Prolonged SARS-CoV-2 RNA virus shedding and lymphopenia are hallmarks of COVID-19 in cancer patients with poor prognosis

  1. Anne-Gaëlle Goubet
  2. Agathe Dubuisson
  3. Arthur Geraud
  4. François-Xavier Danlos
  5. Safae Terrisse
  6. Carolina Alves Costa Silva
  7. Damien Drubay
  8. Lea Touri
  9. Marion Picard
  10. Marine Mazzenga
  11. Aymeric Silvin
  12. Garett Dunsmore
  13. Yacine Haddad
  14. Eugenie Pizzato
  15. Pierre Ly
  16. Caroline Flament
  17. Cléa Melenotte
  18. Eric Solary
  19. Michaela Fontenay
  20. Gabriel Garcia
  21. Corinne Balleyguier
  22. Nathalie Lassau
  23. Markus Maeurer
  24. Claudia Grajeda-Iglesias
  25. Nitharsshini Nirmalathasan
  26. Fanny Aprahamian
  27. Sylvère Durand
  28. Oliver Kepp
  29. Gladys Ferrere
  30. Cassandra Thelemaque
  31. Imran Lahmar
  32. Jean-Eudes Fahrner
  33. Lydia Meziani
  34. Abdelhakim Ahmed-Belkacem
  35. Nadia Saïdani
  36. Bernard La Scola
  37. Didier Raoult
  38. Stéphanie Gentile
  39. Sébastien Cortaredona
  40. Giuseppe Ippolito
  41. Benjamin Lelouvier
  42. Alain Roulet
  43. Fabrice Andre
  44. Fabrice Barlesi
  45. Jean-Charles Soria
  46. Caroline Pradon
  47. Emmanuelle Gallois
  48. Fanny Pommeret
  49. Emeline Colomba
  50. Florent Ginhoux
  51. Suzanne Kazandjian
  52. Arielle Elkrief
  53. Bertrand Routy
  54. Makoto Miyara
  55. Guy Gorochov
  56. Eric Deutsch
  57. Laurence Albiges
  58. Annabelle Stoclin
  59. Bertrand Gachot
  60. Anne Florin
  61. Mansouria Merad
  62. Florian Scotte
  63. Souad Assaad
  64. Guido Kroemer
  65. Jean-Yves Blay
  66. Aurélien Marabelle
  67. Frank Griscelli
  68. Laurence Zitvogel
  69. Lisa Derosa

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Abstract

Patients with cancer are at higher risk of severe coronavirus infectious disease 2019 (COVID-19), but the mechanisms underlying virus–host interactions during cancer therapies remain elusive. When comparing nasopharyngeal swabs from cancer and noncancer patients for RT-qPCR cycle thresholds measuring acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in 1063 patients (58% with cancer), we found that malignant disease favors the magnitude and duration of viral RNA shedding concomitant with prolonged serum elevations of type 1 IFN that anticorrelated with anti-RBD IgG antibodies. Cancer patients with a prolonged SARS-CoV-2 RNA detection exhibited the typical immunopathology of severe COVID-19 at the early phase of infection including circulation of immature neutrophils, depletion of nonconventional monocytes, and a general lymphopenia that, however, was accompanied by a rise in plasmablasts, activated follicular T-helper cells, and non-naive Granzyme B + FasL + , Eomes high TCF-1 high , PD-1 + CD8 + Tc1 cells. Virus-induced lymphopenia worsened cancer-associated lymphocyte loss, and low lymphocyte counts correlated with chronic SARS-CoV-2 RNA shedding, COVID-19 severity, and a higher risk of cancer-related death in the first and second surge of the pandemic. Lymphocyte loss correlated with significant changes in metabolites from the polyamine and biliary salt pathways as well as increased blood DNA from Enterobacteriaceae and Micrococcaceae gut family members in long-term viral carriers. We surmise that cancer therapies may exacerbate the paradoxical association between lymphopenia and COVID-19-related immunopathology, and that the prevention of COVID-19-induced lymphocyte loss may reduce cancer-associated death.

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  1. Version published to 10.1038/s41418-021-00817-9
  2. ScreenIT

    SciScore for 10.1101/2021.04.26.21250357: (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

    Antibodies
    SentencesResources
    Finally, specific antibodies of patients are detected with anti-IgG or -IgA or - IgM secondary antibodies.
    anti-IgG
    suggested: None
    IgM
    suggested: None
    For patients treated by anti-PD-1 monoclonal antibody, the gates including PD-1 were excluded of the analysis.
    anti-PD-1
    suggested: None
    For patients treated by anti-CD38 monoclonal antibody, the gates including CD38 were excluded of the analysis.
    CD38
    suggested: None
    Software and Algorithms
    SentencesResources
    SARS-CoV-2 RNA was detected using one of two available technics at Gustave Roussy: the GeneFinder COVID-19 Plus RealAmp kit (ELITech Group) targeting three regions (RdRp gene, nucleocapsid and envelope genes) on the ELITe InGenius (ELITech Group) or the multiplex real-time RT-PCR diagnostic kit (the Applied Biosystems TaqPath COVID-19
    GeneFinder
    suggested: (GENEFINDER, RRID:SCR_009190)
    The detection of the sequencing fragments was performed using the MiSeq Illumina® technology.
    MiSeq
    suggested: (A5-miseq, RRID:SCR_012148)
    Taxonomic assignment of amplicons into operational taxonomic units (OTUs) was produced by Blast+ v2.2.30+ with the Silva 134 Parc databank.
    Blast+
    suggested: (Japan Bioinformatics, RRID:SCR_012250)
    Spectral flow cytometry: Fcs files were exported and analyzed using FlowJo software using the gating strategy showed in Supplementary material, Figure 2.
    FlowJo
    suggested: (FlowJo, RRID:SCR_008520)
    Data representation was performed with software R v3.3.3 using tidyverse, dplyr, ggplot2, ggpubr, pheatmap, corrplot or Hmisc packages or GraphPad Prism 7.
    ggplot2
    suggested: (ggplot2, RRID:SCR_014601)
    GraphPad Prism
    suggested: (GraphPad Prism, RRID:SCR_002798)
    Statistical analyses: Calculations and statistical tests were performed either with R v3.3.3 or Prism 7 (GraphPad, San Diego, CA, USA).
    Prism
    suggested: (PRISM, RRID:SCR_005375)
    GraphPad
    suggested: (GraphPad Prism, RRID:SCR_002798)
    Spearman correlations were computed using Hmisc and Pheatmap R package.
    Pheatmap
    suggested: (pheatmap, RRID:SCR_016418)
    Hierarchical clustering of the patient’s factors was performed using using the hclust R package.
    hclust
    suggested: (HCLUST, RRID:SCR_009154)
    The redundancy analysis (RDA) was performed using the vegan R package to explore the association between the clinical variables and the biological parameters correlation latent structure.
    vegan
    suggested: (vegan, RRID:SCR_011950)

    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
    NCT04341207RecruitingEpidemiology of SARS-CoV-2 and Mortality to Covid19 Disease …
    NCT04407689RecruitingInterLeukin-7 to Improve Clinical Outcomes in Lymphopenic pA…
    NCT04426201RecruitingInterLeukin-7 to Improve Clinical Outcomes in Lymphopenic Pa…
    NCT04379076RecruitingInterLeukin-7 (CYT107) to Improve Clinical Outcomes in Lymph…

    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.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  3. Version published to 10.1101/2021.04.26.21250357v1 on medRxiv