The Nexus Between Telomere Length and Lymphocyte Count in Seniors Hospitalized With COVID-19

  1. Athanase Benetos
  2. Tsung-Po Lai
  3. Simon Toupance
  4. Carlos Labat
  5. Simon Verhulst
  6. Sylvie Gautier
  7. Marie-Noelle Ungeheuer
  8. Christine Perret-Guillaume
  9. Daniel Levy
  10. Ezra Susser
  11. Abraham Aviv

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Abstract

Profound T-cell lymphopenia is the hallmark of severe coronavirus disease 2019 (COVID-19). T-cell proliferation is telomere length (TL) dependent and telomeres shorten with age. Older COVID-19 patients, we hypothesize, are, therefore, at a higher risk of having TL-dependent lymphopenia. We measured TL by the novel Telomere Shortest Length Assay (TeSLA), and by Southern blotting (SB) of the terminal restriction fragments in peripheral blood mononuclear cells of 17 COVID-19 and 21 non-COVID-19 patients, aged 87 ± 8 (mean ± SD) and 87 ± 9 years, respectively. TeSLA tallies and measures single telomeres, including short telomeres undetected by SB. Such telomeres are relevant to TL-mediated biological processes, including cell viability and senescence. TeSLA yields 2 key metrics: the proportions of telomeres with different lengths (expressed in %) and their mean (TeSLA mTL), (expressed in kb). Lymphocyte count (109/L) was 0.91 ± 0.42 in COVID-19 patients and 1.50 ± 0.50 in non-COVID-19 patients (p < .001). In COVID-19 patients, but not in non-COVID-19 patients, lymphocyte count was inversely correlated with the proportion of telomeres shorter than 2 kb (p = .005) and positively correlated with TeSLA mTL (p = .03). Lymphocyte count was not significantly correlated with SB mTL in either COVID-19 or non-COVID-19 patients. We propose that compromised TL-dependent T-cell proliferative response, driven by short telomere in the TL distribution, contributes to COVID-19 lymphopenia among old adults. We infer that infection with SARS-CoV-2 uncovers the limits of the TL reserves of older persons.

Clinical Trials Registration Number: NCT04325646.

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  1. Version published to 10.1093/gerona/glab026
  2. ScreenIT

    SciScore for 10.1101/2020.10.01.20205393: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board StatementConsent: Eighteen participants signed an informed consent approved by the COMITE DE PROTECTION DES PERSONNES (CPP) ILE DE France III.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot 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:
    We acknowledge limitations of this study. The cross-sectional data we provide do not prove causality. Reverse causation, however, seems unlikely; a low lymphocyte count would not rapidly shorten TL in COVID patients. The detection of the inverse correlation between lymphocyte count and the proportion of very short telomeres required use of TeSLA, a novel and expensive approach available in few laboratories worldwide. Nonetheless, the correlation between lymphocyte count and SB mTL showed a pattern similar to that generated by TeSLA mTL. As TeSLA and SB results are correlated, we anticipate that the TL-COVID-19 connection we highlight might also be captured using SB measurements in larger cohorts. In addition, the clinical picture and outcomes of COVID-19 are complex and multi-factorial and TL dynamics of hematopoietic cells are only a component of the disease. Finally, we studied a small cohort of older persons of European ancestry, all surviving the disease for at least 15 days. This most vulnerable group to severe COVID-19 is not representative of the general population, but studying its members has provided the optimal setting to examine the TL-lymphopenia connection in this disease.10 In conclusion, in a small study of older adults, we tested a model that links lymphopenia in older COVID-19 patients with PBMC TL parameters. Our findings show that comparatively short PBMC telomeres, as expressed in the shortest telomeres of the TL distribution, are associated with diminish...

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

    IdentifierStatusTitle
    NCT04325646RecruitingSero-epidemiological Study of the SARS-CoV-2 Virus Responsib…

    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 10.1101/2020.10.01.20205393v1 on medRxiv