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Introduction: Typhoid fever remains a problem in developing countries, including Pakistan. The emergence of multidrug-resistant and, since 2016, of extensively drug-resistant cases is a continuous challenge for health care workers. The COVID-19 pandemic is making management more difficult., Methodology: In the present study, a total of 52 confirmed cases of typhoid have been studied during 2019. Detailed clinical features, complications and, lab findings were studied. Typhoid culture and sensitivity were recorded and patients were treated accordingly. Patients were asked about risk factors to aim at informing prevention., Results: Out of the 52 having blood culture positive for Salmonella Typhi 47 (90.4%) and Salmonella Paratyphi 5 (9.6%), 4 (7.7%) were sensitive to first-line (Non-resistant), 11 (21.2%) MDR and 37 (71.2%) patient were XDR. One case was resistant to azithromycin. Nausea, vomiting or, abdominal pain was present in 12 (23%), abdominal distension present in 9 (17.3%), abdominal tenderness in 8 (15.4%), hepatomegaly in 10 (19.2%) and, splenomegaly in 22 (42.3%).There were ultrasound abnormalities in 58% of patients and GI complications in 19% of patients. No significant difference was found in clinical findings and complications between resistant and non-resistant cases. Only 23-27% of patients were aware of typhoid prevention and vaccination measures., Conclusions: The increasing prevalence of resistance and higher degree of complications seen in typhoid fever raises the concern further about prevention and effective infection management in the community as well as clinical settings. Moreover, judicial use of antibiotics is much needed in developing countries like Pakistan., Competing Interests: No Conflict of Interest is declared, (Copyright (c) 2021 Samina Fida, Hala Mansoor, Saba Saif, Javed Iqbal, Arif Qayyum Khan.)

Introduction: Typhoid incidence in children is higher in urban areas than in rural areas of Bangladesh. This study examined whether healthy urban children harboured higher levels of Salmonella genes than healthy rural children., Methodology: Stool samples from 140 children were studied: 70 from rural areas and 70 from urban metropolitan areas., Results: The stool samples of urban children contained more Salmonella genes (median 4, IQR 3-4) than those of rural children (median 3, IQR 3-4). This suggests that urban Bangladeshi children have more Salmonella genes in their guts than rural children. Especially, in those under 12 months of age, the Salmonella gene prevalence in urban children was unique. They had more Salmonella genes (median 4, IQR 4-5) than rural children in the same age group (median 3, IQR 2.5-4). We also found more Salmonella genes in urban children who drank tap water (median 4, IQR 3-5) than in rural children whose water source was tube well water (median 3, IQR 2-4) and boiled pond water (median 3, IQR 3-3.5). However, there was no significant difference of Salmonella genes between urban children who drank tap-water and children whose water source was a tube well (median 4, IQR 3-4)., Conclusions: These data suggest that the urban environment, including the drinking water supply system, increases the likelihood of healthy children in urban areas harbouring more potentially pathogenic Salmonella organisms in their gut than found in rural healthy children., Competing Interests: No Conflict of Interest is declared, (Copyright (c) 2021 Shameem Akhter, Jong-Hyeok Jung, Bolormaa Munkhbileg, Jae-Hyeon Jeong, Jahirul Islam, Mohammad Mushfequr Rahman, Shah Mohammad Zahurul Haque Asna, Hwa Jung Kim, Seung Hyeok Seok, Seung-Yong Seong, Sang-Uk Seo.)

Inflammasome activation is an important host response to infectious diseases, but the difference in inflammasome activation between typhoid fever and non-typhoidal Salmonella infection has been rarely studied. To determine whether inflammasome activation in macrophages after S. Typhi and S. Typhimurium infection is different, we measured pyroptosis, caspase-1 activation, and IL-1β secretion in monocyte-derived macrophages infected with S. Typhi or S. Typhimurium both in vitro and ex vivo. The role of Vi capsule and virulence genes in Salmonella pathogenicity island-1 (SPI-1), belonging to type III secretion system, was also examined. S. Typhi caused more pyroptosis, caspase-1 activation, and IL-1β production than S. Typhimurium did, predominantly within 2 h of infection, in the context of high number of infecting bacteria. Mutagenesis and complementation experiments confirmed that SPI-1 effectors but not Vi were associated with greater inflammasome activation. The expression levels of invA and hilA were significantly higher in S. Typhi than in S. Typhimurium at early log phase in SPI-1 environment. Thus, S. Typhi, relative to its non-typhoidal counterpart, S. Typhimurium, induces greater SPI-1-dependent inflammasome activation in monocyte-derived macrophages. This finding may explain why S. Typhi causes a hyperinflammatory state at bacteremic stage in typhoid fever., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Outbreaks of acute undifferentiated febrile illness (AUFI) are common in Nepal, but the exact etiology or risk factors for them often go unrecognized. Diseases like influenza, enteric fever and rickettsial fevers account for majority of such outbreaks. Optimal diagnostic tests to inform treatment decisions are not available at the point-of-care. A proper epidemiological and clinical characterization of such outbreaks is important for appropriate treatment and control efforts., Methods: An investigation was initiated as a response to increased presentation of patients at Patan Hospital from Chalnakhel locality in Dakchinkali municipality, Kathmandu with AUFI from June 10 to July 1, 2016. Focused group discussion with local inhabitants and the epidemiological curve of febrile patients at local primary health care centre confirmed the outbreak. The household-survey was conducted in the area with questionnaire administered on patients to characterize their illnesses and their medical records were reviewed. A different set of questionnaire was administered on the patients and controls to investigate the association with common risk factors. Water samples were collected and analyzed microbiologically., Results: Eighty one patients from 137 households suffered from febrile illness within 6 weeks window before the investigation. All the 67 sampled patients with acute fever had a generalized illness without a discernible focus of infection. Only 38% of the patients had received a clinical diagnosis while the rest were treated empirically without a diagnosis. Three patients had blood culture confirmed enteric fever. Forty-two (63%) patients had been administered antibiotics, most commonly, ofloxacin, cefixime or azithromycin with a mean fever clearance time of 4 days. There was no definite association between several risk factors and fever. Fecal contamination was noted in tap water samples., Conclusion: Based on the pattern of illness, this outbreak was most likely a mixture of self-limiting viral infections and enteric fever. This study shows that even in the absence of a confirmed diagnosis, a detailed characterization of the illness at presentation and the recovery course can suggest the diagnosis and help in formulating appropriate recommendation for treatment and control.

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

A 63-year-old man with a history of gastro-oesophageal reflux disease underwent defunctioning loop ileostomy for obstructing metastatic rectal cancer prior to receiving long-course neoadjuvant chemoradiotherapy. Four months post completion of neoadjuvant therapy, he underwent an uncomplicated elective ultra-low anterior resection with formation of colonic J pouch and first stage liver metastasectomy for bilobar liver disease. At 1 year, he proceeded to an elective closure of loop ileostomy. Unfortunately, his postoperative course was complicated by profuse diarrhoea with subsequent colonic perforation, necessitating an emergency laparotomy and ileocolic resection with end ileostomy formation. Histopathology and stool studies were consistent with Salmonella Typhi infection. At the present time, Salmonella Typhi causing toxic megacolon and subsequent colonic perforation is an uncommon phenomenon in Australia. Here, we present an unusual case and explain why bowel perforation in this instance likely had a multifactorial aetiology., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Salmonella Typhi is a human host-restricted pathogen that is responsible for typhoid fever in approximately 10.9 million people annually 1 . The typhoid toxin is postulated to have a central role in disease pathogenesis, the establishment of chronic infection and human host restriction 2-6 . However, its precise role in typhoid disease in humans is not fully defined. We studied the role of typhoid toxin in acute infection using a randomized, double-blind S. Typhi human challenge model 7 . Forty healthy volunteers were randomized (1:1) to oral challenge with 10 4 colony-forming units of wild-type or an isogenic typhoid toxin deletion mutant (TN) of S. Typhi. We observed no significant difference in the rate of typhoid infection (fever ≥38 °C for ≥12 h and/or S. Typhi bacteremia) between participants challenged with wild-type or TN S. Typhi (15 out of 21 (71%) versus 15 out of 19 (79%); P = 0.58). The duration of bacteremia was significantly longer in participants challenged with the TN strain compared with wild-type (47.6 hours (28.9-97.0) versus 30.3(3.6-49.4); P ≤ 0.001). The clinical syndrome was otherwise indistinguishable between wild-type and TN groups. These data suggest that the typhoid toxin is not required for infection and the development of early typhoid fever symptoms within the context of a human challenge model. Further clinical data are required to assess the role of typhoid toxin in severe disease or the establishment of bacterial carriage.

Aim: Typhoid fever is a vaccine-preventable bacterial disease that causes significant morbidity and mortality throughout Africa. This paper describes an upsurge of typhoid fever cases in Moyale Sub-County (MSC), Kenya, 2014-2015., Methods: We conducted active hospital and health facility surveillance and laboratory and antimicrobial sensitivity testing for all patients presenting with headache, fever, stomach pains, diarrhea, or constipation at five MSC health facilities between December 2014 and January 2015. We also conducted direct observation of the residential areas of the suspected cases to assess potential environmental exposures and transmission mechanisms. Demographic, clinical, and laboratory data were entered into, and descriptive statistics were calculated with, MS Excel., Results: A total of 317 patients were included in the study, with mean age 24 ± 8.1 years, and 51% female. Of the 317 suspect cases, 155 (49%) were positive by Widal antigen reaction test. A total of 188 (59%) specimens were subjected to culture and sensitivity testing, with 71 (38%) culture positive and 54 (76%), 43 (60%), and 33 (46%) sensitive to ceftriaxone, cefuroxime, and ciprofloxacin, respectively. Environmental assessments through direct observations showed that commercial and residential areas had limited (1) clean water sources, (2) latrines, and (3) hygiene stations for street food hawkers and their customers., Conclusions: Typhoid fever is endemic in MSC and causes significant disease across age and sex groups. The local health department should develop policies to (1) assure community access to potable water and hygiene stations and (2) vaccinate specific occupations, such as food and drink handlers, against typhoid.

Background: Workers in clinical microbiology laboratories are exposed to a variety of pathogenic microorganisms. Salmonella species is among the most commonly reported bacterial causes of laboratory-acquired infections. We report on three cases of laboratory-acquired Salmonella enterica serotype Typhi (Salmonella Typhi) infection which occurred over the period 2012 to 2016 in South Africa., Methods: Laboratory investigation included phenotypic and genotypic characterization of isolates. Phenotypic analysis included standard microbiological identification techniques, serotyping and antimicrobial susceptibility testing. Genotypic analysis included the molecular subtyping methodologies of pulsed-field gel electrophoresis analysis, multilocus sequence typing and whole-genome sequencing (WGS); with WGS data analysis including phylogenetic analysis based upon comparison of single nucleotide polymorphism profiles of isolates., Results: All cases of laboratory-acquired infection were most likely the result of lapses in good laboratory practice and laboratory safety. The following critical issues were highlighted. There was misdiagnosis and misreporting of Salmonella Typhi as nontyphoidal Salmonella by a diagnostic laboratory, with associated public health implications. We highlight issues concerning the importance of accurate fluoroquinolone susceptibility testing and interpretation of results according to updated guidelines. We describe potential shortcomings of a single disk susceptibility screening test for fluoroquinolone susceptibility and suggest that confirmatory minimum inhibitory concentration testing should always be performed in cases of invasive Salmonella infections. These antimicrobial susceptibility testing issues resulted in inappropriate ciprofloxacin therapy which may have been responsible for failure in clearance of pathogen from patients. Salmonella Typhi capsular polysaccharide vaccine was not protective in one case, possibly secondarily to a faulty vaccine., Conclusions: Molecular subtyping of isolates proved effective to investigate the genetic relatedness of isolates. Molecular subtyping data interpreted together with epidemiological data allowed us to pinpoint the most likely sources for our cases of laboratory-acquired infection.

Protecting the public from communicable infectious disease outbreaks is one of the most important, and most challenging, functions of public health. Foodborne outbreaks are not uncommon, and they can be especially difficult. This true story of the epidemiologic investigation into a typhoid fever outbreak illustrates the critical importance of timely reporting by front-line clinicians, extensive interprofessional teamwork, and statewide coordination.

Background: On 6 February 2015, Kampala city authorities alerted the Ugandan Ministry of Health of a "strange disease" that killed one person and sickened dozens. We conducted an epidemiologic investigation to identify the nature of the disease, mode of transmission, and risk factors to inform timely and effective control measures., Methods: We defined a suspected case as onset of fever (≥37.5 °C) for more than 3 days with abdominal pain, headache, negative malaria test or failed anti-malaria treatment, and at least 2 of the following: diarrhea, nausea or vomiting, constipation, fatigue. A probable case was defined as a suspected case with a positive TUBEX® TF test. A confirmed case had blood culture yielding Salmonella Typhi. We conducted a case-control study to compare exposures of 33 suspected case-patients and 78 controls, and tested water and juice samples., Results: From 17 February-12 June, we identified 10,230 suspected, 1038 probable, and 51 confirmed cases. Approximately 22.58% (7/31) of case-patients and 2.56% (2/78) of controls drank water sold in small plastic bags (OR M-H  = 8.90; 95%CI = 1.60-49.00); 54.54% (18/33) of case-patients and 19.23% (15/78) of controls consumed locally-made drinks (OR M-H  = 4.60; 95%CI: 1.90-11.00). All isolates were susceptible to ciprofloxacin and ceftriaxone. Water and juice samples exhibited evidence of fecal contamination., Conclusion: Contaminated water and street-vended beverages were likely vehicles of this outbreak. At our recommendation authorities closed unsafe water sources and supplied safe water to affected areas.

This paper analyses how the Colombian medical elites made sense of typhoid fever before and during the inception of bacteriological ideas and practices in the second half of the nineteenth century. Assuming that the identity of typhoid fever has to be understood within the broader concerns of the medical community in question, I show how doctors first identified Bogotá's epidemics as typhoid fever during the 1850s, and how they also attached specificity to the fever amongst other continuous fevers, such as its European and North American counterparts. I also found that, in contrast with the discussions amongst their colleagues from other countries, debates about typhoid fever in 1860-70 among doctors in Colombia were framed within the medico-geographical scheme and strongly shaped by the fear of typhoid fever appearing alongside 'paludic' fevers in the highlands. By arguing in medico-geographical and clinical terms that typhoid fever had specificity in Colombia, and by denying the medico-geographical law of antagonism between typhoid and paludic fevers proposed by the Frenchman Charles Boudin, Colombian doctors managed to question European knowledge and claimed that typhoid fever had distinct features in Colombia. The focus on paludic and typhoid fevers in the highlands might explain why the bacteriological aetiology of typhoid fever was ignored and even contested during the 1880s. Anti-Pasteurian arguments were raised against its germ identity and some physicians even supported the idea of spontaneous origin of the disease. By the 1890s, Pasteurian knowledge had come to shape clinical and hygienic practices.

We analysed the data from the control group in a typhoid vaccine trial in Karachi to assess the differences in individual-, household- and cluster-level characteristics for developing typhoid fever. The annual incidence of typhoid in children aged 2-16 years in the control arm of the vaccine trial was 151/100 000 population. After adjustment, the risk of typhoid was lower with increasing age [risk ratio (RR) 0·89, 95% confidence interval (CI) 0·83-0·95], was higher with an increase in population density (RR 1·13, 95% CI 1·05-1·21) and was lower in the households using a safe drinking-water source (RR 0·63, 95% CI 0·41-0·99). Typhoid fever affects younger children living in areas of high population density and lack of access to safe water in Pakistan. A combination of environmental and biological interventions is required to prevent the continued epidemiological and economic impact of typhoid fever in high-risk areas of Pakistan.

Typhoid fever continues to pose public health problems in Selangor where cases are found sporadically with occasional outbreaks reported. In February 2009, Hospital Tengku Ampuan Rahimah (HTAR) reported a cluster of typhoid fever among four children in the pediatric ward. We investigated the source of the outbreak, risk factors for the infection to propose control measures. We conducted a case-control study to identify the risk factors for the outbreak. A case was defined as a person with S. typhi isolated from blood, urine or stool and had visited Sungai Congkak recreational park on 27th January 2010. Controls were healthy household members of cases who have similar exposure but no isolation of S. typhi in blood, urine or stool. Cases were identified from routine surveillance system, medical record searching from the nearest clinic and contact tracing other than family members including food handlers and construction workers in the recreational park. Immediate control measures were initiated and followed up. Twelve (12) cases were identified from routine surveillance with 75 household controls. The Case-control study showed cases were 17 times more likely to be 12 years or younger (95% CI: 2.10, 137.86) and 13 times more likely to have ingested river water accidentally during swimming (95% CI: 3.07, 58.71). River water was found contaminated with sewage disposal from two public toilets which effluent grew salmonella spp. The typhoid outbreak in Sungai Congkak recreational park resulted from contaminated river water due to poor sanitation. Children who accidentally ingested river water were highly susceptible. Immediate closure and upgrading of public toilet has stopped the outbreak.

The etiological spectrum of bloodstream infections is variable between industrialized and developing countries and even within a defined location over time. We investigated trends in bloodstream infections at an infectious disease hospital in Ho Chi Minh City, Vietnam, from 1994-2008. Amongst 66,111 blood cultures performed, a clinically relevant pathogen was isolated in 7645 episodes (positivity rate; 116/1000 cultures). Salmonella Typhi was the predominant pathogen until 2002; however, a considerable annual decline in the proportion of S. Typhi was observed (OR 0.6993, 95% CI [0.6885, 0.7103], p<0.0001). Conversely, there was a significant increase in the proportions of non-typhoidal Salmonella (NTS), Cryptococcus neoformans and Penicillium marneffei, concurrent with increasing HIV prevalence. These data document a substantial longitudinal shift in bloodstream infection etiology in southern Vietnam. We propose such changes are related to increasing economic prosperity and HIV prevalence, and this pattern marks a substantial change in the epidemiology of invasive salmonellosis in Southeast Asia., (Copyright © 2011 Royal Society of Tropical Medicine and Hygiene. Published by Elsevier Ltd. All rights reserved.)

Typhoid fever is endemic in the Mediterranean North African countries (Morocco, Algeria, Tunisia, Libya, and Egypt) with an estimated incidence of 10-100 cases per 100,000 persons. Outbreaks caused by Salmonella enterica serovar Typhi are common and mainly due to the consumption of untreated or sewage-contaminated water. Salmonella enterica Paratyphi B is more commonly involved in nosocomial cases of enteric fever in North Africa than expected and leads to high mortality rates among infants with congenital anomalies. Prevalence among travellers returning from this region is low, with an estimate of less than one per 100,000. Although multidrug resistant strains of Salmonella Typhi and Paratyphi are prevalent in this region, the re-emergence of chloramphenicol- and ampicillin-susceptible strains has been observed. In order to better understand the epidemiology of enteric fever in the Mediterranean North African region, population-based studies are needed. These will assist the health authorities in the region in preventing and controlling this important disease.

Objective: To identify risk factors for typhoid and propose prevention measures., Methods: Case-control study; we compared hospital-based typhoid cases defined as fever>38 degrees C for >or=3 days with four-fold rise in 'O' antibodies on paired sera (Widal) with community, age and neighbourhood matched controls. We obtained information on drinking water, fruits, vegetables, milk products and sanitation; and calculated matched odds ratios (MOR) and attributable fractions in the population (AFP) for the risk factors or failure to use prevention measures., Results: The 123 typhoid cases (median age: 25 years, 47% female) and 123 controls did not differ with respect to baseline characteristics. Cases were less likely to store drinking water in narrow-mouthed containers (MOR: 0.4, 95% CI: 0.2-0.7, AFP 29%), tip containers to draw water (MOR: 0.4, 95% CI: 0.2-0.7, AFP 33%) and have home latrines (MOR: 0.5, 95% CI: 0.3-0.8, AFP 23%). Cases were more likely to consume butter (OR: 2.3, 95% CI: 1.3-4.1, AFP 28%), yoghurt (OR: 2.3, 95% CI: 1.4-3.7, AFP 34%) and raw fruits and vegetables, including onions (MOR: 2.1, 95% CI: 1.2-3.9, AFP 34%), cabbages (OR: 2.8, 95% CI: 1.7-4.8, AFP 44%) and unwashed guavas (OR: 1.9, 95% CI: 1.2-3, AFP 25%)., Conclusion: Typhoid was associated with unsafe water and sanitation practices as well as with consumption of milk products, fruits and vegetables. We propose to chlorinate drinking water at the point of use, wash/cook raw fruits and vegetables and ensure safer preparation/storage of local milk products.

Objective: To study the epidemiological and etiological characteristics of typhoid and paratyphoid fever in high epidemic areas., Methods: Reported data on typhoid and paratyphoid fever during 1988-2007 in Ningbo were analyzed epidemiologically. Shellfish from the market was collected for laboratory testing and Salmonella typhi strains collected from the patients were also studied., Results: Number of reported cases on both typhoid and paratyphoid fever was 19 404 with 7 deaths, from 1988 to 2007. The annual mean incidence was 17.68 per one hundred thousand with the fatality rate as 0.36 per thousand. Most cases were among adults aged 20-50 years and an obvious regional distribution was observed with high incidence seen in winter and spring. Since 1990s, the advantage strain had changed from Salmonella typhi to Salmonella paratyphi A. Etiologic studies showed that raw Anadara subcrenata and oyster were the main risk factors. One Salmonella paratyphi A strain was detected in both Anadara subcrenata and oysters collected from the market, which contained TEM-1 drug resistance gene. PFGE genotyping showed that PFGE-X2 was the strain which causing pandemic in Ningbo., Conclusion: Eating contaminated raw shellfish like oysters and hairy clams was the primary risk factor, responsible for the outbreaks. Salmonella paratyphi A was the advantages pandemic strain in Ningbo. Strategies as supervision on personal hygiene and health education should be strengthened.

Enteric fever (typhoid and paratyphoid fever) is a major human bacterial infection. Although the disease is not common in industrialised countries, it remains an important and persistent health problem in developing nations. Hospital-based studies and outbreak reports from India indicate that enteric fever is a major public health problem in this country, with Salmonella enterica serovar Typhi (S. Typhi) the most common aetiologic agent but with an apparently increasing number of cases due to S. Paratyphi A (SPA). Because risk factors such as poor sanitation, lack of a safe drinking water supply and low socio economic conditions in resource-poor countries are amplified by the evolution of multidrug resistant salmonellae with reduced susceptibility to fluoroquinolone, treatment failure cases have been reported in India, which is associated with increased mortality and morbidity. Vaccination, which requires strict planning and proper targeting of the vulnerable age groups, is considered to be an effective tool in controlling this disease in endemic areas, given there is development of a conjugate vaccine against both serovars (S. Typhi and S. Para A).

Bacterial enteric infections are often associated with diarrhoea or vomiting, which are clinical presentations commonly referred to as gastroenteritis. However, some enteric pathogens, including typhoidal Salmonella serotypes, Brucella species and enteropathogenic Yersinia species are associated with a clinical syndrome that is characterized by abdominal pain and/or fever and is distinct from acute gastroenteritis. Recent insights into molecular mechanisms of the host-pathogen interaction show that these enteric pathogens share important characteristics that explain why the initial host responses associated with these agents more closely resemble host responses to viral or parasitic infections. Host responses contribute to the clinical presentation of disease and improved understanding of these responses in the laboratory is beginning to bridge the gap between bench and bedside.

Kathmandu, the capital city of Nepal, has been previously coined an enteric fever capital of the world. Several studies have poignantly emphasized the significant burden of enteric fever within the local population and in travellers visiting the area. The population of Kathmandu is increasing and available figures suggest that enteric fever caused by Salmonella serovars Typhi and Paratyphi A show no significant signs of decreasing. Furthermore, our recent research demonstrates that the ratio of disease caused by these two organisms is shifting towards S. Paratyphi A. Here, we outline some of the major features of enteric fever in Kathmandu, including diagnosis, seasonal variation, transmission, and some characteristics of the infecting organisms. Our findings highlight the requirement for better understanding of the disease within the city; in turn, this will aid development of a targeted control strategy.

Salmonella enterica serovar Typhimurium (S. Typhimurium) and certain Escherichia coli are human pathogens that have evolved through the acquisition of multiple virulence determinants by horizontal gene transfer. Similar genetic elements, as pathogenicity islands and virulence plasmids, have driven molecular evolution of virulence in both species. In addition, the contribution of prophages has been recently highlighted as a reservoir for pathogenic diversity. Characterization of horizontally acquired virulence genes has several clinical implications. First, identification of virulence determinants that have a sporadic distribution and are specifically associated with a pathotype and/or a pathology can be useful markers for risk assessment and diagnosis. Secondly, virulence factors widely distributed in pathogenic strains, but absent from non-pathogenic bacteria, are interesting targets for the development of novel antimicrobial chemotherapies and vaccines. Here, we summarize the horizontally acquired virulence factors of S. Typhimurium, enterohemorrhagic E. coli O157:H7 and uropathogenic E. coli, and we describe their use in novel therapeutic approaches.

A prospective clinical and microbiological study was conducted in 145 blood culture positive cases of enteric fever below the age of 18 years over a period of eleven months (June 2004 to April 2005). It aimed to study the clinical profile, the relative magnitude of enteric fever in children, especially in those below the age of two years and to determine the current antibiotic sensitivity pattern of Salmonella typhi and S paratyphi. Enteric fever is a significant problem in the preschool years. Sixty-five per cent of cases were in the age group of 2 to 9 years, 27% in 0-5 years and 13% in age group 0-2 years. Ninety-two per cent of the cases were caused by S typhi. Paratyphoid fever is less common (8%), when occurs is caused by S paratyphi A. In-vitro sensitivity, using the Bauer-Kirby agar disc diffusion method, to ceftriaxone was 99%, cefixime-99%, cefotaxime-99%, cefpodoxime-72%, cefoperazone-93%, among quinolones, ciprofloxacin-95%, ofloxacin-83%, norfloxacin-79%. Sensitivity to the originally used antibiotics is reappearing: Ampicillin-87%, amoxicillin-89%, trimethoprim-sulfamethoxazole-76%, chloramphenicol-86%. Among other drugs, sensitivity to imepenam-100%, azithromycin-49%, aztreonam-65%, amikacin-98%. Nalidixic acid resistance is very high ie, 88%.

We systematically investigated risk factors for typhoid fever in Kamalapur, a poor urban area of Bangladesh, to inform targeted public health measures for its control. We interviewed patients with typhoid fever and two age-matched controls per case about exposures during the 14 days before the onset of illness. The municipal water supply was used by all 41 cases and 81of 82 controls. In multivariate analysis, drinking unboiled water at home was a significant risk factor [adjusted odds ratio (aOR) 12.1, 95% CI 2.2-65.6]. Twenty-three (56%) cases and 21 (26%) controls reported that water from the primary source was foul-smelling (aOR 7.4, 95% CI 2.1-25.4). Eating papaya was associated with illness (aOR 5.2, 95% CI 1.2-22.2). Using a latrine for defecation was significantly protective (aOR 0.1, 95% CI 0.02-0.9). Improved chlorination of the municipal water supply or disinfecting drinking water at the household level may dramatically reduce the risk of typhoid fever in Kamalapur. The protective effect of using latrines, particularly among young children, should be investigated further.

Analysis of epidemiological data on health problems related to international travel helps put into perspective preventive interventions for travelers. To document the epidemiological context of travel health interventions in Québec, we reviewed surveillance data for three infectious diseases. The analysis included data collected in the notifiable diseases surveillance system for hepatitis A, typhoid, and malaria cases reported from 2000 to 2002. Additional data were obtained from the provincial hepatitis risk factor database as well as from regional public health departments. More than 40% of cases of hepatitis A for which risk factor information is available are associated with international travel; 20% of these cases were contracted in Mexico and 22% in the West Indies. The risk of acquiring hepatitis A seems to be higher among travelers under 35 years of age; also, given the number of Quebecers traveling to all regions of the world, this risk is proportionally higher in Africa. Data gathered for typhoid indicate that the risk to travelers from Québec is proportionately higher for Quebecers traveling to the Indian subcontinent and whose purpose is to visit family and friends, and for those who stay abroad for 4 weeks or longer. The risk of malaria is greater in Africa (where contracted cases are mostly caused by Plasmodium falciparum). Over half of malaria cases involve individuals traveling abroad for business (including volunteerism), and almost 75% contracted the disease during a stay of a month or more. Nearly half of the cases had not taken chemoprophylaxis. Available data have limitations for infectious disease surveillance among Québec travelers: imprecise number of cases (underdiagnosis and underreporting), imprecise denominators (number of travelers), and lack of data on the characteristics of trips taken. However, despite its limitations, this profile of infectious diseases among travelers from Québec provides interesting data for preventive intervention.

We conducted a case-control study to assess risk factors for typhoid fever in Diyarbakir, Turkey, a region where transmission of Salmonella typhi is endemic. We prospectively identified febrile patients from Diyarbakir and the surrounding area who were admitted to hospital. Cases were defined as patients who had S. typhi isolated from at least one blood culture. Sixty-four cases with blood culture-confirmed S. typhi were identified between May 2001 and May 2003. In total, 128 age- and sex-matched controls selected from neighbourhoods as cases were enrolled. We hypothesized that consumption of raw vegetables contaminated with sewage would be associated with an increased risk of typhoid fever. Conditional logistic regression modelling revealed that living in a crowded household (OR 3.31, 95% CI 1.58-6.92, P=0.002), eating cig kofte (a traditional raw food) (OR 5.29, 95% CI 2.20-12.69, P=0.000) and lettuce salad (OR 3.55, 95% CI 1.52-8.28, P=0.003) in the 15 days prior to symptoms onset was independently associated with typhoid fever. We conclude that living in a crowded household and consumption of raw vegetables outside the home increase the risk of typhoid fever in this region.

Enteric fever decreased in Israel in the last 50 years, but its current epidemiology is unknown. In a nationwide study, we evaluated all cases of enteric fever from 1995 to 2003. On hundred thirty-six cases met the case definition. During the period studied, the incidence of enteric fever decreased from 0.42 to 0.23/100,000. A total of 57.4% of the cases were acquired abroad. The incidence of endemic enteric fever was 2.7 times higher in Arabs than in Jews. In Arabs, Salmonella Typhi was the causative agent in all cases, and almost all cases were endemic. In Jews, most cases were imported, with a decrease in imported S. typhi, cases and an increase in imported S. Paratyphi A cases. Salmonella Paratyphi B was endemic, and restricted to the Jewish population. The reasons for the difference in causative agents along ethnic lines need further evaluation. A more efficient vaccine for travelers that includes S. Paratyphi A is needed.

We evaluated the association between typhoid fever and Helicobacter pylori infection, as the latter microorganism may influence gastric acid secretion and consequently increase susceptibility to Salmonella typhi infection. Anti-H. pylori IgG and IgA antibody titres (ELISA) and gastrin concentration (RIA) were determined in the plasma of 87 blood culture-confirmed typhoid fever cases (collected after clinical recovery) and 232 random healthy controls without a history of typhoid fever, in the Jatinegara district, Jakarta. Patients with typhoid fever more often than controls were seropositive for H. pylori IgG (67% vs. 50%, P<0.008), when antibody titres were dichotomized around median titres observed in controls. H. pylori IgA seropositivity was not associated with typhoid fever. Plasma gastrin concentrations indicative of hypochlorhydria (i.e. gastrin > or =25 or > or =100 ng/l) were not significantly elevated in typhoid fever cases compared to controls (P=0.54 and P=0.27 respectively). In a multivariate analysis, typhoid fever was independently associated with young age (<33 years, median age of the controls) [odds ratio (OR) 7.93, 95% confidence interval (CI) 3.90-16.10], and H. pylori IgG seropositivity (OR 1.93, 95% CI 1.10-3.40). Typhoid fever was independently associated with H. pylori IgG seropositivity, but not with elevated gastrin concentration. Therefore, the association suggests a common risk of environmental exposure to both bacteria, e.g. poor hygiene, rather than a causal relationship via reduced gastric acid production.

Salmonella enterica serovar Typhi is an important pathogen exclusively for humans and causes typhoid or enteric fever. It has been shown that type IVB pili, encoded by the S. enterica serovar Typhi pil operon located in Salmonella pathogenicity island 7, are important in the pathogenic process. In this study, by using both an adhesion-invasion assay and fluorescence quantitative PCR analysis, we demonstrated that the entry of type IVB piliated S. enterica serovar Typhi A21-6 (pil(+) Km(r)) into human THP-1 monocytic cells was greater than that of a nonpiliated S. enterica serovar Typhi pilS::Km(r) (pil mutant) strain. We have applied a systematic evolution of ligands by exponential enrichment approach to select oligonucleotides (aptamers) as ligands that specifically bind to type IVB pili. Using this approach, we identified a high-affinity single-stranded RNA aptamer (S-PS(8.4)) as a type IVB pilus-specific ligand and further found that the selected aptamer (S-PS(8.4)) could significantly inhibit the entry of the piliated strain (but not that of the nonpiliated strain) into human THP-1 cells. The binding affinities between aptamers and pre-PilS (structural protein of type IVB pili) were determined by nitrocellulose filter-binding assays, and the K(d) value was determined to be 8.56 nM for the S-PS(8.4) aptamer alone. As an example of an aptamer against type IVB pili of S. enterica serovar Typhi, the aptamer S-PS(8.4) can serve as a tool for analysis of bacterial type IVB pilus-host cell interactions and may yield information for the development of putative new drugs against S. enterica serovar Typhi bacterial infections, useful both in prevention of infection and in therapeutic treatment.

Background: Although enteric fever (typhoid and paratyphoid fevers) is a major global public health problem, comparable data on the risks of contracting travel-associated enteric fever in various regions of the world are scarce., Methods: From the Swedish database on notifiable communicable diseases, we retrieved all case records from 1997 to 2003 on typhoid and paratyphoid fevers. The data set was compared with data on travel patterns obtained from a comprehensive travel database with information from interviews with more than 16,000 Swedish residents with recent overnight travel outside Sweden., Results: The overall risk of being notified with enteric fever after travel was 0.42 in 100,000 travelers. The highest risk for typhoid fever was seen in travelers from India and neighboring countries (41.7 in 100,000), the Middle East (5.91 in 100,000), and Central Africa (3.33 in 100,000), whereas the risk was comparatively low in East Asia (0.24 in 100,000). Almost the same risk areas stood out for paratyphoid fever: India and neighbors (37.5 in 100,000), the Middle East (3.64 in 100,000), and East Africa (3.33 in 100,000). The epidemiology of paratyphoid fever was considerably affected by a large outbreak of paratyphoid B in a Turkish tourist resort in 1999. The youngest children were at highest risk for typhoid fever (odds ratio 44.2), whereas youths ages 7 to 18 years were at highest risk for paratyphoid fever (odds ratio 9.7)., Conclusions: Detailed risk data for enteric fever after travel could form the basis for travel advice. Vaccination against typhoid fever should always be considered for travelers to the Indian subcontinent, the Middle East, and Africa but should not routinely be given to travelers to the Malay Peninsula.

While most strains of Salmonella enterica serotype Typhi, the etiologic agent of typhoid fever, have only a phase 1 flagellar antigen, H1-d, variations of the flagellar antigen have been observed. Although H1-j strains (one of the flagellar antigen variants) account for 10 to 50% of S. enterica serotype Typhi strains found in Indonesia, there have been no published data to suggest its existence in other parts of the world. We describe a case of typhoid fever associated with acute appendicitis caused by an S. enterica serotype Typhi H1-j strain in a Chinese woman in Hong Kong. A gram-negative, motile rod was recovered from her blood and stool cultures. Conventional biochemical tests and the Vitek system (GNI+) showed that the bacterium was S. enterica serotype Typhi. The isolate agglutinated with poly(O), 9O, Vi and H1-j Salmonella antisera but not with poly(H) antisera. The patient developed antibodies against only S. enterica serotype Typhi O antigens but not against H1-d antigen by the Widal test. Flagellin C gene (fliC) sequencing showed a 261-bp deletion in the fliC gene of the isolate, confirming that the isolate possessed the H1-j antigen. The patient had no past history of travel to Indonesia or personal contact with any Indonesian. She recovered with appendectomy and antibiotic treatment. Further studies should be performed to determine the prevalence of this unusual S. enterica serotype Typhi strain in our locality.

Objective: This study aims to assess the mood changes induced by mild acute inflammatory stimulation (typhoid vaccination)., Methods: Using a double blind study design, 26 healthy volunteers underwent baseline assessments of mood, financial strain and work stress and were randomised to injection of Salmonella typhi vaccine or placebo injection. Mood, symptoms and body temperature was assessed by a modified version of the Profile of Mood States at 1, 2, 3, 4, 6 and 8 h post injection., Results: Typhoid vaccination induces no increases in physical symptoms or temperature. Mood improved over the day in the placebo but not in the vaccine condition. Negative changes in mood following injection were correlated with chronic stress (financial strain) in the vaccination condition (r=-.65, P<.025)., Conclusion: A mild acute inflammatory stimulus induces transient negative mood, and responses were modulated by chronic stress. Implications for depressed mood in physical illness are discussed.

Salmonella enterica serovar Typhi expresses type IVB pili. We show that the prePilS protein (the soluble precursor form of the structural pilin) interacts with a 15-mer peptide representing the first extracellular domain of the cystic fibrosis transmembrane conductance regulator (CFTR), a recognized human epithelial cell receptor for serovar Typhi (G. B. Pier et al., Nature 393:79-82, 1998). This indicates that after mediating bacterial self-association (C. Morris et al., Infect. Immun. 71:1141-1146, 2003), the pili then act to attach the bacterial clumps to CFTR in the membrane of gut epithelial cells. These sequential type IVB pilus-mediated events cannot be performed by (for example) S. enterica serovar Typhimurium, which may explain why only serovar Typhi causes epidemics of enteric fever in humans.

Infection of bovine ligated loops with the Salmonella enterica serotype Typhimurium wild type but not a sipA sopABDE2 mutant resulted in fluid accumulation, polymorphonuclear cell infiltration, and expression of CXC chemokines, particularly GRO alpha. None of these sipA sopABDE2-dependent responses was observed in murine-ligated loops. The majority of GRO alpha transcripts localized to bovine intestinal epithelium. Thus, different disease outcomes between mice (i.e., no diarrhea) and calves (i.e., diarrhea) may be due to differences in sipA sopABDE2-dependent CXC chemokine gene expression in epithelial cells.

The knowledge about typhoid fever pathogenesis is growing in the last years, mainly about the cellular and molecular phenomena that are responsible by clinical manifestations of this disease. In this article are discussed several recent discoveries, as follows: a) Bacterial type III protein secretion system; b) The five virulence genes of Salmonella spp. that encoding Sips (Salmonella invasion protein) A, B, C, D and E, which are capable of induce apoptosis in macrophages; c) The function of Toll R2 and Toll R4 receptors present in the macrophage surface (discovered in the Drosophila). The Toll family receptors are critical in the signalizing mediated by LPS in macrophages in association with LBP and CD14; d) The lines of immune defense between intestinal lumen and internal organs; e) The fundamental role of the endothelial cells in the inflammatory deviation from bloodstream into infected tissues by bacteria. In addition to above subjects, the authors comment the correlation between the clinical features of typhoid fever and the cellular and molecular phenomena of this disease, as well as the therapeutic consequences of this knowledge.

Previously, it was shown that type IVB pili encoded by the Salmonella enterica serovar Typhi pil operon are used to facilitate bacterial entry into human intestinal epithelial cells in vitro and that such entry is inhibited by purified prepilin (pre-PilS) protein (X.-L. Zhang, I. S. M. Tsui, C. M. C. Yip, A. W. Y. Fung, D. K.-H. Wong, X. Dai, Y. Yang, J. Hackett, and C. Morris, Infect. Immun. 68:3067-3073, 2000). The pil operon concludes with a simple shufflon, and a recombinase gene product (Rci) inverts DNA in the C-terminal region of the pilV gene to allow synthesis of two distinct PilV proteins, PilV1 and PilV2, which are presumptive minor pilus proteins. We show here that the type IVB pili mediate bacterial self-association, but only when the PilV1 and PilV2 proteins are not expressed. This may be achieved in wild-type serovar Typhi by rapid DNA inversion activity of the shufflon. We show that the inversion activity inhibits the expression of genes inserted between the 19-bp inverted repeats used for Rci-mediated recombination and that the activity of Rci increases when DNA is supercoiled. The data suggest that serovar Typhi self-associates under conditions (such as low oxygen tension in the gut) that favor DNA supercoiling. These results explain (i) the function of the serovar Typhi shufflon and (ii) why there are only two possible shufflon states, in contrast to the many possible states of other shufflon systems. The data further indicate that a very early step in serovar Typhi pathogenesis may be type IVB pilus-mediated self-association of bacteria in the anaerobic human small intestine prior to invasion of the human gut epithelium. The suggested type IVB pilus-dependent step in typhoid fever pathogenesis may partially explain the enhanced invasiveness of serovar Typhi for humans.

Although the incidence of typhoid fever in the United States has been low since the 1940s, Salmonella Typhi continues to cause outbreaks. We reviewed reported outbreaks of typhoid fever from 1960 to 1999. There were 60 outbreaks; in 54, exposure occurred within the United States. These 54 outbreaks accounted for 957 total cases (median 10) and 4 deaths. In 36 (67%) outbreaks the route of transmission was identified, and in 16 (62%) of the 26 foodborne outbreaks an asymptomatic carrier was identified by culture or serology. The median incubation period was 2 weeks. Isolates from 10 (40%) of 25 outbreaks were phage type E1. The average frequency of outbreaks decreased from 1.85/year during 1960-79 to 0.85/year during 1980-99 (P=0.0001). S. Typhi outbreaks in the United States are generally small in size but can cause significant morbidity, and are often foodborne, warranting thorough investigation.

Typhoid fever is an acute infectious disease caused by Salmonella enterica serotype typhi. The infection is responsible for endemic or epidemic outbreaks in tropical and subtropical countries, especially in Indian subcontinent, Southeast Asia, Central and South Africa. Latin America, and it occurs sporadically in Poland. We reported two cases of imported typhoid fever after travelling to India and Nepal. In the tourists returning from the area hyperendemic for malaria, visceral leishmaniosis, amoebiasis and haemorrhagic fevers and not following tropical hygiene measures, persistent fever was a source of difficulties in differential diagnosis. In the first case, lack of anti-malarial chemoprophylaxis in the presence of anaemia and thrombocytopenia strongly suggested Plasmodium spp. infection. Two daily peaks of fever with splenomegaly, lymphadenopathy, leucopenia, high transaminases levels and co-existing positive serology for L. donovani pointed to visceral leishmaniosis. Late occurrence of specific anti-S. typhi agglutinins in the Widal test, cross-reactivity with S. paratyphi A and negative urine bacteriological culture were observed. In the second case, gastrointestinal disturbances, including pain, abdominal tenderness and diarrhoea gave a suspicion of amoebic colitis. Stool and urine cultures were negative for S. typhi and cross reactions with S. paratyphi A and C were reported. Typhoid fever was finally confirmed in both patients by an isolation of S. typhi from peripheral blood cultures. The effectiveness of treatment of choice with ciprofloxacin or ceftriaxone in a case of multidrug-resistant (MDR) strain of S. typhi was documented.

This paper examines the trend and possible contributing factors for the occurrence of the food borne diseases outbreaks in Malaysia. These diseases mainly are cholera, typhoid fever, hepatitis A, dysentery and food poisoning. The outbreaks still occur sporadically in certain high risk areas throughout the country. The incidence rate of all the other three major food borne diseases steadily declined from the year 1988 to 1997 except for food poisoning and cholera. Statistic of food poisoning from the year 1996 to 1997 showed that 66.5% of the outbreak occurred in schools whereas only 0.4% originated from the contaminated food sold at various public food outlets. The school age group is always more affected than the general population. Amongst the contributing factors identified are related to unhygienic food handling practices followed by inadequate safe water supply and poor environmental sanitation. A multisectoral approach between Ministry of Health and other government agencies or private agents needs to be undertaken in the management of the food borne diseases in order to curb the incidences of food borne diseases in Malaysia.

A field survey was conducted on four slum, squatter and pavement dweller communities of Mumbai City, India with a total sample size of 1,070 households. Study revealed extremely low water consumption pattern averaging merely 30 l/c x d, no sewerage and safe excreta disposal facilities manifested by high occurrence of water-borne diseases. The annual diarrhoeal, typhoid and malaria cases were estimated to 614, 68 and 126 per thousand populations respectively. At point prevalence scale, at least 30% of all morbidity can be accounted for by water-related infections. In addition to the impacts of neighborhood water pollution and sanitation, such diseases were also found positively correlated with low water consumption and poverty related factors as, poor housing and family income. Analysis of variance also revealed intra-poor gradient both in living standards and health conditions on which the pavement dwellers were observed to be the greatest sufferers of all.

Live attenuated chi8110 Salmonella enterica serovar Typhi ISP1820 vaccine was given in a dose-escalation trial to healthy, adult volunteers. Positive stool and blood cultures were noted, but limited, as were immune responses measured by ELISA and ELISPOT. Only volunteers with bacteremia developed immune responses; however, no symptoms were associated with bacteremia. The vaccine was insufficiently immunogenic for use as a vaccine. It is possible that reduced survival in the gut and reduced immunogenicity may have been due to the thawing of frozen inocula immediately prior to use., (Copyright 2001 Academic Press.)

Typhoid fever is an infectious disease of global distribution. Although there is a wealth of data on Salmonella typhimurium infection in the mouse and the interaction of this serovar with human cell lines in vitro, there is a relatively small amount of data on S. typhi and the pathogenesis of typhoid fever. In this review we focus on three areas: adherence to and invasion of gut epithelial cells, dissemination to systemic sites, and survival and replication within host cells. In addition, we attempt to put current salmonella research into the context of typhoid fever.