Evidence for possible association of vitamin D status with cytokine storm and unregulated inflammation in COVID-19 patients
Ali Daneshkhah, Vasundhara Agrawal, Adam Eshein, Hariharan Subramanian, Hemant Kumar Roy, Vadim Backman
Aging Clinical and Experimental Research, doi:10.1007/s40520-020-01677-y
Objectives We present evidence for a possible role of Vitamin D (VitD) deficiency in unregulated cytokine production and inflammation leading to complications in COVID-19 patients. Design The time-adjusted case mortality ratio (T-CMR) was estimated as the ratio of deceased patients on day N to the confirmed cases on day N-8. The adaptive average of T-CMR (A-CMR) was calculated as a metric of COVID-19 associated mortality. A model based on positivity change (PC) and an estimated prevalence of COVID-19 was used to determine countries with similar screening strategies. A possible association of A-CMR with the mean concentration of 25-hydroxyvitamin D (25(OH)D) in elderly individuals in countries with similar screening strategy was investigated. We considered high C-reactive protein (CRP) in severe COVID-19 patients (CRP ≥ 1 mg/dL) as a surrogate of a cytokine storm. We considered high-sensitivity CRP (hs-CRP) in healthy subjects as hs-CRP ≥ 0.2 mg/dL. Results A link between 25(OH)D and A-CMR in countries with similar screening strategy is evidence for VitD's possible role in reducing unregulated cytokine production and inflammation among patients with severe COVID-19. We observed an odds ratio (OR) of 1.8 with 95% confidence interval (95% CI) (1.2 to 2.6) and an OR of 1.9 with 95% CI (1.4 to 2.7) for hs-CRP in VitD deficient elderly from low-income families and high-income families, respectively. COVID-19 patient-level data show an OR of 3.4 with 95% CI (2.15 to 5.4) for high CRP in severe COVID-19 patients.
Conclusion We conclude that future studies on VitD's role in reducing cytokine storm and COVID-19 mortality are warranted.
Conflict of interest On behalf of all authors, the corresponding author states that there is no conflict of interest. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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References
Abarca-Gómez, Abdeen, Hamid, Worldwide trends in body-mass index, underweight, overweight, and obesity from 1975 to 2016: a pooled analysis of 2416 population-based measurement studies in 128•9 million children, adolescents, and adults, Lancet,
doi:10.1016/S0140-6736(17)32129-3
Adami, Viapiana, Gatti, Relationship between serum parathyroid hormone, vitamin D sufficiency, age, and calcium intake, Bone,
doi:10.1016/j.bone.2007.10.003
Aluisio, Maroof, Chandramohan, Vitamin D3 supplementation and childhood diarrhea: a randomized controlled trial, Pediatrics,
doi:10.1542/peds.2012-3986
Aranow, Vitamin D and the immune system, J Investig Med
Bancos, Bernard, Topham, Phipps, Ibuprofen and other widely used non-steroidal anti-inflammatory drugs inhibit antibody production in human cells, Cell Immunol,
doi:10.1016/j.cellimm.2009.03.007
Basile, Ciardi, Crespi, Assessing serum concentrations of 25-hydroxy-vitamin D in North-Western Italy, J Frailty Aging,
doi:10.14283/jfa.2013.25
Beilfuss, Jorde, Kamycheva, High-sensitivity CRP is associated with serum 25-hydroxyvitamin D levels, but is not affected by 5-Year supplementation with cholecalciferol, J Nutr Health Food Sci,
doi:10.15226/jnhfs.2017.001108
Bellia, Garcovich, Adamo, Serum 25-hydroxyvitamin D levels are inversely associated with systemic inflammation in severe obese subjects, Intern Emerg Med,
doi:10.1007/s11739-011-0559-x
Bergman, Lindh, Björkhem-Bergman, Lindh, Vitamin D and respiratory tract infections: a systematic review and meta-analysis of randomized controlled trials, PLoS ONE,
doi:10.1371/journal.pone.0065835
Burnand, Sloutskis, Gianoli, Serum 25-hydroxyvitamin D: distribution and determinants in the Swiss population, Am J Clin Nutr,
doi:10.1093/ajcn/56.3.537
Cdc, COVIDView, Key Updates for Week 28
Cdcmmwr, Severe Outcomes Among Patients with Coronavirus Disease 2019 (COVID-19)-United States, MMWR Morb Mortal Wkly Rep,
doi:10.15585/mmwr.mm6912e2
Charan, Goyal, Saxena, Yadav, Vitamin D for prevention of respiratory tract infections: a systematic review and meta-analysis, J Pharmacol Pharmacother,
doi:10.4103/0976-500X.103685
Coronavirus, Situation in Switzerland
D'avolio, Avataneo, Manca, 25-Hydroxyvitamin D concentrations are lower in patients with positive PCR for SARS-CoV-2, Nutrients,
doi:10.3390/nu12051359
Docherty, Harrison, Green, Features of 16,749 hospitalised UK patients with COVID-19 using the ISARIC WHO clinical characterisation protocol, medRxiv,
doi:10.1101/2020.04.23.20076042
Dowd, Andriano, Brazel, Demographic science aids in understanding the spread and fatality rates of COVID-19, Proc Natl Acad Sci,
doi:10.1073/pnas.2004911117
Farhud, Mehrabi, Sarafnejad, A comprehensive, epidemiological and ecological descriptive study on vitamin d status in Iran (308005 People, from 2009-2018), Iran J Public Health
Fasano, Cereda, Barichella, COVID-19 in Parkinson's disease patients living in lombardy, Mov Disord,
doi:10.1002/mds.28176
Goncalves-Mendes, Talvas, Dualé, Impact of vitamin D supplementation on influenza vaccine response and immune functions in deficient elderly persons: a randomized placebo-controlled trial, Front Immunol,
doi:10.3389/fimmu.2019.00065
González-Molero, Morcillo, Valdés, Vitamin D deficiency in Spain: a population-based cohort study, Eur J Clin Nutr,
doi:10.1038/ejcn.2010.265
Grant, Giovannucci, The possible roles of solar ultraviolet-B radiation and vitamin D in reducing case-fatality rates from the 1918-1919 influenza pandemic in the United States, Dermatoendocrinol
Gunville, Mourani, Ginde, the role of vitamin d in prevention and treatment of infection, Inflamm Allergy Drug Targets
Hoe, Nathanielsz, Toh, Anti-inflammatory effects of vitamin d on human immune cells in the context of bacterial infection, Nutrients,
doi:10.3390/nu8120806
Hovsepian, Amini, Aminorroaya, Prevalence of vitamin d deficiency among adult population of Isfahan city, Iran J Health Popul Nutr
Khare, Godbole, Pawar, None, Calcitriol
Klenk, Rapp, Denkinger, Seasonality of vitamin D status in older people in Southern Germany: implications for assessment, Age Ageing,
doi:10.1093/ageing/aft042
Li, Dai, Cao, Wang, Association of C-reactive protein and vitamin D deficiency with cardiovascular disease: a nationwide cross-sectional study from National Health and Nutrition Examination Survey 2007 to 2008, Clin Cardiol,
doi:10.1002/clc.23189
Litonjua, Carey, Laranjo, Effect of prenatal supplementation with vitamin D on asthma or recurrent wheezing in offspring by Age 3 Years: The VDAART Randomized Clinical Trial, JAMA,
doi:10.1001/jama.2015.18589
Liu, Voors, Van Veldhuisen, Vitamin D status and outcomes in heart failure patients, Eur J Heart Fail,
doi:10.1093/eurjhf/hfr032
Martineau, Jolliffe, Hooper, Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data, BMJ,
doi:10.1136/bmj.i6583
Mcgregor, Chauss, Freiwald, An autocrine Vitamin D-driven Th1 shutdown program can be exploited for COVID-19, bioRxiv,
doi:10.1101/2020.07.18.210161
Meireles, Kamimura, Dalboni, De Carvalho, Aoike et al., Effect of cholecalciferol on vitamin D-regulatory proteins in monocytes and on inflammatory markers in dialysis patients: a randomized controlled trial, Clin Nutr,
doi:10.1016/j.clnu.2016.04.014
Mellenthin, Wallaschofski, Grotevendt, Völzke, Nauck et al., Association between serum vitamin D concentrations and inflammatory markers in the general adult population, Metabolism,
doi:10.1016/j.metabol.2014.05.002
Merlo, Trummler, Essig, Zeller, Vitamin D deficiency in unselected patients from swiss primary care: a cross-sectional study in two seasons, PLoS ONE,
doi:10.1371/journal.pone.0138613
Morris, Booth, Beck, As coronavirus surges, a frantic Europe scrambles for hospital beds, ventilators, supplies, Wash. Post
Mortensen, Clemmensen, Woodworth, Cyclooxygenase inhibitors impair CD4 T cell immunity and exacerbate Mycobacterium tuberculosis infection in aerosolchallenged mice, Commun Biol,
doi:10.1038/s42003-019-0530-3
Ngo, Sverdlov, Mcneil, Horowitz, Does vitamin D modulate asymmetric dimethylarginine and C-reactive protein concentrations?, Am J Med,
doi:10.1016/j.amjmed.2009.09.024
Nikpouraghdam, Farahani, Alishiri, Epidemiological characteristics of coronavirus disease 2019 (COVID-19) patients in IRAN: a single center study, J Clin Virol,
doi:10.1016/j.jcv.2020.104378
Nnoaham, Low serum vitamin D levels and tuberculosis: a systematic review and meta-analysis, Int J Epidemiol,
doi:10.1093/ije/dym247
Onder, Rezza, Brusaferro, Case-fatality rate and characteristics of patients dying in relation to COVID-19 in Italy, JAMA,
doi:10.1001/jama.2020.4683
Palaniswamy, Gill, Silva, Could vitamin D reduce obesity-associated inflammation? Observational and Mendelian randomization study, Am J Clin Nutr,
doi:10.1093/ajcn/nqaa056
Parlak, Ertürk, Çağ, The effect of inflammatory cytokines and the level of vitamin D on prognosis in Crimean-Congo hemorrhagic fever, Int J Clin Exp Med
Qin, Zhou, Hu, Dysregulation of immune response in patients with COVID-19 in Wuhan, China
Rabenberg, Scheidt-Nave, Busch, Vitamin D status among adults in Germany-results from the German health interview and examination survey for adults (DEGS1), BMC Public Health,
doi:10.1186/s12889-015-2016-7
Rhodes, Subramanian, Laird, Kenny, Editorial: low population mortality from COVID-19 in countries south of latitude 35 degrees North supports vitamin D as a factor determining severity, Aliment Pharmacol Ther,
doi:10.1111/apt.15777
Rossi, Ferroni, Alegiani, Survival of hospitalized COVID-19 patients in Northern Italy: a population-based cohort study by the ITA-COVID19 Network, medRxiv,
doi:10.1101/2020.05.15.20103119
Schultz, Arnold, Properties of four acute phase proteins: C-reactive protein, serum amyloid a protein, α1-acid glycoprotein, and fibrinogen, Semin Arthritis Rheum,
doi:10.1016/0049-0172(90)90055-K
Semba, Houston, Bandinelli, Relationship of 25-hydroxyvitamin D with all-cause and cardiovascular disease mortality in older community-dwelling adults, Eur J Clin Nutr,
doi:10.1038/ejcn.2009.140
Sirota, Shacham, Punsky, Bessler, Ibuprofen affects pro-and anti-inflammatory cytokine production by mononuclear cells of preterm newborns,
doi:10.1159/000047075
Souberbielle, Massart, Brailly-Tabard, Prevalence and determinants of vitamin D deficiency in healthy French adults: the VARIETE study, Endocrine,
doi:10.1007/s12020-016-0960-3
Stagi, Rigante, Lepri, Severe vitamin D deficiency in patients with Kawasaki disease: a potential role in the risk to develop heart vascular abnormalities?, Clin Rheumatol,
doi:10.1007/s10067-015-2970-6
Vernay, Sponga, Salanave, O62 Statut en vitamine D de la population adulte en France : l'étude nationale nutrition santé (ENNS, 2006-2007), Nutrition Clinique et Métabolisme
Wu, Chang, Chen, Calcitriol treatment attenuates inflammation and oxidative stress in hemodialysis patients with secondary hyperparathyroidism, Tohoku J Exp Med,
doi:10.1620/tjem.223.153
Wu, Leung, Bushman, Estimating clinical severity of COVID-19 from the transmission dynamics in Wuhan, China Nat Med,
doi:10.1038/s41591-020-0822-7
Xu, Song, Zhang, The Vitamin D status is associated with serum C-reactive protein and adhesion molecules in patients with renal cell carcinoma, Sci Rep,
doi:10.1038/s41598-019-53395-9
Yegorov, Bromage, Boldbaatar, Ganmaa, Effects of vitamin d supplementation and seasonality on circulating cytokines in adolescents: analysis of data from a feasibility trial in mongolia, Front Nutr,
doi:10.3389/fnut.2019.00166
Yu, Tian, Effect of vitamin d supplementation on some inflammatory biomarkers in type 2 diabetes mellitus subjects: a systematic review and meta-analysis of randomized controlled trials, Ann Nutr Metab,
doi:10.1159/000490358
Yusupov, Li-Ng, Pollack, Vitamin d and serum cytokines in a randomized clinical trial, Int. J. Endocrinol
Zhou, Bentham, Cesare, Worldwide trends in blood pressure from 1975 to 2015: a pooled analysis of 1479 population-based measurement studies with 19•1 million participants, Lancet,
doi:10.1016/S0140-6736(16)31919-5
Zhou, Lu, Hajifathalian, Worldwide trends in diabetes since 1980: a pooled analysis of 751 population-based studies with 4•4 million participants, Lancet,
doi:10.1016/S0140-6736(16)00618-8