Adding Virome Capture Metagenomic Sequencing to Conventional Laboratory Testing Increases Unknown Fever Etiology Determination in Bamako, Mali

Amadou Koné University Clinical Research Center, University of Sciences, Techniques, and Technologies of Bamako, Bamako, Mali;
Global Alliance for Preventing Pandemics, Columbia University, New York, New York;

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Fousseyni Kané University Clinical Research Center, University of Sciences, Techniques, and Technologies of Bamako, Bamako, Mali;
Global Alliance for Preventing Pandemics, Columbia University, New York, New York;

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Aaron Neal Collaborative Clinical Research Branch, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland;

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Issa Konate University Clinical Research Center, University of Sciences, Techniques, and Technologies of Bamako, Bamako, Mali;

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Bintou Coulibaly University Clinical Research Center, University of Sciences, Techniques, and Technologies of Bamako, Bamako, Mali;

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Djeneba K. Dabitao University Clinical Research Center, University of Sciences, Techniques, and Technologies of Bamako, Bamako, Mali;

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Bassirou Diarra University Clinical Research Center, University of Sciences, Techniques, and Technologies of Bamako, Bamako, Mali;

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Ibrahim Sanogo University Clinical Research Center, University of Sciences, Techniques, and Technologies of Bamako, Bamako, Mali;

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Yeya Dit Sadio Sarro University Clinical Research Center, University of Sciences, Techniques, and Technologies of Bamako, Bamako, Mali;

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Tenin A. Coulibaly University Clinical Research Center, University of Sciences, Techniques, and Technologies of Bamako, Bamako, Mali;

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Dramane Diallo University Clinical Research Center, University of Sciences, Techniques, and Technologies of Bamako, Bamako, Mali;
Global Alliance for Preventing Pandemics, Columbia University, New York, New York;

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Seydou Samake University Clinical Research Center, University of Sciences, Techniques, and Technologies of Bamako, Bamako, Mali;

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Ilo Dicko University Clinical Research Center, University of Sciences, Techniques, and Technologies of Bamako, Bamako, Mali;

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Mountaga Diallo University Clinical Research Center, University of Sciences, Techniques, and Technologies of Bamako, Bamako, Mali;

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Ayouba Diarra University Clinical Research Center, University of Sciences, Techniques, and Technologies of Bamako, Bamako, Mali;

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Mamadou D. Coulibaly University Clinical Research Center, University of Sciences, Techniques, and Technologies of Bamako, Bamako, Mali;

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Daouda Keita University Clinical Research Center, University of Sciences, Techniques, and Technologies of Bamako, Bamako, Mali;

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Nadié Coulibaly University Clinical Research Center, University of Sciences, Techniques, and Technologies of Bamako, Bamako, Mali;

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Isaac Koloma University Clinical Research Center, University of Sciences, Techniques, and Technologies of Bamako, Bamako, Mali;

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Mamadou Perou University Clinical Research Center, University of Sciences, Techniques, and Technologies of Bamako, Bamako, Mali;

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Hawa Boukary Diarra University Clinical Research Center, University of Sciences, Techniques, and Technologies of Bamako, Bamako, Mali;

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Boubacar Elmadane Cisse University Clinical Research Center, University of Sciences, Techniques, and Technologies of Bamako, Bamako, Mali;

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Antieme Combo Georges Togo University Clinical Research Center, University of Sciences, Techniques, and Technologies of Bamako, Bamako, Mali;

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Gagni Coulibaly University Clinical Research Center, University of Sciences, Techniques, and Technologies of Bamako, Bamako, Mali;

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Fah Gaoussou Traoré University Clinical Research Center, University of Sciences, Techniques, and Technologies of Bamako, Bamako, Mali;

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Moumine Sanogo University Clinical Research Center, University of Sciences, Techniques, and Technologies of Bamako, Bamako, Mali;

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Mahamadou Diakité University Clinical Research Center, University of Sciences, Techniques, and Technologies of Bamako, Bamako, Mali;

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Jamila Aboulhab Collaborative Clinical Research Branch, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland;

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Esther Akpa Collaborative Clinical Research Branch, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland;

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Karine Fouth-Tchos Collaborative Clinical Research Branch, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland;

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Kathryn Shaw-Saliba Collaborative Clinical Research Branch, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland;

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John Collins Global Alliance for Preventing Pandemics, Columbia University, New York, New York;
Center for Infection and Immunity, Columbia University, New York, New York

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Xiang-Jun Lu Global Alliance for Preventing Pandemics, Columbia University, New York, New York;
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J. Kenneth Wickiser Global Alliance for Preventing Pandemics, Columbia University, New York, New York;
Center for Infection and Immunity, Columbia University, New York, New York

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Thomas Briese Global Alliance for Preventing Pandemics, Columbia University, New York, New York;
Center for Infection and Immunity, Columbia University, New York, New York

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W. Ian Lipkin Global Alliance for Preventing Pandemics, Columbia University, New York, New York;
Center for Infection and Immunity, Columbia University, New York, New York

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Ray Y. Chen Collaborative Clinical Research Branch, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland;

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Seydou Doumbia University Clinical Research Center, University of Sciences, Techniques, and Technologies of Bamako, Bamako, Mali;

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Sounkalo Dao University Clinical Research Center, University of Sciences, Techniques, and Technologies of Bamako, Bamako, Mali;

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ABSTRACT.

Unexplained fever poses significant diagnostic challenges in resource-limited settings like Bamako, Mali, where overlapping endemic diseases include malaria, HIV/AIDS, yellow fever, typhoid, and others. This study aimed to elucidate the infectious etiologies of acute febrile illnesses in this context. Acute febrile patients of any age were enrolled after informed consent or assent. Baseline clinical and demographic data were collected, and samples were analyzed by using rapid diagnostic tests, reverse transcriptase polymerase chain reaction, ELISA, and virus-targeted metagenomic sequencing (virome capture sequencing platform for vertebrate viruses [VirCapSeq-VERT]). Among 108 enrolled subjects, most were male (51.9%) and under 15 years old (56.5%). Measles virus was identified in 39.8% of cases, primarily among children. Other findings included Plasmodium spp. (12%), Salmonella spp. (13%), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; 8.7%). The virome capture sequencing platform for vertebrate viruses was used for 101 subjects, corroborating many routine test results and identifying additional cases of measles virus (1), SARS-CoV-2 (5), and numerous other agents. Notably, nearly all subjects showed evidence of herpesviruses (90%) and anelloviruses (98%). Hemorrhagic fever viruses were not observed. With the inclusion of VirCapSeq-VERT, identifiable pathogens were found in 79.6% of cases, leaving 20.4% without a clear etiology. The identification of more than one concurrent pathogen was common (41.5%). Integrating metagenomic sequencing with routine laboratory diagnostic testing enhances the detection of pathogens in acute febrile illnesses, highlighting its potential value in identifying infectious etiologies in resource-limited settings.

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Author Notes

Financial support: This project has been funded in whole or in part with federal funds from the National Cancer Institute, NIH, under Contract No. 75N91019D00024, Task Order No. 75N91020F00004 and 75N91024F00012. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the United States Government. This work was also supported by the Skoll Foundation and the Moore Charitable Foundation.

Disclosure: This study obtained approval from the ethics committee of the Faculty of Medicine, Pharmacy, and Odontostomatology of the University of Sciences, Techniques, and Technologies of Bamako under number 2018/05/CE/FMPOS on January 10, 2018. Adult subjects enrolled in the study provided informed consent. Children aged 12 and younger provided assent in addition to consent from their parent or legal guardian.

Current contact information: Amadou Koné, Fousseyni Kané, Issa Konate, Bintou Coulibaly, Djeneba K. Dabitao, Bassirou Diarra, Ibrahim Sanogo, Yeya Dit Sadio Sarro, Tenin Aminatou Coulibaly, Dramane Diallo, Seydou Samake, Ilo Dicko, Mountaga Diallo, Ayouba Diarra, Mamadou D. Coulibaly, Daouda Keita, Nadié Coulibaly, Isaac Koloma, Mamadou Perou, Hawa Boukary Diarra, Boubacar Elmadane Cissé, Antieme Combo Georges Togo, Gagni Coulibaly, Fah Gaoussou Traoré, Moumine Sanogo, Mahamadou Diakité, Seydou Doumbia, and Sounkalo Dao, University Clinical Research Center, University of Sciences, Techniques, and Technologies of Bamako, Bamako, Mali, E-mails: amadoukone@icermali.org, fouskane@icermali.org, issakonate@icermali.org, bintoucoulibaly@icermali.org, ddabitao@icermali.org, bdiarra@icermali.org, isanogo@icermali.org, sadio@icermali.org, tenina.coulibaly@icermali.org, dramanediallo@icermali.org, seydousamake@icermali.org, ilo@icermali.org, mountaga.diallo@icermali.org, ayouba.diarra@icermali.org, mdcoulibaly@icermali.org, daouda.keita@icermali.org, nadie@icermali.org, isaacdenisk@icermali.org, mamadouperou@icermali.org, hawa.drame@icermali.org, boubacar-e.cisse@icermali.org, togoacg@icermali.org, gagni@icermali.org, fahgaoussou.traore@icermali.org, smoumine@icermali.org, mdiakite@icermali.org, sdoumbi@icermali.org, and sounkalomdao@yahoo.fr. Aaron Neal, Jamila Aboulhab, Esther Akpa, Karine Fouth-Tchos, Kathryn Shaw-Saliba, and Ray Y. Chen, Collaborative Clinical Research Branch, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, E-mails: aaron.neal@nih.gov, jamila.aboulhab@nih.gov, esther.akpa@nih.gov, karine.fouthtchos@nih.gov, katy.saliba@nih.gov, and ray.chen@nih.gov. John Collins, Xiang-Jun Lu, Mishra Nischay, J. Kenneth Wickiser, Thomas Briese, and W. Ian Lipkin, Global Alliance for Preventing Pandemics and Center for Infection and Immunity, Columbia University, New York, NY, E-mails: jc5966@cumc.columbia.edu, xl2134@columbia.edu, nm2641@cumc.columbia.edu, jkw2161@cumc.columbia.edu, tb2047@cumc.columbia.edu, and wil2001@cumc.columbia.edu.

Address correspondence to Fousseyni Kané, University Clinical Research Center, University of Sciences, Techniques, and Technologies of Bamako, Bamako, Mali. E-mail: fouskane@icermali.org
  • 1.

    Mulders-Manders C, Simon A, Bleeker-Rovers C, 2015. Fever of unknown origin. Clin Med (Lond) 15: 280284.

  • 2.

    Safronetz D et al., 2016. Vectorborne infections, Mali. Emerg Infect Dis 22: 340342.

  • 3.

    Ghansah A et al., Plasmodium Diversity Network Africa, 2019. Targeted next generation sequencing for malaria research in Africa: Current status and outlook. Malar J 18: 324.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4.

    Inzaule SC, Tessema SK, Kebede Y, Ogwell Ouma AE, Nkengasong JN, 2021. Genomic-informed pathogen surveillance in Africa: Opportunities and challenges. Lancet Infect Dis 21: e281e289.

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

    Omotoso OE, Teibo JO, Atiba FA, Oladimeji T, Adebesin AO, Babalghith AO, 2022. Bridging the genomic data gap in Africa: Implications for global disease burdens. Global Health 18: 103.

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

    Briese T, Kapoor A, Mishra N, Jain K, Kumar A, Jabado OJ, Ian LW, 2015. Virome capture sequencing enables sensitive viral diagnosis and comprehensive virome analysis. mBio 6: e01491e01415.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7.

    Kapoor V, Briese T, Ranjan A, Donovan WM, Mansukhani MM, Chowdhary R, Lipkin WI, 2024. Validation of the VirCapSeq-VERT system for differential diagnosis, detection, and surveillance of viral infections. J Clin Microbiol 62: e0061223.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8.

    Diarra B et al., 2016. Laboratory response to 2014 Ebola virus outbreak in Mali. J Infect Dis 214: S164S168.

  • 9.

    Koné A et al., 2023. Dynamics of SARS-CoV-2 variants characterized during different COVID-19 waves in Mali. IJID Reg 6: 2428.

  • 10.

    Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG, 2009. Research electronic data capture (REDCap) – A metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform 42: 377381.

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

    Harris PA et al., REDCap Consortium, 2019. The REDCap consortium: Building an international community of software platform partners. J Biomed Inform 95: 103208.

  • 12.

    Chen S, Zhou Y, Chen Y, Gu J, 2018. Fastp: An ultra-fast all-in-one FASTQ preprocessor. Bioinformatics 34: i884i890.

  • 13.

    Wood DE, Lu J, Langmead B, 2019. Improved metagenomic analysis with Kraken 2. Genome Biol 20: 257.

  • 14.

    Bankevich A et al., 2012. SPAdes: A new genome assembly algorithm and its applications to single-cell sequencing. J Comput Biol 19: 455477.

  • 15.

    Goodacre N, Aljanahi A, Nandakumar S, Mikailov M, Khan AS, 2018. A reference viral database (RVDB) to enhance bioinformatics analysis of high-throughput sequencing for novel virus detection. mSphere 3: e00069-18.

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

    López-Labrador FX et al.; ESCV Network on Next-Generation Sequencing, 2021. Recommendations for the introduction of metagenomic high-throughput sequencing in clinical virology, part I: Wet lab procedure. J Clin Virol 134: 104691.

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

    RStudio Team. The R Project for Statistical Computing. Available at: https://www.r-project.org/. Accessed May 23, 2024.

  • 18.

    Levine ZC et al., 2024. Investigating the etiologies of non-malarial febrile illness in Senegal using metagenomic sequencing. Nat Commun 15: 747.

  • 19.

    Nooh F, Chernet A, Reither K, Okuma J, Brattig NW, Utzinger J, Probst-Hensch N, Paris DH, Dreyfus A, 2023. Prevalence of fever of unidentified aetiology in East African adolescents and adults: A systematic review and meta-analysis. Infect Dis Poverty 12: 55.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20.

    Gutierrez R et al., 2024. Aetiology of non-malaria acute febrile illness fever in children in rural Guinea-Bissau: A prospective cross-sectional investigation. Front Epidemiol 4: 1309149.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21.

    De Vlaminck I et al., 2013. Temporal response of the human virome to immunosuppression and antiviral therapy. Cell 155: 11781187.

  • 22.

    Nampota-Nkomba N et al., 2024. An upsurge of measles cases in mali – A consequence of pandemic-associated disruption in routine immunization. Open Forum Infect Dis 11: ofae154.

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

    Medicins Sans Frontieres, 2020. Measles in Mali: Prevention is Better Than Cure in Timbuktu. Available at: https://www.doctorswithoutborders.ca/measles-in-mali-prevention-is-better-than-cure-in-timbuktu/. Accessed April 11, 2024.

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

    Imperato PJ, Sow O, Fofana B, 1972. The epidemiology of smallpox in the Republic of Mali. Trans R Soc Trop Med Hyg 66: 176182.

  • 25.

    Minta AA et al., 2023. Progress toward measles elimination – Worldwide, 2000–2022. MMWR Morb Mortal Wkly Rep 72: 12621268.

  • 26.

    Wölfel R et al., 2020. Virological assessment of hospitalized patients with COVID-2019. Nature 581: 465469.

  • 27.

    Kaboré B et al., 2021. Aetiology of acute febrile illness in children in a high malaria transmission area in West Africa. Clin Microbiol Infect 27: 590596.

  • 28.

    D’Acremont V, Kilowoko M, Kyungu E, Philipina S, Sangu W, Kahama-Maro J, Lengeler C, Cherpillod P, Kaiser L, Genton B, 2014. Beyond malaria – Causes of fever in outpatient Tanzanian children. N Engl J Med 370: 809817.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29.

    Baba M, Logue CH, Oderinde B, Abdulmaleek H, Williams J, Lewis J, Laws TR, Hewson R, Marcello A, D’ Agaro P, 2013. Evidence of arbovirus co-infection in suspected febrile malaria and typhoid patients in Nigeria. J Infect Dev Ctries 7: 5159.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30.

    Pokharel S, White LJ, Aguas R, Celhay O, Pellé KG, Dittrich S, 2020. Algorithm in the diagnosis of febrile illness using pathogen-specific rapid diagnostic tests. Clin Infect Dis 70: 22622269.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31.

    World Health Organization, 2024. WHO COVID-19 Dashboard. Available at: https://data.who.int/dashboards/covid19/cases?n=c. Accessed April 11, 2024.

  • 32.

    Spengler JR, Ervin ED, Towner JS, Rollin PE, Nichol ST, 2016. Perspectives on West Africa Ebola virus disease outbreak, 2013–2016. Emerg Infect Dis 22: 956963.

  • 33.

    Coltart CEM, Lindsey B, Ghinai I, Johnson AM, Heymann DL, 2017. The Ebola outbreak, 2013–2016: Old lessons for new epidemics. Philos Trans R Soc Lond B Biol Sci 372: 20160297.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34.

    Gire SK et al., 2014. Genomic surveillance elucidates Ebola virus origin and transmission during the 2014 outbreak. Science 345: 13691372.

  • 35.

    Vetter P et al., 2016. The 2014–2015 Ebola outbreak in West Africa: Hands on. Antimicrob Resist Infect Control 5: 17.

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