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The epidemiology of typhoid fever in Lao People's Democratic Republic is poorly defined. Estimating the burden of typhoid fever in endemic countries is complex due to the cost and limitations of population-based surveillance; serological approaches may be a more cost-effective alternative. ELISAs were performed on 937 serum samples (317 children and 620 adults) from across Lao PDR to measure IgG antibody titers against Vi polysaccharide and the experimental protein antigens, CdtB and HlyE. We measured the significance of the differences between antibody titers in adults and children and fitted models to assess the relationship between age and antibody titers. The median IgG titres of both anti-HylE and CdtB were significantly higher in children compared to adults (anti-HylE; 351.7 ELISA Units (EU) vs 198.1 EU, respectively; p<0.0001 and anti-CdtB; 52.6 vs 12.9 EU; p<0.0001). Conversely, the median anti-Vi IgG titer was significantly higher in adults than children (11.3 vs 3.0 U/ml; p<0.0001). A non-linear trend line fitted to the anti-CdtB and anti-HlyE IgG data identified a peak in antibody concentration in children <5 years of age. We identified elevated titers of anti-HlyE and anti-CdtB IgG in the serum of children residing in Lao PDR in comparison to adults. These antigens are associated with seroconversion after typhoid fever and may be a superior measure of disease burden than anti-Vi IgG. This approach is scalable and may be developed to assess the burden of typhoid fever in countries where the disease may be endemic, and evidence is required for the introduction of typhoid vaccines. Author summary: Typhoid fever is a serious bloodstream infection caused by the bacterium Salmonella Typhi. Estimating the burden of typhoid fever is complex due to the limitations, cost, and scalability of current diagnostic surveillance methods. The detection of specific antibody responses against the organism may be a more sustainable manner of measuring exposure and disease burden in endemic location. We measured antibody (IgG) in 937 serum samples (317 children and 620 adults) from across the Lao People's Democratic Republic against a polysaccharide (Vi) and two experimental protein antigens, CdtB and HlyE, that may more appropriate markers of disease exposure. We measured the significance of the differences between antibody titers in adults and children and fitted models to assess the relationship between age and antibody titers. The median IgG titres against HylE and CdtB were significantly higher in children than adults. Conversely, the median IgG titres against Vi was significantly higher in adults than children. We identified a significant association between a peak in IgG titres against CdtB and HlyE in children aged under 5 years. These data are indicative of high level of typhoid fever exposure in children under 5 years of age in Lao PDR and we surmise that IgG titres against HylE and CdtB may be a superior measure of typhoid disease burden than IgG titres against Vi. Our approach is scalable and can be further validated to assess the burden of typhoid fever in countries where the disease may be endemic, and evidence is required for the introduction of typhoid vaccines. [ABSTRACT FROM AUTHOR]

Despite recent advances in typhoid fever control, asymptomatic carriage of Salmonella Typhi in the gallbladder remains poorly understood. Aiming to understand if S. Typhi becomes genetically adapted for long-term colonisation in the gallbladder, we performed whole genome sequencing on a collection of S. Typhi isolated from the gallbladders of typhoid carriers. These sequences were compared to contemporaneously sampled sequences from organisms isolated from the blood of acute patients within the same population. We found that S. Typhi carriage was not restricted to any particular genotype or conformation of antimicrobial resistance genes, but was largely reflective of S. Typhi circulating in the general population. However, gallbladder isolates showed a higher genetic variability than acute isolates, with median pairwise SNP distances of 21 and 13 SNPs (p = 2.8x10-9), respectively. Within gallbladder isolates of the predominant H58 genotype, variation was associated with a higher prevalence of nonsense mutations. Notably, gallbladder isolates displayed a higher frequency of non-synonymous mutations in genes encoding hypothetical proteins, membrane lipoproteins, transport/binding proteins, surface antigens, and carbohydrate degradation. Specifically, we identified several gallbladder-specific non-synonymous mutations involved in LPS synthesis and modification, with some isolates lacking the Vi capsular polysaccharide vaccine target due to the 134Kb deletion of SPI-7. S. Typhi is under strong selective pressure in the human gallbladder, which may be reflected phylogenetically by long terminal branches that may distinguish organisms from chronic and acute infections. Our work shows that selective pressures asserted by the hostile environment of the human gallbladder generate new antigenic variants and raises questions regarding the role of carriage in the epidemiology of typhoid fever. Author summary: Salmonella Typhi is the bacterium that causes typhoid. Salmonella Typhi is infamous for being able to be carried in the gallbladder, with Typhoid Mary being the best-known example of a typhoid carrier. Despite having new tools for typhoid control, we have made little progress in understanding this disease process. Aiming to understand if Salmonella Typhi is adapted for long-term survival in the gallbladder, we sequenced the genomes of 24 Salmonella Typhi isolated from the gallbladders of typhoid carriers. We compared these genomes to Salmonella Typhi from acute typhoid patients within the same population. The carriage of Salmonella Typhi was not restricted to any specific genotype or resistance to antibiotics, but reflective of the organisms causing acute disease. However, gallbladder isolates had higher genetic variability than acute isolates, with a higher frequency of mutations changing the amino acid sequences of hypothetical proteins, membrane lipoproteins, transport/binding proteins, surface antigens, and carbohydrate degradation. We identified several gallbladder-specific mutations involved in polysaccharide synthesis on the bacterial surface. Our work shows that selective pressures asserted by the hostile environment of the human gallbladder generates genetic variation, which is not observed in acute isolates, raising questions regarding the role of carriage in the epidemiology of typhoid. [ABSTRACT FROM AUTHOR]

Empirical data on contact patterns can inform dynamic models of infectious disease transmission. Such information has not been widely reported from Pacific islands, nor strongly multi-ethnic settings, and few attempts have been made to quantify contact patterns relevant for the spread of gastrointestinal infections. As part of enteric fever investigations, we conducted a cross-sectional survey of the general public in Fiji, finding that within the 9,650 mealtime contacts reported by 1,814 participants, there was strong like-with-like mixing by age and ethnicity, with higher contact rates amongst iTaukei than non-iTaukei Fijians. Extra-domiciliary lunchtime contacts follow these mixing patterns, indicating the overall data do not simply reflect household structures. Inter-ethnic mixing was most common amongst school-age children. Serological responses indicative of recent Salmonella Typhi infection were found to be associated, after adjusting for age, with increased contact rates between meal-sharing iTaukei, with no association observed for other contact groups. Animal ownership and travel within the geographical division were common. These are novel data that identify ethnicity as an important social mixing variable, and use retrospective mealtime contacts as a socially acceptable metric of relevance to enteric, contact and respiratory diseases that can be collected in a single visit to participants. Application of these data to other island settings will enable communicable disease models to incorporate locally relevant mixing patterns in parameterisation. [ABSTRACT FROM AUTHOR]

Fiji, an upper-middle income state in the Pacific Ocean, has experienced an increase in confirmed case notifications of enteric fever caused by Salmonella enterica serovar Typhi (S. Typhi). To characterize the epidemiology of typhoid exposure, we conducted a cross-sectional sero-epidemiological survey measuring IgG against the Vi antigen of S. Typhi to estimate the effect of age, ethnicity, and other variables on seroprevalence. Epidemiologically relevant cut-off titres were established using a mixed model analysis of data from recovering culture-confirmed typhoid cases. We enrolled and assayed plasma of 1787 participants for anti-Vi IgG; 1,531 of these were resident in mainland areas that had not been previously vaccinated against S. Typhi (seropositivity 32.3% (95%CI 28.2 to 36.3%)), 256 were resident on Taveuni island, which had been previously vaccinated (seropositivity 71.5% (95%CI 62.1 to 80.9%)). The seroprevalence on the Fijian mainland is one to two orders of magnitude higher than expected from confirmed case surveillance incidence, suggesting substantial subclinical or otherwise unreported typhoid. We found no significant differences in seropositivity prevalences by ethnicity, which is in contrast to disease surveillance data in which the indigenous iTaukei Fijian population are disproportionately affected. Using multivariable logistic regression, seropositivity was associated with increased age (odds ratio 1.3 (95% CI 1.2 to 1.4) per 10 years), the presence of a pit latrine (OR 1.6, 95%CI 1.1 to 2.3) as opposed to a septic tank or piped sewer, and residence in settlements rather than residential housing or villages (OR 1.6, 95% CI 1.0 to 2.7). Increasing seropositivity with age is suggestive of low-level endemic transmission in Fiji. Improved sanitation where pit latrines are used and addressing potential transmission routes in settlements may reduce exposure to S. Typhi. Widespread unreported infection suggests there may be a role for typhoid vaccination in Fiji, in addition to public health management of cases and outbreaks. [ABSTRACT FROM AUTHOR]

Gallbladder carriage of invasive Salmonella is considered fundamental in sustaining typhoid fever transmission. Bile and tissue was obtained from 1,377 individuals undergoing cholecystectomy in Kathmandu to investigate the prevalence, characteristics and relevance of invasive Salmonella in the gallbladder in an endemic area. Twenty percent of bile samples contained a Gram-negative organism, with Salmonella Typhi and Salmonella Paratyphi A isolated from 24 and 22 individuals, respectively. Gallbladders that contained Salmonella were more likely to show evidence of acute inflammation with extensive neutrophil infiltrate than those without Salmonella, corresponding with higher neutrophil and lower lymphocyte counts in the blood of Salmonella positive individuals. Antimicrobial resistance in the invasive Salmonella isolates was limited, indicating that gallbladder colonization is unlikely to be driven by antimicrobial resistance. The overall role of invasive Salmonella carriage in the gallbladder is not understood; here we show that 3.5% of individuals undergoing cholecystectomy in this setting have a high concentration of antimicrobial sensitive, invasive Salmonella in their bile. We predict that such individuals will become increasingly important if current transmission mechanisms are disturbed; prospectively identifying these individuals is, therefore, paramount for rapid local and regional elimination. [ABSTRACT FROM AUTHOR]

Background: Infectious diseases of the central nervous system (CNS) remain common and life-threatening, especially in developing countries. Knowledge of the aetiological agents responsible for these infections is essential to guide empiric therapy and develop a rational public health policy. To date most data has come from patients admitted to tertiary referral hospitals in Asia and there is limited aetiological data at the provincial hospital level where most patients are seen., Methods: We conducted a prospective Provincial Hospital-based descriptive surveillance study in adults and children at thirteen hospitals in central and southern Viet Nam between August 2007-April 2010. The pathogens of CNS infection were confirmed in CSF and blood samples by using classical microbiology, molecular diagnostics and serology., Results: We recruited 1241 patients with clinically suspected infection of the CNS. An aetiological agent was identified in 640/1241 (52%) of the patients. The most common pathogens were Streptococcus suis serotype 2 in patients older than 14 years of age (147/617, 24%) and Japanese encephalitis virus in patients less than 14 years old (142/624, 23%). Mycobacterium tuberculosis was confirmed in 34/617 (6%) adult patients and 11/624 (2%) paediatric patients. The acute case fatality rate (CFR) during hospital admission was 73/617 (12%) in adults and to 42/624 (7%) in children., Conclusions: Zoonotic bacterial and viral pathogens are the most common causes of CNS infection in adults and children in Viet Nam.