Increased prevalence and clinical impact of hypocalcaemia in severe COVID-19 distinguishes it from other forms of infective pneumonia

  1. Meera R Mehta
  2. Hakim Ghani
  3. Felix Chua
  4. Adrian Draper
  5. Sam Calmonson
  6. Meghna Prabhakar
  7. Rijul Shah
  8. Alessio Navarra
  9. Tejal Vaghela
  10. Andrew Barlow
  11. Rama Vancheeswaran

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Abstract

Background

Hypocalcaemia has been reported in the context of acute COVID-19, where it has been associated with an increased risk of hospitalisation and disease severity. Calcium is an important intracellular messenger that controls diverse cellular processes. Two other clinically important coronaviruses, SARS-CoV-1 and Middle East respiratory syndrome (MERS)-CoV, can use calcium ions to enter and replicate within host cells. Calcium may therefore be important in the pathophysiology of COVID-19 infection. We sought to investigate whether calcium derangement was a specific feature of COVID-19 that distinguishes it from other infective pneumonias, and its association with disease severity.

Methods

We conducted a single centre retrospective study of albumin-corrected serum calcium on adult patients with COVID-19 who presented between March 1 st and May 16 th 2020. The primary outcome was maximal level of care based on the World Health Organization Clinical Progression Scale for COVID-19. Cases with community acquired pneumonia (CAP) and viral pneumonia (VP) were identified through a clinical database over three intervals (January to February 2018, January to February 2019 and September to December 2019).

Results

We analysed data from 506 patients with COVID-19, 95 patients with CAP and 152 patients with VP. Hypocalcaemia (serum calcium <2.2mmol/L) was a specific and common clinical finding in patients with COVID-19 that was not present in other respiratory infections. Calcium levels were significantly lower in those with severe disease. Ordinal regression of risk estimates for categorised care levels showed that baseline hypocalcaemia was incrementally associated with odds ratio of 2.33 for higher level of care, superior to other variables that have previously been shown to predict worse COVID-19 outcome. Serial calcium levels showed improvement by day 7-9 of admission, only in in survivors of COVID-19.

Conclusion

Hypocalcaemia may independently predict not only more severe but more progressive disease and warrants detailed prognostic investigation. The fact that decreased serum calcium is observed at the time of clinical presentation in COVID-19, but not other infective pneumonias, suggests that its early derangement is pathophysiological and may influence the deleterious evolution of this disease. If calcium is ultimately shown to be critical to the entry and replication of SARS-CoV-2 in host cells, unravelling how this mechanism could be therapeutically targeted deserves more intensive examination.

Trial registration HRA

20/HRA/2344.

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    SciScore for 10.1101/2021.05.27.21257813: (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

    Software and Algorithms
    SentencesResources
    All analyses were performed using GraphPad Prism V.9.0.2 and STATA, V.16
    GraphPad Prism
    suggested: (GraphPad Prism, RRID:SCR_002798)
    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: 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: 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.

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

    About SciScore

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  2. Version published to 10.1101/2021.05.27.21257813v1 on medRxiv