Reply to Vitamin D deficiency in COVID-19: mixing up cause and consequence
Authors: M. Chakhtoura, G. El Hajj Fuleihan
Journal: Metabolism (2020)

The SARS-Cov-2 tsunami has engulfed the global community into an accelerated search for preventive and therapeutic strategies to halt its devastating toll; immune modulation being the fulcrum of all. The effect of vitamin D role on innate and adaptive immunity is undisputable [1Koivisto O. Hanel A. Carlberg C. Key vitamin D target genes with functions in the immune system.Nutrients. 2020; 12: 1140-1158Crossref Scopus (62) Google Scholar], yet its role in this viral illness is unclear [2Tay M.Z. Poh C.M. Rénia L. MacAry P.A. Ng L.F.P. The trinity of COVID-19: immunity, inflammation and intervention.Nat Rev Immunol. 2020; 20: 363-374Crossref PubMed Scopus (2927) Google Scholar]. While biologic plausibility supports an association between vitamin D status and COVD-19 infection, establishing causality remains elusive. It was not implied in our commentary [3Chakhtoura M. Napoli N. El Hajj Fuleihan G. Commentary: myths and facts on vitamin D amidst the COVID-19 pandemic.Metabolism, Clinical and Experimental. 2020; 109: 154276Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar]. COVID-19 patients often seek medical advice after the onset of symptoms, and past the trigger of its inflammatory cascade. We concur with Smolders et al., reverse causality is a consideration [4Smolders J, van den Ouweland J, Geven C, Pickkers P, Kox M, Vitamin D deficiency in COVID-19: mixing up cause and consequence. Metabolism, Clinical and Experimental [In Press].Google Scholar]. These authors show that the inoculation of 9 healthy volunteers with E.Coli-derived lipopolysaccharide, at a relatively high dose of 4 ng/kg over 4 h [5Fullerton J.N. Segre E. De Maeyer R.P.H. Maini A.A.N. Gilroy D.W. Intravenous endotoxin challenge in healthy humans: an experimental platform to investigate and modulate systemic inflammation.J Vis Exp. 2016; 111: 53913-53921Google Scholar], resulted in a rise in inflammatory markers, and a concomitant drop in mean serum 25-hydroxyvitamin D (25OHD), by 2.6 ng/ml, 2–3 h later [4Smolders J, van den Ouweland J, Geven C, Pickkers P, Kox M, Vitamin D deficiency in COVID-19: mixing up cause and consequence. Metabolism, Clinical and Experimental [In Press].Google Scholar]. Several other small studies (N 19–90) examined changes in 25OHD in acute illnesses, using for the most part standardized assays. These included elective orthopedic [6Reid D. Toole B.J. Knox S. Talwar D. Harten J. O'Reilly D.S.J. et al.The relation between acute changes in the systemic inflammatory response and plasma 25-hydroxyvitamin D concentrations after elective knee arthroplasty.Am J Clin Nutr. 2011; 93: 1006-1011Crossref PubMed Scopus (246) Google Scholar,7Waldron J.L. Ashby H.L. Cornes M.P. Bechervaise J. Razavi C. Thomas O.L. et al.Vitamin D: a negative acute phase reactant.J Clin Pathol. 2013; 66: 620-622Crossref PubMed Scopus (206) Google Scholar], and cardiac surgery [8Krishnan A. Ochola J. Mundy J. Jones M. Kruger P. Duncan E. et al.Acute fluid shifts influence the assessment of serum vitamin D status in critically ill patients.Crit Care. 2010; 14: R216-R223Crossref PubMed Scopus (126) Google Scholar], acute pancreatitis [9Bang U.C. Novovic S. Andersen A.M. Fenger M. Hansen M.B. Jensen J.-E.B. Variations in serum 25-hydroxyvitamin D during acute pancreatitis: an exploratory longitudinal study.Endocr Res. 2011; 36: 135-141Crossref PubMed Scopus (44) Google Scholar], or shock and ICU admissions [10Dayal D. Kumar S. Sachdeva N. Kumar R. Singh M. Singhi S. Fall in vitamin D levels during hospitalization in children.Int J Pediatr. 2014; 2014: 291856-291862PubMed Google Scholar,11Braun A.B. Gibbons F.K. Litonjua A.A. Giovannucci E. Christopher K.B. Low serum 25-hydroxyvitamin D at critical care initiation is associated with increased mortality.Crit Care Med. 2012; 40: 63-72Crossref PubMed Scopus (168) Google Scholar]. The drop in mean 25OHD of 1–12 ng/ml occurred during the first 48 h of admission [6Reid D. Toole B.J. Knox S. Talwar D. Harten J. O'Reilly D.S.J. et al.The relation between acute changes in the systemic inflammatory response and plasma 25-hydroxyvitamin D concentrations after elective knee arthroplasty.Am J Clin Nutr. 2011; 93: 1006-1011Crossref PubMed Scopus (246) Google Scholar, 7Waldron J.L. Ashby H.L. Cornes M.P. Bechervaise J. Razavi C. Thomas O.L. et al.Vitamin D: a negative acute phase reactant.J Clin Pathol. 2013; 66: 620-622Crossref PubMed Scopus (206) Google Scholar, 8Krishnan A. Ochola J. Mundy J. Jones M. Kruger P. Duncan E. et al.Acute fluid shifts influence the assessment of serum vitamin D status in critically ill patients.Crit Care. 2010; 14: R216-R223Crossref PubMed Scopus (126) Google Scholar, 9Bang U.C. Novovic S. Andersen A.M. Fenger M. Hansen M.B. Jensen J.-E.B. Variations in serum 25-hydroxyvitamin D during acute pancreatitis: an exploratory longitudinal study.Endocr Res. 2011; 36: 135-141Crossref PubMed Scopus (44) Google Scholar, 10Dayal D. Kumar S. Sachdeva N. Kumar R. Singh M. Singhi S. Fall in vitamin D levels during hospitalization in children.Int J Pediatr. 2014; 2014: 291856-291862PubMed Google Scholar, 11Braun A.B. Gibbons F.K. Litonjua A.A. Giovannucci E. Christopher K.B. Low serum 25-hydroxyvitamin D at critical care initiation is associated with increased mortality.Crit Care Med. 2012; 40: 63-72Crossref PubMed Scopus (168) Google Scholar]. The response was however quite variable, some studies registering no change or an increase [9Bang U.C. Novovic S. Andersen A.M. Fenger M. Hansen M.B. Jensen J.-E.B. Variations in serum 25-hydroxyvitamin D during acute pancreatitis: an exploratory longitudinal study.Endocr Res. 2011; 36: 135-141Crossref PubMed Scopus (44) Google Scholar,12Barth J.H. Field H.P. Mather A.N. Plein S. Serum 25 hydroxy-vitamin D does not exhibit an acute phase reaction after acute myocardial infarction.Ann Clin Biochem. 2012; 49: 399-401Crossref PubMed Scopus (25) Google Scholar]. Serum 25OHD level may return to baseline within 5–14 days [6Reid D. Toole B.J. Knox S. Talwar D. Harten J. O'Reilly D.S.J. et al.The relation between acute changes in the systemic inflammatory response and plasma 25-hydroxyvitamin D concentrations after elective knee arthroplasty.Am J Clin Nutr. 2011; 93: 1006-1011Crossref PubMed Scopus (246) Google Scholar,8Krishnan A. Ochola J. Mundy J. Jones M. Kruger P. Duncan E. et al.Acute fluid shifts influence the assessment of serum vitamin D status in critically ill patients.Crit Care. 2010; 14: R216-R223Crossref PubMed Scopus (126) Google Scholar,9Bang U.C. Novovic S. Andersen A.M. Fenger M. Hansen M.B. Jensen J.-E.B. Variations in serum 25-hydroxyvitamin D during acute pancreatitis: an exploratory longitudinal study.Endocr Res. 2011; 36: 135-141Crossref PubMed Scopus (44) Google Scholar], but this return was not linked to recovery from illness [12Barth J.H. Field H.P. Mather A.N. Plein S. Serum 25 hydroxy-vitamin D does not exhibit an acute phase reaction after acute myocardial infarction.Ann Clin Biochem. 2012; 49: 399-401Crossref PubMed Scopus (25) Google Scholar]. Both 25OHD and 1,25OH2D decreased similarly by day 5 in one study, but while 25OHD returned to baseline, there was a subsequent overshoot in 1,25OH2D level [8Krishnan A. Ochola J. Mundy J. Jones M. Kruger P. Duncan E. et al.Acute fluid shifts influence the assessment of serum vitamin D status in critically ill patients.Crit Care. 2010; 14: R216-R223Crossref PubMed Scopus (126) Google Scholar]. The reasons for decrements in 25OHD level in acute illness are not clear. The association of CRP and albumin, most frequently assessed predictors for a change in 25OHD during illness, were inconsistent [6Reid D. Toole B.J. Knox S. Talwar D. Harten J. O'Reilly D.S.J. et al.The relation between acute changes in the systemic inflammatory response and plasma 25-hydroxyvitamin D concentrations after elective knee arthroplasty.Am J Clin Nutr. 2011; 93: 1006-1011Crossref PubMed Scopus (246) Google Scholar, 7Waldron J.L. Ashby H.L. Cornes M.P. Bechervaise J. Razavi C. Thomas O.L. et al.Vitamin D: a negative acute phase reactant.J Clin Pathol. 2013; 66: 620-622Crossref PubMed Scopus (206) Google Scholar, 8Krishnan A. Ochola J. Mundy J. Jones M. Kruger P. Duncan E. et al.Acute fluid shifts influence the assessment of serum vitamin D status in critically ill patients.Crit Care. 2010; 14: R216-R223Crossref PubMed Scopus (126) Google Scholar, 9Bang U.C. Novovic S. Andersen A.M. Fenger M. Hansen M.B. Jensen J.-E.B. Variations in serum 25-hydroxyvitamin D during acute pancreatitis: an exploratory longitudinal study.Endocr Res. 2011; 36: 135-141Crossref PubMed Scopus (44) Google Scholar]. The dilutional effects of fluids during illness [6Reid D. Toole B.J. Knox S. Talwar D. Harten J. O'Reilly D.S.J. et al.The relation between acute changes in the systemic inflammatory response and plasma 25-hydroxyvitamin D concentrations after elective knee arthroplasty.Am J Clin Nutr. 2011; 93: 1006-1011Crossref PubMed Scopus (246) Google Scholar], a drop in vitamin D binding protein (VDBP) [7Waldron J.L. Ashby H.L. Cornes M.P. Bechervaise J. Razavi C. Thomas O.L. et al.Vitamin D: a negative acute phase reactant.J Clin Pathol. 2013; 66: 620-622Crossref PubMed Scopus (206) Google Scholar], and a possible increase in 1-α hydroxylation of 25OHD [9Bang U.C. Novovic S. Andersen A.M. Fenger M. Hansen M.B. Jensen J.-E.B. Variations in serum 25-hydroxyvitamin D during acute pancreatitis: an exploratory longitudinal study.Endocr Res. 2011; 36: 135-141Crossref PubMed Scopus (44) Google Scholar], may all contribute. Free 25OHD may also be affected. In a study of 33 patients undergoing knee arthroplasty, levels of total and free 25OHD, and VDBP, decreased by 40% and 15%, respectively, starting day 1 post-operatively [6Reid D. Toole B.J. Knox S. Talwar D. Harten J. O'Reilly D.S.J. et al.The relation between acute changes in the systemic inflammatory response and plasma 25-hydroxyvitamin D concentrations after elective knee arthroplasty.Am J Clin Nutr. 2011; 93: 1006-1011Crossref PubMed Scopus (246) Google Scholar]. The collider effect challenges association studies, reverse causality is one of them [13Griffith G.J. Morris T.T. Tudball M.J. Herbert A. Mancano G. Pike L. et al.Collider bias undermines our understanding of COVID-19 disease risk and severity.Nat Commun. 2020; 11: 5749-5761Crossref PubMed Scopus (457) Google Scholar]. The severity of COVID-19 infection affects the decision for hospitalization, and causal inferences in hospitalized patients might not be well-grounded [13Griffith G.J. Morris T.T. Tudball M.J. Herbert A. Mancano G. Pike L. et al.Collider bias undermines our understanding of COVID-19 disease risk and severity.Nat Commun. 2020; 11: 5749-5761Crossref PubMed Scopus (457) Google Scholar]. A thorough assessment of the evidence available, with particular attention to matters relevant to 25OHD assays [14Heijboer A. Blankenstein M. Kema I. Buijs M. Accuracy of 6 routine 25-hydroxyvitamin D assays: influence of vitamin D binding protein concentration.Clin Chem. 2012; 58: 543-548Crossref PubMed Scopus (312) Google Scholar], reverse causality, and quality assessment, is crucial [15Bassatne A. Basbous M. Chakhtoura M. Rahme M. El Zein O. El-Hajj Fuleihan G. The link between corona vIruses and VItamin D (VIVID): an extensive and rigorous systematic review and meta-analysis.https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=203960Date: 2020Google Scholar]. Such scrutiny provides the framework to provide guidance on vitamin D supplementation, given in a preventive or adjuvant-therapy mode, in the spectrum of COVID-19 illnesses. Well conducted observational studies will also provide the basis, when coupled with forthcoming evidence from vitamin D randomized controlled trials where vitamin D effect may be confounded by the standard use of steroids, to confirm or refute the putative role of vitamin D in Covid-19 illnesses. 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