Typhoid fever

Summary

Control of typhoid fever relies on clinical information, diagnosis, and an understanding for the epidemiology of the disease. Despite the breadth of work done so far, much is not known about the biology of this human-adapted bacterial pathogen and the complexity of the disease in endemic areas, especially those in Africa. The main barriers to control are vaccines that are not immunogenic in very young children and the development of multidrug resistance, which threatens efficacy of antimicrobial chemotherapy. Clinicians, microbiologists, and epidemiologists worldwide need to be familiar with shifting trends in enteric fever. This knowledge is crucial, both to control the disease and to manage cases. Additionally, salmonella serovars that cause human infection can change over time and location. In areas of Asia, multidrug-resistant Salmonella enterica serovar Typhi (S Typhi) has been the main cause of enteric fever, but now S Typhi is being displaced by infections with drug-resistant S enterica serovar Paratyphi A. New conjugate vaccines are imminent and new treatments have been promised, but the engagement of local medical and public health institutions in endemic areas is needed to allow surveillance and to implement control measures.

Introduction

Knowledge of the burden of disease is crucial for several reasons—first, data for effects of the disease on human health and the local economy are essential to inform decision-makers in public health; second, information about local trends is necessary to allocate resources; and third, understanding of local and regional disease trends is needed to provide informed guidance to travellers. Global estimates for the burden of typhoid fever (defined as symptomatic infection with S Typhi) are published regularly (26·9 million cases of typhoid fever were reported in 2010¹) and general mortality data are available from global and regional mortality studies (figure 1).² However, detailed local surveillance data from endemic regions remain poor. In this article, we provide an update on the previous Seminar by providing an update on information on typhoid fever in endemic regions of the world.

Recent reviews of diagnosis and treatment of typhoid fever3, 4 make it clear that the laboratory diagnosis of typhoid fever is largely dependent on the detection of organisms in blood by PCR (best suited to epidemiological surveys) or culture (although sensitivity remains a limitation).4, 5, 6 The Widal test for antibody production is unreliable and new-generation serology tests such as typhidot and tubex have not proved reliable in Africa7, 8, 9 or Asia.10, 11 One new test format that shows promise is the typhoid–paratyphoid diagnostic assay,¹² which detects IgA. This method has specificity of detection of circulating IgA for the diagnosis of typhoid fever with use of ELISA¹¹ and improves the sensitivity (to 100%) through amplification of the signal by isolation and incubation of peripheral blood lymphocytes.¹³ Treatment with fluoroquinolones, azithromycin, and third-generation cephalosporin drugs is the main treatment, with chloramphenicol used in regions in which susceptible strains are present (panel 1).⁸

Despite the genetic similarity of S Typhi and S enterica serovar Typhimurium (90% of genes are shared), understanding is poor for the genetic differences that underlie the ability of S Typhi, but not S Typhimurium, to cause enteric fever.¹⁵ Large-scale transposon knockout libraries¹⁶ allow researchers to assess function at the genome level and show differences between S Typhi and S Typhimurium.¹⁷ The same genes in S Typhi and S Typhimurium might have different regulatory pathways and possibly different functions.¹⁸ This exciting new technology might provide targets for vaccine development and new antibacterial drugs for S Typhi in endemic regions. The investigation of why S Typhi infects human beings, but not mice, has led to the development of two mouse-studies for typhoid fever: one is based on mice grafted with human haemopoietic stem cells¹⁹ and the other is based on mice grafted with bacterial flagella recognition cells with Toll-like receptor-11 knockouts.²⁰ Research has also led to the description of gtgE, a virulence gene present in S Typhimurium but not in S Typhi that allows S Typhi to infect mouse macrophages. Although still to be verified, these models could allow the previously impossible investigation of pathogenesis and immunity for this human-restricted pathogen. The importance of these new models is shown by the use of the humanised mouse model to describe receptor-binding specificity and delivery mechanisms for the typhoid toxin encoded by ctdB and pltA²¹ and so to define a potential new vaccine target.