key: cord-0890820-jdw8wl5o
authors: Siniorakis, Eftychios E.; Arvanitakis, Spyridon G.; Elkouris, Maximilianos J.
title: Letter to the Editor in response to article: Hypocalcemia is associated with severe COVID-19: A systematic review and meta-analysis (Martha et al.)
date: 2021-03-24
journal: Diabetes Metab Syndr
DOI: 10.1016/j.dsx.2021.03.009
sha: 1521f06edac9ed29a46d28dbeff668481d96578c
doc_id: 890820
cord_uid: jdw8wl5o

nan

We read the meta-analysis by Martha and colleagues reporting hypocalcemia as a predictor of poor outcome in patients with COVID-19 [1] . There are some caveats that obscure the results of studies examining the impact of serum calcium on COVID-19 severity. Most of them focus on the circulating levels of total calcium, while very few correct calcium to the concentration of albumin [2] . To further dispute the predictive value of total serum calcium, there are publications relating hypocalcemia with COVID-19 of only mild severity [3] , whereas the most severe cases displayed hypercalcemia [4] . Targeting the total serum calcium, significant parameters of calcium homeostasis regulating the intracellular life of coronavirus are overlooked. It is known that total calcium represents a sum of three components: 45% proteinbound, 15% complexed to anions and 40% free or ionized calcium Ca 2+ . This free Ca 2+ is the biologically active component that mediates the intracellular homeostasis of calcium and determines the viral damage on host cells.

In order to ensure their intracellular life cycle, coronaviruses activate specific calcium channels on the plasma membrane as well as the endoplasmic reticulum, to increase Ca 2+ , that favors viral internalization, replication and budding of virions [5] . Low levels of serum calcium, defined by hypocalcemia, are not able to block these efforts of coronaviruses to increase the intracellular Ca 2+ , given that a small percentage of extracellular calcium contributes to the amount of cytoplasmic Ca 2+ . The main buffer of intracellular Ca 2+ is the endoplasmic reticulum which through its organelle membranes maintains the Ca 2+ supply, even in case of hypocalcemia [6] . The intracellular transduction pathways signaled by Ca 2+ are important for coronavirus survival and represent therapeutic targets of various evolutionary drugs, including calcium channel blockers, cardiac glycosides, thapsigargin and colchicine [7, 8] .

None of the above pharmaceutical substances are related to serum calcium levels.

Besides, it is the Ca 2+ mediated intracellular machinery that offers an explanation for hypocalcemia encountered in some COVID-19 infections. Serum calcium depletion constitutes a host's attempt to prevent coronavirus from creating an intracellular Ca 2+ storm. Whether hosts fall victims themselves to this over-reaction, is unpredictable.

In conclusion, the meta-analysis by Martha On behalf of all authors I am declaring that there are no conflicts of interest. In addition, no external funding was received for the preparation of the above mentioned manuscript.

Dr. S. Arvanitakis

Hypocalcemia is associated with severe COVID-19: A systematic review and meta-analysis

Vitamin D deficiency and low serum calcium as predictors of poor prognosis in patients with severe COVID-19

High prevalence of hypocalcemia in non-severe COVID-19 patients: A retrospective case-control study

Associations of essential and toxic metals/metalloids in whole blood with both disease severity and mortality in patients with COVID-19

Repurposing calcium channel blockers as antiviral drugs

ER functions are exploited by viruses to support distinct stages of their life cycle

Evidence for mechanistic alterations of Ca 2+ homeostasis in type 2 diabetes mellitus

Colchicine modulates calcium homeostasis and electrical property of HL-1 cells