The challenge of enteric fever
Introduction
Enteric fever is a systemic infection caused by Salmonella enterica subspecies enterica serovars Typhi (S. Typhi, causing typhoid fever) or Paratyphi A, B or C (S. Paratyphi A, B or C, causing paratyphoid fever). Enteric fever is common in resource-poor regions of the world, where poor sanitation and inadequate clean water provision facilitate the spread of infection via faeco-oral transmission.
Enteric fever produces a wide range of non-specific symptoms and is clinically indistinguishable from many other diseases, both infectious and non-infectious. Prompt treatment minimises illness severity, but late presentation to health care facilities often delays initiation of appropriate antibiotic therapy. Treatment delay is compounded by a lack of reliable diagnostic tests.
Although typhoid could be controlled by improvements in public infrastructure (for example, clean water and separate sewage systems), the significant funding investments required in many regions are unlikely to be forthcoming in the near future. Fortunately, disease control in the interim may be possible through effective vaccination. Indeed, prevention of typhoid fever has been attempted through vaccination for over 100 years.1 Three licensed vaccines for typhoid fever exist, but are only moderately efficacious and unsuitable for infant immunisation. There are currently no licensed vaccines to prevent paratyphoid infection. The implementation of existing vaccines and development of new efficacious vaccines has been hindered by a lack of understanding of typhoid immunobiology. S. Typhi and Paratyphi are human restricted pathogens and require a relatively high dose to cause infection. Consequently the development of a suitable vaccine could lead to the eradication of enteric fever. To reach this goal, an improved understanding of the immunobiology of typhoid fever is needed.
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Epidemiology
Typhoid fever is estimated to affect at least 26.9 million people per year, of whom 1% will die.2 Paratyphoid fever has been estimated to affect 5.4 million people per year,3 and appears to be increasingly prevalent, with recent reports attributing up to half of all enteric fever cases to paratyphoid infection in some Asian countries.4, 5 The incidence of paratyphoid fever in returning travellers is also increasing.6, 7 The majority of the global disease burden is borne by children and
Acute typhoid fever
Enteric fever is a highly variable, non-specific illness. Typhoid fever and paratyphoid fever cannot be distinguished on clinical grounds.6 Fever is the most frequent and universal symptom with other frequent symptoms being malaise, chills, anorexia, diarrhoea, headache, weight loss, abdominal pain and rash.23, 24 Nausea, constipation, myalgia, arthralgia and cough are also reported.25, 26, 27 Severity of symptoms is highly variable, with some patients able to continue normal activity and some
Chronic carriage
In 1902, Robert Koch postulated that healthy people could carry disease causing organisms and serve as reservoirs of infection.29 Applying this idea to typhoid fever, Koch noted that humans were the only source of S. Typhi, and hypothesised that a carrier state could bridge the gap between one typhoid outbreak and the next. Prospective studies of patients with typhoid fever in Germany confirmed this, with identification of ongoing excretion of S. Typhi in the stool of symptomatic individuals.29
Diagnosis
Prompt diagnosis and treatment of typhoid fever decreases disease complications and limits opportunity for disease spread.12 Achieving a prompt and reliable diagnosis is difficult however. Enteric fever leads to a diverse range of clinical symptoms and signs, and cannot be reliably distinguished on clinical grounds from other diseases that are common in endemic regions, including malaria, tuberculosis, dengue fever and brucellosis.12 Diagnostic tests that are both sensitive and specific are
Sanitation and clean water
Endemic enteric fever results from a lack of basic hygiene and sanitation infrastructure which facilitates disease spread. The importance of sanitation and clean water in the prevention of endemic typhoid fever has long been recognised.67 During the early part of the 20th century, resource-rich countries saw a marked decline in the incidence of typhoid fever following the routine provision of sanitation and clean water, along with the advent of antibiotics that limited infectivity.68, 69
Novel vaccine strategies
The development of novel vaccines has been facilitated by scientific advances allowing precise manipulation of bacteria to introduce attenuating mutations.123 Approaches to strain attenuation, including mutations in biochemical pathways, heat shock proteins, regulatory genes and putative virulence genes have all been tried. The availability of the complete genome of strain CT 18124 and subsequently of Ty2125 has facilitated this approach. Despite these advances, the lack of an animal model in
Controlled human infection studies with Salmonella Typhi
Animal models of typhoid fever are limited in their applicability to human infection as S. Typhi is a human restricted pathogen. In order to assess typhoid fever vaccines quantitatively,158 controlled human infection experiments with S. Typhi were conducted at the University of Maryland from the 1950s to the 1970s.119 As well as permitting the investigation of typhoid vaccines, these investigations allowed insights into the disease and its pathogenesis to be gained.159, 160 Since that time,
Establishing a 21st century challenge model
Novel, affordable typhoid vaccines with improved efficacy over existing vaccines that can be used in infants are desperately needed. Vaccine development is a long, costly and challenging process with many potential vaccines failing to progress on the path to licensure.164 The poor understanding of typhoid immunobiology, and, in particular, the absence of a correlate of protection for typhoid fever that could be used in efficacy trials was highlighted as a rate-limiting factor in the slow
Conclusion
Infections caused by S. Typhi and S. Paratyphi cause a considerable world-wide burden of disease. Clinical diagnosis is difficult and reliable diagnostic tests are not available. Moderately efficacious vaccines against typhoid fever are available today but have not been widely deployed and none are suitable for young children. Novel vaccines are needed, and there are several promising strategies on the horizon. However, as a human restricted pathogen, clinically relevant models for appraising
Conflict of interest
The authors have no conflict of interest to report.
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