Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Primer
  • Published:

Typhoid fever

Abstract

Typhoid fever is an invasive bacterial disease associated with bloodstream infection that causes a high burden of disease in Africa and Asia. Typhoid primarily affects individuals ranging from infants through to young adults. The causative organism, Salmonella enterica subsp. enterica serovar Typhi is transmitted via the faecal–oral route, crossing the intestinal epithelium and disseminating to systemic and intracellular sites, causing an undifferentiated febrile illness. Blood culture remains the practical reference standard for diagnosis of typhoid fever, where culture testing is available, but novel diagnostic modalities are an important priority under investigation. Since 2017, remarkable progress has been made in defining the global burden of both typhoid fever and antimicrobial resistance; in understanding disease pathogenesis and immunological protection through the use of controlled human infection; and in advancing effective vaccination programmes through strategic multipartner collaboration and targeted clinical trials in multiple high-incidence priority settings. This Primer thus offers a timely update of progress and perspective on future priorities for the global scientific community.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Global incidence of typhoid fever.
Fig. 2: S. Typhi genotype prevalence by world region.
Fig. 3: Pathogenesis of typhoid fever following pathogen ingestion.
Fig. 4: Clinical signs and symptoms of typhoid fever.

Similar content being viewed by others

References

  1. Dougan, G. & Baker, S. Salmonella enterica serovar Typhi and the pathogenesis of typhoid fever. Annu. Rev. Microbiol. 68, 317–336 (2014).

    Article  CAS  PubMed  Google Scholar 

  2. World Health Organization. Typhoid: vaccine preventable diseases surveillance standards. WHO https://www.who.int/publications/m/item/vaccine-preventable-diseases-surveillance-standards-typhoid (2018).

  3. Basnyat, B., Qamar, F. N., Rupali, P., Ahmed, T. & Parry, C. M. Enteric fever. BMJ 372, n437 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Von Drigalski, K. W. Ueber Ergebnisse bei der Bekämpfung des Typhus nach Robert Koch [German]. Zentralbl. Bakteriol. 35, 776 (1904).

    Google Scholar 

  5. Kirchhelle, C., Pollard, A. J. & Vanderslott, S. Typhoid – from past to future. Clin. Infect. Dis. 69, S375–s376 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  6. Ames, W. R. & Robins, M. Age and sex as factors in the development of the typhoid carrier state, and a method for estimating carrier prevalence. Am. J. Public. Health Nations Health 33, 221–230 (1943).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Antillon, M., Saad, N. J., Baker, S., Pollard, A. J. & Pitzer, V. E. The relationship between blood sample volume and diagnostic sensitivity of blood culture for typhoid and paratyphoid fever: a systematic review and meta-analysis. J. Infect. Dis. 218, S255–S267 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  8. Nizamuddin, S., Khan, E. A., Chattaway, M. A. & Godbole, G. Case of carbapenem-resistant Salmonella Typhi infection, Pakistan, 2022. Emerg. Infect. Dis. J. 29, 2395–2397 (2023).

    Article  Google Scholar 

  9. Phillips, M. T., Owers, K. A., Grenfell, B. T. & Pitzer, V. E. Changes in historical typhoid transmission across 16 U.S. cities, 1889-1931: quantifying the impact of investments in water and sewer infrastructures. PLoS Negl. Trop. Dis. 14, e0008048 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  10. Vanderslott, S., Phillips, M. T., Pitzer, V. E. & Kirchhelle, C. Water and filth: reevaluating the first era of sanitary typhoid intervention (1840-1940). Clin. Infect. Dis. 69, S377–S384 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  11. GBD 2017 Typhoid and Paratyphoid Collaborators The global burden of typhoid and paratyphoid fevers: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Infect. Dis. 19, 369–381 (2019).

    Article  Google Scholar 

  12. Crump, J. A. Progress in typhoid fever epidemiology. Clin. Infect. Dis. 68, S4–S9 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Appiah, G. D. et al. Typhoid outbreaks, 1989-2018: implications for prevention and control. Am. J. Trop. Med. Hyg. 102, 1296–1305 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Reller et al. Presented at the 39th Annual Meeting of the Infectious Diseases Society of America (2022).

  15. Mitscherlich, E. & Marth, E. H. Microbial survival in the environment (eds Mitscherlich, E. & Marth E.H.) 1–560 (Springer, 1984).

  16. Cho, J.-C. & Kim, S. J. Viable, but non-culturable, state of a green fluorescence protein-tagged environmental isolate of Salmonella Typhi in groundwater and pond water. FEMS Microbiol. Lett. 170, 257–264 (1999).

    Article  CAS  PubMed  Google Scholar 

  17. Kingsley, R. A. et al. Functional analysis of Salmonella Typhi adaptation to survival in water. Env. Microbiol. 20, 4079–4090 (2018).

    Article  CAS  Google Scholar 

  18. Andrews, J. R. et al. Environmental surveillance as a tool for identifying high-risk settings for typhoid transmission. Clin. Infect. Dis. 71, S71–S78 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Deen, J. et al. Community-acquired bacterial bloodstream infections in developing countries in south and southeast Asia: a systematic review. Lancet Infect. Dis. 12, 480–487 (2012).

    Article  PubMed  Google Scholar 

  20. Reddy, E. A., Shaw, A. V. & Crump, J. A. Community acquired bloodstream infections in Africa: a systematic review and meta-analysis. Lancet Infect. Dis. 10, 417–432 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  21. Marchello, C. S., Dale, A. P., Pisharody, S., Rubach, M. P. & Crump, J. A. Prevalence of community-onset bloodstream infections among hospitalized patients in Africa and Asia: a systematic review and meta-analysis. Antimicrob. Agents Chemother. 64, e01974-19 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  22. Garrett, D. O. et al. Incidence of typhoid and paratyphoid fever in Bangladesh, Nepal, and Pakistan: results of the Surveillance for Enteric Fever in Asia Project. Lancet Glob. Health 10, e978–e988 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Marks, F. et al. The Severe Typhoid in Africa Program: incidences of typhoid fever in Burkina Faso, Democratic Republic of Congo, Ethiopia, Ghana, Madagascar, and Nigeria. Preprint at https://ssrn.com/abstract=4292849 (2022).

  24. Marks, F. et al. Incidence of invasive Salmonella disease in sub-Saharan Africa: a multicentre population-based surveillance study. Lancet Glob. Health 5, e310–e323 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  25. Meiring, J. E. et al. Burden of enteric fever at three urban sites in Africa and Asia: a multicentre population-based study. Lancet Glob. Health 9, e1688–e1696 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. John, J. et al. Burden of typhoid and paratyphoid fever in India. N. Engl. J. Med. 388, 1491–1500 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Crump, J. A., Luby, S. P. & Mintz, E. D. The global burden of typhoid fever. Bull. World Health Organ. 82, 346–353 (2004).

    PubMed  PubMed Central  Google Scholar 

  28. Antillón, M. et al. The burden of typhoid fever in low- and middle-income countries: a meta-regression approach. PLoS Negl. Trop. Dis. 11, e0005376 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Mogasale, V. et al. Burden of typhoid fever in low-income and middle-income countries: a systematic, literature-based update with risk-factor adjustment. Lancet Glob. Health 2, e570–e580 (2014).

    Article  PubMed  Google Scholar 

  30. Buckle, G. C., Walker, C. L. & Black, R. E. Typhoid fever and paratyphoid fever: systematic review to estimate global morbidity and mortality for 2010. J. Glob. Health 2, 10401 (2012).

    Article  Google Scholar 

  31. Institute of Health Metrics and Evaluation. Global incidence of typhoid fever. IHME https://vizhub.healthdata.org/gbd-compare/ (2019).

  32. Crump, J. A. & Kirk, M. D. Estimating the burden of febrile illnesses. PLoS Negl. Trop. Dis. 9, e0004040 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  33. Marchello, C. S., Hong, C. Y. & Crump, J. A. Global typhoid fever incidence: a systematic review and meta-analysis. Clin. Infect. Dis. 68, S105–S116 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  34. Crump, J. A. et al. Estimating the incidence of typhoid fever and other febrile illnesses in developing countries. Emerg. Infect. Dis. 9, 539–544 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  35. Marchello, C. S., Birkhold, M. & Crump, J. A. Complications and mortality of typhoid fever: a global systematic review and meta-analysis. J. Infect. 81, 902–910 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  36. Gibani, M. M. et al. Homologous and heterologous re-challenge with Salmonella Typhi and Salmonella Paratyphi A in a randomised controlled human infection model. PLoS Negl. Trop. Dis. 14, e0008783 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Im, J. et al. Protection conferred by typhoid fever against recurrent typhoid fever in urban Kolkata. PLoS Negl. Trop. Dis. 14, e0008530 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  38. Brockett, S. et al. Associations among water, sanitation, and hygiene, and food exposures and typhoid fever in case-control studies: a systematic review and meta-analysis. Am. J. Trop. Med. Hyg. 103, 1020–1031 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  39. Tadesse, B. T. et al. Prevention of typhoid by Vi conjugate vaccine and achievable improvements in household water, sanitation, and hygiene: evidence from a cluster-randomized trial in Dhaka, Bangladesh. Clin. Infect. Dis. 75, 1681–1687 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  40. Gunn, J. S. et al. Salmonella chronic carriage: epidemiology, diagnosis, and gallbladder persistence. Trends Microbiol. 22, 648–655 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Dunstan, S. J. et al. Variation at HLA-DRB1 is associated with resistance to enteric fever. Nat. Genet. 46, 1333–1336 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Saad, N. J. et al. Seasonal dynamics of typhoid and paratyphoid fever. Sci. Rep. 8, 6870 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  43. Thindwa, D., Chipeta, M. G., Henrion, M. Y. R. & Gordon, M. A. Distinct climate influences on the risk of typhoid compared to invasive non-typhoid Salmonella disease in Blantyre, Malawi. Sci. Rep. 9, 20310 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Levy, K., Smith, S. M. & Carlton, E. J. Climate change impacts on waterborne diseases: moving toward designing interventions. Curr. Env. Health Rep. 5, 272–282 (2018).

    Article  Google Scholar 

  45. Gao, Q. et al. Impact of temperature and rainfall on typhoid/paratyphoid fever in Taizhou, China: effect estimation and vulnerable group identification. Am. J. Trop. Med. Hyg. 106, 532–542 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Hickman-Brenner, F. W. & Farmer, J. J. III Bacteriophage types of Salmonella typhi in the United States from 1974 through 1981. J. Clin. Microbiol. 17, 172–174 (1983).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Chattaway, M. A., Langridge, G. C. & Wain, J. Salmonella nomenclature in the genomic era: a time for change. Sci. Rep. 11, 7494 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Wong, V. K. et al. Phylogeographical analysis of the dominant multidrug-resistant H58 clade of Salmonella Typhi identifies inter- and intracontinental transmission events. Nat. Genet. 47, 632–639 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Tanmoy, A. M. et al. Paratype: a genotyping tool for Salmonella Paratyphi A reveals its global genomic diversity. Nat. Commun. 13, 7912 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Kariuki, S. et al. Multiple introductions of multidrug-resistant typhoid associated with acute infection and asymptomatic carriage, Kenya. Elife 10, e67852 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Dyson, Z. A. et al. Genomic epidemiology and antimicrobial resistance transmission of Salmonella Typhi and Paratyphi A at three urban sites in Africa and Asia. Preprint at medRxiv https://doi.org/10.1101/2023.03.11.23286741 (2023).

  52. Wong, V. K. et al. An extended genotyping framework for Salmonella enterica serovar Typhi, the cause of human typhoid. Nat. Commun. 7, 12827 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Dyson, Z. A. & Holt, K. E. Five years of GenoTyphi: updates to the Global Salmonella Typhi Genotyping Framework. J. Infect. Dis. 224, S775–S780 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  54. Carey, M. E. et al. Global diversity and antimicrobial resistance of typhoid fever pathogens: insights from a meta-analysis of 13,000 Salmonella Typhi genomes. eLife 12, e85867 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  55. da Silva, K. E. et al. The international and intercontinental spread and expansion of antimicrobial-resistant Salmonella Typhi: a genomic epidemiology study. Lancet Microbe 3, e567–e577 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  56. Park, S. E. et al. The phylogeography and incidence of multi-drug resistant typhoid fever in sub-Saharan Africa. Nat. Commun. 9, 5094 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  57. Guevara, P. D. et al. A genomic snapshot of Salmonella enterica serovar Typhi in Colombia. PLoS Negl. Trop. Dis. 15, e0009755 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Maes, M. et al. Whole genome sequence analysis of Salmonella Typhi provides evidence of phylogenetic linkage between cases of typhoid fever in Santiago, Chile in the 1980s and 2010–2016. PLoS Negl. Trop. Dis. 16, e0010178 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Sikorski, M. J. et al. Persistence of rare Salmonella Typhi genotypes susceptible to first-line antibiotics in the remote islands of Samoa. mBio 13, e0192022 (2022).

    Article  PubMed  Google Scholar 

  60. Davies, M. R. et al. Genomic epidemiology of Salmonella Typhi in central division, Fiji, 2012 to 2016. Lancet Reg. Health West. Pac. 24, 100488 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  61. Wirth, T. Massive lineage replacements and cryptic outbreaks of Salmonella Typhi in eastern and southern Africa. Nat. Genet. 47, 565–567 (2015).

    Article  CAS  PubMed  Google Scholar 

  62. Gibani, M. M., Britto, C. & Pollard, A. J. Typhoid and paratyphoid fever: a call to action. Curr. Opin. Infect. Dis. 31, 440–448 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  63. Johnson, R., Mylona, E. & Frankel, G. Typhoidal Salmonella: distinctive virulence factors and pathogenesis. Cell Microbiol. 20, e12939 (2018).

    Article  PubMed  Google Scholar 

  64. McClelland, M. et al. Comparison of genome degradation in Paratyphi A and Typhi, human-restricted serovars of Salmonella enterica that cause typhoid. Nat. Genet. 36, 1268–1274 (2004).

    Article  CAS  PubMed  Google Scholar 

  65. Parkhill, J. et al. Complete genome sequence of a multiple drug resistant Salmonella enterica serovar Typhi CT18. Nature 413, 848–852 (2001).

    Article  CAS  PubMed  Google Scholar 

  66. Holt, K. E. et al. High-throughput bacterial SNP typing identifies distinct clusters of Salmonella Typhi causing typhoid in Nepalese children. BMC Infect. Dis. 10, 144 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  67. Hiyoshi, H., Tiffany, C. R., Bronner, D. N. & Bäumler, A. J. Typhoidal Salmonella serovars: ecological opportunity and the evolution of a new pathovar. FEMS Microbiol. Rev. 42, 527–541 (2018).

    CAS  PubMed  Google Scholar 

  68. Rogers, A. W. L., Tsolis, R. M. & Bäumler, A. J. Salmonella versus the microbiome. Microbiol. Mol. Biol. Rev. 85, e00027-19 (2021).

    Article  PubMed  Google Scholar 

  69. Bronner, D. N. et al. Genetic ablation of butyrate utilization attenuates gastrointestinal Salmonella disease. Cell Host Microbe 23, 266–273.e4 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Winter, S. E. et al. The flagellar regulator TviA reduces pyroptosis by Salmonella enterica serovar Typhi. Infect. Immun. 83, 1546–1555 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Pickard, D. et al. Composition, acquisition, and distribution of the Vi exopolysaccharide-encoding Salmonella enterica pathogenicity island SPI-7. J. Bacteriol. 185, 5055–5065 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Ménard, S. et al. Cross-talk between the intestinal epithelium and Salmonella typhimurium. Front. Microbiol. 13, 906238 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  73. Dillon, A. & Lo, D. D. M cells: intelligent engineering of mucosal immune surveillance. Front. Immunol. 10, 1499 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Watson, K. G. & Holden, D. W. Dynamics of growth and dissemination of Salmonella in vivo. Cell Microbiol. 12, 1389–1397 (2010).

    Article  CAS  PubMed  Google Scholar 

  75. Hart, P. J. et al. Differential killing of Salmonella enterica serovar Typhi by antibodies targeting Vi and lipopolysaccharide O:9 antigen. PLoS ONE 11, e0145945 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  76. Waddington, C. S. et al. An outpatient, ambulant-design, controlled human infection model using escalating doses of Salmonella Typhi challenge delivered in sodium bicarbonate solution. Clin. Infect. Dis. 58, 1230–1240 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Waddington, C. S. et al. Advancing the management and control of typhoid fever: a review of the historical role of human challenge studies. J. Infect. 68, 405–418 (2014).

    Article  PubMed  Google Scholar 

  78. Dobinson, H. C. et al. Evaluation of the clinical and microbiological response to Salmonella Paratyphi a infection in the first paratyphoid human challenge model. Clin. Infect. Dis. 64, 1066–1073 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Darton, T. C. et al. Blood culture-PCR to optimise typhoid fever diagnosis after controlled human infection identifies frequent asymptomatic cases and evidence of primary bacteraemia. J. Infect. 74, 358–366 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  80. Blohmke, C. J. et al. Interferon-driven alterations of the host’s amino acid metabolism in the pathogenesis of typhoid fever. J. Exp. Med. 213, 1061–1077 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Darton, T. C. et al. Rapidly escalating hepcidin and associated serum iron starvation are features of the acute response to typhoid infection in humans. PLoS Negl. Trop. Dis. 9, e0004029 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  82. Darton, T. C. et al. Identification of novel serodiagnostic signatures of typhoid fever using a Salmonella proteome array. Front. Microbiol. 8, 1794 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  83. Blohmke, C. J. et al. Diagnostic host gene signature for distinguishing enteric fever from other febrile diseases. EMBO Mol. Med. 11, e10431 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Song, J., Gao, X. & Galán, J. E. Structure and function of the Salmonella Typhi chimaeric A2B5 typhoid toxin. Nature 499, 350–354 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Del Bel Belluz, L. et al. The typhoid toxin promotes host survival and the establishment of a persistent asymptomatic infection. PLoS Pathog. 12, e1005528 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  86. den Bakker, H. C. et al. Genome sequencing reveals diversification of virulence factor content and possible host adaptation in distinct subpopulations of Salmonella enterica. BMC Genomics 12, 425 (2011).

    Article  Google Scholar 

  87. Rodriguez-Rivera, L. D., Bowen, B. M., den Bakker, H. C., Duhamel, G. E. & Wiedmann, M. Characterization of the cytolethal distending toxin (typhoid toxin) in non-typhoidal Salmonella serovars. Gut Pathog. 7, 19 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  88. Gibani, M. M. et al. Investigation of the role of typhoid toxin in acute typhoid fever in a human challenge model. Nat. Med. 25, 1082–1088 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Pitzer, V. E. et al. Predicting the impact of vaccination on the transmission dynamics of typhoid in South Asia: a mathematical modeling study. PLoS Negl. Trop. Dis. 8, e2642 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  90. Saul, A., Smith, T. & Maire, N. Stochastic simulation of endemic Salmonella enterica serovar Typhi: the importance of long lasting immunity and the carrier state. PLoS ONE 8, e74097 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Gibani, M. M. et al. The impact of vaccination and prior exposure on stool shedding of Salmonella Typhi and Salmonella Paratyphi in 6 controlled human infection studies. Clin. Infect. Dis. 68, 1265–1273 (2019).

    Article  CAS  PubMed  Google Scholar 

  92. Marchello, C. S., Carr, S. D. & Crump, J. A. A systematic review on antimicrobial resistance among Salmonella Typhi worldwide. Am. J. Trop. Med. Hyg. 103, 2518–2527 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Britto, C. D., Wong, V. K., Dougan, G. & Pollard, A. J. A systematic review of antimicrobial resistance in Salmonella enterica serovar Typhi, the etiological agent of typhoid. PLoS Negl. Trop. Dis. 12, e0006779 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Bowe, F. et al. At least four percent of the Salmonella Typhimurium genome is required for fatal infection of mice. Infect. Immun. 66, 3372–3377 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Chau, T. T. et al. Antimicrobial drug resistance of Salmonella enterica serovar Typhi in Asia and molecular mechanism of reduced susceptibility to the fluoroquinolones. Antimicrob. Agents chemother. 51, 4315–4323 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  96. Day, M. R. et al. Comparison of phenotypic and WGS-derived antimicrobial resistance profiles of Salmonella enterica serovars Typhi and Paratyphi. J. Antimicrob. Chemother. 73, 365–372 (2018).

    Article  CAS  PubMed  Google Scholar 

  97. Qamar, F. N. et al. Antimicrobial resistance in typhoidal Salmonella: Surveillance for Enteric Fever in Asia Project, 2016-2019. Clin. Infect. Dis. 71, S276–S284 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Akram, J. et al. Extensively drug-resistant (XDR) typhoid: evolution, prevention, and its management. Biomed. Res. Int. 2020, 6432580 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  99. Posen, H. J. et al. Travel-associated extensively drug-resistant typhoid fever: a case series to inform management in non-endemic regions. J. Travel Med. 30, taac086 (2023).

    Article  PubMed  Google Scholar 

  100. Herdman, M. T. et al. Increasingly limited options for the treatment of enteric fever in travellers returning to England, 2014-2019: a cross-sectional analytical study. J. Med. Microbiol. 70, 001359 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Ashton, P. M. et al. The rapid emergence of Salmonella Typhi with decreased ciprofloxacin susceptibility following an increase in ciprofloxacin prescriptions in Blantyre, Malawi. Preprint at medRxiv https://doi.org/10.1101/2023.03.27.23287794 (2023).

  102. Wijedoru, L., Mallett, S. & Parry, C. M. Rapid diagnostic tests for typhoid and paratyphoid (enteric) fever. Cochrane Database Syst. Rev. 5, CD008892 (2017).

    PubMed  Google Scholar 

  103. Azmatullah, A., Qamar, F. N., Thaver, D., Zaidi, A. K. & Bhutta, Z. A. Systematic review of the global epidemiology, clinical and laboratory profile of enteric fever. J. Glob. Health 5, 020407 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  104. Aiemjoy, K. et al. Diagnostic value of clinical features to distinguish enteric fever from other febrile illnesses in Bangladesh, Nepal, and Pakistan. Clin. Infect. Dis. 71, S257–S265 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  105. Andrews, J. R. et al. High rates of enteric fever diagnosis and lower burden of culture-confirmed disease in peri-urban and rural Nepal. J. Infect. Dis. 218, S214–S221 (2018).

    Article  PubMed  Google Scholar 

  106. Wain, J. et al. Quantitation of bacteria in blood of typhoid fever patients and relationship between counts and clinical features, transmissibility, and antibiotic resistance. J. Clin. Microbiol. 36, 1683–1687 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Gilman, R. H., Terminel, M., Levine, M. M., Hernandez-Mendoza, P. & Hornick, R. B. Relative efficacy of blood, urine, rectal swab, bone-marrow, and rose-spot cultures for recovery of Salmonella Typhi in typhoid fever. Lancet 1, 1211–1213 (1975).

    Article  CAS  PubMed  Google Scholar 

  108. Mogasale, V., Ramani, E., Mogasale, V. V. & Park, J. What proportion of Salmonella Typhi cases are detected by blood culture? A systematic literature review. Ann. Clin. Microbiol. Antimicrob. 15, 32 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  109. Wain, J. et al. Specimens and culture media for the laboratory diagnosis of typhoid fever. J. Infect. Dev. Ctries 2, 469–474 (2008).

    Article  PubMed  Google Scholar 

  110. Neupane, D. P., Dulal, H. P. & Song, J. Enteric fever diagnosis: current challenges and future directions. Pathogens 10, 410 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Tennant, S. M. et al. Detection of typhoidal and paratyphoidal Salmonella in blood by real-time polymerase chain reaction. Clin. Infect. Dis. 61, S241–S250 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Sapkota, J. et al. Comparative analysis of commercially available typhoid point-of-care tests: results of a prospective and hybrid retrospective multicenter diagnostic accuracy study in Kenya and Pakistan. J. Clin. Microbiol. 60, e0100022 (2022).

    Article  PubMed  Google Scholar 

  113. Charles, R. C. et al. Immunoproteomic analysis of antibody in lymphocyte supernatant in patients with typhoid fever in Bangladesh. Clin. Vaccin. Immunol. 21, 280–285 (2014).

    Article  Google Scholar 

  114. Liang, L. et al. Immune profiling with a Salmonella Typhi antigen microarray identifies new diagnostic biomarkers of human typhoid. Sci. Rep. 3, 1043 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  115. Andrews, J. R. et al. Plasma immunoglobulin a responses against 2 Salmonella Typhi antigens identify patients with typhoid fever. Clin. Infect. Dis. 68, 949–955 (2019).

    Article  CAS  PubMed  Google Scholar 

  116. Näsström, E. et al. Reproducible diagnostic metabolites in plasma from typhoid fever patients in Asia and Africa. eLife 6, e15651 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  117. Aiemjoy, K. et al. Estimating typhoid incidence from community-based serosurveys: a multicohort study. Lancet Microbe 3, e578–e587 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Mylona, E. et al. The identification of enteric fever-specific antigens for population-based serosurveillance. J. Infect. Dis. https://doi.org/10.1093/infdis/jiad242 (2023).

    Article  PubMed  Google Scholar 

  119. Parry, C. M., Hien, T. T., Dougan, G., White, N. J. & Farrar, J. J. Typhoid fever. N. Engl. J. Med. 347, 1770–1782 (2002).

    Article  CAS  PubMed  Google Scholar 

  120. Stuart, B. M. & Pullen, R. L. Typhoid; clinical analysis of 360 cases. Arch. Intern. Med. 78, 629–661 (1946).

    Article  CAS  Google Scholar 

  121. Crump, J. A., Sjölund-Karlsson, M., Gordon, M. A. & Parry, C. M. Epidemiology, clinical presentation, laboratory diagnosis, antimicrobial resistance, and antimicrobial management of invasive Salmonella infections. Clin. Microbiol. Rev. 28, 901–937 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Hosoglu, S. et al. Risk factors for enteric perforation in patients with typhoid fever. Am. J. Epidemiol. 160, 46–50 (2004).

    Article  PubMed  Google Scholar 

  123. Birkhold, M. et al. Morbidity and mortality of typhoid intestinal perforation among children in sub-Saharan Africa 1995-2019: a scoping review. World J. Surg. 44, 2892–2902 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  124. Neil, K. P. et al. A large outbreak of typhoid fever associated with a high rate of intestinal perforation in Kasese District, Uganda, 2008-2009. Clin. Infect. Dis. 54, 1091–1099 (2012).

    Article  PubMed  Google Scholar 

  125. Mogasale, V. et al. Case fatality rate and length of hospital stay among patients with typhoid intestinal perforation in developing countries: a systematic literature review. PLoS ONE 9, e93784 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  126. Osuntokun, B. O., Bademosi, O., Ogunremi, K. & Wright, S. G. Neuropsychiatric manifestations of typhoid fever in 959 patients. Arch. Neurol. 27, 7–13 (1972).

    Article  CAS  PubMed  Google Scholar 

  127. Lutterloh, E. et al. Multidrug-resistant typhoid fever with neurologic findings on the Malawi-Mozambique border. Clin. Infect. Dis. 54, 1100–1106 (2012).

    Article  PubMed  Google Scholar 

  128. Britto, C. D. et al. Laboratory and molecular surveillance of paediatric typhoidal Salmonella in Nepal: antimicrobial resistance and implications for vaccine policy. PLoS Negl. Trop. Dis. 12, e0006408 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  129. Britto, C., Pollard, A. J., Voysey, M. & Blohmke, C. J. An appraisal of the clinical features of pediatric enteric fever: systematic review and meta-analysis of the age-stratified disease occurrence. Clin. Infect. Dis. 64, 1604–1611 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  130. Cruz Espinoza, L. M. et al. Occurrence of typhoid fever complications and their relation to duration of illness preceding hospitalization: a systematic literature review and meta-analysis. Clin. Infect. Dis. 69, S435–S448 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  131. Al-Emran, H. M. et al. A multicountry molecular analysis of Salmonella enterica serovar typhi with reduced susceptibility to ciprofloxacin in sub-Saharan Africa. Clin. Infect. Dis. 62, S42–S46 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Levine, M. M., Black, R. E. & Lanata, C. Precise estimation of the numbers of chronic carriers of Salmonella Typhi in Santiago, Chile, an endemic area. J. Infect. Dis. 146, 724–726 (1982).

    Article  CAS  PubMed  Google Scholar 

  133. Khatri, N. S. et al. Gallbladder carriage of Salmonella paratyphi A may be an important factor in the increasing incidence of this infection in South Asia. Ann. Intern. Med. 150, 567–568 (2009).

    Article  PubMed  Google Scholar 

  134. Gonzalez-Escobedo, G., Marshall, J. M. & Gunn, J. S. Chronic and acute infection of the gall bladder by Salmonella Typhi: understanding the carrier state. Nat. Rev. Microbiol. 9, 9–14 (2011).

    Article  CAS  PubMed  Google Scholar 

  135. Crawford, R. W. et al. Gallstones play a significant role in Salmonella spp. gallbladder colonization and carriage. Proc. Natl Acad. Sci. USA 107, 4353–4358 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Dongol, S. et al. The microbiological and clinical characteristics of invasive Salmonella in gallbladders from cholecystectomy patients in Kathmandu, Nepal. PLoS ONE 7, e47342 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Schiøler, H., Christiansen, E. D., Høybye, G., Rasmussen, S. N. & Greibe, J. Biliary calculi in chronic Salmonella carriers and healthy controls: a controlled study. Scand. J. Infect. Dis. 15, 17–19 (1983).

    Article  PubMed  Google Scholar 

  138. Olsen, S. J. et al. Outbreaks of typhoid fever in the United States, 1960-99. Epidemiol. Infect. 130, 13–21 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Bokkenheuser, V. Detection of typhoid carriers. Am. J. Public. Health Nations Health 54, 477–486 (1964).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Avendano, A. et al. Duodenal string cultures: practicality and sensitivity for diagnosing enteric fever in children. J. Infect. Dis. 153, 359–362 (1986).

    Article  CAS  PubMed  Google Scholar 

  141. Hoffman, S. A., Sikorski, M. J. & Levine, M. M. Chronic Salmonella Typhi carriage at sites other than the gallbladder. PLoS Negl. Trop. Dis. 17, e0011168 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  142. Lin, F. Y. et al. Restaurant-associated outbreak of typhoid fever in Maryland: identification of carrier facilitated by measurement of serum Vi antibodies. J. Clin. Microbiol. 26, 1194–1197 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Gupta, A. et al. Evaluation of community-based serologic screening for identification of chronic Salmonella Typhi carriers in Vietnam. Int. J. Infect. Dis. 10, 309–314 (2006).

    Article  CAS  PubMed  Google Scholar 

  144. Ferreccio, C. et al. The detection of chronic Salmonella Typhi carriers: a practical method applied to food handlers [Spanish]. Rev. Med. Chil. 118, 33–37 (1990).

    CAS  PubMed  Google Scholar 

  145. Lanata, C. F. et al. Vi serology in detection of chronic Salmonella Typhi carriers in an endemic area. Lancet 2, 441–443 (1983).

    Article  CAS  PubMed  Google Scholar 

  146. Thompson, L. J. et al. Transcriptional response in the peripheral blood of patients infected with Salmonella enterica serovar Typhi. Proc. Natl Acad. Sci. USA 106, 22433–22438 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Tran Vu Thieu, N. et al. An evaluation of purified Salmonella Typhi protein antigens for the serological diagnosis of acute typhoid fever. J. Infect. 75, 104–114 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  148. Näsström, E. et al. Diagnostic metabolite biomarkers of chronic typhoid carriage. PLoS Negl. Trop. Dis. 12, e0006215 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  149. Gauld, J. S., Hu, H., Klein, D. J. & Levine, M. M. Typhoid fever in Santiago, Chile: insights from a mathematical model utilizing venerable archived data from a successful disease control program. PLoS Negl. Trop. Dis. 12, e0006759 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  150. Ng’eno, E. et al. Dynamic incidence of typhoid fever over a 10-year period (2010-2019) in Kibera, an Urban Informal Settlement in Nairobi, Kenya. Am. J. Trop. Med. Hyg. 109, 22–31 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  151. Sikorski, M. J. & Levine, M. M. Reviving the “Moore swab”: a classic environmental surveillance tool involving filtration of flowing surface water and sewage water to recover typhoidal Salmonella bacteria. Appl. Environ. Microbiol. 86, e00060-20 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  152. Kim, C. et al. Associations of water, sanitation, and hygiene with typhoid fever in case-control studies: a systematic review and meta-analysis. BMC Infect. Dis. 23, 562 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  153. Stanaway, J. D., Atuhebwe, P. L., Luby, S. P. & Crump, J. A. Assessing the feasibility of typhoid elimination. Clin. Infect. Dis. 71, S179–S184 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  154. Hejfec, L. B. Results of the study of typhoid vaccines in four controlled field trials in the USSR. Bull. World Health Organ. 32, 1–14 (1965).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. WHO. Typhoid vaccines: WHO position paper. Wkly Epidemiol. Rec. 83, 49–59 (2008).

    Google Scholar 

  156. Engels, E. A., Falagas, M. E., Lau, J. & Bennish, M. L. Typhoid fever vaccines: a meta-analysis of studies on efficacy and toxicity. BMJ 316, 110–116 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Milligan, R., Paul, M., Richardson, M. & Neuberger, A. Vaccines for preventing typhoid fever. Cochrane Database Syst. Rev. 5, CD001261 (2018).

    PubMed  Google Scholar 

  158. Goldblatt, D. Conjugate vaccines. Clin. Exp. Immunol. 119, 1–3 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. WHO. Typhoid vaccines: WHO position paper – March 2018. Wkly Epidemiol. Rec. 93, 153–172 (2018).

    Google Scholar 

  160. Mohan, V. K. et al. Safety and immunogenicity of a Vi polysaccharide-tetanus toxoid conjugate vaccine (Typbar-TCV) in healthy infants, children, and adults in typhoid endemic areas: a multicenter, 2-cohort, open-label, double-blind, randomized controlled phase 3 study. Clin. Infect. Dis. 61, 393–402 (2015).

    Article  CAS  PubMed  Google Scholar 

  161. Jin, C. et al. Efficacy and immunogenicity of a Vi-tetanus toxoid conjugate vaccine in the prevention of typhoid fever using a controlled human infection model of Salmonella Typhi: a randomised controlled, phase 2b trial. Lancet 390, 2472–2480 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Meiring, J. E., Giubilini, A., Savulescu, J., Pitzer, V. E. & Pollard, A. J. Generating the evidence for typhoid vaccine introduction: considerations for global disease burden estimates and vaccine testing through human challenge. Clin. Infect. Dis. 69, S402–S407 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  163. Nampota, N. et al. Safety and immunogenicity of a typhoid conjugate vaccine among children aged 9 months through 12 years in Malawi: results from a randomised, double-blind, controlled trial. Lancet Glob. Health 10, e1326–e1335 (2022).

    Article  Google Scholar 

  164. Sirima, S. B. et al. Safety and immunogenicity of co-administration of meningococcal type A and measles-rubella vaccines with typhoid conjugate vaccine in children aged 15-23 months in Burkina Faso. Int. J. Infect. Dis. 102, 517–523 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Patel, P. D. et al. Safety and efficacy of a typhoid conjugate vaccine in Malawian children. N. Engl. J. Med. 385, 1104–1115 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Meiring, J. E. et al. Typhoid Vaccine Acceleration Consortium Malawi: a phase III, randomized, double-blind, controlled trial of the clinical efficacy of typhoid conjugate vaccine among children in Blantyre, Malawi. Clin. Infect. Dis. 68, S50–S58 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Colin-Jones, R. et al. Logistics of implementing a large-scale typhoid vaccine trial in Kathmandu, Nepal. Clin. Infect. Dis. 68, S138–S145 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  168. Shakya, M. et al. Phase 3 efficacy analysis of a typhoid conjugate vaccine trial in Nepal. N. Engl. J. Med. 381, 2209–2218 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Patel, P. et al. Efficacy of typhoid conjugate vaccine: final analysis of a four-year, randomised controlled trial in Malawian children. Preprint at https://ssrn.com/abstract=4411421 (2023).

  170. Theiss-Nyland, K. et al. Assessing the impact of a Vi-polysaccharide conjugate vaccine in preventing typhoid infection among Bangladeshi children: a protocol for a phase IIIb trial. Clin. Infect. Dis. 68, S74–S82 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  171. Qadri, F. et al. Protection by vaccination of children against typhoid fever with a Vi-tetanus toxoid conjugate vaccine in urban Bangladesh: a cluster-randomised trial. Lancet 398, 675–684 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  172. Khanam, F. et al. Assessment of vaccine herd protection in a cluster-randomised trial of Vi conjugate vaccine against typhoid fever: results of further analysis. eClinicalMedicine 58, 101925 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  173. Hoffman, S. A. et al. Programmatic effectiveness of a pediatric typhoid conjugate vaccine campaign in Navi Mumbai, India. Clin. Infect. Dis. 77, 138–144 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  174. Yousafzai, M. T. et al. Effectiveness of typhoid conjugate vaccine against culture-confirmed Salmonella enterica serotype Typhi in an extensively drug-resistant outbreak setting of Hyderabad, Pakistan: a cohort study. Lancet Glob. Health 9, e1154–e1162 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Lightowler, M. S. et al. Effectiveness of typhoid conjugate vaccine in Zimbabwe used in response to an outbreak among children and young adults: a matched case control study. Vaccine 40, 4199–4210 (2022).

    Article  CAS  PubMed  Google Scholar 

  176. Nampota-Nkomba, N., Carey, M. E., Jamka, L. P., Fecteau, N. & Neuzil, K. M. Using typhoid conjugate vaccines to prevent disease, promote health equity, and counter drug-resistant typhoid fever. Open. Forum Infect. Dis. 10, S6–S12 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  177. Khanam, F., Ross, A. G., McMillan, N. A. J. & Qadri, F. Toward typhoid fever elimination. Int. J. Infect. Dis. 119, 41–43 (2022).

    Article  PubMed  Google Scholar 

  178. Nga, T. V. T., Duy, P. T., Lan, N. P. H., Chau, N. V. V. & Baker, S. The control of typhoid fever in Vietnam. Am. J. Trop. Med. Hyg. 99, 72–78 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  179. Browne, A. J. et al. Drug-resistant enteric fever worldwide, 1990 to 2018: a systematic review and meta-analysis. BMC Med. 18, 1 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  180. Bhutta, Z. A. Impact of age and drug resistance on mortality in typhoid fever. Arch. Dis. Child. 75, 214–217 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Parry, C. M. The treatment of multidrug-resistant and nalidixic acid-resistant typhoid fever in Viet Nam. Trans. R. Soc. Trop. Med. Hyg. 98, 413–422 (2004).

    Article  CAS  PubMed  Google Scholar 

  182. Nabarro, L. E. et al. British Infection Association guidelines for the diagnosis and management of enteric fever in England. J. Infect. 84, 469–489 (2022).

    Article  CAS  PubMed  Google Scholar 

  183. Dolecek, C., Pokharel, S., Basnyat, B. & Olliaro, P. Antibiotics for typhoid fever. in The selection and use of essential medicines. WHO Technical Report Series No. 1021. 19–26 https://apps.who.int/iris/bitstream/handle/10665/330668/9789241210300-eng.pdf?ua=1 (WHO, 2019).

  184. Carey, M. E. et al. Spontaneous emergence of azithromycin resistance in independent lineages of Salmonella Typhi in Northern India. Clin. Infect. Dis. 72, e120–e127 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Duy, P. T. et al. The emergence of azithromycin-resistant Salmonella Typhi in Nepal. JAC Antimicrob. Resist. 2, dlaa109 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  186. Effa, E. E. & Bukirwa, H. Azithromycin for treating uncomplicated typhoid and paratyphoid fever (enteric fever). Cochrane Database Syst Rev 4, CD006083 (2008).

    Google Scholar 

  187. Effa, E. E. et al. Fluoroquinolones for treating typhoid and paratyphoid fever (enteric fever). Cochrane Database Syst. Rev. 2011, CD004530 (2011).

    PubMed  PubMed Central  Google Scholar 

  188. Eliakim-Raz, N. et al. Efficacy and safety of chloramphenicol: joining the revival of old antibiotics? Systematic review and meta-analysis of randomized controlled trials. J. Antimicrob. Chemother. 70, 979–996 (2015).

    Article  CAS  PubMed  Google Scholar 

  189. Qamar, F. N. et al. Outbreak investigation of ceftriaxone-resistant Salmonella enterica serotype Typhi and its risk factors among the general population in Hyderabad, Pakistan: a matched case-control study. Lancet Infect. Dis. 18, 1368–1376 (2018).

    Article  PubMed  Google Scholar 

  190. Argimón, S. et al. Circulation of third-generation cephalosporin resistant Salmonella Typhi in Mumbai, India. Clin. Infect. Dis. 74, 2234–2237 (2022).

    Article  PubMed  Google Scholar 

  191. Samajpati, S., Pragasam, A. K., Mandal, S., Balaji, V. & Dutta, S. Emergence of ceftriaxone resistant Salmonella enterica serovar Typhi in Eastern India. Infect., Genet. Evolution 96, 105093 (2021).

    Article  CAS  Google Scholar 

  192. Qureshi, S. et al. Response of extensively drug resistant Salmonella Typhi to treatment with meropenem and azithromycin, in Pakistan. PLoS Negl. Trop. Dis. 14, e0008682 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Van Be Bay, P. et al. Quantitative bacterial counts in the bone marrow of Vietnamese patients with typhoid fever. Trans. R. Soc. Trop. Med. Hyg. 116, 736–744 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  194. Pascual, A., Conejo, M. C., García, I. & Perea, E. J. Factors affecting the intracellular accumulation and activity of azithromycin. J. Antimicrob. Chemother. 35, 85–93 (1995).

    Article  CAS  PubMed  Google Scholar 

  195. Zmora, N. et al. Open label comparative trial of mono versus dual antibiotic therapy for typhoid fever in adults. PLoS Negl. Trop. Dis. 12, e0006380 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  196. Giri, A. et al. Azithromycin and cefixime combination versus azithromycin alone for the out-patient treatment of clinically suspected or confirmed uncomplicated typhoid fever in South Asia: a randomised controlled trial protocol. Wellcome Open. Res. 6, 207 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  197. Butler, T. et al. Typhoid fever complicated by intestinal perforation: a persisting fatal disease requiring surgical management. Rev. Infect. Dis. 7, 244–256 (1985).

    Article  CAS  PubMed  Google Scholar 

  198. Hoffman, S. L. et al. Reduction of mortality in chloramphenicol-treated severe typhoid fever by high-dose dexamethasone. N. Engl. J. Med. 310, 82–88 (1984).

    Article  CAS  PubMed  Google Scholar 

  199. Contopoulos-Ioannidis, D. G. & Ioannidis, J. P. Claims for improved survival from systemic corticosteroids in diverse conditions: an umbrella review. Eur. J. Clin. Invest. 42, 233–244 (2012).

    Article  PubMed  Google Scholar 

  200. McCann, N., Scott, P., Parry, C. M. & Brown, M. Antimicrobial agents for the treatment of enteric fever chronic carriage: a systematic review. PLoS ONE 17, e0272043 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Luthra, K. et al. A review of the economic evidence of typhoid fever and typhoid vaccines. Clin. Infect. Dis. 68, S83–S95 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Riewpaiboon, A. et al. Cost of illness due to typhoid fever in Pemba, Zanzibar, East Africa. J. Health Popul. Nutr. 32, 377–385 (2014).

    PubMed  PubMed Central  Google Scholar 

  203. Bahl, R. et al. Costs of illness due to typhoid fever in an Indian urban slum community: implications for vaccination policy. J. Health Popul. Nutr. 22, 304–310 (2004).

    PubMed  Google Scholar 

  204. Kaljee, L. M. et al. Social and economic burden associated with typhoid fever in Kathmandu and surrounding areas: a qualitative study. J. Infect. Dis. 218, S243–S249 (2018).

    Article  PubMed  Google Scholar 

  205. Limani, F. et al. Estimating the economic burden of typhoid in children and adults in Blantyre, Malawi: a costing cohort study. PLoS ONE 17, e0277419 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Mejia, N. et al. Typhoid and paratyphoid cost of illness in Nepal: patient and health facility costs from the Surveillance for Enteric Fever in Asia Project II. Clin. Infect. Dis. 71, S306–S318 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  207. Mejia, N. et al. Typhoid and paratyphoid cost of illness in Bangladesh: patient and health facility costs from the Surveillance for Enteric Fever in Asia Project II. Clin. Infect. Dis. 71, S293–S305 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  208. Mejia, N. et al. Typhoid and paratyphoid cost of illness in Pakistan: patient and health facility costs from the Surveillance for Enteric Fever in Asia Project II. Clin. Infect. Dis. 71, S319–S335 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  209. Bilcke, J. et al. Cost-effectiveness of routine and campaign use of typhoid Vi-conjugate vaccine in Gavi-eligible countries: a modelling study. Lancet Infect. Dis. 19, 728–739 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  210. Seyi-Olajide, J. O. et al. Catastrophic healthcare expenditure from typhoid perforation in children in Nigeria. Surg. Infect. 21, 586–591 (2020).

    Article  Google Scholar 

  211. Kumar, D. et al. Cost of illness due to severe enteric fever in India. J. Infect. Dis. 224, S540–S547 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  212. Malik A. Comparison of cost of illness of extensively drug resistant (XDR) vs. non-XDR typhoid fever in Pakistan: policy implications for typhoid vaccine. Coalition Against Typhoid Conference https://www.coalitionagainsttyphoid.org/wp-content/uploads/2019/04/ABSTRACT9_Pres5_Malik.pdf (2019).

  213. Birkhold, M., Mwisongo, A., Pollard, A. J. & Neuzil, K. M. Typhoid conjugate vaccine in Africa and Asia: status of clinical evaluation and vaccine introduction. J. Infect. Dis. https://doi.org/10.1093/infdis/jiab449 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  214. WHO. Meeting of the Strategic Advisory Group of Experts on Immunization, April 2022: conclusions and recommendations. Wkly Epidemiol. Rec. 97, 261–276 (2022).

    Google Scholar 

  215. Gavi the Vaccine Alliance. Typhoid conjugate vaccine (TCV) support. Gavi https://www.gavi.org/types-support/vaccine-support/typhoid (2023).

  216. Lo, N. C. et al. Comparison of strategies and incidence thresholds for Vi conjugate vaccines against typhoid fever: a cost-effectiveness modeling study. J. Infect. Dis. 218, S232–S242 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  217. Burrows, H. et al. Comparison of model predictions of typhoid conjugate vaccine public health impact and cost-effectiveness. Vaccine 41, 965–975 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  218. Chauhan, A. S. et al. Cost effectiveness of typhoid vaccination in India. Vaccine 39, 4089–4098 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  219. Ryckman, T. et al. Comparison of strategies for typhoid conjugate vaccine introduction in India: a cost-effectiveness modeling study. J. Infect. Dis. 224, S612–S624 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  220. Carey, M. E., McCann, N. S. & Gibani, M. M. Typhoid fever control in the 21st century: where are we now? Curr. Opin. Infect. Dis. 35, 424–430 (2022).

    Article  PubMed  Google Scholar 

  221. MacLennan, C. A., Stanaway, J., Grow, S., Vannice, K. & Steele, A. D. Salmonella combination vaccines: moving beyond typhoid. Open. Forum Infect. Dis. 10, S58–S66 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  222. Shakya, M. et al. Efficacy of typhoid conjugate vaccine in Nepal: final results of a phase 3, randomised, controlled trial. Lancet Glob. Health 9, e1561–e1568 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  223. Batool, R. et al. Effectiveness of typhoid conjugate vaccine against culture-confirmed typhoid in a peri-urban setting in Karachi: a case-control study. Vaccine 39, 5858–5865 (2021).

    Article  PubMed  Google Scholar 

  224. Juel, H. B. et al. Salmonella Typhi bactericidal antibodies reduce disease severity but do not protect against typhoid fever in a controlled human infection model. Front. Immunol. 8, 1916 (2017).

    Article  PubMed  Google Scholar 

  225. Jones, E. et al. A Salmonella Typhi controlled human infection study for assessing correlation between bactericidal antibodies and protection against infection induced by typhoid vaccination. Microorganisms 9, 1394 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  226. Jin, C. et al. Treatment responses to azithromycin and ciprofloxacin in uncomplicated Salmonella Typhi infection: a comparison of clinical and microbiological data from a controlled human infection model. PLoS Negl. Trop. Dis. 13, e0007955 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  227. Jin, C. et al. Vi-specific serological correlates of protection for typhoid fever. J. Exp. Med. 218, e20201116 (2021).

    Article  CAS  PubMed  Google Scholar 

  228. Dahora, L. C. et al. IgA and IgG1 specific to Vi polysaccharide of Salmonella typhi correlate with protection status in a typhoid fever controlled human infection model. Front. Immunol. 10, 2582 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  229. Cross, D. L. et al. Vi-vaccinations induce heterogeneous plasma cell responses that associate with protection from typhoid fever. Front. Immunol. 11, 574057 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Contributions

Introduction (M.A.G. and J.E.M.); Epidemiology (M.A.G., J.A.C., B.B., F.Q., S.K., F.K. and J.E.M.); Mechanisms/pathophysiology (M.A.G., K.E.H., A.J.P. and J.E.M.); Diagnosis, screening and prevention (M.A.G., R.C.C., C.M.P. and J.E.M.); Management (M.A.G., B.B., F.Q., C.M.P., F.K. and J.E.M.); Quality of life (M.A.G., V.E.P., J.E.M. and F.D.); Outlook (M.A.G., E.M. A.J.P., K.M.N., V.E.P. and J.E.M.); Overview of the Primer (J.E.M. and M.A.G.).

Corresponding author

Correspondence to Melita A. Gordon.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Reviews Disease Primers thanks S. Luby and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Meiring, J.E., Khanam, F., Basnyat, B. et al. Typhoid fever. Nat Rev Dis Primers 9, 71 (2023). https://doi.org/10.1038/s41572-023-00480-z

Download citation

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41572-023-00480-z

This article is cited by

Search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research