Association between low serum vitamin D and increased mortality and severity due to COVID-19: reverse causality?
Abstract
We are very close to completing two years since the start of the COVID-19 pandemic. Even though vaccines have been developed and applied to more than 4 billion people in the world, SARS-CoV-2 continues to be a challenge for humanity. Therefore, it is important to study modifiable risk factors that may increase the severity of COVID-19, and one of the most discussed has been vitamin D. Currently, there is some evidence of association between low serum 25-hydroxyvitamin D [25(OH)D3] and increased mortality and severity due to SARS-CoV-2 infection. Before the pandemic, experimental evidence in animal and human studies had reported that an acute inflammatory process can cause a secondary decrease in 25(OH)D3. COVID-19 can be associated with a severe inflammatory process with an elevation of inflammatory markers; in this light, the reported association between low 25(OH)D3 and COVID-19 severity and/or mortality may be an epiphenomenon of the inflammatory process induced by SARS-CoV-2 and be an example of reverse causality.
Keywords: SARS-CoV-2COVID-19Vitamin D25-hydroxyvitamin Dseveritymortality
References
- Johns Hopkins University. Coronavirus COVID-19 Global Cases Map & Statistics by Johns Hopkins Center for Systems Science and Engineering. https://coronavirus.jhu.edu/map.html (7.01.2022).
- Chakraborty C, Sharma AR, Bhattacharya M, et al. Evolution, mode of transmission, and mutational landscape of newly emerging sars-cov-2 variants. mBio. 2021; 12(4): e0114021.
- Walensky RP, Walke HT, Fauci AS. SARS-CoV-2 variants of concern in the united states-challenges and opportunities. JAMA. 2021; 325(11): 1037–1038.
- Pereira M, Dantas Damascena A, Galvão Azevedo LM, et al. Vitamin D deficiency aggravates COVID-19: systematic review and meta-analysis. Crit Rev Food Sci Nutr. 2022; 62(5): 1308–1316.
- Liu N, Sun J, Wang X, et al. Low vitamin D status is associated with coronavirus disease 2019 outcomes: a systematic review and meta-analysis. Int J Infect Dis. 2021; 104: 58–64.
- Munshi R, Hussein MH, Toraih EA, et al. Vitamin D insufficiency as a potential culprit in critical COVID-19 patients. J Med Virol. 2021; 93(2): 733–740.
- Kazemi A, Mohammadi V, Aghababaee SK, et al. Association of vitamin D status with SARS-CoV-2 infection or COVID-19 severity: a systematic review and meta-analysis. Adv Nutr. 2021; 12(5): 1636–1658.
- Shah K, Varna VP, Pandya A, et al. Low vitamin D levels and prognosis in a COVID-19 pediatric population: a systematic review. QJM. 2021; 114(7): 447–453.
- Ben-Eltriki M, Hopefl R, Wright JM, et al. Association between vitamin D status and risk of developing severe COVID-19 infection: a meta-analysis of observational studies. J Am Coll Nutr. 2021 [Epub ahead of print]: 1–11.
- Vitamin D and COVID-19: why the controversy? The Lancet Diabetes & Endocrinology. 2021; 9(2): 53.
- Stroehlein JK, Wallqvist J, Iannizzi C, et al. Vitamin D supplementation for the treatment of COVID-19: a living systematic review. Cochrane Database Syst Rev. 2021; 5: CD015043.
- Rawat D, Roy A, Maitra S, et al. "Vitamin D supplementation and COVID-19 treatment: A systematic review and meta-analysis". Diabetes Metab Syndr. 2021; 15(4): 102189.
- Ghashut RA, Talwar D, Kinsella J, et al. The effect of the systemic inflammatory response on plasma vitamin 25 (OH) D concentrations adjusted for albumin. PLoS One. 2014; 9(3): e92614.
- Ul Afshan F, Nissar B, Chowdri NA, et al. Relevance of vitamin D in COVID-19 infection. Gene Rep. 2021; 24: 101270.
- Clements DN, Bruce G, Ryan JM, et al. Effects of surgery on free and total 25 hydroxyvitamin D concentrations in dogs. J Vet Intern Med. 2020; 34(6): 2617–2621.
- Silva MC, Furlanetto TW. Does serum 25-hydroxyvitamin D decrease during acute-phase response? A systematic review. Nutr Res. 2015; 35(2): 91–96.
- Waldron JL, Ashby HL, Cornes MP, et al. Vitamin D: a negative acute phase reactant. J Clin Pathol. 2013; 66(7): 620–622.
- Reid D, Toole B, Knox S, et al. The relation between acute changes in the systemic inflammatory response and plasma 25-hydroxyvitamin D concentrations after elective knee arthroplasty. The American Journal of Clinical Nutrition. 2011; 93(5): 1006–1011.
- Louw JA, Werbeck A, Louw ME, et al. Blood vitamin concentrations during the acute-phase response. Crit Care Med. 1992; 20(7): 934–941.
- Barth JH, Field HP, Mather AN, et al. Serum 25 hydroxy-vitamin D does not exhibit an acute phase reaction after acute myocardial infarction. Ann Clin Biochem. 2012; 49(Pt 4): 399–401.
- Bang UC, Novovic S, Andersen AM, et al. Variations in serum 25-hydroxyvitamin D during acute pancreatitis: an exploratory longitudinal study. Endocr Res. 2011; 36(4): 135–141.
- Bertoldo F, Pancheri S, Zenari S, et al. Serum 25-hydroxyvitamin D levels modulate the acute-phase response associated with the first nitrogen-containing bisphosphonate infusion. J Bone Miner Res. 2010; 25(3): 447–454.
- Krishnan A, Ochola J, Mundy J, et al. Acute fluid shifts influence the assessment of serum vitamin D status in critically ill patients. Crit Care. 2010; 14(6): R216.
- Binkley N, Coursin D, Krueger D, et al. Surgery alters parameters of vitamin D status and other laboratory results. Osteoporos Int. 2017; 28(3): 1013–1020.
- Smolders J, van den Ouweland J, Geven C, et al. Letter to the Editor: Vitamin D deficiency in COVID-19: Mixing up cause and consequence. Metabolism. 2021; 115: 154434.
- Henriksen VT, Rogers VE, Rasmussen GL, et al. Pro-inflammatory cytokines mediate the decrease in serum 25(OH)D concentrations after total knee arthroplasty? Med Hypotheses. 2014; 82(2): 134–137.
- Barker T, Martins TB, Kjeldsberg CR, et al. Circulating interferon-γ correlates with 1,25(OH)D and the 1,25(OH)D-to-25(OH)D ratio. Cytokine. 2012; 60(1): 23–26.
- Edfeldt K, Liu PT, Chun R, et al. T-cell cytokines differentially control human monocyte antimicrobial responses by regulating vitamin D metabolism. Proc Natl Acad Sci U S A. 2010; 107(52): 22593–22598.
- Koeffler HP, Reichel H, Bishop J, et al. γ-interferon stimulates production of 1,25-dihydroxyvitamin D3 by normal human macrophages. Biochemical and Biophysical Research Communications. 1985; 127(2): 596–603.
- Stoffels K, Overbergh L, Giulietti A, et al. Immune regulation of 25-hydroxyvitamin-d3-1α-hydroxylase in human monocytes. Journal of Bone and Mineral Research. 2005; 21(1): 37–47.
- Pryke AM, Duggan C, White CP, et al. Tumor necrosis factor-alpha induces vitamin D-1-hydroxylase activity in normal human alveolar macrophages. Journal of Cellular Physiology. 1990; 142(3): 652–656.
- Hill A. The environment and disease: association or causation? Proc R Soc Med. 1965; 58(5): 295–300.
- Rothman KJ, Greenland S. Causation and causal inference in epidemiology. Am J Public Health. 2005; 95 Suppl 1: S144–S150.
- McLinden T. Which is the cart and which is the horse? Getting more out of cross-sectional epidemiological studies. Public Health Nutr. 2019 [Epub ahead of print]: 1–3.
- Banack HR, Bea JW, Kaufman JS, et al. The effects of reverse causality and selective attrition on the relationship between body mass index and mortality in postmenopausal women. Am J Epidemiol. 2019; 188(10): 1838–1848.
- Flegal KM, Graubard BI, Williamson DF, et al. Reverse causation and illness-related weight loss in observational studies of body weight and mortality. Am J Epidemiol. 2011; 173(1): 1–9.
- Flanders WD, Augestad LB. Adjusting for reverse causality in the relationship between obesity and mortality. Int J Obes (Lond). 2008; 32 Suppl 3: S42–S46.
- Sattar N, Preiss D. Reverse causality in cardiovascular epidemiological research. Circulation. 2017; 135(24): 2369–2372.
- Angelantonio EDi, Bhupathiraju S, Wormser D, et al. Body-mass index and all-cause mortality: individual-participant-data meta-analysis of 239 prospective studies in four continents. The Lancet. 2016; 388(10046): 776–786.
- Trompet S, Jukema JW, Katan MB, et al. Apolipoprotein E genotype, plasma cholesterol, and cancer: a mendelian randomization study. American Journal of Epidemiology. 2009; 170(11): 1415–1421.
- Currie C, Peters J, Tynan A, et al. Survival as a function of HbA1c in people with type 2 diabetes: a retrospective cohort study. The Lancet. 2010; 375(9713): 481–489.
- Rhodes J, Dunstan F, Laird E, et al. COVID-19 mortality increases with northerly latitude after adjustment for age suggesting a link with ultraviolet and vitamin D. BMJ Nutr Prev Health. 2020; 3(1): 118–120.
- Mariani J, Giménez VM, Bergam I, et al. Association between vitamin D deficiency and COVID-19 incidence, complications, and mortality in 46 countries: an ecological study. Health Secur. 2021; 19(3): 302–308.
- Butler-Laporte G, Nakanishi T, Mooser V, et al. Vitamin D and COVID-19 susceptibility and severity in the COVID-19 host genetics initiative: a mendelian randomization study. PLOS Medicine. 2021; 18(6): e1003605.
- Patchen BK, Clark AG, Gaddis N, et al. Genetically predicted serum vitamin D and COVID-19: a Mendelian randomisation study. BMJ Nutr Prev Health. 2021; 4(1): 213–225.
- Cui Z, Tian Y. Using genetic variants to evaluate the causal effect of serum vitamin D concentration on COVID-19 susceptibility, severity and hospitalization traits: a Mendelian randomization study. J Transl Med. 2021; 19(1): 300.
- Oscanoa T, Amado J, Ghashut R, et al. Relationship between serum 25-hydroxyvitamin D concentration and acute inflammatory markers in hospitalized patients with SARS-CoV-2 infection. Disaster and Emergency Medicine Journal. 2021; 6(3): 144–153.
- Rashad N, Abdelhamid Y, Mekhael N, et al. Vitamin D level in patients with COVID-19 and its relationship with severity of the clinical course. The Egyptian Journal of Hospital Medicine. 2021; 85(1): 3054–3060.
- Relationship between vitamin D and IL6 in convalescent healthcare workers with covid-19 in baquba hospitals in diyala province. Indian Journal of Forensic Medicine & Toxicology. 2021.
- Silberstein M. Correlation between premorbid IL-6 levels and COVID-19 mortality: Potential role for Vitamin D. Int Immunopharmacol. 2020; 88: 106995.
- Bayraktar N, Turan H, Bayraktar M, et al. Analysis of serum cytokine and protective vitamin D levels in severe cases of COVID‐19. Journal of Medical Virology. 2021; 94(1): 154–160.
- Gameil MA, Marzouk RE, Elsebaie AH, et al. Long-term clinical and biochemical residue after COVID-19 recovery. Egypt Liver J. 2021; 11(1): 74.
- Gupta D, Menon S, Criqui M, et al. Temporal association of reduced serum vitamin D with COVID-19 infection: A single-institution case-control and historical cohort study. [preprint]. 2021.
- Gallelli L, Mannino GC, Luciani F, et al. Vitamin D serum levels in subjects tested for SARS-CoV-2: what are the differences among acute, healed, and negative COVID-19 patients? A multicenter real-practice study. Nutrients. 2021; 13(11).
- Chen J, Mei K, Xie L, et al. Low vitamin D levels do not aggravate COVID-19 risk or death, and vitamin D supplementation does not improve outcomes in hospitalized patients with COVID-19: a meta-analysis and GRADE assessment of cohort studies and RCTs. Nutr J. 2021; 20(1): 89.
- Pal R, Banerjee M, Bhadada SK, et al. Vitamin D supplementation and clinical outcomes in COVID-19: a systematic review and meta-analysis. J Endocrinol Invest. 2022; 45(1): 53–68.
- Murai I, Fernandes A, Sales L, et al. Effect of a single high dose of vitamin D on hospital length of stay in patients with moderate to severe COVID-19. JAMA. 2021; 325(11): 1053.
- Lakkireddy M, Gadiga SG, Malathi RD, et al. Impact of daily high dose oral vitamin D therapy on the inflammatory markers in patients with COVID 19 disease. Sci Rep. 2021; 11(1): 10641.
- Sattar N, Welsh P, Panarelli M, et al. Increasing requests for vitamin D measurement: costly, confusing, and without credibility. The Lancet. 2012; 379(9811): 95–96.
- Hashemipour S, Ghobadi A, Hadizadeh Khairkhah SM, et al. Association of weekly or biweekly use of 50 000 IU vitamin D3 with hypervitaminosis D. Br J Clin Pharmacol. 2021 [Epub ahead of print].
- Collins amadi, bright amadi. Fallout following unproven prophylactic use of exogenous vitamin d for COVID-19. Sci J Clin Med. 2021; 10(4): 147–51.
- Fuentes-Gonzalez MF, Ordinola Navarro A, Carmona-Aguilera Z, et al. Outpatient prescription patterns of COVID-19 drugs in the metropolitan area of Mexico City. Fam Pract. 2022; 39(3): 515–518.
- Kaur P, Mishra SK, Mithal A. Vitamin D toxicity resulting from overzealous correction of vitamin D deficiency. Clin Endocrinol (Oxf). 2015; 83(3): 327–331.
- Chowdry AM, Azad H, Najar MS, et al. Acute kidney injury due to overcorrection of hypovitaminosis D: A tertiary center experience in the Kashmir Valley of India. Saudi J Kidney Dis Transpl. 2017; 28(6): 1321–1329.
- Gonzalez-Chica D, Stocks N. Changes to the frequency and appropriateness of vitamin D testing after the introduction of new Medicare criteria for rebates in Australian general practice: evidence from 1.5 million patients in the NPS MedicineInsight database. BMJ Open. 2019; 9(3): e024797.
- Essig S, Merlo C, Reich O, et al. Potentially inappropriate testing for vitamin D deficiency: a cross-sectional study in Switzerland. BMC Health Services Research. 2020; 20(1).
- Bilinski K, Boyages S. The rise and rise of vitamin D testing. BMJ. 2012; 345: e4743.
- Carbonell-Abella C. Why concerns about vitamin D deficiency should not lead to over testing and overtreatment. European Journal of General Practice. 2020; 26(1): 163–165.
- Arroyo-Díaz J, Julve J, Vlacho B, et al. Previous vitamin D supplementation and morbidity and mortality outcomes in people hospitalised for COVID19: a cross-sectional study. Frontiers in Public Health. 2021; 9.