Clonal hematopoiesis is associated with risk of severe Covid-19

  1. Kelly L. Bolton
  2. Youngil Koh
  3. Michael B. Foote
  4. Hogune Im
  5. Justin Jee
  6. Choong Hyun Sun
  7. Anton Safonov
  8. Ryan Ptashkin
  9. Joon Ho Moon
  10. Ji Yeon Lee
  11. Jongtak Jung
  12. Chang Kyung Kang
  13. Kyoung-Ho Song
  14. Pyoeng Gyun Choe
  15. Wan Beom Park
  16. Hong Bin Kim
  17. Myoung-don Oh
  18. Han Song
  19. Sugyeong Kim
  20. Minal Patel
  21. Andriy Derkach
  22. Erika Gedvilaite
  23. Kaitlyn A. Tkachuk
  24. Brian J. Wiley
  25. Ireaneus C. Chan
  26. Lior Z. Braunstein
  27. Teng Gao
  28. Elli Papaemmanuil
  29. N. Esther Babady
  30. Melissa S. Pessin
  31. Mini Kamboj
  32. Luis A. Diaz
  33. Marc Ladanyi
  34. Michael J. Rauh
  35. Pradeep Natarajan
  36. Mitchell J. Machiela
  37. Philip Awadalla
  38. Vijai Joseph
  39. Kenneth Offit
  40. Larry Norton
  41. Michael F. Berger
  42. Ross L. Levine
  43. Eu Suk Kim
  44. Nam Joong Kim
  45. Ahmet Zehir

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Abstract

Acquired somatic mutations in hematopoietic stem and progenitor cells (clonal hematopoiesis or CH) are associated with advanced age, increased risk of cardiovascular and malignant diseases, and decreased overall survival. These adverse sequelae may be mediated by altered inflammatory profiles observed in patients with CH. A pro-inflammatory immunologic profile is also associated with worse outcomes of certain infections, including SARS-CoV-2 and its associated disease Covid-19. Whether CH predisposes to severe Covid-19 or other infections is unknown. Among 525 individuals with Covid-19 from Memorial Sloan Kettering (MSK) and the Korean Clonal Hematopoiesis (KoCH) consortia, we show that CH is associated with severe Covid-19 outcomes (OR = 1.85, 95%=1.15–2.99, p = 0.01), in particular CH characterized by non-cancer driver mutations (OR = 2.01, 95% CI = 1.15–3.50, p = 0.01). We further explore the relationship between CH and risk of other infections in 14,211 solid tumor patients at MSK. CH is significantly associated with risk of Clostridium Difficile (HR = 2.01, 95% CI: 1.22–3.30, p = 6×10 −3 ) and Streptococcus/Enterococcus infections (HR = 1.56, 95% CI = 1.15–2.13, p = 5×10 −3 ). These findings suggest a relationship between CH and risk of severe infections that warrants further investigation.

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  1. Version published to 10.1038/s41467-021-26138-6
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    SciScore for 10.1101/2020.11.25.20233163: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board Statementnot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    We annotated variants as oncogenic if they fulfilled any of the following criteria: 1) truncating variants in NF1, DNMT3A, TET2, IKZF1, RAD21, WT1, KMT2D, SH2B3, TP53, CEBPA, ASXL1, RUNX1, BCOR, KDM6A, STAG2, PHF6, KMT2C, PPM1D, ATM, ARID1A, ARID2, ASXL2, CHEK2, CREBBP, ETV6, EZH2, FBXW7, MGA, MPL, RB1, SETD2, SUZ12, ZRSR2 or in CALR exon 9; 2) any truncating mutations (nonsense, essential splice site or frameshift indel) in known tumor suppressor genes as per the Cancer Gene Census, OncoKB, or the scientific literature; 3) translation start site mutations in SH2B3; 4) TERT promoter mutations; 5) FLT3-ITDs; 6) in-frame indels in CALR, CEBPA, CHEK2, ETV6, EZH2; 7) any variant occurring in the COSMIC “haematopoietic and lymphoid” category greater than or equal to 10 times; 8) any variant reported as somatic at least 20 times in COSMIC; 9) any variant noted as potentially oncogenic in an in-house dataset of 7,000 individuals with myeloid neoplasm greater than or equal to 5 times; 10) any loci (defined by the amino acid location) reported as having at least 5 missense mutations and at least one exact mutational match in TopMed6.
    OncoKB
    suggested: (OncoKB, RRID:SCR_014782)
    COSMIC
    suggested: None

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    Results from TrialIdentifier: We found the following clinical trial numbers in your paper:

    IdentifierStatusTitle
    NCT01775072RecruitingGenomic Profiling in Cancer Patients

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

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  3. Version published to 10.1101/2020.11.25.20233163v1 on medRxiv