Academic literature on the topic 'Enteric Fever and Hepatomegaly'

Enteric (or typhoid) fever is a systemic infection mainly caused by Salmonella Typhi and Salmonella Paratyphi A. The disease is common in areas with poor water quality and insufficient sanitation. Humans are the only reservoir for transmission of the disease. The presence of asymptomatic chronic carriers is a complicating factor for the transmission. There are major limitations regarding the current diagnostic methods both for acute infection and chronic carriage. Metabolomics is a methodology studying metabolites in biological systems under influence of environmental or physiological perturbations. It has been applied to study several infectious diseases, with the goal of detecting diagnostic biomarkers. In this thesis, a mass spectrometry-based metabolomics approach, including chemometric bioinformatics techniques for data analysis, has been used to evaluate the potential of metabolite biomarker patterns for diagnosis of enteric fever at different stages of the disease. In Paper I, metabolite patterns related to acute enteric fever were investigated. Human plasma samples from patients in Nepal with culture-confirmed S. Typhi or S. Paratyphi A infection were compared to afebrile controls. A metabolite pattern discriminating between acute enteric fever and afebrile controls, as well as between the two causative agents of enteric fever was detected. The strength of using a panel of metabolites instead of single metabolites as biomarkers was also highlighted. In Paper II, metabolite patterns for acute enteric fever, this time focusing only on S. Typhi infections, were investigated. Human plasma from patients in Bangladesh with culture-positive or -negative but clinically suspected S. Typhi infection were compared to febrile controls. Differences were found in metabolite patterns between the culture-positive S. Typhi group and the febrile controls with a heterogeneity among the suspected S. Typhi samples. Consistencies in metabolite patterns were found to the results from Paper I. In addition, a validation cohort with culture-positive S. Typhi samples and a control group including patients with malaria and infections caused by other pathogens was analysed. Differences in metabolite patterns were detected between S. Typhi samples and all controls as well as between S. Typhi and malaria. Consistencies in metabolite patterns were found to the primary Bangladeshi cohort and the Nepali cohort from Paper I. Paper III focused on chronic Salmonella carriers. Human plasma samples from patients in Nepal undergoing cholecystectomy with confirmed S. Typhi or S. Paratyphi A gallbladder carriage were compared to non-carriage controls. The Salmonella carriage samples were distinguished from the non-carriage controls and differential signatures were also found between the S. Typhi and S. Paratyphi A carriage samples. Comparing metabolites found during chronic carriage and acute enteric fever (in Paper I) resulted in a panel of metabolites significant only during chronic carriage. This work has contributed to highlight the potential of using metabolomics as a tool to find diagnostic biomarker patterns associated with different stages of enteric fever.

Enteric fever caused by Salmonella enterica serovars Typhi and Paratyphi A are a major public health concern in Kathmandu. The aim of this thesis was to identify and assess the population most at risk by investigating epidemiologic trends of enteric fever within a subset population of Kathmandu. Therefore,the burden and incidence of enteric fever within the study population and the seasonal and gender distribution of enteric fever was assessed. Considerable burden of enteric fever, unrelated to population density, correlating with the seasonal fluctuations in rainfall was observed. This thesis also aimed to improve the understanding of enteric fever transmission by identifying probable transmission routes,hence various water and food samples were analysed and the extent of faecal contamination in them was determined. S. Typhi isolates were sequenced and genotyped and combined with GPS data to longitudinally study the local distribution and infer transmission of this human restricted bacterial pathogen. Extensive clustering of typhoid independent of population size and density and existence of an extensive range of genotypes within typhoid clusters including individual households with multiple cases was observed. These observations predict that indirect transmission had an overwhelming contribution for disease persistence, potentially through contaminated water. Consistent with this hypothesis, S. Typhi and S. Paratyphi A were detected in water supplies and it was observed that typhoid was spatially associated with public water sources and low elevation. A concurrent case-control study was also conducted which allowed for the determination of risk factors in the population at risk. These studies imply that resources should be allocated toward controlling the most important vectors of enteric fever, including food sold by vendors, chlorination of drinking water, construction of proper water distribution and sewage networks,vaccination campaigns and hygiene education.

Typhoid fever is a life-threating systemic infection caused by <i>Salmonella enterica</i> sub-species <i>enterica</i> serovars Typhi (<i>S.</i> Typhi) and Paratyphi A (<i>S.</i> Paratyphi A). While the disease is mainly travel-associated in developed countries, it still causes significant burden in the poorest areas in developing countries where safe water and adequate sanitation and food hygiene remain limited. Typhoid management largely relies on antimicrobial therapy; however, antimicrobial resistance (AMR) in these causative pathogens has become a global threat, compromising the effectiveness of the treatment therapy and signifying the burden of this disease. Understanding the epidemiology of typhoid fever in different endemic settings as well as the impact of AMR on the disease outcome is crucial for disease control and management. First, this thesis utilized whole genome sequences of <i>S.</i> Typhi combined with clinical data from a randomized controlled trial to investigate the impact of AMR and bacterial genotype on the disease outcome. A novel subclade of ciprofloxacin-resistant H58 <i>S.</i> Typhi associated with increased treatment failure was identified and these organisms were likely widespread in Indian subcontinent. Subsequently, this study combined bacterial genomics with conventional epidemiological tools to reveal the population structure and spatiotemporal dynamics of <i>S.</i> Paratyphi A isolates in Nepal. The Nepalese <i>S.</i> Paratyphi A population was highly dynamic with evidences of regular inter-country transmission, clonal expansion and replacement of distinct genotypes during the study period. A number of localized spatiotemporal clusters of <i>S.</i> Paratyphi A cases were also identified. A molecular epidemiological investigation was also performed to provide insights into the AMR, epidemiological features and population structure and dynamics of <i>S.</i> Typhi in rural areas of Siem Reap, Cambodia. A substantial burden of pediatric typhoid fever was revealed and communes with high-risk of infection were identified. Multidrug resistant H58 <i>S.</i> Typhi with reduced susceptibility to fluoroquinolones was dominant in this setting. This study also investigated the phylogenetic relationship between acute and carriage <i>S.</i> Typhi isolates in Nepal and deciphered the genetic characteristics associated with carriage isolates. My study suggested that typhoid carriage was likely not an important source of new infections in endemic area.

Enteric fever continues to affect people living in endemic settings substantially causing at least 20 million cases of febrile illnesses every year with 1% mortality. Over the last decade there has been considerable debate surrounding the burden and disease profile of enteric fever in the paediatric population. This is partially due to the similarity of the clinical features of paediatric enteric fever to most other febrile illness seen in endemic settings. The treatment of enteric fever is proving to be a challenge with the emergence of antimicrobial resistant strains, particularly the 4.3.1 genotype (H58 haplotype), which is spreading rapidly. Multi-drug resistant (MDR) enteric fever, defined as infection with typhoidal Salmonellae that exhibit a combined resistance to ampicillin, cotrimoxazole and chloramphenicol emerged in the 1990s and was mediated primarily via the 4.3.1 genotype population through the horizontal acquisition of antimicrobial resistance determinants. Subsequently, fluoroquinolones became the drug of choice and the treatment of enteric fever following which fluoroquinolone resistance emerged, again through the 4.3.1 genotype. However, these antimicrobial trends may not be uniform across endemic regions and an understanding of these differing patterns as well the temporal changes in these trends are important in planning treatment strategies. In the short and medium term work needs to be focused on achieving the greatest benefits from the prudent use of the recently WHO pre-qualified Vi-TT conjugate vaccine candidate. Whilst the long term vision towards eradicating enteric fever needs to focus on better understanding the underlying the biology of this disease through the use of contemporary technologies while simultaneously improving infrastructure for the provision of clean water, adequate sanitation and hygiene. This thesis aims to age-characterise the disease burden of typhoid fever in endemic regions of South and South-East Asia as well as the African continent. Following this, the molecular epidemiology of enteric fever in two endemic settings in the Indian subcontinent is delineated with a keen focus on the 4.3.1 genotype (H58) population as well the phenotypic patterns and molecular determinants of antimicrobial resistance. This thesis finally systematically reviews the global trends of antimicrobial resistance of S. Typhi isolates over time both from a phenotypic and molecular perspective. The key results from this thesis include; the age stratification of disease occurrence in endemic regions which showed a substantial proportion occurs in the youngest age group in both Africa and Asia, the uniform dominance of 4.3.1 genotypes conferring a high degree of fluoroquinolone resistance contrary to earlier suggestions of younger children being more susceptible to a broader range of infecting genotypes, the dissimilarities between the antimicrobial resistance carrying capabilities of lineage I and lineage II strains of the 4.3.1 genotype as well as novel AMR gene arrangements and finally the temporal trends of AMR in S. Typhi which were different between Asia an Africa. The high prevalence of lineage I strains in Africa and South-East Asia in contrast to the high prevalence of lineage II strains in the Indian subcontinent reflect the antimicrobial selection pressures as well the evolutionary characteristics of circulating pathogen populations in these regions. The implications of the data reported in this thesis have implications for treatment and prevention strategies. For the first time in history an opportunity has risen to effectively vaccinate the youngest age group (0-4 years) from typhoid through the Vi-TT conjugate vaccine. As highlighted in this thesis the youngest age group (0-4 years) have a high disease occurrence in endemic areas as seen in a meta-analysis as well as through data from two endemic sites collated and reported in this thesis. The older age groups also suffer greatly from this disease calling for a broad based vaccine strategy. The implications for treatment of enteric fever are however more relevant in the immediate term which suggest that in endemic regions in Asia, fluoroquinolones have little role to play in treatment protocols while fluoroquinolones are still relevant in the African setting. In Asia, reverting back to former first-line antimicrobials might be an option but the possibility of re-emergence of widespread resistance to these currently sensitive antimicrobials is very high exemplifying the ability of S. Typhi to adapt to changing antimicrobial pressures.

Enteric fever remains the most common febrile illness in urban Nepal. Some individuals may have recurrent infection and some may even progress to become long term chronic carriers. The aim of this thesis was to investigate the rate and factors leading to relapse with typhoid fever in patients who were enrolled in clinical treatment trials for acute enteric fever. The results show that relapses in enteric fever is a common complication and is more likely to be associated with the treatment antimicrobial, cefixime. Gallbladder carriage of invasive Salmonella is considered fundamental in sustaining enteric fever transmission as humans are the only known natural host. This thesis, therefore, also aimed to investigate the prevalence, characteristics, immunological responses, and mechanism of carriage of invasive Salmonella in the gallbladder by examining bile and tissue obtained from individuals who underwent cholecystectomy in Kathmandu. Data presented here demonstrate that S. Paratyphi A is almost as prevalent as S. Typhi in the gallbladder and that carriage may not be driven by antimicrobial resistance. Gallbladders that contained Salmonella were more likely to show evidence of acute inflammation with extensive neutrophil infiltrate. Chronic carriers were found to have dramatically elevated levels of IgG to O:2 and Vi antigens with high bactericidal activity yet low pro-inflammatory cytokine levels suggesting that Salmonella are stimulating a constant immunological response, in the form of antibody. S. Typhi may be controlling the inflammatory process through the expression of the Vi capsule in the gallbladder. Genome sequencing of S. Typhi isolated from chronic carriers were different from those S. Typhi causing acute disease. These data question the current dogmas surrounding the carriage of S. Typhi in gallbladder and predict a pivotal role of Vi capsule and gallstones in maintaining carriage. Therefore, prospectively identifying these individuals is paramount for rapid local and regional elimination. Furthermore, combining cytokine profiles and antibody levels may be a method of prospectively detecting carriers in the general population.

Typhoid disease, caused by infection with S. Typhi, is a significant cause of mortality and morbidity in resource–poor countries. Efforts have been made to generate a new generation of vaccines that are efficacious and can be given to infants, but have been hindered by a poor understanding of the protective immune response to S. Typhi infection, and in particular by the absence of a correlate of protection. Controlled human infection studies (‘challenge studies’) provide a model for investigating infectious diseases and appraising novel vaccines, including in typhoid disease. This DPhil described the development of a human challenge model of typhoid fever using <en>S. Typhi Quailes strain administered to healthy adults in a sodium bicarbonate buffer. The careful characterisation and manufactured of the strain is described. Following ingestion of 10³ CFU of S. Typhi 55% of participants developed typhoid disease, whilst ingestion of 10⁴ CFU gave a higher attack rate of 65%. At this attack rate vaccine efficacy against human challenge should be demonstrable with a modest sample size. Validity of the model in the appraisal of vaccines was demonstrated using Ty21a, a live, oral, attenuated vaccine. Protective efficacy of Ty21a compared to placebo against challenge was 35%, comparable to that observed in some endemic settings, and the estimated protection in the first year after vaccination in Cochrane meta-analysis. Clinical, microbiological and humoral immune responses were investigated in participants challenged during model development. Typhoid disease was associated with a high fever in most, but not all participants, and a range of symptoms. Severity of disease was variable, and included asymptomatic bacteraemia, as well as fever and symptoms in participants in whom bacteraemia could not be demonstrated. Typhoid disease was associated with a strong humoral immune response to the flagellin and lipopolysaccharide antigens of S. Typhi but not the Vi polysaccharide capsule. Humoral immune responses were not demonstrated in participants without typhoid fever. There was a dose-response relationship to the clinical, microbiological and humoral responses with participants challenged with 10⁴ CFU having more marked responses than those challenged with 10³ CFU. Future success of challenge studies relies on the willing participation of healthy adult volunteers. The motivations for participation, and experiences of participants, were appraised by questionnaire. Whilst financial compensation was an important motivator, it was not the sole motivator. Participants were positive about their experiences, and most would participate again.