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.

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.

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%.

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.

An inducible and secreted eukaryote-like serine/threonine kinase of Salmonella enterica serovar Typhi promotes intracellular survival and pathogenesis.

Eukaryote-like serine/threonine kinases (eSTKs) constitute an important family of bacterial virulence factors. Genome analysis had predicted putative eSTKs in Salmonella enterica serovar Typhi, although their functional characterization and the elucidation of their role in pathogenesis are still awaited. We show here that the primary sequence and secondary structure of the t4519 locus of Salmonella Typhi Ty2 have all the signatures of eukaryotic superfamily kinases. t4519 encodes a ∼39-kDa protein (T4519), which shows serine/threonine kinase activities in vitro. Recombinant T4519 (rT4519) is autophosphorylated and phosphorylates the universal substrate myelin basic protein. Infection of macrophages results in decreased viability of the mutant (Ty2Δt4519) strain, which is reversed by gene complementation. Moreover, reactive oxygen species produced by the macrophages signal to the bacteria to induce T4519, which is translocated to the host cell cytoplasm. That T4519 may target a host substrate(s) is further supported by the activation of host cellular signaling pathways and the induction of cytokines/chemokines. Finally, the role of T4519 in the pathogenesis of Salmonella Typhi is underscored by the significantly decreased mortality of mice infected with the Ty2Δt4519 strain and the fact that the competitive index of this strain for causing systemic infection is 0.25% that of the wild-type strain. This study characterizes the first eSTK of Salmonella Typhi and demonstrates its role in promoting phagosomal survival of the bacteria within macrophages, which is a key determinant of pathogenesis. This, to the best of our knowledge, is the first study to describe the essential role of eSTKs in the in vivo pathogenesis of Salmonella spp.

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.

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.

Declining Mortality Inequality within Cities during the Health Transition.

In the United States in the late 19th and early 20th century, large cities had extremely high death rates from infectious disease. Within major cities such as New York City and Philadelphia, there was significant variation at any point in time in the mortality rate across neighborhoods. Between 1900 and 1930 neighborhood mortality convergence took place in New York City and Philadelphia. We document these trends and discuss their consequences for neighborhood quality of life dynamics and the economic incidence of who gains from effective public health interventions.

Predictors of mortality in children with typhoid ileal perforation in a Nigerian tertiary hospital.

PURPOSE: Childhood typhoid ileal perforation is associated with high morbidity and mortality. Our aim was to ascertain the predictors of survival in children. MATERIALS AND METHODS: This is a tertiary hospital-based retrospective review of patients aged ≤15 years managed for typhoid ileal perforations between January 2005 and December 2013. The details of their biodata, potential risk factors and outcome were evaluated. RESULTS: Forty-five children out of a total of 97 with typhoid fever had typhoid ileal perforation. The age range was 2-15 years, mean (±SD) = 9.3 (±3.31) years, median = 10 years. There were more males than females (26:19). Thirty-nine (86.7%) patients were >5 years old. There were nine deaths (20% mortality). The mean (±SD) age of survivors was 9.8 (±2.9) years and 7.1 (±4.2) for non-survivors (p = 0.026). The duration of illness at presentation, gender, admission temperature, nutritional status and packed cell volume, perforation-operation interval, number of perforations, surgical procedure, and the duration of surgery did not statistically influence survival (p > 0.05). The age of the patients and burst abdomen attained statistical significance (p < 0.05). CONCLUSION: The patients' age and postoperative burst abdomen were significant determinants of survival in children with typhoid ileal perforation.

Medical causes of death in a teaching hospital in South-Eastern Nigeria: A 16 year review.

BACKGROUND: Most developing regions of the world are undergoing gradual epidemiological transition resulting in high burden of both communicable and noncommunicable diseases. This affects the pattern of death in this region. OBJECTIVE: The objective of this study is to determine the causes of death in the medical wards of the University of Nigeria Teaching Hospital, Ituku/Ozalla, Enugu, South-East Nigeria from 1995 to 2010. MATERIALS AND METHODS: Data were collected retrospectively from January 1995 to December 2010. STATISTICAL ANALYSIS USED: Statistical Package for Social Sciences (SPSS Inc. Chicago, IL, USA) version 17.0 was used. Simple descriptive statistics were done. Student's t-test was used to compare means of continuous variables, while Chi-square test was used to test significance of differences between two proportions. RESULTS: The mortality rate was 22.8% (6250/27,514) admissions. The male to female ratio was 1.7:1. Infections (20.2%) were the most common cause of death. However, chronic kidney disease was the single most common disease entity causing death (12.3%). Other important causes of death in order of prevalence were cerebrovascular accident (10.5%), acquired immune deficiency syndrome and tuberculosis either alone or as co-infection (10.3%), heart failure (8.8%), chronic liver disease (7.0%), septicemia (6.5%), respiratory failure (5.3%), diabetes mellitus (4.6%), cardiac arrhythmias (2.9%), and primary liver cell carcinoma (2.7%). There were few deaths from tetanus, malaria, typhoid fever, and coronary artery disease. CONCLUSION: Mortality is high in our medical wards and reflects the emerging trend of mixed disease spectrum comprising communicable and noncommunicable diseases.

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.

Predictor of mortality in children with typhoid intestinal perforation in a Tertiary Hospital in Nigeria.

PURPOSE: Typhoid intestinal perforation (TIP) exerts a great toll both on the patients and the surgeons in resource poor countries. Factors that predict mortality in patients with TIP remain controversial. The study aims to determine factors that predict mortality in a Nigerian tertiary facility and to offer strategies for improvement. MATERIALS AND METHODS: We conducted a retrospective analysis of data of 153 children who underwent surgery for TIP at a Tertiary Hospital in Nigeria over a period of 8 years (January 2002 to December 2009). Data collected included patient demographics, presentation, haemoglobin level (Hgb), presentation-operation interval, type of surgical procedure, nature of peritoneal collection, the number of perforations and duration of surgery. Postoperative complications, duration of hospital stay and outcome were also examined. RESULTS: There were 99 (64.7%) boys and 54 (35.3%) girls aged 3-15 years, mean (SD) = 9.4 (±3.6) years. There were 105 single perforations and 46 multiple perforations (range 1-32). The surgical procedure was simple 2-layer closure in 128 (83.7%) and segmental resection in 9 (5.9%) children. The mortality was 16 (10.4%). The mean (SD) age of children who survived and those who died was 9.3 (±3.6) years and 10.1 (±4.0) years, respectively; p = 0.446, the mean duration of symptom in children who survived and those who died was 10.3 (±4.9) days and 12.3 (±5.6) days; p = 0.164, and the mean interval between presentation and operation in those who died and those who survived was 29.3 (±25) h and 28.4 (±13.4) h; p = 0.896. Temperature ≥ 38.5°C (p = 0.040), anastomotic leak (p = 0.029) and faecal fistula (p = 0.000) were significantly associated with mortality. Age <5 years (p = 0.675), male gender (p = 0.845), presentation-operation interval ≥24 h (p = 0.940), Hgb less than 8 g/dL (p = 0.058), faeculent peritoneal collection (p = 0.757), number of perforations (p = 0.518) and the surgical technique (p = 0.375) were not related to mortality. Logistic regression analysis showed that only postoperative faecal fistula (p = 0.001; OR = 13.7) independently predicted mortality. CONCLUSION: Development of postoperative fecal fistula significantly predicted mortality. Prioritizing the prevention of typhoid fever than its treatment and attention to surgical details may significantly reduce mortality of TIP in children in this setting.

Trends and disease burden of enteric fever in Guangxi province, China, 1994-2004.

OBJECTIVE: To determine the burden of enteric fever through trends in morbidity and mortality, bacterial species and antimicrobial resistance in Guangxi, a southern, subtropical, coastal province of China with a disproportionally large burden of enteric fever. METHODS: Data on morbidity and mortality caused by enteric fever between 1994 and 2004 were extracted from the Guangxi Center for Disease Control and Prevention. Laboratory-based surveillance and outbreak investigations were integrated with reports of notifiable infectious diseases to estimate the bacterial species-specific incidence of enteric fever. To adjust for underreporting, survey data were collected from three prefectures that represent the hyper-, moderate- and low-endemic regions of Guangxi province. FINDINGS: In Guangxi province, enteric fever incidence rate varied over the study period, with a peak of 13.5 cases per 100 000 population in 1995 and a low of 6.5 in 2003. The disease occurred most frequently during the summer and autumn months and in the group aged 10-49 years. The incidence of enteric fever varied by region within Guangxi province. During the 11-year period covered by the study, 61 outbreaks of enteric fever were reported, and Salmonella paratyphi A (SPA) became the predominant causative agent in the province. CONCLUSION: Prospective studies may provide a better understanding of the reason for the shifting epidemiology of enteric fever in Guangxi province. Given the emergence of resistance to first- and second-line antimicrobials for the treatment of enteric fever, a bivalent vaccine against both SPA and S. typhi would facilitate for disease control.

[Primary ileostomy for typhoid-related ileal perforation: a 62-case series in Ouagadougou, Burkina Faso]. / Iléostomie première des perforations iléales d'origine typhique: 62 cas à Ouagadougou (Burkina Faso).

OBJECTIVES: The purpose of this report is to evaluate the efficacy of primary ileostomy for treatment of typhoid-related ileal perforation based on our experience. METHODS: This retrospective study included all cases of typhoid-related ileal perforation treated by primary ileostomy in the Visceral Surgery Department of the Yalgado Ouedraogo Teaching Hospital in Ouagadougou, Burkina Faso from January 2006 to June 2008. Diagnosis was based mainly on peroperative findings revealing specific anatomical lesions. There were 45 men (72.6%) and 17 women (27.4%) with a mean age of 26 years (range, 14 to 68). Asthenic forms were observed in 41 cases (66.1%) and sthenic forms in 21 (33.9%). The mean delay for seeking treatment was 6 days (range, 1 to 30 days). RESULTS: Primary ileostomy was used for treatment of typhoid-related ileal perforation in 78.5% of cases. Most cases (80.6%) involved single perforations. A temporary ileostomy was performed in 55 cases (88.7%) and terminal ileostomy was performed in 7 (11.3%). Complications were observed in 18 patients (29.03%) including suppuration of wall in 8 cases. The mean duration for re-establishing continuity and of hospital stay was 34 and 41 days respectively. Four deaths occurred due to hypovolemic shock. CONCLUSION: In our department, primary ileostomy for typhoid-related ileal perforation reduced mortality despite high morbidity.

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.

Epidemiology of typhoid and paratyphoid fever hospitalizations in Spain (1997-2005).

BACKGROUND AND OBJECTIVE: This epidemiological survey was undertaken to estimate the burden of hospitalizations for typhoid and paratyphoid fever in Spain over a nine-year period (1997-2005). RESULTS: There were 1,106 hospitalizations for typhoid and paratyphoid fever during the study period. The annual hospitalization rate was 0.31 cases per 100,000 population. The mortality and case fatality rates were 0.003 per 100,000 population and 0.9%, respectively. The average length of hospitalization was 10.19 days. These hospitalizations impose an annual direct cost of euro334,000. PATIENTS AND METHODS: Hospital discharges for typhoid or paratyphoid fever reported during a nine-year period in Spanish hospitals were obtained from the national surveillance system for hospital data, which is maintained by the Ministry of Health and covers more than 97% of Spanish hospitals. CONCLUSIONS: Preventive measures are vital to reduce the occurrence of typhoid fever and avoid new outbreaks. Effective prevention would result in large cost savings to the National Health Care System.

An outbreak of peritonitis caused by multidrug-resistant Salmonella Typhi in Kinshasa, Democratic Republic of Congo.

Between October 2004 and January 2005, 144 patients with peritonitis were admitted to the surgical wards of Kinshasa General Hospital and a few private city clinics. 63 patients (44%) underwent surgical intervention because of intestinal perforation consistent with typhoid fever; the case fatality rate was 53%. The majority of patients had received a course of first-line antibiotics such as chloramphenicol, ampicillin or co-trimoxazole before admission. On bacteriological investigation, Salmonella Typhi was isolated from the blood of 11 patients with peritonitis. The isolates were all resistant to ampicillin, chloramphenicol, tetracycline and co-trimoxazole, but sensitive to third-generation cephalosporins, quinolone (nalidixic acid, ciprofloxacine) and amoxicillin-clavulanic acid. Several factors contributed to the poor outcome of this disease including a) the use of inappropriate antibiotics, b) long delay in diagnosis, c) difficult access to health facilities. This is the first documented outbreak of typhoid fever caused by a multidrug-resistant S. Typhi in Kinshasa.

[Complications of typhoid fever and its causes in an epidemic focus].

Autopsy records, case histories, and archival organ and tissue samples were studied in 109 Soviet military men during the Afghanistan war, who had died of typhoid fever in 1980-1986. Morphological and statistical studies demonstrated that the current pattern and frequency of complications and immediate causes of death with the epidemic incidence in the endemic focus largely corresponded to those in the preantibiotic period. The specific features were the higher rate and early development of enteric complications, infectious myocarditis, and infectious-toxic shock, the higher, as compared with the past years, proportion of deaths from circulatory diseases and a reduction of cases of total intoxication. Acute cardiovascular insufficiency associated with infectious myocarditis and infectious-toxic shock was one of the main causes of death in the first 2 weeks of typhoid fever. Most patients died of perforative peritonitis and pneumonia in the later period.

[Family practice in a rural environment in the west of France (1908-1920): chronicle of mortality]. / Médecine de famille en milieu rural dans l'Ouest de la France (1908-1920): chronique de mortalité.

This paper reports about a manuscript from Doctor Pelletier who accounted the causes of death rate in a village of the Vendée: pneumopathy, typhoid, diarrhoea linked to unhealthiness provoked by stagnant waters.

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.