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Background:
Typhoid fever is endemic in some Pacific Island Countries including Fiji and Samoa yet genomic surveillance is not routine in such settings. Previous studies suggested imports of the global H58 clade of Salmonella enterica var Typhi (Salmonella Typhi) contribute to disease in these countries which, given the MDR potential of H58, does not auger well for treatment. The objective of the study was to define the genomic epidemiology of Salmonella Typhi in Fiji.
Methods:
Genomic sequencing approaches were implemented to study the distribution of 255 Salmonella Typhi isolates from the Central Division of Fiji. We augmented epidemiological surveillance and Bayesian phylogenomic approaches with a multi-year typhoid case-control study to define geospatial patterns among typhoid cases.
Findings:
Genomic analyses showed Salmonella Typhi from Fiji resolved into 2 non-H58 genotypes with isolates from the two dominant ethnic groups, the Indigenous (iTaukei) and non-iTaukei genetically indistinguishable. Low rates of international importation of clones was observed and overall, there were very low levels an antibiotic resistance within the endemic Fijian typhoid genotypes. Genomic epidemiological investigations were able to identify previously unlinked case clusters. Bayesian phylodynamic analyses suggested that genomic variation within the larger endemic Salmonella Typhi genotype expanded at discreet times, then contracted.
Interpretation:
Cyclones and flooding drove 'waves' of typhoid outbreaks in Fiji which, through population aggregation, poor sanitation and water safety, and then mobility of the population, spread clones more widely. Minimal international importations of new typhoid clones suggest that targeted local intervention strategies may be useful in controlling endemic typhoid infection. These findings add to our understanding of typhoid transmission networks in an endemic island country with broad implications, particularly across Pacific Island Countries.
Funding:
This work was supported by the Coalition Against Typhoid through the Bill and Melinda Gates Foundation [grant number OPP1017518], the Victorian Government, the National Health and Medical Research Council Australia, the Australian Research Council, and the Fiji Ministry of Health and Medical Services.
Background: Understanding the dynamics of infection and carriage of typhoid in endemic settings is critical to finding solutions to prevention and control.
Methods: In a 3 year case-control study, we investigated typhoid among children aged <16 years (4,670 febrile cases and 8,549 age matched controls) living in an informal settlement, Nairobi, Kenya.
Results: 148 S. Typhi isolates from cases and 95 from controls (stool culture) were identified; a carriage frequency of 1%. Whole-genome sequencing showed 97% of cases and 88% of controls were genotype 4.3.1 (Haplotype 58), with the majority of each (76% and 88%) being multidrug-resistant strains in 3 sublineages of H58 genotype (East Africa 1 (EA1), EA2, and EA3), with sequences from cases and carriers intermingled.
Conclusions: The high rate of multidrug-resistant H58 S.Typhi, and the close phylogenetic relationships between cases and controls, provides evidence for the role of carriers as a reservoir for the community spread of typhoid in this setting.
Salmonella is a gram-negative, motile, nonsporulating, facultative anaerobic bacillus, belongs to the family Enterobacteriaceae. The bacteria were first identified in 1884. It is transmitted through direct contact with an infected person or indirect contact by the consumption of contaminated food and water. More than 2500 serotypes of Salmonella enterica have been identified but less than 100 serotypes are known to cause infections in humans. S. enterica serovar typhi (S. typhi) and S. enterica serovar paratyphi (S. paratyphi A B C) cause enteric fever, whereas nontyphoidal Salmonella serotypes (NTS) cause diarrhea. NTS commonly presents with gastroenteritis and is a self-limiting disease. Enteric fever is a potentially life-threatening acute febrile systemic infection and is diagnosed by isolating a pathogen on culture. With the emergence of the extensive drug-resistant (XDR) S. typhi clone, limited treatment options are available. Vaccination of persons at risk, improvement of sanitation, promotion of food hygiene, and detection and control of chronic carriers are essential preventive control measures of enteric fever.
Abstract The geographical overlaps of malaria parasites and Salmonella spp. can lead to co-infection of these two pathogens, especially in the tropics where malaria is endemic. Moreover, few literatures suggested that malaria infection was associated with Salmonella bacteremia. Therefore, this study quantified pooled prevalence of typhoidal/non-typhoidal Salmonella (NTS) and probability of typhoidal/NTS and malaria co-infection among febrile patients. The systematic review protocol was registered at PROSPERO (CRD42021252322). Studies on co-infection of typhoidal/NTS and malaria were searched in PubMed, Scopus, and Web of Science. The risk of bias of the included studies was assessed using the checklist for analytical cross-sectional studies developed by the Joanna Briggs Institute. Meta-analyses on the following criteria were performed: (1) pooled prevalence of typhoidal/NTS and malaria co-infection among febrile patients, (2) pooled prevalence of typhoidal/NTS among malaria patients, (3) pooled prevalence of malaria infections among patients with Salmonella spp. infection, and (4) probability of typhoidal/NTS and malaria co-infection among febrile patients. Additionally, the case fatality rate and mean difference of malarial parasitemia between typhoidal/NTS and malaria co-infection and Plasmodium monoinfection were also determined. The subgroup analyses of typhoidal/NTS, regions (Africa and Asia), countries, time (publication year), characteristics of participants, and diagnostic tests for identifying Salmonella spp. were also conducted. A sensitivity test was performed to determine the robustness of the study outcomes. Publication bias among the included studies was evaluated using the funnel plot and Egger’s test. All analyses were performed using Stata version 15 (StataCorp LLC, Texas, USA) with a p-value
Every individual harbours a complex, diverse and mutualistic microbial flora in their intestine and over the time it became an integral part of the body, affecting a plethora of activities of the host. Interaction between host and gut-microbiota affects several aspects of host physiology. Gut-microbiota affects host metabolism by fermenting unabsorbed/undigested carbohydrates in the large intestine. Not only the metabolic functions, any disturbances in the composition of the gut-microbiota during first 2-3 years of life may impact on the brain development and later affects cognition and behaviour. Thus, gut-dysbiosis causes certain serious pathological conditions in the host including metabolic disorders, inflammatory bowel disease and mood alterations, etc. Microbial-metabolites in recent times have emerged as key mediators and are responsible for microbiota induced beneficial effects on host. This review provides an overview of the mechanism of microbial-metabolite production, their respective physiological functions and the impact of gut-microbiome in health and diseases. Metabolites from dietary fibres, aromatic amino acids such as tryptophan, primary bile acids and others are the potential substances and link microbiota to host physiology. Many of these metabolites act as signalling molecules to a number of cells types and also help in the secretion of hormones. Moreover, interaction of microbiota derived metabolites with their host, immunity boosting mechanisms, protection against pathogens and modulation of metabolism is also highlighted here. Understanding all these functional attributes of metabolites produced from gut-microbiota may lead to the opening of a new avenue for preventing and developing potent therapies against several diseases.
While Salmonella enterica is seen as an archetypal facultative intracellular bacterial pathogen where protection is mediated by CD4 ⁺ T cells, identifying circulating protective cells has proved very difficult, inhibiting steps to identify key antigen specificities. Exploiting a mouse model of vaccination, we show that the spleens of C57BL/6 mice vaccinated with live-attenuated Salmonella serovar Typhimurium ( S . Typhimurium) strains carried a pool of IFN-γ ⁺ CD4 ⁺ T cells that could adoptively transfer protection, but only transiently. Circulating Salmonella -reactive CD4 ⁺ T cells expressed the liver-homing chemokine receptor CXCR6, accumulated over time in the liver and assumed phenotypic characteristics associated with tissue-associated T cells. Liver memory CD4 ⁺ T cells showed TCR selection bias and their accumulation in the liver could be inhibited by blocking CXCL16. These data showed that the circulation of CD4 ⁺ T cells mediating immunity to Salmonella is limited to a brief window after which Salmonella -specific CD4 ⁺ T cells migrate to peripheral tissues. Our observations highlight the importance of triggering tissue-specific immunity against systemic infections.
One characteristic of the few Salmonella enterica serovars that produce typhoid-like infections is that disease-free persistent infection can occur for months or years in a small number of individuals post-convalescence. The bacteria continue to be shed intermittently which is a key component of the epidemiology of these infections. Persistent chronic infection occurs despite high levels of circulating specific IgG. We have reviewed the information on the basis for persistence in S. Typhi, S. Dublin, S. Gallinarum, S. Pullorum, S. Abortusovis and also S. Typhimurium in mice as a model of persistence. Persistence appears to occur in macrophages in the spleen and liver with shedding either from the gall bladder and gut or the reproductive tract. The involvement of host genetic background in defining persistence is clear from studies with the mouse but less so with human and poultry infections. There is increasing evidence that the organisms (i) modulate the host response away from the typical Th1-type response normally associated with immune clearance of an acute infection to Th2-type or an anti-inflammatory response, and that (ii) the bacteria modulate transformation of macrophage from M1 to M2 type. The bacterial factors involved in this are not yet fully understood. There are early indications that it might be possible to remodulate the response back towards a Th1 response by using cytokine therapy.
Epidemiological evidence reveal a very close association of malignancies with chronic inflammation as a result of persistent bacterial infection. Recently, more studies have provided experimental evidence for an etiological role of bacterial factors disposing infected tissue towards carcinoma. When healthy cells accumulate genomic insults resulting in DNA damage, they may sustain proliferative signalling, resist apoptotic signals, evade growth suppressors, enable replicative immortality, and induce angiogenesis, thus boosting active invasion and metastasis. Moreover, these cells must be able to deregulate cellular energetics and have the ability to evade immune destruction. How bacterial infection leads to mutations and enriches a tumour-promoting inflammatory response or micro-environment is still not clear. In this review we showcase well-studied bacteria and their virulence factors that are tightly associated with carcinoma and the various mechanisms and pathways that could have carcinogenic properties.
The risk of the geographic transmission of emerging infectious diseases through air travel varies greatly. In this study, we collected data on cases of food-borne diseases between the years 2011 and 2020 in Taiwan to access the epidemiological features, differences, and trends in domestic and imported cases of typhoid and paratyphoid in terms of patient sex, age, month of confirmation, and area of residence. In this study, we made use of the open data website provided by Taiwan’s Centers for Disease Control (TCDC) to extract the reported numbers of cases of typhoid and paratyphoid between January and December from 2011 to 2020 for comparison. Univariate analysis was performed using the Chi-square test for categorical variables. Fisher’s exact test was performed if an expected frequency was less than 5. A total of 226 typhoid cases and 61 paratyphoid cases were analyzed from the database. The incidences of typhoid and paratyphoid per million of the population were 0.42–2.11 and 0–0.39, respectively. There was a significant difference in the incidence of the diseases between the age groups (p= 0.019), with a gradual increase in the 20–40 years group. A distinct seasonal (between fall and spring) variation was also observed (p= 0.012). There were 34 cases of children with typhoid in the period 2011–2015 and 12 cases of children with typhoid in the period 2016–2020. During these periods, there were two cases of paratyphoid. This study indicated that the risk of children suffering from typhoid has been significantly reduced in the last five years. Furthermore, we found that more women have acquired typhoid and paratyphoid than men, and that living in the Taipei metropolitan area and the northern area was a potential risk factor. Furthermore, the number of imported cases of typhoid (n = 3) and paratyphoid (n = 0) reported during the COVID-19 pandemic was lower than that reported for the same disease from 2011 to 2020. More typhoid and paratyphoid cases were imported from Indonesia, India, Myanmar, and Cambodia. This study represents the first report on confirmed cases of acquired typhoid and paratyphoid from surveillance data from Taiwan’s CDC for the period 2011–2020. This study also demonstrates that the cases of typhoid and paratyphoid decreased in Taiwan during the COVID pandemic. Big data were used in this study, which may inform future surveillance and research efforts in Taiwan.
The burden of Salmonella Typhi shedding in stool and its contribution to transmission in endemic settings is unknown. During passive surveillance S. Typhi shedding was seen during convalescence in 332 bacteremic typhoid patients although none persisted at one-year follow-up. Anti-Vi-IgG titres were measured in age-stratified cohort of serosurveillance participants. Systematic stool sampling of 303 participants with high anti-Vi-IgG titres identified one asymptomatic carrier shedding. These findings suggest ongoing S. Typhi transmission in this setting is more likely to occur from acute convalescent cases although better approaches are needed to identify true chronic carriers in the community to enable typhoid elimination.
Typhoid is endemic in many countries in South Asia and sub-Saharan Africa. The high burden of this age-old, preventable disease exacerbates constraints on the health systems of these countries. Currently, most patients are treated effectively in the community or outpatient departments, however, with rising antimicrobial resistance and the dearth of novel antimicrobials in the horizon, we risk losing our primary defense against typhoid. Extensively drug-resistant Salmonella Typhi is spreading, and azithromycin is the last oral drug to continue treating typhoid in the community. With increasing azithromycin resistance, emergence of pan-oral drug resistant Salmonella Typhi is imminent. The high burden of typhoid is also an underlying cause of the unnecessary use of antimicrobials. In addition to implementing water sanitation and hygiene interventions to prevent typhoid, it is imperative to rapidly roll out typhoid conjugate vaccines in endemic countries. This will not only reduce the burden of typhoid, but also aid in interrupting the trend of increasing antimicrobial resistance.
Decisions about typhoid fever prevention and control are based on estimates of typhoid incidence and their uncertainty. Lack of specific clinical diagnostic criteria, poorly sensitive diagnostic tests, and scarcity of accurate and complete datasets contribute to difficulties in calculating age‐specific population‐level typhoid incidence. Using data from the Strategic Typhoid Alliance across Africa and Asia program, we integrated demographic censuses, healthcare utilization surveys, facility‐based surveillance, and serological surveillance from Malawi, Nepal, and Bangladesh to account for under‐detection of cases. We developed a Bayesian approach that adjusts the count of reported blood‐culture‐positive cases for blood culture detection, blood culture collection, and healthcare seeking—and how these factors vary by age—while combining information from prior published studies. We validated the model using simulated data. The ratio of observed to adjusted incidence rates was 7.7 (95% credible interval [CrI]: 6.0‐12.4) in Malawi, 14.4 (95% CrI: 9.3‐24.9) in Nepal, and 7.0 (95% CrI: 5.6‐9.2) in Bangladesh. The probability of blood culture collection led to the largest adjustment in Malawi, while the probability of seeking healthcare contributed the most in Nepal and Bangladesh; adjustment factors varied by age. Adjusted incidence rates were within or below the seroincidence rate limits of typhoid infection. Estimates of blood‐culture‐confirmed typhoid fever without these adjustments results in considerable underestimation of the true incidence of typhoid fever. Our approach allows each phase of the reporting process to be synthesized to estimate the adjusted incidence of typhoid fever while correctly characterizing uncertainty, which can inform decision‐making for typhoid prevention and control.
Enteric fever and helminth infestation coinfection is commonly seen among children below the age of 5, living in areas with poor sanitation in Africa. These can be explained due to the fact that both enteric fever and ascariasis, are contracted via fecal-oral routes. Although the immune system of children is presumed to be stronger and capable of eliminating several infectious agents, it is not applicable to children below the age of 5. Balanced nutrition also plays a vital role in sustaining strong immunity in children of all age groups and so, it could be one of the contributing factors to high susceptibility to co-infectious diseases among children living in poor countries. Soil-transmitted helminths (STH) are very common in developing countries. They are caused by infection with roundworm, hookworm, or whipworm. Both typhoid fever and helminth infestation in children presents with almost similar clinical symptoms. We present a case of coinfection with typhoid fever caused by Salmonella typhi bacteria and helminth in a 4-year-old child from Nigeria.
Background
Salmonella infection (salmonellosis) is a common infectious disease leading to gastroenteritis, dehydration, uveitis, etc. Internet search is a new method to monitor the outbreak of infectious disease. An internet-based surveillance system using internet data is logistically advantageous and economical to show term-related diseases. In this study, we tried to determine the relationship between salmonellosis and Google Trends in the USA from January 2004 to December 2017.
Methods
We downloaded the reported salmonellosis in the USA from the National Outbreak Reporting System (NORS) from January 2004 to December 2017. Additionally, we downloaded the Google search terms related to salmonellosis from Google Trends in the same period. Cross-correlation analysis and multiple regression analysis were conducted.
Results
The results showed that 6 Google Trends search terms appeared earlier than reported salmonellosis, 26 Google Trends search terms coincided with salmonellosis, and 16 Google Trends search terms appeared after salmonellosis were reported. When the search terms preceded outbreaks, “foods” (t = 2.927, P = 0.004) was a predictor of salmonellosis. When the search terms coincided with outbreaks, “hotel” (t = 1.854, P = 0.066), “poor sanitation” (t = 2.895, P = 0.004), “blueberries” (t = 2.441, P = 0.016), and “hypovolemic shock” (t = 2.001, P = 0.047) were predictors of salmonellosis. When the search terms appeared after outbreaks, “ice cream” (t = 3.077, P = 0.002) was the predictor of salmonellosis. Finally, we identified the most important indicators of Google Trends search terms, including “hotel” (t = 1.854, P = 0.066), “poor sanitation” (t = 2.895, P = 0.004), “blueberries” (t = 2.441, P = 0.016), and “hypovolemic shock” (t = 2.001, P = 0.047). In the future, the increased search activities of these terms might indicate the salmonellosis.
Conclusion
We evaluated the related Google Trends search terms with salmonellosis and identified the most important predictors of salmonellosis outbreak.
Salmonella enterica serovar Typhi (S. Typhi), a causative agent of typhoid fever, is a Gram-negative, human-restricted pathogen that causes significant morbidity and mortality, particularly in developing countries. The currently available typhoid vaccines are not recommended to children below six years of age and have poor long-term efficacy. Due to these limitations and the emerging threat of multidrug-resistance (MDR) strains, the development of a new vaccine is urgently needed. The present study aims to design a multiepitope-based subunit vaccine (MESV) against MDR S. Typhi str. CT18 using a computational-based approach comprising subtractive proteomics and immunoinformatics. Firstly, we investigated the proteome of S. Typhi str. CT18 using subtractive proteomics and identified twelve essential, virulent, host non-homologous, and antigenic outer membrane proteins (OMPs) as potential vaccine candidates with low transmembrane helices (≤1) and molecular weight (≤110 kDa). The OMPs were mapped for cytotoxic T lymphocyte (CTL) epitopes, helper T lymphocyte (HTL) epitopes, and linear B lymphocyte (LBL) epitopes using various immunoinformatics tools and servers. A total of 6, 12, and 11 CTL, HTL, and LBL epitopes were shortlisted, respectively, based on their immunogenicity, antigenicity, allergenicity, toxicity, and hydropathicity potential. Four MESV constructs (MESVCs), MESVC-1, MESVC-2, MESVC-3, and MESVC-4, were designed by linking the CTL, HTL, and LBL epitopes with immune-modulating adjuvants, linkers, and PADRE (Pan HLA DR-binding epitope) sequences. The MESVCs were evaluated for their physicochemical properties, allergenicity, antigenicity, toxicity, and solubility potential to ensure their safety and immunogenic behavior. Secondary and tertiary structures of shortlisted MESVCs (MESVC-1, MESVC-3, and MESVC-4) were predicted, modeled, refined, validated, and then docked with various MHC I, MHC II, and TLR4/MD2 complex. Molecular dynamics (MD) simulation of the final selected MESVC-4 with TLR4/MD2 complex confirms its binding affinity and stability. Codon optimization and in silico cloning verified the translation efficiency and successful expression of MESVC-4 in E. coli str. K12. Finally, the efficiency of MESVC-4 to trigger an effective immune response was assessed by an in silico immune simulation. In conclusion, our findings show that the designed MESVC-4 can elicit humoral and cellular immune responses, implying that it may be used for prophylactic or therapeutic purposes. Therefore, it should be subjected to further experimental validations.
Salmonella enterica serovar Typhi ( S. Typhi ) causes chronic infections by establishing biofilms on cholesterol gallstones. Production of extracellular polymeric substances (EPSs) is key to biofilm development and biofilm architecture depends on which EPSs are made. The presence and spatial distribution of Salmonella EPSs produced in vitro and in vivo were investigated in S. Typhi murium and S. Typhi biofilms by confocal microscopy. Comparisons between serovars and EPS-mutant bacteria were examined by growth on cholesterol-coated surfaces, with human gallstones in ox or human bile, and in mice with gallstones. On cholesterol-coated surfaces, major differences in EPS biomass were not found between serovars. Co-culture biofilms containing wild-type (WT) and EPS-mutant bacteria demonstrated WT compensation for EPS mutations. Biofilm EPS analysis from gallbladder-mimicking conditions found that culture in human bile more consistently replicated the relative abundance and spatial organization of each EPS on gallstones from the chronic mouse model than culture in ox bile. S. Typhi murium biofilms cultured in vitro on gallstones in ox bile exhibited co-localized pairings of curli fimbriae/lipopolysaccharide and O antigen capsule/cellulose while these associations were not present in S. Typhi biofilms or in mouse gallstone biofilms. In general, inclusion of human bile with gallstones in vitro replicated biofilm development on gallstones in vivo , demonstrating its strength as a model for studying biofilm parameters or EPS-directed therapeutic treatments.
Typhoid fever is usually a mild clinical disease. Typhoid fever with massive intestinal hemorrhage is rare in the antibiotic era. Acute acalculous cholecystitis (AAC) is also rare in adults. Here, we describe the first adult case of typhoid fever with both complications due to Vi-negative and fluoroquinolone-insensitive Salmonella enterica serovar Typhi ( S . Typhi) infection. We aim to alert physicians to this rare condition.
Background. The diagnosis of typhoid fever based on the Widal slide agglutination test remains a major hurdle in developing countries due to varied perceptions of the value of the Widal test in determining clinical decision-making. We undertook a study to evaluate the diagnostic performance of the Widal test and the Typhidot immunoassay in patients suspected of having typhoid fever in the Menoua division, West Region of Cameroon. Methods. Blood and stool samples were collected from 558 consenting febrile patients on the basis of suspicion of typhoid fever. These patients attended three district health services of the Menoua division between April 2018 and September 2019. These patients had clinical symptoms suggestive of typhoid fever as determined by their consultant. Serum was used for the Widal slide agglutination test and for the Typhidot rapid immunoassay test based on manufacturer’s guidelines. A composite reference of fever plus positive coproculture for Salmonella typhi and Salmonella paratyphi was used as the reference. The sensitivity, specificity, and predictive values of the positive and negative tests were calculated as well as Cohen’s kappa for agreement between the two tests. Results. Of 558 patients, 12.90% tested positive for the reference method, 57.17% tested positive for the Widal slide agglutination test, while 15.59% were positive for Typhidot-IgM. The overall sensitivity, specificity, and predictive values of the positive and negative tests were 80.56%, 94.03%, 66.6%, and 97.03% for Typhidot-IgM and 94.44%, 48.35%, 21.32%, and 98.33% for the Widal slide agglutination test, respectively. Cohen’s kappa estimates were 0.1660 (0.121–0.211) and 0.386 (0.312–0.460) for the Widal test and Typhidot immunoassay for 53.6% and 76.16% agreements of all observations, respectively. Conclusion. The Widal test was found to have a lower predictive value for the diagnosis of typhoid fever in our setting. However, the Typhidot test, although better, was not ideal. Diagnosis of typhoid fever should therefore rely on adequate clinical suspicion and a positive Typhidot test to improve the clinical management of typhoid fever in our setting.
1. Background
Enteric fever caused by Salmonella typhi and Salmonella paratyphi remains a major burden in developing countries due to varied perceptions of the value of the Widal test in determining clinical decision-making. The burden of typhoid fever, worldwide, shows that it causes 16.6 million new infections and about 600,000 deaths each year [1]. However, the incidence of typhoid fever has dropped to about 10/100,000 population/year in developed countries due to improved living standard, proper hygiene and sanitation, and better healthcare systems, but the incidence is still higher, 100/100,000 population/year, in less developed countries [2]. A key challenge to the effective control of typhoid fever is related to poor diagnosis. Diagnosis of typhoid fever in clinical settings is complicated because of overlapping symptoms with other common infections such as malaria, dengue, and viral enteritis [3–5]. For proper diagnosis, a test with a good diagnostic performance, especially in children with febrile diseases [6, 7], is of great importance. In addition, the misuse of antibiotics via automedication makes diagnosis difficult on a clinical basis [8]. The gold standard for the diagnosis of enteric fever is blood culture, but this test not only has a poor sensitivity in clinical settings but also is time consuming and expensive for patients and clinics in remote settings where culture facilities may not be always available and the population is poor [9]. The main diagnostic in such settings is based on the Widal slide agglutination test which is difficult to interpret for several reasons: cross-reactivities, time lag between infection and production of antibodies, and persistence of target antibodies long after treatment with very low correlation with active disease [10, 11]. The tube dilution technique enables a quantification of specific antibodies, and a change in titer can indicate active disease, but it is not very accessible. Many studies suggest that the Typhidot test, a plausible alternative based on the detection of antibody production against the outer membrane preparation common to Salmonella typhi and Salmonella paratyphi, has better performance characteristics. However, variations in sensitivity and specificity in the diagnosis of enteric fever among adults and children have also been noted [12–14]. The assay gives good results during early infections with a sensitivity of 68–95% and a specificity of 75–95% [15, 16]. An increase in the negative predictive value is important in endemic areas [17]. Recommendations from the World Health Organization for typhoid rapid antibody testing [18] and some studies that have evaluated the Typhidot ability to detect antibodies have shown variations in sensitivity and specificity [15] in different settings. Although comparative studies have relied on the use of imperfect gold standard tests, a composite reference has been suggested to improve diagnostic values, but no agreement has been reached on which combinations can form a good composite reference standard, Storey et al. [19]. In this study, we undertook to evaluate the diagnostic performance of the Widal and Typhidot tests against a composite reference made of a combination of fever (≥37.50 C), 3–7 days or more, and a positive stool culture test for Salmonella typhi and/or paratyphi in combination with one or more of the following clinical symptoms: persistent headache, abdominal discomfort, vomiting, and nausea. The choice of this combination was based on the feasibility and independence of the tests conditional to the disease, and although less specific, measures were taken to exclude other common febrile conditions such as malaria and respiratory tract infections. This was done in a bid to find a local strategy to better diagnose typhoid fever.
2. Methods
2.1. Study Area and Period
The Menoua division, one of the six divisions of the West Region of Cameroon, covers a surface area of 1380 km²; it is divided into six subdivisions (Figure 1) as follows: Dschang, Santchou, Nkong-Ni, Penka-Michel, Fokoue, and Fongo-Tongo. The altitude ranges from 600 to 800 m in Santchou through Dschang at 1500 m and Djuititsa at an altitude of 2200 m. The division has an average rainfall of about 1717.7 mm, and temperature ranges from 13.6°C to 25.35°C. About four in every five indigenes practice subsistence and/or smallholder farming, and the most important food stuffs grown include cabbage, carrot, onion, maize, banana, tomato, plantain, and beans. As of 2005, the division had a total population of 285,764. The capital of this division is Dschang.
The emergence of antimicrobial resistance (AMR) to first- and second-line treatment regimens of enteric fever is a global public-health problem, and routine genomic surveillance to inform clinical and public-health management guidance is essential. Here, we present the prospective analysis of genomic data to monitor trends in incidence, AMR and travel, and assess hierarchical clustering (HierCC) methodology of 1742 isolates of typhoidal salmonellae. Trend analysis of Salmonella Typhi and S . Paratyphi A cases per year increased 48 and 17.3%, respectively, between 2016 and 2019 in England, mainly associated with travel to South Asia. S . Paratyphi B cases have remained stable and are mainly associated with travel to the Middle East and South America. There has been an increase in the number of S . Typhi exhibiting a multidrug-resistant (MDR) profile and the emergence of extensively drug resistant (XDR) profiles. HierCC was a robust method to categorize clonal groups into clades and clusters associated with travel and AMR profiles. The majority of cases that had XDR S . Typhi reported recent travel to Pakistan (94 %) and belonged to a subpopulation of the 4.3.1 (H58) clone (HC5_1452). The phenotypic and genotypic AMR results showed high concordance for S . Typhi and S . Paratyphi A, B and C, with 99.99 % concordance and only three (0.01 %) discordant results out of a possible 23 178 isolate/antibiotic combinations. Genomic surveillance of enteric fever has shown the recent emergence and increase of MDR and XDR S . Typhi strains, resulting in a review of clinical guidelines to improve management of imported infections.
Infectious diseases (IDs) are life-threatening illnesses, which result from the spread of pathogenic microorganisms such as bacteria, viruses, fungi, and parasites. IDs are a major challenge for the healthcare systems around the world, leading to a wide variety of clinical manifestations and complications. Despite the capability of frontline-approved medications to partially prevent or mitigate the invasion and subsequent damage of IDs to host tissues and cells, problems such as drug resistance, insufficient efficacy, unpleasant side effects, and high expenses stand in the way of their beneficial applications. One strategy is to evaluate currently explored and available bioactive compounds as possible anti-microbial agents. The natural polyphenol curcumin has been postulated to possess various properties including anti-microbial activities. Studies have shown that it possess pleiotropic effects against bacterial- and parasitic-associating IDs including drug-resistant strains. Curcumin can also potentiate the efficacy of available anti-bacterial and anti-parasitic drugs in a synergistic fashion. In this review, we summarize the findings of these studies along with reported controversies of native curcumin and its analogues, alone and in combination, toward its application in future studies as a natural anti-bacterial and anti-parasitic agent.
Non-typhoidal Salmonella (NTS) is a common cause for self-limiting gastroenteritis, representing a public health concern globally. NTS is one of the leading causes of foodborne illnesses in China; however, the invasive infection caused by NTS is largely underappreciated. Here, we reported an NTS invasive infection caused by an infrequently reported serovar Telelkebir (13,23:d:e,n,z15) strain FJ001 in China, which carries antimicrobial-resistant genes [fosA7 and aac(6′)-Iaa] and typhoid-toxin genes (cdtB, pltA, and pltB). By conducting the whole genomic sequencing, we also investigated the relatedness of this strain with an additional 120 global contextual Salmonella enterica serovar Telelkebir (S. Telelkebir) isolates, and assessed the antimicrobial-resistant determinants and key virulence factors using the available genomic dataset. Notably, all 121 (100%) of the S. Telelkebir strains possessed the typhoid toxin genes cdtB, pltA, and pltB, and 58.67% (71/121) of S. Telelkebir harbored antimicrobial-resistant gene fosaA7. The study by core genome multilocus sequence typing (cgMLST) and core single-nucleotide polymorphism (SNP)-based phylogenomic analysis demonstrated that the S. Telelkebir isolates from different sources and locations clustered together. This suggests that regular international travels might increase the likelihood of rapid and extensive transmissions of potentially pathogenic bacteria. For the first time, our study revealed the antimicrobial resistance, virulence patterns, and genetic diversity of the serovar S. Telelkebir isolate in humans and similar isolates over the world. The present study also suggests that genomic investigation can facilitate surveillance and could offer added knowledge of a previously unknown threat with the unique combination of virulent and antimicrobial-resistant determinants.
Aims:
This study evaluated detection methods for Salmonella Typhi (S. Typhi) in the environment, to establish a novel pathway from field sampling to isolation of viable organisms and molecular confirmation from complex environmental samples, thus enabling environmental surveillance of typhoid.
Methods and results:
Multiple media were assessed using clinical isolates from the Public Health England's (PHE) Culture collection. The culture pathway selected consisted of a primary 2% bile broth and secondary Selenite F broth, followed by modified Chromogenic Agar for Salmonella Esterase (mCASE). A qPCR assay was adapted from a validated S. Typhi PCR panel for confirmation of isolates, with comparison to biochemical and serological tests showing good specificity. Sampling locations in Blantyre, Malawi were used to compare sampling methods. Viable S. Typhi were isolated from a mixture of trap and grab river water samples on six occasions.
Conclusions:
Culture of viable S. Typhi from environmental samples was possible using effective capture and culture techniques.
Significance and impact of study:
Whilst several studies have attempted to detect S. Typhi from the environment, this is the first successful attempt to isolate the organism from river water since the 1980's. Supplementing clinical data with environmental screening offers the potential for enhanced surveillance, which might inform interventions and assess vaccination programmes.
Typhoid fever was estimated to produce 17.8 million cases each year among low-and-middle-income countries of the world. This study aimed to identify the socio-environmental factors that influence care-seeking preferences for typhoid fever treatment among students of Secondary Schools. The study adopted a cross-sectional design guided by behavioural theories that employed quantitative methods of data collection. A multistage sampling technique was used to select five (5) schools from five wards in the study area. A total of 422 students were recruited for this study but only 417 questionnaires were correctly and completely analysed. A self-administered questionnaire was used for data collection and the data was analysed using, descriptive statistics, chart, mean, standard deviation and inferential statistics of correlation, and multiple regression. The respondents’ ages ranged from 10-19 years with a mean of 15.3 ± 1.7 years. Results demonstrated that the socio-environmental factors that influence the respondents’ health-seeking behaviour for typhoid treatment were the decision of parents on the type of treatment they can receive as well as the cost of the treatment The study further revealed that of the respondents who have had typhoid fever in their lifetime, less than half sought treatment in hospitals. This study recommends that good healthcare-seeking behaviour health promotion programmes should be targeted at parents since they are stakeholders in the healthcare-seeking decision-making of adolescents.
Introduction
Mucosal vaccines have several advantages over parenteral vaccines. They induce both systemic and mucosal antigen-specific immune responses, allow easy administration, and bypass the need for trained medical personnel.
Areas covered
Eye mucosa is a novel route of mucosal vaccine administration. Eyedrop vaccination induces systemic and mucosal immune responses similar to other forms of mucosal vaccines such as oral and intranasal vaccines.
Expert opinion
Eyedrop vaccines are free of serious adverse side effects like the infiltration of CNS by pathogens. Studies over the years have shown promising results for eyedrop vaccines against infectious agents like influenza virus, Salmonella typhi and Escherichia coli in animal models. Such efficacy and safety of eyedrop vaccination enable application of eyedrop vaccines against other infectious diseases as well as chronic diseases. In this review of published literature, we examine the mechanism, efficacy and safety of eyedrop vaccines and contemplate their role in times of a pandemic.
Background:
Children suffer the highest burden of the typhoid fever, with a considerable proportion shedding Salmonella Typhi in stool, potentially resulting in transmission of S Typhi.
Methods:
We enrolled 70 children with blood culture-confirmed typhoid fever (index cases), from 63 households, during community-based fever surveillance in India. The index cases and their household contacts were followed up with stool samples at multiple time points over 3 weeks and 1 week, respectively. S Typhi was detected using quantitative real-time polymerase chain reaction.
Results:
Fifteen of 70 (21.4%) children with culture-confirmed typhoid fever shed S Typhi in stool after onset of fever. Ten of 15 children shed S Typhi for a median of 11.5 (range, 3-61) days from the day of completion of antibiotics. Of 172 household contacts from 56 of the 63 index case households, 12 (7%) contacts in 11 (19.6%) households had S Typhi in stool. Five of the 12 contacts who were shedding S Typhi were asymptomatic, whereas 7 reported recent fever.
Conclusions:
One in 5 children with typhoid fever shed S Typhi, with shedding persisting even after antibiotics. One in 5 households had at least 1 contact of the child shedding S Typhi, highlighting potential concurrent typhoid infections in households in settings with poor water and sanitation.
Objectives
: Enteric fever is predominantly managed as an outpatient condition in endemic settings but there is little evidence to support this approach in non-endemic settings. This study aims to review the outcomes of outpatients treated for enteric fever at the Hospital of Tropical Diseases in London, UK.
Methods
: We conducted a retrospective analysis of all patients with confirmed enteric fever between August 2009 and September 2020. Demographic, clinical, laboratory and microbiological data were collected and compared between the inpatient and outpatient populations. Outcomes investigated were complicated enteric fever, treatment failure and relapse.
Results
: Overall, 93 patients (59% male, median age 31) were identified with blood and/or stool culture confirmed enteric fever and 49 (53%) of these were managed as outpatients. The commonest empirical treatment for outpatients was azithromycin (70%) and for inpatients was ceftriaxone (84%). Outpatients were more likely than inpatients to receive only one antibiotic (57% vs 19%, p <0.01) and receive a shorter duration of antibiotics (median 7 vs 11 days, p <0.01). There were no cases of complicated disease or relapse in either the inpatient or outpatient groups. There was one treatment failure in the outpatient group. Azithromycin was well-tolerated with no reported side effects.
Conclusions
: Our findings suggest that outpatient management of uncomplicated imported enteric fever is safe and effective with the use of oral azithromycin. Careful monitoring of patients is recommended as treatment failure can occur.
Salmonella enterica serotype Typhi (S. Typhi) causes typhoid fever and is responsible for an estimated nine million cases and 110,000 deaths globally per annum. Typhoid fever is endemic in areas where water, sanitation, and hygiene (WaSH) infrastructure is poor. Serious complications develop in approximately 10-15% of patients if left untreated and this is driven by inadequate diagnostic methods and the high burden of antibiotic resistant strains, complicating clinical management and ultimately prognosis. Asymptomatic chronic carriers, in addition to acutely infected patients, contribute to the continued transmission through the shedding of the organism in the feces. The high morbidity and mortality of typhoid fever in low and middle-income countries reinforces the need for an integrated control approach which may ultimately lead to elimination in the 21st century. Here we discuss the challenges faced for the elimination of the disease.
Some serovars of Salmonella are not or rare found to cause salmonellosis in human. In our clinic-based surveillance, three rare Salmonella 4,5,12:a:- strains were recovered from three patients with diarrhea. To explore their genetic and epidemiological characteristics and pathogenesis, we conducted whole-genome sequencing, in vitro invasion assays in mammalian cells, and in vivo virulence assays in an animal model. The three isolates had indistinguishable molecular patterns and similar genome sequences, and clustered together with an isolate from edible fish traded among countries. The isolates had biochemical reactions identical with those of Salmonella subspecies enterica but belonged to subspecies salamae according to genome phylogeny, revealing a new serovar, S. enterica subsp. II serovar 4,5,12:a:-. The strains contained multiple virulence genes, elicited temporary bacteremia and enteritidis and caused cell damage in the mouse liver and cecum. This study provides evidence that this new Salmonella salamae serovar can infect humans and cause clusters of cases, and whole-genome sequencing detection and surveillance of Salmonella can help to accurately define Salmonella classification and clonality, improve diagnosis, facilitate outbreak detection and aid in the source tracing of salmonellosis epidemics.
Salmonella enterica serovar Typhi (S. typhi) is an intracellular pathogen belonging to the Enterobacteriaceae family, where biofilm (aggregation and colonization of cells) formation is one of their advantageous traits. Salmonella typhi is the causative agent of typhoid fever in the human body and is exceptionally host specific. It is transmitted through the fecal–oral route by consuming contaminated food or water. This subspecies is quite intelligent to evade the innate detection and immune response of the host body, leading to systemic dissemination. Consequently, during the period of illness, the gallbladder becomes a harbor and may develop antibiotic resistance. Afterwards, they start contributing to the continuous damage of epithelium cells and make the host asymptomatic and potential carriers of this pathogen for an extended period. Statistically, almost 5% of infected people with Salmonella typhi become chronic carriers and are ready to contribute to future transmission by biofilm formation. Biofilm development is already recognized to link with pathogenicity and plays a crucial role in persistency within the human body. This review seeks to discuss some of the crucial factors related to biofilm development and its mechanism of interaction causing pathogenicity. Understanding the connections between these things will open up a new avenue for finding therapeutic approaches to combat pathogenicity.
In addition to being implicated in bacterial immunity and genome editing, the CRISPR-Cas system has recently been demonstrated to regulate endogenous gene expression and biofilm formation. While the function of individual cas genes in controlling Salmonella biofilm has been explored, the regulatory role of CRISPR arrays in biofilm is less studied.
Introduction. Fluoroquinolone (FQ) resistant Salmonella are classified as high priority pathogens by WHO. FQ resistance among Salmonella Typhi has emerged rapidly and is predominantly mediated by mutations in the topoisomerase genes gyrA , and parC . Mutations in GyrA result in classical FQ resistance (DCS-NAR) i.e. decreased susceptibility to ciprofloxacin (MIC of 0.12 to 0.5 µg ml ⁻¹ ) (DCS) and resistance to nalidixic acid (NAR). Previously a nalidixic acid disc test was proposed for detection of DCS. Recently isolates with non-classical FQ resistance caused by plasmid-mediated quinolone resistance (PMQR) and mutations in GyrB have emerged. These mechanisms also result in DCS but are nalidixic acid susceptible (NAS) and thus pose diagnostic challenges. CLSI and EUCAST have recommended use of 5 µg pefloxacin discs for detection of DCS in Salmonella .
Hypothesis. The CLSI and EUCAST recommendations for use of 5 µg pefloxacin for detection of DCS has not been validated on typhoidal Salmonella and resistance mediated by GyrB mutation in Salmonella species.
Aim. The aim of the present study was to validate the performance of the 5 µg pefloxacin discs to detect isolates of S . Typhi with DCS with special reference to GyrB mutations.
Methodology. A total of 180 clinical isolates of Salmonella Typhi (2005–2014) were investigated for genetic mechanisms of resistance. Zone diameters for nalidixic acid (30μg), ciprofloxacin (5μg) and pefloxacin (5µg) and minimum inhibitory concentration (MIC) for ciprofloxacin were determined using CLSI guidelines. Performance of the three discs was evaluated to detect FQ resistance in S . Typhi.
Results. Topoisomerase mutations in GyrB +/ ParC and GyrB were detected in 112 and 34 isolates respectively. Different mutations have a varied effect on the MIC for ciprofloxacin. The current breakpoints for susceptible (≤0.06 µg ml ⁻¹ ) and non-susceptible (≥0.125 µg ml ⁻¹ ), failed to detect all isolates with a resistance mechanism. Performance of both ciprofloxacin and pefloxacin discs were excellent compared to nalidixic acid in differentiating isolates with non-classical resistance mediated by GyrB from wild-type.
Conclusion. The pefloxacin disc can be used to detect FQ resistance among S . Typhi. This is the first report of validation of pefloxacin for detection of FQ resistance in S . Typhi mediated by GyrB mutation.
Salmonella spp. cause significant morbidity and mortality worldwide. Typhoidal spp. (e.g., S. Typhi) cause a systemic disease typically treated with antibiotics.
Typhoid toxin is an essential virulence factor for Salmonella Typhi, the cause of typhoid fever in humans. This toxin has an unusual biology in that it is produced by Salmonella Typhi only when located within host cells. Once synthesized, the toxin is secreted to the lumen of the Salmonella -containing vacuole from where it is transported to the extracellular space by vesicle carrier intermediates. Here we report the identification of the typhoid toxin sorting receptor and components of the cellular machinery that packages the toxin into vesicle carriers, and exports it to the extracellular space. We found that the cation-independent mannose-6-phosphate receptor serves as typhoid toxin sorting receptor and that the coat protein COPII and the GTPase Sar1 mediate its packaging into vesicle carriers. Formation of the typhoid toxin carriers requires the specific environment of the Salmonella Typhi-containing vacuole, which is determined by the activities of specific effectors of its type III protein secretion systems. We also found that Rab11B and its interacting protein Rip11 control the intracellular transport of the typhoid toxin carriers, and the SNARE proteins VAMP7, SNAP23, and Syntaxin 4 their fusion to the plasma membrane. Typhoid toxin's cooption of specific cellular machinery for its transport to the extracellular space illustrates the remarkable adaptation of an exotoxin to exert its function in the context of an intracellular pathogen.
Salmonella enterica serotype typhi is a gram-negative, rod-shaped bacterium, and has flagella with the human body as its only reservoir. Typhoid fever was found to cause 21.7 million illnesses and 216,000 fatalities worldwide in 2000, and the International Vaccine Institute estimated 11.9 million cases and 129,000 deaths in low- and middle-income countries in 2010. More than 10 million patients were infected with S. typhi each year and the mortality rate is associated with more than 0.1 million patients. Moreover, it is also associated with drug resistance globally which makes the disease more dreadful. Other than antibiotics, various flavonoids showed medicinal effects against many diseases including S. typhi infection. Flavonoids are a type of plant bioactive metabolite that have potential medicinal efficacy. The goal of this study was to see if certain flavonoids (ellagic acid, eriodictyol, and naringenin) could interact with the outer membrane of osmoporin (PDB ID: 3uu2) receptor in Salmonella and helps in inhibiting its growth. To look for probable ligand-receptor binding relationships, we used Pyrxmolecular docking software. The molecular docking results were analyzed using the Biovia discovery studio visualizer. The current study discovered that selected plant-based compounds interacted with an outer membrane of the osmoporin receptor, resulting in minimization of energy in the range of-6.6 to -7.8 Kcal/mol.
Resumen
Los géneros Salmonella y Yersinia están conformados por diversas especies que pueden condicionar cuadros clínicos a nivel gastrointestinal y sistémico. Salmonella presenta una gran variedad de serotipos capaces de infectar a animales y al ser humano. Se dividen en dos grupos según la clínica que producen, las salmonelas no tifoideas que originan cuadros gastrointestinales, aunque a veces producen afectación extraintestinal con especial relevancia en pacientes inmunosuprimidos o con patología cardiovascular; y los serotipos que producen fiebre tifoidea, caracterizada por fiebre elevada y afectación sistémica. Yersinia, al igual que el género anterior, presenta dos grupos en función de la clínica que desarrollan. Y. enterocolítica y Y. pseudotuberculosis causantes de enterocolitis con mayor prevalencia en países con clima frío. Pueden producir cuadros de adenitis mesentérica e ileítis terminal que se puede confundir con apendicitis aguda y, en un 10%-20% de los casos, producen secuelas postinfecciosas como el eritema nodoso y la artritis reactiva. Y. pestis es el agente causal de la peste, cuadro clínico de enorme gravedad, especialmente en su forma neumónica, que ha dado lugar en los últimos años a importantes brotes en países de África.
Background
Typhoid fever, a systemic infection caused by Salmonella enterica serovar Typhi, remains a considerable public health threat in impoverished regions within many low- and middle-income settings. However, we still lack a detailed understanding of the emergence, population structure, molecular mechanisms of antimicrobial resistance (AMR), and transmission dynamics of S . Typhi across many settings, particularly throughout the Asia-Pacific islands. Here we present a comprehensive whole genome sequence (WGS) based overview of S . Typhi populations circulating in Papua New Guinea (PNG) over 30 years.
Principle findings
Bioinformatic analysis of 86 S . Typhi isolates collected between 1980–2010 demonstrated that the population structure of PNG is dominated by a single genotype (2.1.7) that appears to have emerged in the Indonesian archipelago in the mid-twentieth century with minimal evidence of inter-country transmission. Genotypic and phenotypic data demonstrated that the PNG S . Typhi population appears to be susceptible to former first line drugs for treating typhoid fever (chloramphenicol, ampicillin and co-trimoxazole), as well as fluoroquinolones, third generation cephalosporins, and macrolides. PNG genotype 2.1.7 was genetically conserved, with very few deletions, and no evidence of plasmid or prophage acquisition. Genetic variation among this population was attributed to either single point mutations, or homologous recombination adjacent to repetitive ribosomal RNA operons.
Significance
Antimicrobials remain an effective option for the treatment of typhoid fever in PNG, along with other intervention strategies including improvements to water, sanitation and hygiene (WaSH) related infrastructure and potentially the introduction of Vi-conjugate vaccines. However, continued genomic surveillance is warranted to monitor for the emergence of AMR within local populations, or the introduction of AMR associated genotypes of S . Typhi in this setting.
While typhoid fever has largely been eliminated in high-income regions which have developed modern water, sanitation, and hygiene facilities, it remains a significant public health burden resulting in morbidity and mortality among millions of individuals in resource-constrained settings. Prevention and control efforts are needed that integrate several high-impact interventions targeting facilities and infrastructure, including those addressing improvements in sanitation, access to safe water, and planned urbanization, together with parallel efforts directed at effective strategies for use of typhoid conjugate vaccines (TCV). The use of TCVs is a critical tool with the potential of having a rapid impact on typhoid fever disease burden; their introduction will also serve as an important strategy to combat evolving antimicrobial resistance to currently available typhoid fever treatments. Well-designed epidemiological surveillance studies play a critical role in establishing the need for, and monitoring the impact of, typhoid fever control and prevention strategies implemented by public health authorities. Here, we present a perspective based on a narrative review of the impact of typhoid fever on morbidity and mortality in sub-Saharan Africa and discuss ongoing surveillance activities and the role of vaccination in prevention and control efforts.
During their co-evolution with pathogens, hosts acquired defensive health strategies that allow them to maintain their health or promote recovery when challenged with infections. The cooperative defense system is a largely unexplored branch of these evolved defense strategies. Cooperative defenses limit physiological damage and promote health without having a negative impact on a pathogen’s ability to survive and replicate within the host. Here, we review recent discoveries in the new field of cooperative defenses using the model pathogens Citrobacter rodentium and Salmonella enterica. We discuss not only host-encoded but also pathogen-encoded mechanisms of cooperative defenses. Cooperative defenses remain an untapped resource in clinical medicine. With a global pandemic exacerbated by a lack of vaccine access and a worldwide rise in antibiotic resistance, the study of cooperative defenses offers an opportunity to safeguard health in the face of pathogenic infection.
Background
Enteric fever is a systemic disease caused by Salmonella enterica serovar Typhi or Salmonella enterica serovar Paratyphi, characterized by high fever and abdominal pain. Most patients with enteric fever improve within a few days after antibiotic treatment. However, some patients do not recover as easily and develop fatal life-threatening complications, including intestinal hemorrhage. Lower gastrointestinal bleeding has been reported in 10% of cases. However, upper gastrointestinal bleeding has rarely been reported in patients with enteric fever. We present a case of gastric ulcer hemorrhage caused by enteric fever.
Case presentation
A 32-year-old woman, complaining of fever lasting four days and right upper quadrant pain and melena that started one day before admission, consulted our hospital. Abdominal computed tomography revealed mild hepatomegaly and gastroscopy revealed multiple active gastric ulcers with flat black hemorrhagic spots. The melena of the patient stopped on the third day. On the fifth admission day, she developed hematochezia. At that time, Salmonella enterica serovar Typhi was isolated from the blood culture. The antibiotic regimen was switched to ceftriaxone. Her hematochezia spontaneously resolved the following day. Finally, the patient was discharged on the 12th admission day without clinical symptoms. However, her fever recurred one month after discharge, and she was readmitted and Salmonella enterica serovar Typhi was confirmed again via blood culture. She was treated with ceftriaxone for one month, and was discharged without complications.
Conclusion
Our case showed that although rare, active gastric ulcers can develop in patients with enteric fever. Therefore, upper and lower gastrointestinal bleeding should be suspected in patients with enteric fever, especially showing relapsing bacteremia.
Consecutive exposures to different pathogens are highly prevalent and often alter the host immune response. However, it remains unknown how a secondary bacterial infection affects an ongoing adaptive immune response elicited against primary invading pathogens. We demonstrated that recruitment of Sca-1⁺ monocytes into lymphoid organs during Salmonella Typhimurium (STm) infection disrupted pre-existing germinal center (GC) reactions. GC responses induced by influenza, plasmodium, or commensals deteriorated following STm infection. GC disruption was independent of the direct bacterial interactions with B cells and instead was induced through recruitment of CCR2-dependent Sca-1⁺ monocytes into the lymphoid organs. GC collapse was associated with impaired cellular respiration and was dependent on TNFα and IFNγ, the latter of which was essential for Sca-1⁺ monocyte differentiation. Monocyte recruitment and GC disruption also occurred during LPS-supplemented vaccination and Listeria monocytogenes infection. Thus, systemic activation of the innate immune response upon severe bacterial infection is induced at the expense of antibody-mediated immunity.
A cross-sectional observational study was done on 180 fever patients to assess the diagnostic accuracy of rapid serological tests in early detection (<5 days of fever) of S. typhi and S. paratyphi in comparison to blood culture and Widal test Blood culture was positive in 58 (32.22%) cases. The diagnostic accuracy (<5 days of fever) of rapid antigen test, rapid antibody test, and Widal test was 45.56%, 42.22%, and 41.11% (p = 0.675) while sensitivity was 68.97%, 48.28%, and 46.55%, respectively. In conclusion, rapid antigen test holds moderately higher sensitivity in the first five days of fever as compared to rapid antibody and Widal tests. It is recommended that the antigen detection tests should be used for screening enteric fever in the first week of presentation.
The gut microbiome is not a silent ecosystem but exerts several physiological and immunological functions. For many decades, lactobacilli have been used as an effective therapy for treatment of several pathological conditions displaying an overall positive safety profile. The present article gives an account of updated information on pharmacological properties such as anti-fungal activity, anti-viral activity, Activity on vaginal pathogens, immunomodulatory activity, Cholesterol lowering activity and various other important properties. Because of blocking effect, selected probiotic lactobacilli may be used as biological preservative, so, the aim of this study was to present some data on lactobacillus as probiotic bacteria. Lactobacilli originally isolated from meat products are the best candidates as probiotic bacteria to improve the microbiological safety of these foods. Finally, we need to determine the adequate number of bacteria to be delivered in order to achieve the best clinical efficacy decreasing the risk of side effects.
Lay Summary
Enteric fever (EF) is an infection caused by the bacteria called Salmonella Typhi or Paratyphi. Infection is acquired through swallowing contaminated food or water. Most EF in England occurs in people returning from South Asia and other places where EF is common; catching EF in England is rare. The main symptom is fever, but stomach pain, diarrhoea, muscle aches, rash and other symptoms may occur. EF is diagnosed by culturing the bacteria from blood and/or stool in a microbiology laboratory.
EF usually responds well to antibiotic treatment. Depending on how unwell the individual is, antibiotics may be administered by mouth or by injection. Over the past several years, there has been an overall increase in resistance to antibiotics used to treat enteric fever, in all endemic areas. Additionally, since 2016, there has been an ongoing outbreak of drug-resistant EF in Pakistan. This infection is called extensively drug-resistant, or XDR, EF and only responds to a limited number of antibiotics.
Occasionally individuals develop complications of EF including confusion, bleeding, a hole in the gut or an infection of the bones or elsewhere. Some people may continue to carry the bacteria in their stool for a longtime following treatment for the initial illness. These people may need treatment with a longer course of antibiotics to eradicate infection.
Travellers can reduce their risk of acquiring EF by following safe food and water practices and by receiving the vaccine at least a few weeks before travel.
These guidelines aim to help doctors do the correct tests and treat patients for enteric fever in England but may also be useful to doctors and public health professionals in other similar countries.
Typhoid fever is caused by the bacteria Salmonella enterica subspecies enterica serovar Typhi (S. Typhi) and remains a significant health problem in many developing countries. Lack of adequate diagnostic capabilities has contributed greatly in making typhoid fever endemic in these regions. Reliable and inexpensive diagnostic tests are needed to improve the management of this disease burden. We evaluated the ability of staA, viaB and sopE genes to detect and differentiate between the three most prevalent Salmonella spp. in Kenya (S. Typhi, S. Typhimurium and S. Enteritidis) using conventional polymerase chain reaction (PCR). The staA primers and viaB primers were found to be specific only for the different strains of S. Typhi, producing PCR products of 585 bp and 540 bp, respectively. The sopE primers was demonstrated to be specific for all Salmonella spp. producing a 465 bp PCR product with no amplification with E. coli and S. boydii bacterial strains.
The impact of temperature and rainfall on the occurrence of typhoid/paratyphoid fever are not fully understood. This study aimed to characterize the effect of daily ambient temperature and total rainfall on the incidence of typhoid/paratyphoid in a sub-tropical climate city of China and to identify the vulnerable groups for disease prevention. Daily notified typhoid/paratyphoid fever cases and meteorological data for Taizhou from 2005 to 2013 were extracted from the National Notifiable Disease Surveillance System and the Meteorological Data Sharing Service System, respectively. Distributed lag nonlinear model was used to quantify the association between daily mean temperature, total rainfall, and typhoid/paratyphoid fever. Subgroup analyses by gender, age, and occupation were conducted to identify the vulnerable groups. A total of 625 typhoid fever cases and 1,353 paratyphoid fever cases were reported during the study period. An increased risk of typhoid fever was detected with the increase of temperature (Each 2°C rise resulted in 6%, 95% [confidence interval] CI: 2–10 increase in typhoid cases), while the increased risk was associated with the higher temperature for paratyphoid (the highest cumulative risk of temperature was 33.40 [95% CI: 12.23–91.19] at 33°C). After the onset of mild precipitation, the relative risk of typhoid fever increased in a short-lasting and with a 13–26 days delay, and the risk was no significant after the continuous increase of precipitation (the highest cumulative risk of rainfall was 24.96 [95% CI: 4.54–87.21] at 100 mm). Whereas the risk of paratyphoid fever was immediate and long lasting, and increase rapidly with the increase of rainfall (each 100 mm increase was associated with 26% increase in paratyphoid fever cases). Significant temperature-typhoid/paratyphoid fever and rainfall-typhoid/paratyphoid fever associations were found in both genders and those aged 0–4 years old, 15–60 years old, farmers, and children. Characterized with a lagged, nonlinear, and cumulative effect, high temperature and rainfall could increase the risk of typhoid/paratyphoid fever in regions with a subtropical climate. Public health interventions such as early warning and community health education should be taken to prevent the increased risk of typhoid/paratyphoid fever, especially for the vulnerable groups.
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.
Background:
Typhoid fever remains a major public health problem in India. Recently, the Surveillance for Enteric Fever in India program completed a multisite surveillance study. However, data on subnational variation in typhoid fever are needed to guide the introduction of the new typhoid conjugate vaccine in India.
Methods:
We applied a geospatial statistical model to estimate typhoid fever incidence across India, using data from 4 cohort studies and 6 hybrid surveillance sites from October 2017 to March 2020. We collected geocoded data from the Demographic and Health Survey in India as predictors of typhoid fever incidence. We used a log linear regression model to predict a primary outcome of typhoid incidence.
Results:
We estimated a national incidence of typhoid fever in India of 360 cases (95% confidence interval [CI], 297-494) per 100 000 person-years, with an annual estimate of 4.5 million cases (95% CI, 3.7-6.1 million) and 8930 deaths (95% CI, 7360-12 260), assuming a 0.2% case-fatality rate. We found substantial geographic variation of typhoid incidence across the country, with higher incidence in southwestern states and urban centers in the north.
Conclusions:
There is a large burden of typhoid fever in India with substantial heterogeneity across the country, with higher burden in urban centers.
While traditional laboratory techniques and animal models have provided valuable knowledge in discerning virulence mechanisms of enteric pathogens, the complexity of the human gastrointestinal tract has hindered our understanding of physiologically relevant, human-specific interactions and, thus, has significantly delayed successful vaccine development. The human intestinal organoid-derived epithelial monolayer (HIODEM) model closely recapitulates the diverse cell populations of the intestine, allowing for the study of human-specific infections.
Typhoid fever is common in developing countries. The licensed typhoid vaccines confer only about 70 percent immunity, do not protect young children, and are not used for routine vaccination. A newly devised conjugate of the capsular polysaccharide of Salmonella typhi, Vi, bound to nontoxic recombinant Pseudomonas aeruginosa exotoxin A (rEPA), has enhanced immunogenicity in adults and in children 5 to 14 years old and has elicited a booster response in children 2 to 4 years old.
In a double-blind, randomized trial, we evaluated the safety, immunogenicity, and efficacy of the Vi-rEPA vaccine in children two to five years old in 16 communes in Dong Thap Province, Vietnam. Each of the 11,091 children received two injections six weeks apart of either Vi-rEPA or a saline placebo. Cases of typhoid, diagnosed by the isolation of S. typhi from blood cultures after 3 or more days of fever (a temperature of 37.5 degrees C or higher), were identified by active surveillance over a period of 27 months. We estimated efficacy by comparing the attack rate of typhoid in the vaccine group with that in the placebo group.
S. typhi was isolated from 4 of the 5525 children who were fully vaccinated with Vi-rEPA and from 47 of the 5566 children who received both injections of placebo (efficacy, 91.5 percent; 95 percent confidence interval, 77.1 to 96.6; P<0.001). Among the 771 children who received only one injection, there was 1 case of typhoid in the vaccine group and 8 cases in the placebo group. Cases were distributed evenly among all age groups and throughout the study period. No serious adverse reactions were observed. In all 36 children studied four weeks after the second injection of the vaccine, levels of serum IgG Vi antibodies had increased by a factor of 10 or more.
The Vi-rEPA conjugate typhoid vaccine is safe and immunogenic and has more than 90 percent efficacy in children two to five years old. The antibody responses and the efficacy suggest that this vaccine should be at least as protective in persons who are more than five years old.
Detection of Salmonella typhi in blood by culture of the mononuclear cell-platelet layer was compared with other methods currently used for the diagnosis of typhoid fever. Colonies of S. typhi were present in all mononuclear cell-platelet layer-positive cultures within 18 h of plating and were identified within an additional 10 min by a coagglutination technique. In contrast, identification of all positive cultures by conventional blood culture required 3 days.
Typhoid fever is an important endemic health problem in Santiago, Chile. Its incidence has more than doubled in recent years, during which access to potable water and sewage disposal in the home became almost universal in the city. A matched case-control study was carried out to identify risk factors and vehicles of transmission of paediatric typhoid fever; 81 children in the 3-14-years age group with typhoid fever were compared with controls, matched with respect to age, sex, and neighbourhood. It was found that case children more frequently bought lunch at school and shared food with classmates. Also, case children more often consumed flavoured ices bought outside the home; none of 41 other food items considered in the study was associated with a higher risk of typhoid fever. Only two food handlers for cases and one for controls were positive for Salmonella typhi, indicating that persons preparing food solely for their own family were not the main source of S. typhi infection. Rather, the risk factors identified in this study are consistent with the hypothesis that paediatric endemic typhoid fever in Santiago is largely spread by consumption of food-stuffs that are prepared outside the individual's home and are shared with or sold to children.
In 1992 it was decided to re-evaluate the Widal slide agglutination test as a rapid diagnostic test for typhoid fever in Papua New Guinea. This was in response to an apparent increase in the number of false positive Widal slide agglutinations occurring using an O cut-off titre greater than or equal to 40 which was previously shown to be appropriate in 1987. The results of the re-evaluation indicated that the Widal test using a diagnostic cut-off titre of > or = 40 lacked specificity and was no longer appropriate for this population. A new O antibody titre of > or = 160 was recommended as a diagnostic titre for typhoid fever in PNG. The fall in the specificity of the Widal slide agglutination test over the five-year period between the initial assessment and the re-evaluation is due to an increase in general population antibody levels caused by the changing pattern of typhoid in the community. Before 1987 typhoid fever occurred as sporadic, isolated outbreaks and most people living in the highlands of PNG were immunologically naive. By 1992 typhoid fever had become a well-established endemic disease and many more people had been exposed to Salmonella typhi and as a result developed antibodies. We have been able to demonstrate clearly a remarkable change in the immune status of the community, in which the proportion of healthy individuals with a Widal tube O agglutination titre of 40 or more rose from 0 to 56% in the short span of five years.(ABSTRACT TRUNCATED AT 250 WORDS)
A polymerase chain reaction (PCR)-based test was developed for the detection of Salmonella typhi in the blood specimens from patients with typhoid fever. Two pairs of oligonucleotide primers were designed to amplify a 343-bp fragment of the flagellin gene of S. typhi. Amplified products were analyzed by agarose gel electrophoresis and Southern blot hybridization by using a 32P-labeled 40-base probe internal to the amplified DNA. The nested PCR with two pairs of primers could detect 10 organisms of S. typhi as determined by serial dilutions of DNA from S. typhi. The peripheral mononuclear cells from 11 of 12 patients with typhoid fever confirmed by blood culture were positive for DNA fragment of the flagellin gene of S. typhi, whereas 10 blood specimens of patients with other febrile diseases were negative. With the nested PCR, S. typhi DNAs were detected from blood specimens of four patients with suspected typhoid fever on the basis of clinical features but with negative cultures. We suggest that the PCR technique could be used as a novel diagnostic method of typhoid fever, particularly in culture-negative cases.
Eighteen children with bacteriologically confirmed severe typhoid fever were initially treated intravenously with ciprofloxacin
(10 mg/kg of body weight per day). Clinical cure with eradication of multiresistant Salmonella typhi infection was observed
in 17 patients (94.4%; 95% confidence interval [CI], 84 to 100%). Children regained normal consciousness within an average
of 2 days (95% CI, 1.8 to 2.2 days). The temperatures of the children returned to normal within 3.3 days (95% CI, 3.1 to 3.5
days). Complications were not observed during the hospital stay or a 3-month follow-up period. Relapse and carrier state were
also not encountered during the follow-up period.
Sir, Ciprofloxacin is now the first-line drug for the treatment of enteric fever and at the PHLS Laboratory of Enteric Pathogens (LEP) all strains of Salmonella enterica sero- types Typhi and Paratyphi A, B and C are tested for resist- ance to ciprofloxacin using an agar dilution breakpoint method.1 The levels of ciprofloxacin incorporated into the media are 0.125 and 1 mg/L. Strains resistant at 0.125 mg/L but susceptible at 1 mg/L are regarded as exhibiting low- level resistance or decreased susceptibility to this anti- microbial (CpL), whereas those resistant at 1 mg/L are regarded as showing high-level resistance (CpH). Since 1994, an increasing number of strains of S. Typhi from patients in the UK have exhibited CpL, often in addi- tion to resistance to chloramphenicol, ampicillin and tri- methoprim. In 1999, 23% of 179 strains exhibited CpL, of which 59% were also resistant to chloramphenicol, ampi- cillin and trimethoprim.2 In 2000 the proportion of CpL iso- lates had again increased, with 36% of 194 S. Typhi isolates exhibiting such resistance. Of these, 52% were additionally resistant to chloramphenicol, ampicillin and trimethoprim. CpL was particularly common in strains of Vi-phage type E1, but was also identified in five other phage types, includ- ing A, E9, UVS, DVS and Vi-negative. A similar increase in CpL isolates has also been observed in S. Paratyphi A, with 33 of the 148 (22%) strains isolated in 2000 exhibiting CpL. Of these CpL isolates, 5% were also resistant to chloramphenicol, ampicillin and trimethoprim. In contrast, in 1999 only 12 of 162 (7%) isolates exhibited decreased susceptibility to ciprofloxacin. None of these iso- lates was resistant to other antimicrobials. When studied by breakpoint with doubling concentrations of ciprofloxacin incorporated into the agar, the MICs for isolates of both CpL S. Typhi and S. Paratyphi A ranged from 0.25 to 1 mg/L. The majority of such strains also exhibited high-level resistance to nalidixic acid (MIC > 256 mg/L).2 As yet no strains of either serotype with CpH have been identified. The most common method of testing for resistance to ciprofloxacin in clinical laboratories is by disc diffusion, using discs with concentrations of ciprofloxacin ranging from 1 to 5 mg/L. As a consequence of this, in several cases decreased susceptibility to ciprofloxacin has not been detected and treatment failures have been reported.2,3 This has been particularly evident when nalidixic acid has not been included in the antimicrobials tested. Since 1999, the policy of the LEP has been to use the Etest for the deter- mination of levels of resistance to ciprofloxacin in strains of S. Typhi and S. Paratyphi A resistant to nalidixic acid and with resistance to ciprofloxacin at 0.125 mg/L by break- point. A total of 81 strains of S. Typhi (30 in 1999, 51 in 2000) and 34 strains of S. Paratyphi A (eight in 1999, 26 in 2000) with CpL have now been studied by this method (Table). The results are interesting in that they demon- strate a substantial difference in MIC range between the two serotypes, with the most common MIC for S. Typhi being 0.25 mg/L and that for S. Paratyphi A being 0.5 mg/L. The primary mechanism of resistance to nalidixic acid and
Strains of Salmonella typhi which are resistant to the three first-line antibiotics, chloramphenicol, trimethoprim-sulphamethoxazole and amoxycillin, are increasingly prevalent in tropical countries. These strains retain sensitivity both to the fluoroquinolones and to the third-generation cephalosporins in vitro, although therapeutic responses following fluoroquinolone treatment are superior. In studies involving over 300 adults and children in Viet Nam with uncomplicated multidrug-resistant typhoid fever treatment, 3-5 day courses of oral ofloxacin or fleroxacin gave cure rates of between 96 and 100% and were well tolerated. A short course of fluoroquinolones may become the treatment of choice for enteric fever in areas where multidrug-resistant strains of S. typhi are prevalent.
(C) Lippincott-Raven Publishers.
To identify risk factors for typhoid fever in Semarang city and its surroundings, 75 culture-proven typhoid fever patients discharged 2 weeks earlier from hospital and 75 controls were studied. Control subjects were neighbours of cases with no history of typhoid fever, not family members, randomly selected and matched for gender and age. Both cases and controls were interviewed at home by the same trained interviewer using a standardized questionnaire. A structured observation of their living environment inside and outside the house was performed during the visit and home drinking water samples were tested bacteriologically. Univariate analysis showed the following risk factors for typhoid fever: never or rarely washing hands before eating (OR=3.28; 95% CI=1.41–7.65); eating outdoors at least once a week (OR=3.00; 95% CI=1.09–8.25); eating outdoors at a street food stall or mobile food vendor (OR=3.86; 95% CI=1.30–11.48); consuming ice cubes in beverage in the 2-week period before getting ill (OR=3.00, 95% CI=1.09–8.25) and buying ice cubes from a street vendor (OR=5.82; 95% CI=1.69–20.12). Water quality and living environment of cases were worse than that of controls, e.g. cases less often used clean water for taking a bath (OR=6.50; 95% CI= 1.47–28.80), for brushing teeth (OR=4.33; 95% CI=1.25–15.20) and for drinking (OR=3.67; 95% CI=1.02–13.14). Cases tended to live in houses without water supply from the municipal network (OR=11.00; 95% CI=1.42–85.2), with open sewers (OR=2.80; 95% CI=1.0–7.77) and without tiles in the kitchen (OR=2.67; 95% CI=1.04–6.81). Multivariate analysis showed that living in a house without water supply from the municipal network (OR=29.18; 95% CI=2.12–400.8) and with open sewers (OR=7.19; 95% CI=1.33–38.82) was associated with typhoid fever. Never or rarely washing hands before eating (OR=3.97; 95% CI=1.22–12.93) and being unemployed or having a part-time job (OR=31.3; 95% CI=3.08–317.4) also were risk factors. In this population typhoid fever was associated with poor housing and inadequate food and personal hygiene.
The recovery of Salmonella typhi from blood, rectal swab, urine, bone-marrow, and rose spots was compared in 62 patients with typhoid fever, most of whom had received some antibiotic therapy before presentation. S. typhi was isolated from culture of bone-marrow in 56 patients (90%); in contrast, S. typhi was recovered from blood in only 25 (40%), from stool in 23 (37%), and urine in 4 (7%). S. typhi was isolated from 24 (63%) of 38 patients who had rose-spot cultures. If culture sites had been limited to blood, stool, and urine, the bacteriological diagnosis would have been missed in 24 patients.
Patients with typhoid fever were studied to determine whether disseminated intravascular coagulation (DIC), circulating bacteria, and endotoxemia were responsible for the signs and symptoms of their illnesses. Coagulation tests in 28 patients detected thrombocytopenia in 17, hypofibrinogenemia in nine, and elevated titers of fibrinogen-related antigens in 20. Repeated testing during convalescence showed a return toward normal values. Intestinal bleeding, however, did not correlate with abnormalities of coagulation tests. Thus, DIC occurred commonly but appeared to be a subclinical event in these patients. In 25 patients with positive blood cultures for Salmonella typhi, quantitative cultures detected from less than 10 to 9 x 10(2) bacteria/ml. Limulus tests for endotoxin in plasma were negative in all 21 patients tested. These results indicated that the concentrations of circulating bacteria and endotoxin in typhoid fever are lower than in other Gram-negative bacterial infections and suggested that circulating bacteria and endotoxin do not play a major role in the pathogenesis of typhoid fever.
Until the last few years, chloramphenicol was recognized positively as the drug of choice in the treatment of acute typhoid fever. Its hematoxicity, as well as the recently observed epidemic and the present endemic occurrence of S. typhi strains with R-factor-mediated resistance to chloramphenicol in Mexico, India and South-EAst Asia, render the clinical evaluation of new antibacterial agents extremely important. By means of a literature review on controlled comparative trials, the value of thiamphenicol, ampicillin, amoxycillin, furazolidone and co-trimoxazole as alternative drugs for the treatment of acute typhoid fever is examined. Co-trimoxazole seems to be the drug of choice in the treatment of acute typhoid fever. For the treatment of the chronic typhoid carrier ampicillin is most frequently used, but amoxycillin and co-trimoxazole seem to be just as effective.
Sixteen multiple drug resistant strains of Salmonella typhi belonging to Vi-phage types E1 (14) and O (2) and isolated in Southeast India in 1991 were characterized. All strains were resistant to chloramphenicol and the majority to trimethoprim and ampicillin. In all strains these resistances were encoded by plasmids of the H1 incompatibility group with molecular weights ranging from 110 to 120 megadaltons. Physicians in European countries should be aware that treatment may fail if patients with typhoid fever who have recently returned from the Indian sub-continent are given first-line treatment with chloramphenicol, trimethoprim or ampicillin. With the possible exception of young children, ciprofloxacin is currently the best choice for treatment of such patients.
A previously healthy breast-fed baby was admitted at 10 days of age to a hospital in the north of Pakistan with diarrhoea and fever. He was treated for suspected sepsis with intravenous cefotaxime and tobramycin. Cultures of blood and faeces at that time proved negative. At 12 days of age, seizures began and examination of CSF revealed evidence of pyogenic meningitis but bacteria were neither seen microscopically nor isolated in culture. Ceftazidime was substituted for cefotaxime and carbenicillin was given also. Since the baby's condition continued to deteriorate with persistent fever, vomiting and recurrent seizures, he was transferred to the Aga Khan University Hospital, Karachi. Examination of CSF there confirmed the diagnosis of pyogenic meningitis and revealed Gram-negative bacteria. Cultures of CSF and faeces yielded Salmonella paratyphi A but the blood culture was negative. The isolate was found to be multiple antimicrobially resistant but sensitive to ciprofloxacin. Treatment with this drug was therefore started 3 days after the baby's admission to the Aga Khan Hospital. Within 36 h, improvement was observed. From then onwards, the baby made a progressive recovery and was healthy when seen at 7 months of age.
When tested under conditions of moderate transmission of typhoid fever, a liquid formulation of the oral typhoid fever vaccine Ty21a had a protective efficacy of 96% in Egypt, and an enteric coated capsule formulation had an efficacy of 67% in Chile. We compared the two formulations under conditions of intense transmission of typhoid fever in Indonesia in a randomised, double-blind trial. 20,543 subjects (age range 3-44 years) received either three doses of enteric coated capsules containing placebo or live Ty21a, or three doses of lyophilised placebo or live Ty21a reconstituted with phosphate buffer. During 30 months of follow-up, the rate of blood-culture-positive typhoid fever among controls was 810/100,000 per year. Rates of typhoid fever were 379/100,000 per year for subjects who received the liquid formulation of vaccine and 468/100,000 per year for subjects who received enteric coated capsules. The protective efficacies of the liquid and enteric coated formulations were 53% and 42%, respectively. Neither formulation protected against infection with Salmonella paratyphi A. No major side-effects were noted, but the overall incidence of side-effects was greater in the vaccine groups. Under conditions of intense transmission, Ty21a protected against typhoid fever; however, because Ty21a will not protect all individuals, there is a need for additional approaches to prevent the disease.
Eight cases of typhoid and paratyphoid fever were identified during a 4-year period in a cohort of 117 patients who were positive for human immunodeficiency virus in Lima, Peru. Asymptomatic patients with human immunodeficiency virus infection and patients with the lymphadenopathy syndrome had a typical clinical presentation and response to therapy. Patients with the acquired immunodeficiency syndrome who were culture positive for Salmonella typhi or Salmonella paratyphi presented with fulminant diarrhea and/or colitis; the two patients for whom at least 2 months of follow-up were available relapsed. In our cohort there were 0.06 cases of typhoid or paratyphoid per patient year of observation; this rate is approximately 60 times that in the general population in Lima, and 25 times that in the 15- to 35-year-old age group. Our data indicate that patients who are positive for human immunodeficiency virus are at significantly increased risk for infection with S typhi and S paratyphi, and suggest that the clinical presentation of these diseases in patients with the acquired immunodeficiency syndrome differs from that seen immunocompetent hosts.
Features of typhoid fever were correlated with age and gender through a review of the charts of 552 hospitalized culture-positive
patients with diarrhea in Bangladesh. Seizures occurred more frequently in children from birth through 10 years of age (5%–11%)
and pneumonia more frequently in children from birth through 5 years of age (8%–15%) than in older age groups (P < .O5), whereas intestinal perforation occurred more frequently in patients ⩾11 years of age (5%–25%) than in younger age
groups (P < .05). Compared with older age groups, children from birth through 10 years of age were more anemic, those from birth through
5 years of age had a higher mean white blood cell count, and those from birth through 1 year of age had a lower mean blood
carbon dioxide content (all P < .05). Female patients were more severely anemic than male patients (P < .O5). The case-fatality rate was 4.3% overall, with the highest rates for children from birth through 1 year of age (11%)and
adults ⩾31 years of age (10%). Female patients had a higher case-fatality rate (6%) than male patients (3%), although the
difference was not significant (P >.05). Death was independently associated with seizures, intestinal perforation, pneumonia, and delirium or coma. These results
indicated that the patients with typhoid fever who were at highest risk of complications and death were children from birth
through 1 year of age and adults ⩾31 years of age.
We investigated the effect of hydrocortisone on mortality and complications in chloramphenicol-treated severe typhoid fever (STF) in Goroka, Papua New Guinea. Of 374 culture-positive patients, 146 formed a retrospective comparison group, of whom 41 had STF. Of 228 patients in the intervention group, 58 had STF. Patients without STF had low mortality (2.5%) with standard treatment. In the intervention group, hydrocortisone was used in two dosage schedules, 100 mg for 12 doses (23 patients) and 400 mg for 12 doses (23 patients). There was no difference in mortality between steroid-treated and comparison STF patients (44.8% versus 43.9%) or in complications, and we conclude that moderate doses of steroids are not beneficial in severe typhoid fever.
We report the recovery of Salmonella typhi that acquired resistance to ampicillin, chloramphenicol, trimethoprim-sulfamethoxazole,
and gentamicin subsequent to multiple antibiotic therapy. Escherichia coli and Klebsiella pneumoniae isolates which were recovered
from the same stool sample displayed identical resistance patterns. Agarose gel electrophoresis revealed that S. typhi and
laboratory-derived transconjugants contained a high-molecular-weight plasmid present in the resistant intestinal bacteria.
Three doses, given within one week, of Ty21a attenuated Salmonella typhi oral vaccine in an enteric-coated formulation provided 67% efficacy for at least 3 years in a randomised, placebo-controlled field trial involving 109,000 schoolchildren in Santiago, Chile. Increasing the interval between doses to twenty-one days did not enhance protection. Significantly less protection followed administration of vaccine in gelatin capsules with sodium bicarbonate. Ty21a provides the same level of protection as the heat/phenol-inactivated whole cell parenteral vaccine but differs in not causing adverse reactions. Ty21a may now be regarded as a practical public health tool.
The protective efficacy against typhoid fever of a single intramuscular injection of 25 micrograms of the Vi capsular polysaccharide (CPS) was assessed in a randomised double-blind controlled trial. Vaccination of 11,384 children was followed by 21 months' surveillance. 47 blood-culture-proven cases of typhoid occurred in children who received meningococcal A + C CPS vaccine and 19 cases in those vaccinated with Vi CPS. Protective efficacy was 60% calculated from the day of vaccination and 64% from 6 weeks after vaccination. Surveillance also included 11,691 unvaccinated children; 173 cases occurred in this group. Protective efficacy in relation to the unvaccinated group was 77.4% and 81.0% after 21 months, calculated immediately and 6 weeks after vaccination, respectively. Vaccination was associated with minimum local side-effects, and an increase in anti-Vi antibodies occurred, as measured by radioimmunoassay and enzyme-linked immunosorbent assay. Antibody levels remained significantly raised at 6 and 12 months post vaccination. Vi CPS is thus a safe and effective means of typhoid vaccination.
In spite of extensive DNA homology among IncHI1 plasmids, ApaI and XbaI restriction digests of plasmids from Peruvian Salmonella
typhi varied considerably from other IncHI1 plasmids isolated previously. IncHI1 plasmids appear to be undergoing a process
of modular evolution, probably by sequential acquisition of resistance determinants.
We compared the sensitivities of bone marrow aspirate culture (BMAC), 3 ml 1:4 and 8 ml 1:10 blood-to-broth ratio blood cultures (BC), 8 ml streptokinase clot culture (STKCC) and rectal swab culture (RSC) for isolating Salmonella typhi and S. paratyphi A from 61 patients with typhoid or paratyphoid fever in Jakarta, Indonesia. BMAC (92%) was significantly more sensitive than 8 ml BC (62%), 8 ml STKCC (51%), 3 ml BC (44%), RSC (56%) and the 19 ml combination of all three BC methods (71%). The combination of the three BC methods and RSC had an isolation rate of 87%. In Jakarta the diagnosis of typhoid fever cannot be confidently excluded unless a BMAC is done.
Fourteen cases of typhoid fever complicating pregnancy are presented. The diagnosis was confirmed by blood cultures in 13 patients and by a rising Widal titer in one. Stool cultures were positive in only two out of five patients; urine cultures in 12 patients and cervical cultures in five patients were all negative. The clinical presentation was similar to the description in older reports, except for the absence of relative bradycardia. Hypothermic response to antipyretics was frequently observed. Patients were treated with either chloramphenicol, ampicillin, or amoxicillin, with satisfactory response. Typhoid fever diagnosed in the latter part of the second trimester and third trimester and treated early did not seem to alter the neonatal outcome.
In trials in Chile we were able to obtain a cure rate of only 58% (15 of 26 chronic carriers) after administering amoxicillin (6 g/d) and probenecid for 28 d. In an effort to identify an alternative antimicrobial agent that could be administered orally, we treated 12 chronic S. typhi carriers with ciprofloxacin (Miles Pharmaceuticals, West Haven, Conn), a newly described quinoline-carboxylic acid derivative. Ciprofloxacin has excellent in vitro activity against S. typhi, appears to be efficacious in treatment of acute typhoid fever, and is known to have good biliary penetration.
The number of cases of typhoid fever in Bangkok, Thailand, began to increase sharply in 1974 and peaked in 1976. In 1977,
as part of a national typhoid immunization program, Thai schoolchildren aged seven to 12 years began to receive annually a
single 0.25-ml subcutaneous dose (2.5 × 108 organisms) of a heat/phenol-inactivated typhoid vaccine. Isolations of Salmonella typhi in Bangkok decreased from 880 (4.6% of all blood cultures) in 1976 to 54 (0.3% of all blood cultures) in 1985. The case ratio
of S. typhi to Salmonella paratyphi A infection declined from 4.1:1 before the epidemic (1970–1973) to 0.9:1 after the epidemic (1984–1985), and the proportion
of cases of typhoid fever occurring among children aged seven to 12 years significantly decreased from 30% to 10%. During
the same periods S. paratyphi A isolation rates did not significantly decrease (in terms of either total number or percentage of cases) in school-aged
children. Thus, mass vaccination of schoolchildren in Thailand with the heat-inactivated typhoid vaccine has been closely
associated with a sharp decline in typhoid fever in Bangkok during an epidemic and with continuous control after the epidemic.
We conducted a pilot study followed by a large clinical trial in Nepal of the use of the capsular polysaccharide of Salmonella typhi (Vi) as a vaccine to prevent typhoid fever. In the pilot study, involving 274 Nepalese, there were no significant side effects of the Vi vaccine; about 75 percent responded with a rise in serum antibodies of fourfold or more. In the clinical trial, residents of five villages were given intramuscular injections of either Vi or, as a control, pneumococcus vaccine dispensed in coded, randomly arranged, single-dose syringes. There were 6907 participants, of whom 6438 were members of the target population (5 to 44 years of age); each was visited every two days. Those with temperatures of 37.8 degrees C or higher for three consecutive days were examined and asked to give blood for culture. Typhoid was diagnosed as either blood culture-positive or clinically suspected on the basis of bradycardia, splenomegaly, and fever, with a negative blood culture. Seventeen months after vaccination, the codes were broken for the 71 patients meeting the criteria for either culture-positive or clinically suspected typhoid. The attack rate of typhoid was 16.2 per 1000 among the controls and 4.1 per 1000 among those immunized with Vi (P less than 0.00001). The efficacy of Vi was 72 percent in the culture-positive cases, 80 percent in the clinically suspected cases, and 75 percent in the two groups combined. These data provide evidence that Vi antibodies confer protection against typhoid. Surveillance continues to determine the duration of Vi-induced immunity.
The appropriate therapy for intestinal perforation in typhoid fever has been controversial since the late 1880s. Around the
turn of the century, surgery became the established mode of therapy, with a mortality of 69% based on 166 patients in the
English-language medical literature, and continued to be the preferred treatment until the advent of chloramphenicol in 1948.
At this time the surgical mortality was ∼50%. Following the recovery of a few patients with perforation treated only with
antimicrobial agents (six initially, then eventually 22), nonsurgical therapy became the accepted mode of treatment. This
change was never justified and this review demonstrates this. Appropriate therapy is virtually always surgical, usually consisting
of simple closure and irrigation. Chloramphenicol alone is inadequate antimicrobial therapy in a patient with perforation
and must be supplemented by other antimicrobials directed against enteric aerobic gram-negative bacilli and enteric anaerobes.
The relative efficacy of cultures made from duodenal contents (obtained by string capsules), bone marrow, blood and rectal swab was compared in 118 pediatric patients, 2 to 13 years old with suspected typhoid fever. Only 47% of children 2 to 6 years old tolerated the string device, as compared with 89% in children 7 to 13 years old (P less than 0.05). The four culture techniques were performed and at least one was positive for Salmonella typhi in 43 patients. Bone marrow cultures were positive in 84% of the confirmed cases, a sensitivity significantly greater than for duodenal contents (42%), blood (44%) and stool (65%) cultures. Higher recovery rates for blood cultures were found during the first week of illness than later (70 vs. 22%). Bone marrow cultures remain the most effective method for the recovery of S. typhi. Stool cultures appear to be more effective in children than in adults. Duodenal contents cultures offer little advantage in young (2 to 6 years old) children.
This article has no abstract; the first 100 words appear below.
Contribution of Bacterial Endotoxin Endotoxin is obviously an important component of any gram-negative rod such as the typhoid bacillus. Vi antigen appears important in enhancing human virulence of typhoid strains. It is not as simple to define the importance of endotoxin since this substance has many biologic and pharmacologic activities. Attempts were made in the course of these investigations to gather information on the role of purified endotoxin in the pathogenesis of typhoid fever by quantitating the response to endotoxin's pyrogenic activity in volunteers with and without typhoid fever. When 0.25 µg of a purified endotoxin from S. typhosa was . . .
*From the Division of Infectious Diseases, University of Maryland School of Medicine (address reprint requests to Dr. Hornick at the Division of Infectious Diseases, University of Maryland School of Medicine, 29 S. Greene St., Baltimore, Md. 21201).
Supported by a contract (DA-49–193-MD-2867) with the Department of the Army and in part by a grant-in-aid from the World Health Organization.
The conditions attendant to volunteer studies as outlined in the Declaration of Helsinki were adhered to in these investigations. Initial peer review and approval for these studies was given unanimously by members of the Armed Forces Epidemiological Board. Subsequently, annual reviews were performed by the various commissions of the Board. Intramural approval was achieved by peer-group review. Since the Public Health Service requirement in 1966 for the establishment of volunteer committees, protocols have been approved by this committee at the University of Maryland School of Medicine.
Volunteers in these studies were informed inmates at the Maryland House of Correction. Each was asked to participate after having the nature of the study explained. No coercion was used, and each man was free to withdraw at any time. The willingness of these men to volunteer for subsequent studies and their repeated requests to enter these and similar infectious disease studies during the past 10 years attests to the acceptability of the program. This excellent co-operation is greatly appreciated and has been publicly acknowledged. The officials of the Maryland Prison System have been extremely helpful in the conduct of the study. Many fellows, nurses, technicians and secretaries have given invaluable assistance, and their aid is gratefully acknowledged.
This article has no abstract; the first 100 words appear below.
TYPHOID fever is a disease unique to man. No other animal species acquires an illness simulating typhoid fever after oral ingestion of the organism. This lack of a suitable experimental animal has hindered the acquisition of knowledge on pathogenesis and control. This presentation will summarize the experience gained in the study of healthy volunteers infected with typhoid bacilli. The purpose of these ongoing investigations has been to develop better methods of prevention and control of disease. The primary objective has been the quantitative evaluation of experimental and conventional vaccines. Such studies have permitted a careful analysis of pathogenesis. Typhoid vaccine . . .
*From the Division of Infectious Diseases, University of Maryland School of Medicine (address reprint requests to Dr. Hornick at the Division of Infectious Diseases, University of Maryland School of Medicine, 29 S. Greene St., Baltimore, Md. 21201).
Supported by a contract (DA-49–193-MD-2867) with the Department of the Army and in part by a grant-in-aid from the World Health Organization.
A passive haemagglutination assay measuring antibody to highly purified Vi antigen, known to be sensitive and specific for the detection of chronic Salmonella typhi carriers in a non-endemic area, was assessed in an endemic area. A reciprocal serum Vi antibody titre of 160 was found to have a sensitivity of 75%, specificity of 92%, and a high predictive value in screening for chronic S typhi carriers in high-risk population group (eg, women over 40 years). This simple assay can screen for chronic S typhi carriers even in areas where typhoid fever is highly endemic.
We compared high-dose dexamethasone (initial dose, 3 mg per kilogram of body weight) with placebo in a randomized, double-blind trial involving 38 patients with culture-positive, specifically defined severe typhoid fever. The patients in the two treatment groups ranged in age from 5 to 54 and were comparable at the outset. All patients received chloramphenicol. The case-fatality rate of 10 per cent (2 of 20 patients) in the dexamethasone group was significantly lower than the fatality rate of 55.6 per cent (10 of 18) in the placebo group (P = 0.003). There was no significant difference in the incidence of complications among the survivors in either group. Delirium, obtundation, and stupor were grave prognostic signs that were useful for predicting which patients were at high risk of dying before they became comatose or went into shock. Dexamethasone is unnecessary for most patients with typhoid but is recommended for all patients with suspected typhoid fever who are delirious, obtunded, stuporous, comatose, or in shock.
Blood cultures were systematically performed in children under 2 years of age with fever who were seen at 2 health centers in Santiago Chile during the peak months for typhoid fever to determine whether the very low reported incidence of typhoid fever in this age group reflects lack of consumption of the vehicles that transmit Salmonella typhi or whether infant hosts manifest an atypical response that goes unrecognized. S. typhi was isolated from 4 (2%) of the 197 blood cultures S. paratyphi B from 2 (1%) cultures and S. paratyphi A from 1 (0.5%) culture. The clinical syndrome in these infants was mild consisting of fever for 1-5 days and coughing. All infections resolved without complications even though the mothers spontaneously discontinued chloramphenicol therapy when the symptoms disappeared. The results of this study the 1st ot systematically examine the incidence of typhoid fever in children under 2 years indicate that infants become infected at a higher rate (3.6%) than is commonly assumed and manifest a very mild clinical illness.
A controlled field trial of Salmonella typhi strain Ty 21a oral vaccine against typhoid was carried out in Alexandria, Egypt, from March 1978 to March 1981. A total of
32,388 children was included in the study. The children were divided in two comparable groups, one given three doses of vaccine
and the other three doses of placebo. Each dose of vaccine contained 1-8 × 109 live Ty 21a bacteria. The population was monitored, and each suspected case of typhoid was investigated bacteriologically
and serologically. The effectiveness of the vaccine was assessed by analyzing the number of confirmed cases of typhoid fever
in the two groups. The incidence of typhoid fever was 4.9 cases per 10,000 children per year in the control group and 0.2
cases per 10,000 children per year in the vaccine group. The results indicate that, in the dose schedule used, the Ty 21a
mutant strain, which is stable and safe, is protective for a period of at least three years.