Longitudinal Analysis of COVID-19 Patients Shows Age-Associated T Cell Changes Independent of Ongoing Ill-Health

  1. Liam Townsend
  2. Adam H. Dyer
  3. Aifric Naughton
  4. Rachel Kiersey
  5. Dean Holden
  6. Mary Gardiner
  7. Joanne Dowds
  8. Kate O’Brien
  9. Ciaran Bannan
  10. Parthiban Nadarajan
  11. Jean Dunne
  12. Ignacio Martin-Loeches
  13. Padraic G. Fallon
  14. Colm Bergin
  15. Cliona O’Farrelly
  16. Cliona Ni Cheallaigh
  17. Nollaig M. Bourke
  18. Niall Conlon

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Abstract

The immunological and inflammatory changes following acute COVID-19 are hugely variable. Persistent clinical symptoms following resolution of initial infection, termed long COVID , are also hugely variable, but association with immunological changes has not been described. We investigate changing immunological parameters in convalescent COVID-19 and interrogate their potential relationships with persistent symptoms.

Methods

We performed paired immunophenotyping at initial SARS-CoV-2 infection and convalescence (n=40, median 68 days) and validated findings in 71 further patients at median 101 days convalescence. Results were compared to 40 pre-pandemic controls. Fatigue and exercise tolerance were assessed as cardinal features of long COVID using the Chalder Fatigue Scale and 6-minute-walk test. The relationships between these clinical outcomes and convalescent immunological results were investigated.

Results

We identify persistent expansion of intermediate monocytes, effector CD8+, activated CD4+ and CD8+ T cells, and reduced naïve CD4+ and CD8+ T cells at 68 days, with activated CD8+ T cells remaining increased at 101 days. Patients >60 years also demonstrate reduced naïve CD4+ and CD8+ T cells and expanded activated CD4+ T cells at 101 days. Ill-health, fatigue, and reduced exercise tolerance were common in this cohort. These symptoms were not associated with immune cell populations or circulating inflammatory cytokines.

Conclusion

We demonstrate myeloid recovery but persistent T cell abnormalities in convalescent COVID-19 patients more than three months after initial infection. These changes are more marked with age and are independent of ongoing subjective ill-health, fatigue and reduced exercise tolerance.

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  1. Version published to 10.3389/fimmu.2021.676932
  2. ScreenIT

    SciScore for 10.1101/2020.12.17.20248401: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board StatementIRB: Study approval: Ethical approval for the current study was obtained from the Tallaght University Hospital (TUH)/St James’s Hospital (SJH) Joint Research Ethics Committee (reference REC 2020-03).
    Consent: Informed consent was obtained from all participants in the current study in accordance with the Declaration of Helsinki (57).
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Immunophenotyping by flow cytometry was carried out on fresh whole EDTA-treated blood and samples were analysed on a FACS Canto II Flow Cytometer (BD San Jose USA), using BD DIVA v8 and FLO Jo v10 software.
    BD DIVA
    suggested: None
    BD FACSCanto™ clinical software was used for acquisition of BD Multitest™ 6-colour TBNK and TruCount tubes.
    BD FACSCanto™
    suggested: None
    Statistical analysis: All statistical analysis was carried out using STATA v15.0 (Texas, USA) and statistical significance considered p<0.05.
    STATA
    suggested: (Stata, RRID:SCR_012763)

    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:
    Our study has several limitations worth noting. It is a single-centre study at a single medium-term interval. However, we have two separate convalescent time points, in addition to data from acute illness. This allows a disease and recovery trajectory to be plotted. We have loss to follow-up, with 31% of patients attending their outpatient appointments. This is a common challenge seen in research conducted in clinical ambulatory care settings. However, our cohort may have an increased burden of symptoms following COVID-19 than that seen in the entire affected population. The results reported here provide insights into the immune consequences of SARS-CoV-2 infection, as well as the age effects on immune recovery. It provides possible mechanisms for immunopathology and should inform the design of ongoing studies into the immunological consequences of COVID-19 and associations with long COVID clinical features. In conclusion, we report several key findings that add significant knowledge regarding resolution of the immunological responses in the convalescent period of COVID-19 infection. Encouragingly, our matched longitudinal patient data shows that all cell counts return towards levels of healthy controls. Although there are persistent lymphocyte and monocyte abnormalities at 68 days, these had resolved by 101 days post infection with the exception of a persistent expansion of activated CD8+ T cells. We show that age, while being strongly associated with poor outcome in acute C...

    Results from TrialIdentifier: No clinical trial numbers were referenced.

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

    Results from JetFighter: Please consider improving the rainbow (“jet”) colormap(s) used on page 59. At least one figure is not accessible to readers with colorblindness and/or is not true to the data, i.e. not perceptually uniform.

    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.
    • Thank you for including a protocol registration statement.

    About SciScore

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  3. Version published to 10.1101/2020.12.17.20248401v1 on medRxiv