Multiple introductions of multidrug-resistant typhoid associated with acute infection and asymptomatic carriage, Kenya

  1. Samuel Kariuki  Is a corresponding author
  2. Zoe A Dyson
  3. Cecilia Mbae
  4. Ronald Ngetich
  5. Susan M Kavai
  6. Celestine Wairimu
  7. Stephen Anyona
  8. Naomi Gitau
  9. Robert Sanaya Onsare
  10. Beatrice Ongandi
  11. Sebastian Duchene
  12. Mohamed Ali
  13. John David Clemens
  14. Kathryn E Holt
  15. Gordon Dougan
  1. Kenya Medical Research Institute, Kenya
  2. Monash University, Australia
  3. University of Melbourne, Australia
  4. John Hopkins University, United States
  5. International Centre for Diarrheal Diseases Research B, Bangladesh
  6. University of Cambridge, United Kingdom

Abstract

Background: Understanding the dynamics of infection and carriage of typhoid in endemic settings is critical to finding solutions to prevention and control.

Methods: In a 3 year case-control study, we investigated typhoid among children aged <16 years (4,670 febrile cases and 8,549 age matched controls) living in an informal settlement, Nairobi, Kenya.

Results: 148 S. Typhi isolates from cases and 95 from controls (stool culture) were identified; a carriage frequency of 1%. Whole-genome sequencing showed 97% of cases and 88% of controls were genotype 4.3.1 (Haplotype 58), with the majority of each (76% and 88%) being multidrug-resistant strains in 3 sublineages of H58 genotype (East Africa 1 (EA1), EA2, and EA3), with sequences from cases and carriers intermingled.

Conclusions: The high rate of multidrug-resistant H58 S.Typhi, and the close phylogenetic relationships between cases and controls, provides evidence for the role of carriers as a reservoir for the community spread of typhoid in this setting.

Funding: National Institutes of Health (R01AI099525); Wellcome Trust (106158/Z/14/Z); European Commission (TyphiNET No 845681); National Institute for Health Research (NIHR); Bill and Melinda Gates Foundation (OPP1175797).

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.Raw Illumina sequence reads have been submitted to the European Nucleotide Archive (ENA) under accession PRJEB19289. Individual sequence accession numbers are listed in Table S1

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Samuel Kariuki

    Microbiology, Kenya Medical Research Institute, Nairobi, Kenya
    For correspondence
    samkariuki2@gmail.com
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3209-9503
  2. Zoe A Dyson

    Department of Infectious Diseases, Monash University, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  3. Cecilia Mbae

    Microbiology, Kenya Medical Research Institute, Nairobi, Kenya
    Competing interests
    The authors declare that no competing interests exist.
  4. Ronald Ngetich

    Microbiology, Kenya Medical Research Institute, Nairobi, Kenya
    Competing interests
    The authors declare that no competing interests exist.
  5. Susan M Kavai

    Microbiology, Kenya Medical Research Institute, Nairobi, Kenya
    Competing interests
    The authors declare that no competing interests exist.
  6. Celestine Wairimu

    Microbiology, Kenya Medical Research Institute, Nairobi, Kenya
    Competing interests
    The authors declare that no competing interests exist.
  7. Stephen Anyona

    Microbiology, Kenya Medical Research Institute, Nairobi, Kenya
    Competing interests
    The authors declare that no competing interests exist.
  8. Naomi Gitau

    Microbiology, Kenya Medical Research Institute, Nairobi, Kenya
    Competing interests
    The authors declare that no competing interests exist.
  9. Robert Sanaya Onsare

    Microbiology, Kenya Medical Research Institute, Nairobi, Kenya
    Competing interests
    The authors declare that no competing interests exist.
  10. Beatrice Ongandi

    Microbiology, Kenya Medical Research Institute, Nairobi, Kenya
    Competing interests
    The authors declare that no competing interests exist.
  11. Sebastian Duchene

    University of Melbourne, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  12. Mohamed Ali

    Global Health, John Hopkins University, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. John David Clemens

    Infectious Diseases, International Centre for Diarrheal Diseases Research B, Dhaka, Bangladesh
    Competing interests
    The authors declare that no competing interests exist.
  14. Kathryn E Holt

    Department of Infectious Diseases, Monash University, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  15. Gordon Dougan

    Department of Medicine, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

Funding

National Institutes of Health (R01AI099525)

  • Samuel Kariuki

Wellcome Trust (106158/Z/14/Z)

  • Zoe A Dyson

European Commission (TyphiNET No 845681)

  • Zoe A Dyson

National Institute for Health Research (AMR Theme)

  • Gordon Dougan

Bill and Melinda Gates Foundation (OPP1175797)

  • Kathryn E Holt

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: The study was approved by the Scientific and Ethics Review Unit (SERU) of the Kenya Medical Research Institute (KEMRI) (Scientific Steering Committee No. 2076). All parents and/or guardians of participating children were informed of the study objectives and voluntary written consent was sought and obtained before inclusion.

Reviewing Editor

  1. Joseph Lewnard, University of California Berkeley, United States

Publication history

  1. Received: February 24, 2021
  2. Preprint posted: March 10, 2021 (view preprint)
  3. Accepted: September 8, 2021
  4. Accepted Manuscript published: September 13, 2021 (version 1)
  5. Accepted Manuscript updated: September 15, 2021 (version 2)
  6. Accepted Manuscript updated: September 17, 2021 (version 3)
  7. Version of Record published: October 6, 2021 (version 4)

Copyright

© 2021, Kariuki et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 871
    Page views
  • 112
    Downloads
  • 9
    Citations

Article citation count generated by polling the highest count across the following sources: PubMed Central, Crossref, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Samuel Kariuki
  2. Zoe A Dyson
  3. Cecilia Mbae
  4. Ronald Ngetich
  5. Susan M Kavai
  6. Celestine Wairimu
  7. Stephen Anyona
  8. Naomi Gitau
  9. Robert Sanaya Onsare
  10. Beatrice Ongandi
  11. Sebastian Duchene
  12. Mohamed Ali
  13. John David Clemens
  14. Kathryn E Holt
  15. Gordon Dougan
(2021)
Multiple introductions of multidrug-resistant typhoid associated with acute infection and asymptomatic carriage, Kenya
eLife 10:e67852.
https://doi.org/10.7554/eLife.67852

Further reading

    1. Epidemiology and Global Health
    2. Medicine
    Qing Shen, Huan Song ... Unnur Valdimarsdóttir
    Research Article Updated

    Background:

    The association between cardiovascular disease (CVD) and selected psychiatric disorders has frequently been suggested while the potential role of familial factors and comorbidities in such association has rarely been investigated.

    Methods:

    We identified 869,056 patients newly diagnosed with CVD from 1987 to 2016 in Sweden with no history of psychiatric disorders, and 910,178 full siblings of these patients as well as 10 individually age- and sex-matched unrelated population controls (N = 8,690,560). Adjusting for multiple comorbid conditions, we used flexible parametric models and Cox models to estimate the association of CVD with risk of all subsequent psychiatric disorders, comparing rates of first incident psychiatric disorder among CVD patients with rates among unaffected full siblings and population controls.

    Results:

    The median age at diagnosis was 60 years for patients with CVD and 59.2% were male. During up to 30 years of follow-up, the crude incidence rates of psychiatric disorder were 7.1, 4.6, and 4.0 per 1000 person-years for patients with CVD, their siblings and population controls. In the sibling comparison, we observed an increased risk of psychiatric disorder during the first year after CVD diagnosis (hazard ratio [HR], 2.74; 95% confidence interval [CI], 2.62–2.87) and thereafter (1.45; 95% CI, 1.42–1.48). Increased risks were observed for all types of psychiatric disorders and among all diagnoses of CVD. We observed similar associations in the population comparison. CVD patients who developed a comorbid psychiatric disorder during the first year after diagnosis were at elevated risk of subsequent CVD death compared to patients without such comorbidity (HR, 1.55; 95% CI, 1.44–1.67).

    Conclusions:

    Patients diagnosed with CVD are at an elevated risk for subsequent psychiatric disorders independent of shared familial factors and comorbid conditions. Comorbid psychiatric disorders in patients with CVD are associated with higher risk of cardiovascular mortality suggesting that surveillance and treatment of psychiatric comorbidities should be considered as an integral part of clinical management of newly diagnosed CVD patients.

    Funding:

    This work was supported by the EU Horizon 2020 Research and Innovation Action Grant (CoMorMent, grant no. 847776 to UV, PFS, and FF), Grant of Excellence, Icelandic Research Fund (grant no. 163362-051 to UV), ERC Consolidator Grant (StressGene, grant no. 726413 to UV), Swedish Research Council (grant no. D0886501 to PFS), and US NIMH R01 MH123724 (to PFS).

    1. Epidemiology and Global Health
    Bingyi Yang, Bernardo García-Carreras ... Derek A Cummings
    Research Article

    Background: Over a life-course, human adaptive immunity to antigenically mutable pathogens exhibits competitive and facilitative interactions. We hypothesize that such interactions may lead to cyclic dynamics in immune responses over a lifetime.

    Methods: To investigate the cyclic behavior, we analyzed hemagglutination inhibition titers against 21 historical influenza A(H3N2) strains spanning 47 years from a cohort in Guangzhou, China and applied Fourier spectrum analysis. To investigate possible biological mechanisms, we simulated individual antibody profiles encompassing known feedbacks and interactions due to generally recognized immunological mechanisms.

    Results: We demonstrated a long-term periodicity (about 24 years) in individual antibody responses. The reported cycles were robust to analytic and sampling approaches. Simulations suggested that individual-level cross-reaction between antigenically similar strains likely explain the reported cycle. We showed that the reported cycles are predictable at both individual and birth-cohort level and that cohorts show a diversity of phases of these cycles. Phase of cycle was associated with the risk of seroconversion to circulating strains, after accounting for age and pre-existing titers of the circulating strains.

    Conclusions: Our findings reveal the existence of long-term periodicities in individual antibody responses to A(H3N2). We hypothesize that these cycles are driven by pre-existing antibody responses blunting responses to antigenically similar pathogens (by preventing infection and/or robust antibody responses upon infection), leading to reductions in antigen specific responses over time until individual's increasing risk leads to an infection with an antigenically distant enough virus to generate a robust immune response. These findings could help disentangle cohort-effects from individual-level exposure histories, improve our understanding of observed heterogeneous antibody responses to immunizations, and inform targeted vaccine strategy.

    Funding: This study was supported by grants from the NIH R56AG048075 (D.A.T.C., J.L.), NIH R01AI114703 (D.A.T.C., B.Y.), the Wellcome Trust 200861/Z/16/Z (S.R.) and 200187/Z/15/Z (S.R.). This work was also supported by research grants from Guangdong Government HZQB-KCZYZ-2021014 and 2019B121205009 (Y.G. and H.Z.). D.A.T.C., J.M.R. and S.R. acknowledge support from the National Institutes of Health Fogarty Institute (R01TW0008246). J.M.R. acknowledges support from the Medical Research Council (MR/S004793/1) and the Engineering and Physical Sciences Research Council (EP/N014499/1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.