title: An investigation into clinical, epidemiological and genomic changes in epidemic Salmonella blood stream infection in Malawi
Creators: name: Feasey, Nicholas
Publisher: name: University of Liverpool Repository
Year: 2014

description: Bloodstream infection (BSI) caused by nontyphoidal serotypes of Salmonella is one of the most important causes of morbidity and mortality in sub-Saharan Africa (SSA). Invasive nontyphoidal Salmonella disease (iNTS) is especially associated with HIV in adults and HIV, malaria and malnutrition in children in this setting. HIV-infected subjects are at particular risk of recurrent disease, both from recrudescence from a sanctuary site and re-infection. Whole- genome sequencing has revealed a novel sequence type (ST) of S. Typhimurium, ST313, is particularly associated with iNTS in SSA and that ST313 display the genomic signature of differential host adaptation. Little is known about African strains of S. Enteritidis. The Malawi Liverpool Wellcome Trust Clinical Research Programme (MLW) has conducted BSI surveillance in adult and paediatric medical patients in Blantyre, Malawi since 1998, enabling long term trends in iNTS to be described. Paediatric iNTS disease has been placed in the context of malaria, malnutrition and seasonality using structural equation modelling. An observational cohort was recruited to describe changes in adult BSI cases following the roll-out of ART in Blantyre. A longitudinal cohort study with enhanced microbiological surveillance was undertaken to investigate the site of persistence of NTS in HIV infected adults and the effect of recurrence upon the emergence of antimicrobial resistance. Lastly whole-genome sequencing was undertaken to compare invasive, African strains of S. Enteritidis with a reference isolate and to construct a global phylogeny of this serotype. There have been three epidemics of invasive Salmonella disease in Blantyre, all of which were preceded by the emergence of a multidrug resistant (MDR) strain. These were caused initially by S. Enteritidis which was then followed by S. Typhimurium, but most recently an epidemic of MDR S. Typhi has started. NTS has declined from epidemic levels, but remains an important cause of BSI in Blantyre and has been demonstrated to acquire cephalosporin iv and fluoroquinolone resistance just once through an IncHI2 plasmid. The decline in paediatric malaria is complex and multi-factorial. It cannot be attributed solely to malaria control interventions as has been the case in other settings. All causes of BSI are falling in adults and this is likely to be attributable in part to the hugely successful HIV treatment programme in Blantyre. The rapid initiation of ART appears to rapidly confer protection against recurrence of iNTS and even though more adult patients are surviving into convalescence, in this cohort, no further emergence of extended resistance was seen. Just as there is a distinct African clade of S. Typhimurium, a distinct clade of S. Enteritidis has emerged in SSA, which also possess the genomic signature of differential host adaptation, a novel prophage repertoire and a novel, MDR plasmid. In Blantyre, iNTS disease has declined from its epidemic peaks, but remains an important cause of BSI. The epidemiology of iNTS is more complex in Blantyre than other settings, but it seems likely that improved in-patient care and measures to control the HIV-pandemic impact on survival and recurrence. Two clades of NTS have emerged from host promiscuous serotypes, both of which have genomic degradation in genes governing potential host range and there is a critical need to understand the environmental niches and transmission pathways of these differentially adapted, invasive clades.