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

BackgroundHypocalcaemia 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. MethodsWe conducted a single centre retrospective study of albumin-corrected serum calcium on adult patients with COVID-19 who presented between March 1st and May 16th 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). ResultsWe 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. ConclusionHypocalcaemia 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 HRA20/HRA/2344.