Typhoid Fever: A Reduction and a Resurgence

James E. Meiring Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom;

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Peter I. Johnston Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, United Kingdom;
Malawi Liverpool Wellcome Research Programme, Blantyre, Malawi

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Several population-based studies have recently published data on the incidence of typhoid fever.14 These studies redress gaps in our knowledge of disease burden in specific locations and contribute to improved estimates of the global burden of typhoid fever.5 These data are increasingly important to decision-makers in typhoid-endemic countries as they consider implementing typhoid conjugate vaccine (TCV) programs and apply for GAVI funding.6

Although typhoid incidence estimates are informative, we should be cautious in generalizing their findings beyond the period during which data were collected. Typhoid incidence is dynamic, with increases following the introduction of new strains with increased antimicrobial resistance,7,8 and reductions following the introduction of disease control interventions.9 Long-term incidence data from single-sites is rare, but can provide crucial insights into how various factors influence rates of typhoid fever.10 This is why the study by Ng’eno et al., published in a recent issue of the American Journal of Tropical Medicine and Hygiene, is so relevant.11

Ng’eno et al. provide a decade of typhoid incidence data from the informal Kenyan settlement of Kibera. The authors report crude incidence rates ranging from 144 to 233 per 100,000 person-years of observation (pyo) between 2010 and 2012. This was followed by a decline in typhoid incidence from 2013 to 2017. Cases rebounded in the final two years of surveillance, reaching 130 per 100,000 pyo in 2019. The authors speculate that government-instituted improvements in the supply of clean water (introduced in 2010) might explain the reduced incidence rates observed between 2013 and 2017. The subsequent resurgence in cases from 2019 serves an important reminder: in a world facing climate change and extreme weather events, population growth, and urbanization, typhoid fever remains at risk of resurging in populations without typhoid-specific immunity throughout south Asia and Africa.

The other benefit of this longitudinal study is that changes in antimicrobial resistance (AMR) patterns can be observed over time. The authors report that more than 70% of Salmonella enterica serovar Typhi (S. Typhi) isolates recovered from blood cultures were multidrug resistant (MDR) (resistant to ampicillin, chloramphenicol, and co-trimoxazole). While the proportion of MDR isolates remained relatively stable over time, nonsusceptibility to ciprofloxacin (CipNS) increased during the study period.

AMR patterns seen in this study are consistent with those seen in other studies from Africa12 and the findings from a large analysis of global typhoid genomes produced by Carey et al.13 Their analysis of almost 13,000 S. Typhi genomes showed that MDR S. Typhi remains widespread in Kenya and Malawi, although it has become less prevalent in Nigeria, India, Nepal, and Bangladesh.13 Longitudinal datasets allow us to develop hypotheses about how resistance patterns emerge and to monitor interventions. 19% of the MDR isolates in Kenya showed chromosomal integration of the MDR transposon, which carries less of a fitness-cost than plasmid-mediated MDR determinants.13

Similarly, the authors draw timely attention to the increased proportion of CipNS seen over time in Kibera (from 33% in 2014–41% in 2019). This corresponds with findings from Carey and colleagues’ genomic analysis, where the proportion of CipNS S. Typhi isolates in Kenya increased from 20% in 2012–65% in 2016.13 Longitudinal changes in resistance patterns may result in future outbreaks of disease. Multiple introductions of the MDR-associated H58 lineage of S.Typhi were associated with large-scale outbreaks in South Asia and Africa.14 Typhoid outbreaks in Pakistan’s Sindh province heralded the emergence of extensively drug resistant (XDR) S. Typhi15 (defined as MDR, with additional resistance to fluoroquinolones and third-generation cephalosporins). Several XDR variants are now circulating within Pakistan.16 The threat of XDR S. Typhi emerging in Africa means that long term sentinel-site surveillance, such as that presented by Ng’eno et al., is vital. Data such as these will also inform treatment guidelines, especially in settings where high typhoid incidence coincides with a lack of access to blood culture and antimicrobial susceptibility testing facilities.17

Typhoid fever is a disease that reflects global inequalities. In industrialised nations typhoid fever all but disappeared following improvements in sanitation during the early twentieth century.18 In contrast, typhoid remains among the commonest causes of fever and bloodstream infection throughout South Asia, Africa, and parts of Oceania. However, with new data on the efficacy of TCV the global community now has the tools to address this global inequality. Randomized controlled trials from Malawi,19 Nepal20,21 and Bangladesh22 all demonstrated protective efficacy of almost 80% and above after a single dose of TCV in children between 6 months and 15 years of age. In addition, effectiveness studies from Pakistan and India showed high levels of protection from a single dose of TCV, including against XDR S. Typhi.23,24 As typhoid endemic countries begin to incorporate TCV into their national immunization programs, studies that report longitudinal incidence data – such as this one from Ng’eno et al. – will be essential to understand the impact of vaccination on typhoid incidence and S. Typhi resistance.

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    • PubMed
    • Search Google Scholar
    • Export Citation
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    Garrett DO et al., 2022. 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: e978e988.

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    • Search Google Scholar
    • Export Citation
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    John J et al., 2023. Burden of typhoid and paratyphoid fever in India. N Engl J Med 388: 14911500.

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    Stanaway JD et al., 2019. The global burden of typhoid and paratyphoid fevers: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Infect Dis 19: 369381.

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    Vanderslott S, Phillips MT, Pitzer VE, Kirchhelle C, 2019. Water and filth: reevaluating the first era of sanitary typhoid intervention (1840-1940). Nephrol Dial Transplant 69: S377S384.

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    Musicha P et al., 2017. Trends in antimicrobial resistance in bloodstream infection isolates at a large urban hospital in Malawi (1998-2016): a surveillance study. Lancet Infect Dis 17: 10421052.

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    Ng’eno E et al., 2023. Dynamic incidence of typhoid fever over a ten-year period (2010-2019) in Kibera, an informal settlement in Nairobi, Kenya. Am J Trop Med Hyg 109: 2231.

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    Ashton PM et al., 2023. The rapid emergence of Salmonella Typhi with decreased ciprofloxacin susceptibility following an increase in ciprofloxacin prescriptions in Blantyre, Malawi. medRxiv 2023.2003.2027.23287794. doi: 10.1101/2023.03.27.23287794.

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    Qamar FN et al., 2018. 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: 13681376.

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    Kamal R, Ching C, Zaman MH, Sultan F, Abbas S, Khan E, Mirza S, Nizamuddin S, 2023. Identification of multiple variant extensively drug-resistant typhoid infections across Pakistan. Am J Trop Med Hyg 108: 278284.

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    Patel PD et al., 2021. Safety and efficacy of a typhoid conjugate vaccine in Malawian children. N Engl J Med 385: 11041115.

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    Shakya M et al., 2019. Phase 3 efficacy analysis of a typhoid conjugate vaccine trial in Nepal. N Engl J Med 381: 22092218.

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    Shakya M et al., 2021. Efficacy of typhoid conjugate vaccine in Nepal: final results of a phase 3, randomised, controlled trial. Lancet Glob Health 9: e1561e1568.

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    Qadri F et al., 2021. Protection by vaccination of children against typhoid fever with a Vi-tetanus toxoid conjugate vaccine in urban Bangladesh: a cluster-randomised trial. Lancet 398: 675684.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23.

    Hoffman SA et al., 2023. Programmatic effectiveness of a pediatric typhoid conjugate vaccine campaign in Navi Mumbai, India. Clin Infect Dis. doi: 10.1093/cid/ciad132.

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    • Search Google Scholar
    • Export Citation
  • 24.

    Yousafzai MT et al., 2021. 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: e1154e1162.

    • PubMed
    • Search Google Scholar
    • Export Citation

Author Notes

Address correspondence to James E. Meiring, Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Western Bank, Sheffield S10 2TN, United Kingdom. E-mail: j.meiring@sheffield.ac.uk

Financial support: James E. Meiring is supported in an academic clinical lectureship funded by the National Institute for Health Research, United Kingdom. Peter I. Johnston is supported through the Liverpool Clinical PhD Programme for Health Priorities in the Global South, funded by The Wellcome Trust. This work was supported by the Bill and Melinda Gates Foundation.

Authors’ addresses: James E. Meiring, Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom, E-mail: j.meiring@sheffield.ac.uk. Peter I. Johnston, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, United Kingdom, and Malawi Liverpool Wellcome Research Programme, Blantyre, Malawi, E-mail: peter.johnston@liverpool.ac.uk.

  • 1.

    Meiring JE et al., 2021. Burden of enteric fever at three urban sites in Africa and Asia: a multicentre population-based study with 626,219 person-years of observation. Lancet Glob Health 9: e1688e1696.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2.

    Garrett DO et al., 2022. 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: e978e988.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3.

    John J et al., 2023. Burden of typhoid and paratyphoid fever in India. N Engl J Med 388: 14911500.

  • 4.

    Marks F et al., 2017. Incidence of invasive Salmonella disease in sub-Saharan Africa: a multicentre population-based surveillance study. Lancet Glob Health 5: e310e323.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5.

    Stanaway JD et al., 2019. The global burden of typhoid and paratyphoid fevers: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Infect Dis 19: 369381.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6.

    Gavi the Vaccine Alliance 2017. Available at: https://www.gavi.org/news/media-room/millions-children-set-be-protected-against-typhoid-fever. Accessed April 1, 2023.

    • PubMed
    • Export Citation
  • 7.

    Feasey NA et al., 2015. Rapid emergence of multidrug resistant, H58-lineage Salmonella typhi in Blantyre, Malawi. PLoS Negl Trop Dis 9: e0003748.

  • 8.

    Lightowler MS et al., 2022. 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: 41994210.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9.

    Vanderslott S, Phillips MT, Pitzer VE, Kirchhelle C, 2019. Water and filth: reevaluating the first era of sanitary typhoid intervention (1840-1940). Nephrol Dial Transplant 69: S377S384.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10.

    Musicha P et al., 2017. Trends in antimicrobial resistance in bloodstream infection isolates at a large urban hospital in Malawi (1998-2016): a surveillance study. Lancet Infect Dis 17: 10421052.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11.

    Ng’eno E et al., 2023. Dynamic incidence of typhoid fever over a ten-year period (2010-2019) in Kibera, an informal settlement in Nairobi, Kenya. Am J Trop Med Hyg 109: 2231.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12.

    Ashton PM et al., 2023. The rapid emergence of Salmonella Typhi with decreased ciprofloxacin susceptibility following an increase in ciprofloxacin prescriptions in Blantyre, Malawi. medRxiv 2023.2003.2027.23287794. doi: 10.1101/2023.03.27.23287794.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13.

    Carey ME et al., 2022. Global diversity and antimicrobial resistance of typhoid fever pathogens: insights from 13,000 Salmonella Typhi genomes. medRxiv 2022.2012.2028.22283969. doi: 10.1101/2022.12.28.22283969.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14.

    Wong VK et al., 2015. Phylogeographical analysis of the dominant multidrug-resistant H58 clade of Salmonella Typhi identifies inter- and intracontinental transmission events. Nat Genet 47: 632639.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15.

    Qamar FN et al., 2018. 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: 13681376.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16.

    Kamal R, Ching C, Zaman MH, Sultan F, Abbas S, Khan E, Mirza S, Nizamuddin S, 2023. Identification of multiple variant extensively drug-resistant typhoid infections across Pakistan. Am J Trop Med Hyg 108: 278284.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17.

    Nabarro LE et al., 2022. British infection association guidelines for the diagnosis and management of enteric fever in England. J Infect 84: 469489.

  • 18.

    Phillips MT, Owers KA, Grenfell BT, Pitzer VE, 2020. 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.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19.

    Patel PD et al., 2021. Safety and efficacy of a typhoid conjugate vaccine in Malawian children. N Engl J Med 385: 11041115.

  • 20.

    Shakya M et al., 2019. Phase 3 efficacy analysis of a typhoid conjugate vaccine trial in Nepal. N Engl J Med 381: 22092218.

  • 21.

    Shakya M et al., 2021. Efficacy of typhoid conjugate vaccine in Nepal: final results of a phase 3, randomised, controlled trial. Lancet Glob Health 9: e1561e1568.

  • 22.

    Qadri F et al., 2021. Protection by vaccination of children against typhoid fever with a Vi-tetanus toxoid conjugate vaccine in urban Bangladesh: a cluster-randomised trial. Lancet 398: 675684.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23.

    Hoffman SA et al., 2023. Programmatic effectiveness of a pediatric typhoid conjugate vaccine campaign in Navi Mumbai, India. Clin Infect Dis. doi: 10.1093/cid/ciad132.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24.

    Yousafzai MT et al., 2021. 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: e1154e1162.

    • PubMed
    • Search Google Scholar
    • Export Citation
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