Clinical and immunological signatures of severe COVID-19 in previously healthy patients with clonal hematopoiesis

  1. Chang Kyung Kang
  2. Baekgyu Choi
  3. Sugyeong Kim
  4. Seongwan Park
  5. Soon Ho Yoon
  6. Dohoon Lee
  7. Andrew J. Lee
  8. Yuji Ko
  9. Euijin Chang
  10. Jongtak Jung
  11. Pyoeng Gyun Choe
  12. Wan Beom Park
  13. Eu Suk Kim
  14. Hong Bin Kim
  15. Nam Joong Kim
  16. Myoung-don Oh
  17. Suk-jo Kang
  18. Kyuho Kang
  19. Sun Kim
  20. Hogune Im
  21. Joohae Kim
  22. Yong Hoon Lee
  23. Jaehee Lee
  24. Ji Yeon Lee
  25. Joon Ho Moon
  26. Kyoung-Ho Song
  27. Youngil Koh
  28. Inkyung Jung

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Abstract

Identifying additional risk factors for COVID-19 severity in numerous previously healthy patients without canonical clinical risk factors remains challenging. In this study, we investigate whether clonal hematopoiesis of indeterminate potential (CHIP), a common aging-related process that predisposes various inflammatory responses, may exert COVID-19 severity. We examine the clinical impact of CHIP in 143 laboratory-confirmed COVID-19 patients. Both stratified analyses and logistic regression including the interaction between canonical risk factors and CHIP show that CHIP is an independent risk factor for severe COVID-19, especially in previously healthy patients. Analyses of 60,310 single-cell immune transcriptome profiles identify distinct immunological signatures for CHIP (+) severe COVID-19 patients, particularly in classical monocytes, with a marked increase in pro-inflammatory cytokine responses and potent IFN-γ mediated hyperinflammation signature. We further demonstrate that the enhanced expression of CHIP (+) specific IFN-γ response genes is attributed to the CHIP mutation-dependent epigenetic reprogramming of poised or bivalent cis -regulatory elements. Our results highlight a unique immunopathogenic mechanism of CHIP in the progression of severe COVID-19, which could be extended to elucidate how CHIP contributes to a variety of human infectious diseases.

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    SciScore for 10.1101/2021.10.05.463271: (What is this?)

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

    Table 1: Rigor

    Ethicsnot detected.
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    No key resources detected.

    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: We detected the following sentences addressing limitations in the study:
    There are several limitations in the present study. First, sample sizes of either entire cohort or scRNA-seq-analyzed patients were limited. Second, the proportion of severe COVID-19 was high in the present study since it was conducted mainly in tertiary-care hospitals. Although we could show an apparent incline to severe COVID-19 in CHIP (+) patients and its distinctive immune signature in this study, further validations in a larger prospective cohort representing general COVID-19 patients are warranted. Third, scRNA-seq was performed with PBMCs instead of lung fluid or infected lung tissues limiting our analysis in exploring systemic inflammation as a result of COVID-19 pulmonary disease. Lastly, further studies are needed to reveal the exact epigenetic differences between mutant and wild type monocytes in CHIP patients and the real time point when CHIP mutant monocytes stir hyperinflammation. Lastly, in terms of therapeutic strategy, Syk inhibitors have been implicated in suppressing these pathogenic immune responses (Extended Data Fig. 5b) induced by CHIP. An in vitro study on Syk inhibitor fostamatinib suggested its therapeutic effect against COVID-1957, and we have pending results of a randomized placebo-controlled trial with the drug (NCT04579393). As the therapeutic efficacy of Syk inhibitors could be more potent in CHIP (+) patients, it is worth evaluating treatment outcomes involving Syk inhibitors according to CHIP status. In summary, despite such limitations, we s...

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

    IdentifierStatusTitle
    NCT04579393CompletedFostamatinib for Hospitalized Adults With COVID-19

    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.

    Results from scite Reference Check: We found no unreliable references.

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  2. Version published to 10.1101/2021.10.05.463271 on bioRxiv