Vitamin D, vitamin D-binding protein, free vitamin D and COVID-19 mortality in hospitalized patients

Sreedhar Subramanian; Jonathan M Rhodes; Joseph M Taylor; Anna M Milan; Steven Lane; Martin Hewison; Rene F Chun; Andrea Jorgensen; Paul Richardson; Darshan Nitchingham; Joseph Aslan; Maya Shah; Coonoor R Chandrasekar; Amanda Wood; Mike Beadsworth; Munir Pirmohamed

doi:10.1093/ajcn/nqac027

Vitamin D, vitamin D-binding protein, free vitamin D and COVID-19 mortality in hospitalized patients

Sreedhar Subramanian^*, Jonathan M Rhodes, Joseph M Taylor, Anna M Milan, Steven Lane, Martin Hewison, Rene F Chun, Andrea Jorgensen, Paul Richardson, Darshan Nitchingham, Joseph Aslan, Maya Shah, Coonoor R Chandrasekar, Amanda Wood, Mike Beadsworth, Munir Pirmohamed

^*Corresponding author for this work

Metabolism and Systems Research

Research output: Contribution to journal › Article › peer-review

Abstract

BACKGROUND: Vitamin D deficiency has been associated with worse coronavirus disease 2019 (COVID-19) outcomes, but circulating 25-hydroxyvitamin D [25(OH)D] is largely bound to vitamin D-binding protein (DBP) or albumin, both of which tend to fall in illness, making the 25(OH)D status hard to interpret. Because of this, measurements of unbound ("free") and albumin-bound ("bioavailable") 25(OH)D have been proposed.

OBJECTIVES: We aimed to examine the relationship between vitamin D status and mortality from COVID-19.

METHODS: In this observational study conducted in Liverpool, UK, hospitalized COVID-19 patients with surplus sera available for 25(OH)D analysis were studied. Clinical data, including age, ethnicity, and comorbidities, were extracted from case notes. Serum 25(OH)D, DBP, and albumin concentrations were measured. Free and bioavailable 25(OH)D were calculated. Relationships between total, free, and bioavailable 25(OH)D and 28-day mortality were analyzed by logistic regression.

RESULTS: There were 472 patients with COVID-19 included, of whom 112 (23.7%) died within 28 days. Nonsurvivors were older (mean age, 73 years; range, 34-98 years) than survivors (mean age, 65 years; range, 19-95 years; P = 0.003) and were more likely to be male (67%; P = 0.02). The frequency of vitamin D deficiency [25(OH)D < 50 nmol/L] was similar between nonsurvivors (71/112; 63.4%) and survivors (204/360; 56.7%; P = 0.15) but, after adjustments for age, sex, and comorbidities, increased odds for mortality were present in those with severe deficiency [25(OH)D < 25 nmol/L: OR, 2.37; 95% CI, 1.17-4.78] or a high 25(OH)D (≥100 nmol/L; OR, 4.65; 95% CI, 1.51-14.34) compared with a 25(OH)D value of 50-74 nmol/L (reference). Serum DBP levels were not associated with mortality after adjustments for 25(OH)D, age, sex, and comorbidities. Neither free nor bioavailable 25(OH)D values were associated with mortality.

CONCLUSIONS: Vitamin D deficiency, as commonly defined by serum 25(OH)D levels (<50 nmol/L), is not associated with increased mortality from COVID-19, but extremely low (<25 nmol/L) and high (>100 nmol/L) levels may be associated with mortality risks. Neither free nor bioavailable 25(OH)D values are associated with mortality risk. The study protocol was approved by the London-Surrey Research Ethics Committee (20/HRA/2282).

Original language	English
Pages (from-to)	1367-1377
Number of pages	11
Journal	The American journal of clinical nutrition
Volume	115
Issue number	5
Early online date	31 Jan 2022
DOIs	https://doi.org/10.1093/ajcn/nqac027
Publication status	Published - May 2022

Bibliographical note

Keywords

Aged
Albumins/metabolism
COVID-19
Female
Humans
Male
Vitamin D
Vitamin D Deficiency/complications
Vitamin D-Binding Protein
Vitamins

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https://livrepository.liverpool.ac.uk/3155035/

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Subramanian, S., Rhodes, J. M., Taylor, J. M., Milan, A. M., Lane, S., Hewison, M., Chun, R. F., Jorgensen, A., Richardson, P., Nitchingham, D., Aslan, J., Shah, M., Chandrasekar, C. R., Wood, A., Beadsworth, M., & Pirmohamed, M. (2022). Vitamin D, vitamin D-binding protein, free vitamin D and COVID-19 mortality in hospitalized patients. The American journal of clinical nutrition, 115(5), 1367-1377. https://doi.org/10.1093/ajcn/nqac027

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title = "Vitamin D, vitamin D-binding protein, free vitamin D and COVID-19 mortality in hospitalized patients",

abstract = "BACKGROUND: Vitamin D deficiency has been associated with worse coronavirus disease 2019 (COVID-19) outcomes, but circulating 25-hydroxyvitamin D [25(OH)D] is largely bound to vitamin D-binding protein (DBP) or albumin, both of which tend to fall in illness, making the 25(OH)D status hard to interpret. Because of this, measurements of unbound ({"}free{"}) and albumin-bound ({"}bioavailable{"}) 25(OH)D have been proposed.OBJECTIVES: We aimed to examine the relationship between vitamin D status and mortality from COVID-19.METHODS: In this observational study conducted in Liverpool, UK, hospitalized COVID-19 patients with surplus sera available for 25(OH)D analysis were studied. Clinical data, including age, ethnicity, and comorbidities, were extracted from case notes. Serum 25(OH)D, DBP, and albumin concentrations were measured. Free and bioavailable 25(OH)D were calculated. Relationships between total, free, and bioavailable 25(OH)D and 28-day mortality were analyzed by logistic regression.RESULTS: There were 472 patients with COVID-19 included, of whom 112 (23.7%) died within 28 days. Nonsurvivors were older (mean age, 73 years; range, 34-98 years) than survivors (mean age, 65 years; range, 19-95 years; P = 0.003) and were more likely to be male (67%; P = 0.02). The frequency of vitamin D deficiency [25(OH)D < 50 nmol/L] was similar between nonsurvivors (71/112; 63.4%) and survivors (204/360; 56.7%; P = 0.15) but, after adjustments for age, sex, and comorbidities, increased odds for mortality were present in those with severe deficiency [25(OH)D < 25 nmol/L: OR, 2.37; 95% CI, 1.17-4.78] or a high 25(OH)D (≥100 nmol/L; OR, 4.65; 95% CI, 1.51-14.34) compared with a 25(OH)D value of 50-74 nmol/L (reference). Serum DBP levels were not associated with mortality after adjustments for 25(OH)D, age, sex, and comorbidities. Neither free nor bioavailable 25(OH)D values were associated with mortality.CONCLUSIONS: Vitamin D deficiency, as commonly defined by serum 25(OH)D levels (<50 nmol/L), is not associated with increased mortality from COVID-19, but extremely low (<25 nmol/L) and high (>100 nmol/L) levels may be associated with mortality risks. Neither free nor bioavailable 25(OH)D values are associated with mortality risk. The study protocol was approved by the London-Surrey Research Ethics Committee (20/HRA/2282).",

keywords = "Aged, Albumins/metabolism, COVID-19, Female, Humans, Male, Vitamin D, Vitamin D Deficiency/complications, Vitamin D-Binding Protein, Vitamins",

author = "Sreedhar Subramanian and Rhodes, {Jonathan M} and Taylor, {Joseph M} and Milan, {Anna M} and Steven Lane and Martin Hewison and Chun, {Rene F} and Andrea Jorgensen and Paul Richardson and Darshan Nitchingham and Joseph Aslan and Maya Shah and Chandrasekar, {Coonoor R} and Amanda Wood and Mike Beadsworth and Munir Pirmohamed",

year = "2022",

month = may,

doi = "10.1093/ajcn/nqac027",

language = "English",

volume = "115",

pages = "1367--1377",

journal = "The American journal of clinical nutrition",

issn = "0002-9165",

publisher = "American Society for Nutrition",

number = "5",

}

Subramanian, S, Rhodes, JM, Taylor, JM, Milan, AM, Lane, S, Hewison, M, Chun, RF, Jorgensen, A, Richardson, P, Nitchingham, D, Aslan, J, Shah, M, Chandrasekar, CR, Wood, A, Beadsworth, M & Pirmohamed, M 2022, 'Vitamin D, vitamin D-binding protein, free vitamin D and COVID-19 mortality in hospitalized patients', The American journal of clinical nutrition, vol. 115, no. 5, pp. 1367-1377. https://doi.org/10.1093/ajcn/nqac027

TY - JOUR

T1 - Vitamin D, vitamin D-binding protein, free vitamin D and COVID-19 mortality in hospitalized patients

AU - Subramanian, Sreedhar

AU - Rhodes, Jonathan M

AU - Taylor, Joseph M

AU - Milan, Anna M

AU - Lane, Steven

AU - Hewison, Martin

AU - Chun, Rene F

AU - Jorgensen, Andrea

AU - Richardson, Paul

AU - Nitchingham, Darshan

AU - Aslan, Joseph

AU - Shah, Maya

AU - Chandrasekar, Coonoor R

AU - Wood, Amanda

AU - Beadsworth, Mike

AU - Pirmohamed, Munir

PY - 2022/5

Y1 - 2022/5

N2 - BACKGROUND: Vitamin D deficiency has been associated with worse coronavirus disease 2019 (COVID-19) outcomes, but circulating 25-hydroxyvitamin D [25(OH)D] is largely bound to vitamin D-binding protein (DBP) or albumin, both of which tend to fall in illness, making the 25(OH)D status hard to interpret. Because of this, measurements of unbound ("free") and albumin-bound ("bioavailable") 25(OH)D have been proposed.OBJECTIVES: We aimed to examine the relationship between vitamin D status and mortality from COVID-19.METHODS: In this observational study conducted in Liverpool, UK, hospitalized COVID-19 patients with surplus sera available for 25(OH)D analysis were studied. Clinical data, including age, ethnicity, and comorbidities, were extracted from case notes. Serum 25(OH)D, DBP, and albumin concentrations were measured. Free and bioavailable 25(OH)D were calculated. Relationships between total, free, and bioavailable 25(OH)D and 28-day mortality were analyzed by logistic regression.RESULTS: There were 472 patients with COVID-19 included, of whom 112 (23.7%) died within 28 days. Nonsurvivors were older (mean age, 73 years; range, 34-98 years) than survivors (mean age, 65 years; range, 19-95 years; P = 0.003) and were more likely to be male (67%; P = 0.02). The frequency of vitamin D deficiency [25(OH)D < 50 nmol/L] was similar between nonsurvivors (71/112; 63.4%) and survivors (204/360; 56.7%; P = 0.15) but, after adjustments for age, sex, and comorbidities, increased odds for mortality were present in those with severe deficiency [25(OH)D < 25 nmol/L: OR, 2.37; 95% CI, 1.17-4.78] or a high 25(OH)D (≥100 nmol/L; OR, 4.65; 95% CI, 1.51-14.34) compared with a 25(OH)D value of 50-74 nmol/L (reference). Serum DBP levels were not associated with mortality after adjustments for 25(OH)D, age, sex, and comorbidities. Neither free nor bioavailable 25(OH)D values were associated with mortality.CONCLUSIONS: Vitamin D deficiency, as commonly defined by serum 25(OH)D levels (<50 nmol/L), is not associated with increased mortality from COVID-19, but extremely low (<25 nmol/L) and high (>100 nmol/L) levels may be associated with mortality risks. Neither free nor bioavailable 25(OH)D values are associated with mortality risk. The study protocol was approved by the London-Surrey Research Ethics Committee (20/HRA/2282).

AB - BACKGROUND: Vitamin D deficiency has been associated with worse coronavirus disease 2019 (COVID-19) outcomes, but circulating 25-hydroxyvitamin D [25(OH)D] is largely bound to vitamin D-binding protein (DBP) or albumin, both of which tend to fall in illness, making the 25(OH)D status hard to interpret. Because of this, measurements of unbound ("free") and albumin-bound ("bioavailable") 25(OH)D have been proposed.OBJECTIVES: We aimed to examine the relationship between vitamin D status and mortality from COVID-19.METHODS: In this observational study conducted in Liverpool, UK, hospitalized COVID-19 patients with surplus sera available for 25(OH)D analysis were studied. Clinical data, including age, ethnicity, and comorbidities, were extracted from case notes. Serum 25(OH)D, DBP, and albumin concentrations were measured. Free and bioavailable 25(OH)D were calculated. Relationships between total, free, and bioavailable 25(OH)D and 28-day mortality were analyzed by logistic regression.RESULTS: There were 472 patients with COVID-19 included, of whom 112 (23.7%) died within 28 days. Nonsurvivors were older (mean age, 73 years; range, 34-98 years) than survivors (mean age, 65 years; range, 19-95 years; P = 0.003) and were more likely to be male (67%; P = 0.02). The frequency of vitamin D deficiency [25(OH)D < 50 nmol/L] was similar between nonsurvivors (71/112; 63.4%) and survivors (204/360; 56.7%; P = 0.15) but, after adjustments for age, sex, and comorbidities, increased odds for mortality were present in those with severe deficiency [25(OH)D < 25 nmol/L: OR, 2.37; 95% CI, 1.17-4.78] or a high 25(OH)D (≥100 nmol/L; OR, 4.65; 95% CI, 1.51-14.34) compared with a 25(OH)D value of 50-74 nmol/L (reference). Serum DBP levels were not associated with mortality after adjustments for 25(OH)D, age, sex, and comorbidities. Neither free nor bioavailable 25(OH)D values were associated with mortality.CONCLUSIONS: Vitamin D deficiency, as commonly defined by serum 25(OH)D levels (<50 nmol/L), is not associated with increased mortality from COVID-19, but extremely low (<25 nmol/L) and high (>100 nmol/L) levels may be associated with mortality risks. Neither free nor bioavailable 25(OH)D values are associated with mortality risk. The study protocol was approved by the London-Surrey Research Ethics Committee (20/HRA/2282).

KW - Aged

KW - Albumins/metabolism

KW - COVID-19

KW - Female

KW - Humans

KW - Male

KW - Vitamin D

KW - Vitamin D Deficiency/complications

KW - Vitamin D-Binding Protein

KW - Vitamins

U2 - 10.1093/ajcn/nqac027

DO - 10.1093/ajcn/nqac027

M3 - Article

C2 - 35102371

SN - 0002-9165

VL - 115

SP - 1367

EP - 1377

JO - The American journal of clinical nutrition

JF - The American journal of clinical nutrition

IS - 5

ER -

Vitamin D, vitamin D-binding protein, free vitamin D and COVID-19 mortality in hospitalized patients

Abstract

Bibliographical note

Keywords

Access to Document

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