Associations between predicted vitamin D status, vitamin D intake, and risk of SARS-CoV-2 infection and Coronavirus Disease 2019 severity
ScD Wenjie Ma, MD Long H Nguyen, MS Yiyang Yue, ScD Ming Ding, PhD David A Drew, MD, PhD Kai Wang, PhD Jordi Merino, ScD Janet W Rich-Edwards, MD, ScD Qi Sun, MD, DrPH Carlos A Camargo Jr, MD, ScD Edward Giovannucci, MD, DrPH Walter Willett, MD, DrPH Joann E Manson, MD, ScD Mingyang Song, PhD Shilpa N Bhupathiraju, MD, MPH Andrew T Chan
doi:10.1093/ajcn/nqab389/6448988
Background: Vitamin D may have a role in immune responses to viral infections. However, data on the association between vitamin D and SARS-CoV-2 infection and Coronavirus Disease 2019 (COVID-19) severity have been limited and inconsistent. Objective: We examined the associations of predicted vitamin D status and intake with risk of SARS-CoV-2 infection and COVID-19 severity. Design: We used data from periodic surveys (May 2020 to March 2021) within the Nurses' Health Study II. Among 39,315 participants, 1,768 reported a positive test for SARS-CoV-2 infection. Usual vitamin D intake from foods and supplements were measured using a semi-quantitative, pre-pandemic food frequency questionnaire in 2015. Predicted 25-hydroxyvitamin D [25(OH)D] levels were calculated based on a previously validated model including dietary and supplementary vitamin D intake, ultraviolet-B (UVB), and other behavioral predictors of vitamin D status. Results: Higher predicted 25(OH)D levels, but not vitamin D intake, were associated with a lower risk of SARS-CoV-2 infection. Comparing participants in the highest quintile of predicted 25(OH)D levels to the lowest, the multivariable-adjusted odds ratio was 0.76 (95% CI: 0.58, 0.99; P-trend=0.04). Participants in the highest quartile of UVB (OR: 0.76; 95% CI: 0.66, 0.87; P-trend=0.002) and UVA (OR: 0.76; 95% CI: 0.66, 0.88; P-trend<0.001) also had lower risk of SARS-CoV-2 infection compared
93 Logistic regression models were used in the analysis. The number of participants included in the analysis was 39,315, and the number of participants who reported a positive SARS-CoV-2 infection was 1,768. Model 1 was adjusted for age, white race, smoking pack-years (0, 0.1-10.0, 10.1-20.0, >20.0), and the Alternate Healthy Eating Index (quintiles). Vitamin D intakes from foods and supplements were mutually adjusted. Model 2 was further adjusted for body mass index (<22.5, 22.5-24.9, 25.0-27.4, 27.5-29.9, 30-34.9, ≥35.0 kg/m 2 ), physical activity (quintiles), and alcohol intake (0, 0.1-5.0, 5.1-10.0, >10 g/d). Model 3 was further adjusted for being a frontline healthcare worker, chronic comorbidities including hypertension, hypercholesterolemia, diabetes, heart disease, cancer, and asthma, and 2010 census tract median income (quintiles). P-trend was evaluated using the median value in each category as a continuous variable. Abbreviations: 25(OH)D, 25-hydroxyvitamin D. .001 Logistic regression models were used in the analysis. The number of participants included in the analysis was 39,315, and the number of participants who reported a positive SARS-CoV-2 infection was 1,768. Model 1 was adjusted for age, white race, smoking pack-years (0, 0.1-10.0, 10.1-20.0, >20.0), and the Alternate Healthy Eating Index (quintiles). Model 2 was further adjusted for body mass index (<22.5, 22.5-24.9, 25.0-27.4, 27.5-29.9, 30-34.9, ≥35.0 kg/m 2 ), physical activity..
References
Age, None
Ananthakrishnan, Khalili, Higuchi, Bao, Korzenik et al., Higher predicted vitamin D status is associated with reduced risk of Crohn's disease, Gastroenterology,
doi:10.1053/j.gastro.2011.11.040Annweiler, Corvaisier, Gautier, Dubee, Legrand et al., Vitamin D Supplementation Associated to Better Survival in Hospitalized Frail Elderly COVID-19 Patients: The GERIA-COVID Quasi-Experimental Study, Nutrients,
doi:10.3390/nu12113377Bennouar, Cherif, Kessira, Bennouar, Abdi, Vitamin D Deficiency and Low Serum Calcium as Predictors of Poor Prognosis in Patients with Severe COVID-19, J Am Coll Nutr,
doi:10.1080/07315724.2020.1856013Bertone-Johnson, Hankinson, Bendich, Johnson, Willett et al., Calcium and vitamin D intake and risk of incident premenstrual syndrome, Arch Intern Med,
doi:10.1001/archinte.165.11.1246Bertrand, Chang, Abel, Zhang, Spiegelman et al., Sunlight exposure, vitamin D, and risk of non-Hodgkin lymphoma in the Nurses' Health Study, Cancer Causes Control,
doi:10.1007/s10552-011-9849-xBertrand, Giovannucci, Liu, Malspeis, Eliassen et al., Determinants of plasma 25-hydroxyvitamin D and development of prediction models in three US cohorts, Br J Nutr,
doi:10.1017/S0007114511007409Bowe, Xie, Gibson, Cai, Van Donkelaar et al., Ambient fine particulate matter air pollution and the risk of hospitalization among COVID-19 positive individuals: Cohort study, Environ Int,
doi:10.1016/j.envint.2021.106564Carleton, Cornetet, Huybers, Meng, Proctor, Global evidence for ultraviolet radiation decreasing COVID-19 growth rates, Proc Natl Acad Sci U S A,
doi:10.1073/pnas.2012370118Castillo, Costa, Barrios, Diaz, Miranda et al., Effect of calcifediol treatment and best available therapy versus best available therapy on intensive care unit admission and mortality among patients hospitalized for COVID-19: A pilot randomized clinical study, J Steroid Biochem Mol Biol,
doi:10.1016/j.jsbmb.2020.105751Cherrie, Clemens, Colandrea, Feng, Webb et al., Ultraviolet A radiation and COVID-19 deaths in the USA with replication studies in England and Italy, Br J Dermatol,
doi:10.1111/bjd.20093Cozier, Castro-Webb, Hochberg, Rosenberg, Albert et al., Lower serum 25(OH)D levels associated with higher risk of COVID-19 infection in U.S. Black women, PLoS One,
doi:10.1371/journal.pone.0255132Ding, Rocheleau, Boiano, Kang, Brcene et al., American Frontline Healthcare Personnel's Access to and Use of Personal Protective Equipment Early in the Coronavirus Disease
Fears, Bird, Dt, Sagebiel, Gail et al., Average midrange ultraviolet radiation flux and time outdoors predict melanoma risk, Cancer Res
Fuchs, Yuan, Sato, Niedzwiecki, Ye et al., Predicted vitamin D status and colon cancer recurrence and mortality in CALGB 89803 (Alliance), Ann Oncol,
doi:10.1093/annonc/mdx109Giovannucci, Liu, Rimm, Hollis, Fuchs et al., Prospective study of predictors of vitamin D status and cancer incidence and mortality in men, J Natl Cancer Inst,
doi:10.1093/jnci/djj101Hernandez, Nan, Fernandez-Ayala, Garcia-Unzueta, Hernandez-Hernandez et al., Vitamin D Status in Hospitalized Patients with SARS-CoV-2 Infection, J Clin Endocrinol Metab,
doi:10.1210/clinem/dgaa733Holick, Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease, Am J Clin Nutr,
doi:10.1093/ajcn/80.6.1678SJude, Ling, Allcock, Yeap, Pappachan, Vitamin D deficiency is associated with higher hospitalisation risk from COVID-19: a retrospective case-control study, J Clin Endocrinol Metab,
doi:10.1210/clinem/dgab439Kaufman, Niles, Kroll, Bi, Holick, SARS-CoV-2 positivity rates associated with circulating 25-hydroxyvitamin D levels, PLoS One,
doi:10.1371/journal.pone.0239252Louca, Murray, Klaser, Graham, Mazidi et al., Dietary supplements during the COVID-19 pandemic: insights from 1.4M users of the COVID Symptom Study app -a longitudinal app-based community survey, medRxiv,
doi:10.1101/2020.11.27.20239087Luo, Liao, Shen, Li, Cheng, Vitamin D Deficiency Is Inversely Associated with COVID-19 Incidence and Disease Severity in Chinese People, J Nutr,
doi:10.1093/jn/nxaa332Ma, Zhou, Heianza, Qi, Habitual use of vitamin D supplements and risk of coronavirus disease 2019 (COVID-19) infection: a prospective study in UK Biobank, Am J Clin Nutr,
doi:10.1093/ajcn/nqaa381Meltzer, Best, Zhang, Vokes, Arora et al., Association of Vitamin D Levels, Race/Ethnicity, and Clinical Characteristics With COVID-19 Test Results, JAMA Netw Open,
doi:10.1001/jamanetworkopen.2021.4117Meltzer, Best, Zhang, Vokes, Arora et al., Association of Vitamin D Status and Other Clinical Characteristics With COVID-19 Test Results, JAMA Netw Open,
doi:10.1001/jamanetworkopen.2020.19722Merzon, Tworowski, Gorohovski, Vinker, Cohen et al., Low plasma 25(OH) vitamin D level is associated with increased risk of COVID-19 infection: an Israeli population-based study, FEBS J,
doi:10.1111/febs.15495Moozhipurath, Kraft, Skiera, Evidence of protective role of Ultraviolet-B (UVB) radiation in reducing COVID-19 deaths, Sci Rep,
doi:10.1038/s41598-020-74825-zMurai, Fernandes, Sales, Pinto, Goessler et al., Effect of a Single High Dose of Vitamin D3 on Hospital Length of Stay in Patients With Moderate to Severe COVID-19: A Randomized Clinical Trial, JAMA,
doi:10.1001/jama.2020.26848Ng, Wolpin, Meyerhardt, Wu, Chan et al., Prospective study of predictors of vitamin D status and survival in patients with colorectal cancer, Br J Cancer,
doi:10.1038/sj.bjc.6605262Oristrell, Oliva, Casado, Subirana, Dominguez et al., Vitamin D supplementation and COVID-19 risk: a population-based, cohort study, J Endocrinol Invest,
doi:10.1007/s40618-021-01639-9Pal, Banerjee, Bhadada, Shetty, Singh et al., Vitamin D supplementation and clinical outcomes in COVID-19: a systematic review and metaanalysis, J Endocrinol Invest,
doi:10.1007/s40618-021-01614-4Panagiotou, Tee, Ihsan, Athar, Marchitelli et al., Low serum 25-hydroxyvitamin D (25[OH]D) levels in patients hospitalized with COVID-19 are associated with greater disease severity, Clin Endocrinol (Oxf),
doi:10.1111/cen.14276Ratnesar-Shumate, Williams, Green, Krause, Holland et al., Simulated Sunlight Rapidly Inactivates SARS-CoV-2 on Surfaces, J Infect Dis,
doi:10.1093/infdis/jiaa274Rimm, Giovannucci, Stampfer, Colditz, Litin et al., Reproducibility and validity of an expanded self-administered semiquantitative food frequency questionnaire among male health professionals, Am J Epidemiol
Sabico, Enani, Sheshah, Aljohani, Aldisi et al., Effects of a 2-Week 5000 IU versus
Smet, Smet, Herroelen, Gryspeerdt, Martens, Serum 25(OH)D Level on Hospital Admission Associated With COVID-19 Stage and Mortality, Am J Clin Pathol,
doi:10.1093/ajcp/aqaa252Smolders, Van Den Ouweland, Geven, Pickkers, Kox, Letter to the Editor: Vitamin D deficiency in COVID-19: Mixing up cause and consequence, Metabolism,
doi:10.1016/j.metabol.2020.154434Wang, Degruttola, Lei, Mayer, Redline et al., The vitamin D for COVID-19 (VIVID) trial: A pragmatic
Wise, Covid-19: Evidence is lacking to support vitamin D's role in treatment and prevention, BMJ,
doi:10.1136/bmj.m4912DOI record:
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"abstract": "<jats:title>Abstract</jats:title>\n <jats:sec>\n <jats:title>Background</jats:title>\n <jats:p>Vitamin D may have a role in immune responses to viral infections. However, data on the association between vitamin D and SARS-CoV-2 infection and Coronavirus Disease 2019 (COVID-19) severity have been limited and inconsistent.</jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Objective</jats:title>\n <jats:p>We examined the associations of predicted vitamin D status and intake with risk of SARS-CoV-2 infection and COVID-19 severity.</jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Design</jats:title>\n <jats:p>We used data from periodic surveys (May 2020 to March 2021) within the Nurses’ Health Study II. Among 39,315 participants, 1,768 reported a positive test for SARS-CoV-2 infection. Usual vitamin D intake from foods and supplements were measured using a semi-quantitative, pre-pandemic food frequency questionnaire in 2015. Predicted 25-hydroxyvitamin D [25(OH)D] levels were calculated based on a previously validated model including dietary and supplementary vitamin D intake, ultraviolet-B (UVB), and other behavioral predictors of vitamin D status.</jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Results</jats:title>\n <jats:p>Higher predicted 25(OH)D levels, but not vitamin D intake, were associated with a lower risk of SARS-CoV-2 infection. Comparing participants in the highest quintile of predicted 25(OH)D levels to the lowest, the multivariable-adjusted odds ratio was 0.76 (95% CI: 0.58, 0.99; P-trend = 0.04). Participants in the highest quartile of UVB (OR: 0.76; 95% CI: 0.66, 0.87; P-trend = 0.002) and UVA (OR: 0.76; 95% CI: 0.66, 0.88; P-trend&lt;0.001) also had lower risk of SARS-CoV-2 infection compared to the lowest. High intake of vitamin D from supplements (≥400 IU/d) was associated with a lower risk of hospitalization (OR: 0.51; 95% CI: 0.29, 0.91; P-trend = 0.04).</jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Conclusions</jats:title>\n <jats:p>Our study provides suggestive evidence on the association between higher predicted circulating 25(OH)D levels and a lower risk of SARS-CoV-2 infection. Greater intake of vitamin D supplements was associated with a lower risk of hospitalization. Our data also support an association between exposure to UVB or UVA, independent of vitamin D, and SARS-CoV-2 infection, so results for predicted 25(OH)D need to be interpreted cautiously.</jats:p>\n </jats:sec>",
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