting to the selected sites. Among typhoid fever patients with known HIV status, 19.3% (29/150) were HIV-infected. In adult females, HIV prevalence in typhoid fever patients was 43.2% (19/44) versus 15.7% national HIV seroprevalence (P < .001); in adult males, 16.3% (7/43) versus 12.3% national HIV seroprevalence (P = .2). H58 represented 11.9% (22/185) of Salmonella Typhi isolates tested. Increased mortality was associated with HIV infection (AOR 10.7; 95% CI 2.3-50.3) and disease severity (AOR 9.8; 95% CI 1.6-60.0) on multivariate analysis. CONCLUSIONS: Typhoid fever incidence in South Africa was largely unchanged from 2003-2013. Typhoid fever mortality was associated disease severity. HIV infection may be a contributing factor. Interventions mandate improved health care access, including to HIV management programmes as well as patient education. Further studies are necessary to clarify relationships between HIV infection and typhoid fever in adults.

Vaccination Method Affects Immune Response and Bacterial Growth but Not Protection in the Salmonella Typhimurium Animal Model of Typhoid.

Understanding immune responses elicited by vaccines, together with immune responses required for protection, is fundamental to designing effective vaccines and immunisation programs. This study examines the effects of the route of administration of a live attenuated vaccine on its interactions with, and stimulation of, the murine immune system as well as its ability to increase survival and provide protection from colonisation by a virulent challenge strain. We assess the effect of administration method using the murine model for typhoid, where animals are infected with S. Typhimurium. Mice were vaccinated either intravenously or orally with the same live attenuated S. Typhimurium strain and data were collected on vaccine strain growth, shedding and stimulation of antibodies and cytokines. Following vaccination, mice were challenged with a virulent strain of S. Typhimurium and the protection conferred by the different vaccination routes was measured in terms of challenge suppression and animal survival. The main difference in immune stimulation found in this study was the development of a secretory IgA response in orally-vaccinated mice, which was absent in IV vaccinated mice. While both strains showed similar protection in terms of challenge suppression in systemic organs (spleen and liver) as well as survival, they differed in terms of challenge suppression of virulent pathogens in gut-associated organs. This difference in gut colonisation presents important questions around the ability of vaccines to prevent shedding and transmission. These findings demonstrate that while protection conferred by two vaccines can appear to be the same, the mechanisms controlling the protection can differ and have important implications for infection dynamics within a population.

A Perspective on Invasive Salmonella Disease in Africa.

Salmonella enterica is a leading cause of community-acquired bloodstream infection in Africa. The contribution of typhoidal and nontyphoidal Salmonella serovars to invasive disease varies considerably in place and time, even within the same country. Nonetheless, many African countries are now thought to experience typhoid fever incidence >100 per 100,000 per year with approximately 1% of patients dying. Invasive nontyphoidal Salmonella (iNTS) disease was estimated to cause 3.4 million illnesses and 681 316 deaths in 2010, with the most disease in Africa. Antimicrobial drug resistance is a growing problem in S. enterica that threatens to further compromise patient outcomes. Reservoirs for nontyphoidal Salmonella and the predominant routes of transmission for typhoidal and nontyphoidal Salmonella are not well understood in Africa, hampering the design of evidence-based, non-vaccine- and vaccine-based prevention measures. It is difficult to distinguish clinically invasive Salmonella disease from febrile illnesses caused by other pathogens. Blood cultures are the mainstay of laboratory diagnosis, but lack sensitivity due to the low magnitude of bacteremia, do not produce results at point of care, and are not widely available in Africa. Serologic approaches to diagnosis remain inaccurate, and nucleic acid amplification tests are also compromised by low concentrations of bacteria. High-throughput whole-genome sequencing, together with a range of novel analytic pipelines, has provided new insights into the complex pattern of epidemiology, pathogenesis, and host adaptation. Concerted efforts are therefore needed to apply these new tools in the context of high-quality field surveillance to improve diagnosis, patient management, control, and prevention of invasive Salmonella infections in Africa.

Control of Invasive Salmonella Disease in Africa: Is There a Role for Human Challenge Models?

Invasive Salmonella disease in Africa is a major public health concern. With evidence of the transcontinental spread of the Salmonella Typhi H58 haplotype, improved estimates of the burden of infection and understanding of the complex interplay of factors affecting disease transmission are needed to assist with efforts aimed at disease control. In addition to Salmonella Typhi, invasive nontyphoidal Salmonella are increasingly recognized as an important cause of febrile illness and mortality in sub-Saharan Africa. Human experimental oral challenge studies with Salmonella can be used as a model to offer unique insights into host-pathogen interactions as well as a platform to efficiently test new diagnostic and vaccine candidates. In this article, we review the background and use of human challenge studies to date and discuss how findings from these studies may lead to progress in the control of invasive Salmonella disease in Africa.