Lymphocytopaenia is associated with severe SARS-CoV-2 disease: A Systematic Review and Meta-Analysis of Clinical Data

  1. Robin Brown
  2. Jane Barnard
  3. Eva Harris-Skillman
  4. Bronwen Harbinson
  5. Beata Dunne
  6. Jonathan Drake
  7. Sophie Roche
  8. Edward Harris
  9. James Gunnell
  10. Joshua Frost
  11. Brian Angus
  12. Susanne H Hodgson

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Abstract

Background

Most patients infected by SARS-CoV-2 have favourable outcomes, however some develop severe disease which may progress to acute respiratory distress syndrome, multi-organ failure, and death. Markers that could predict patients at risk of poor outcomes would be extremely useful clinically. Evidence has emerged that low lymphocyte count is associated with increased disease severity.

Methods

We performed a systematic review and meta-analysis to assess the association between lymphocyte count and severity of SARS-CoV-2 associated clinical disease.

Results

Seven papers were included in the meta-analysis. These papers included data from 2083 patients, 25% (n=521) with severe SAR-CoV-2 disease and 75% (n=1562) with non-severe SAR-CoV-2 disease. Heterogenicity was seen in the definition of severe disease. Metanalysis produced metamedians of 1×10 9 /L (95% CI 1-1.1) and 0.7×10 9 /L (95% CI 0.63-0.8) lymphocytes for patients with non-severe and severe disease respectively ( p- value of p=0.006 Wilcoxon test ). Calculation of metamedians from the two papers classifying severe disease according to death alone gave 1.1 1×10 9 /L lymphocytes (95% CI 1.0-1.1) for ‘survivors’ (n=163) and 0.63 1×10 9 /L lymphocytes (95% CI 0.60-0.63) for ‘non-survivors’ (n=253) of SAR-CoV-2 disease.

Conclusions

Lower lymphocyte counts are significantly associated with more severe disease in patients with SARS-CoV-2 infection. Lymphocytopenia may therefore be useful laboratory measure to allow prognostication of patients presenting with SARS-CoV-2 infection.

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  1. ScreenIT

    SciScore for 10.1101/2020.04.14.20064659: (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 conducted a systematic review using Embase and Medline, searching for articles relating to the current COVID-19 outbreak from November 2019 until 30 March 2020.
    Embase
    suggested: (EMBASE, RRID:SCR_001650)
    Medline
    suggested: (MEDLINE, RRID:SCR_002185)

    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 to be considered in this finding. Firstly, we do not know the temporal relationship between a decline in lymphocyte count and the onset of more severe disease, and so it is unclear how early this measure could be used to predict disease severity. It is also of note that as the largest multicentre study did not list the centres used in their analysis, so there is a possibility that some patients were counted twice in papers included in our metanalysis15. However, despite these limitations, this review confirms what anecdotally clinicians have widely observed, that lymphocytopenia is associated with severe COVID-19 disease6. Lymphocytopaenia was demonstrated to be a feature of SARS (SARS-CoV) infection19. Autopsy studies revealed this was due to targeted toxicity to lymphocytes and lymphoid tissue21. Given the genetic similarity to SARS-CoV, it may be that similar pathology is a feature of infection with SARS-CoV-222. The correlation between lymphocyte count and severity of COVID-19 infection complements two recent meta-analyses by Lippi et al. 2020 which showed a correlation between thrombocytopenia and procalcitonin levels and severity of COVID-19 disease23,24. Lymphocyte count could therefore be used alongside these and other laboratory measures to assess the severity of illness in patients with SARs-CoV-2 infection and potentially to predict outcome.

    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: 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.

    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.

  2. Version published to 10.1101/2020.04.14.20064659v1 on medRxiv