PMC:9672358 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/9672358","sourcedb":"PMC","sourceid":"9672358","source_url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC9672358","text":"Vitamin D status and severity of COVID-19\n\nAbstract\nWe explored the association between COVID-19 severity and vitamin D status using information from Danish nation-wide health registers, the COVID-19 surveillance database and stored blood samples from the national biobank. 25-hydroxyvitamin D (25(OH)D) was measured using tandem mass spectroscopy. The association between 25(OH)D levels and COVID-19 severity, classified hierarchical as non-hospitalized, hospitalized but not admitted to an intensive care unit (ICU), admitted to ICU, and death, was evaluated by proportional odds ratios (POR) assuming proportionality between the four degrees of severity. Among 447 adults tested SARS-CoV-2 positive in the spring of 2020, low levels of 25(OH)D were associated with a higher risk of severe COVID-19. Thus, odds of experiencing more severe COVID-19 among individuals with insufficient (25 to \u003c 50 nmol/L) and sufficient (≥ 50 nmol/L) 25(OH)D levels were approximately 50% of that among individuals with deficient levels (\u003c 25 nmol/L) (POR = 0.49 (95% CI 0.25–0.94), POR = 0.51 (95% CI 0.27–0.96), respectively). Dividing sufficient vitamin D levels into 50 to \u003c 75 nmol/L and ≥ 75 nmol/L revealed no additional beneficial effect of higher 25(OH)D levels. In this observational study, low levels of 25(OH)D were associated with a higher risk of severe COVID-19. A possible therapeutic role of vitamin D should be evaluated in well-designed interventional studies.\n\nIntroduction\nThe majority of those infected with SARS-CoV-2 will have mild symptoms, but some will experience severe clinical symptoms necessitating hospitalization, and in worst cases, death1,2. It is still uncertain why some are more prone to develop a more severe outcome of COVID-19, but risk factors such as older age, male sex, obesity, non-white race and co-morbidities seem to be of importance2. Findings of a potential beneficial effect of vitamin D on the incidence and the severity of acute respiratory tract infections suggests that vitamin D deficiency also could be linked to the outcome of COVID-19 illness3,4.\nSeveral studies have reported lower levels of vitamin D among individuals who test positive for SARS-CoV-2 as compared with those who test negative5–7. Other studies were not supportive of an association between vitamin D status and risk of SARS-CoV-2 infection8–10 but, in at least one case, the null result could be explained by the use of vitamin D levels measured several years in the past10. Clinical severity among hospitalized COVID-19 patients, evaluated according to the possible existence of unconsciousness, respiratory symptoms, organ dysfunction, need of invasive mechanical ventilation, or death have also been linked to lower vitamin D levels in some studies11–15, but not all16–19.\nDespite the discrepancy in previous studies, findings from many of the systematic reviews and meta-analyses support the hypothesis that vitamin D deficiency is related to a higher SARS-CoV-2 infection risk and worse disease outcome20–23. However, clinical and methodological heterogeneity hamper comparison of the previous studies resulting in less reliable pooled risk estimates22. Especially selection bias, lack of adjustment for relevant confounders, timing of vitamin D measurements, and varying definitions of vitamin D deficiency are issues of great concern5,6,12,14–16,18,22,24–26.\nVitamin D is known to modulate the immune system, and a possible beneficial effect of vitamin D on the outcome of COVID-19 could be through the prevention of the overreaction of the immune system e.g. the cytokine storm characteristic of severe COVID-1927,28. Vitamin D may also play a role in the production of antimicrobial peptides in the respiratory epithelium, the maintenance of the integrity of the cellular junctions and the control of cellular proliferation and angiogenesis27,28. Furthermore, genetic variations in the vitamin D binding protein gene, specifically SNP in rs7041 locus, have been found to correlate with the prevalence of COVID-19 and mortality rates, suggesting that genetic factors may also have a role29,30.\nCOVID-19 hospitalizations continue, despite the availability of COVID-19 vaccines, and it is therefore urgent to determine whether vitamin D deficiency has a role in the severity of COVID-19 infection. In the present study, we assess the association between vitamin D status and COVID-19 severity among Danish COVID-19 patients using the Danish National Patient Registry, the Cancer Registry, the COVID-19 surveillance database, which contains information on all SARS-CoV-2 PCR tests carried out in Denmark, and blood samples stored in the National Biobank. Using these resources enable us to select the most suitable blood sample for every COVID-19 patient and adjust for relevant confounders.\n\nMethods\n\nThe study cohort\nResidual blood samples from clinical biochemistry departments at two major hospitals in the Capital Region of Copenhagen have routinely been sent to and stored by the Danish National Biobank (DNB) at Statens Serum Institut (SSI). Biological samples in the DNB are by the unique personal ID number assigned to every Danish citizen by the Civil Registration System (CRS)31 linked to the National Patient Registry (NPR)32,33 which enabled us to match stored blood samples in DNB drawn from individuals registered with a hospital contact due to COVID-19 up to the beginning of May 2020.\n\nSelection of blood samples for vitamin D measurements\nA blood sample collected 1–30 days before registration of a COVID-19 diagnosis was preferred. If this was not possible, a blood sample drawn on the date of registration or 1–2 days after was selected, and if this could not be fulfilled, we selected the most recent blood sample collected up to 24 months before the COVID-19 registration. If none of the blood samples were drawn in this period, the person was excluded from the study.\n\nMeasurements of vitamin D\nFor each participants’ sample, 25-hydroxyvitamin D (25(OH)D) was measured using 30 µl of blood plasma. We measured 25-hydroxyvitamin D3, (25(OH)D3), which is the main circulating form of vitamin D, and the related ergosterol derived-form 25-hydroxyvitamin D2 (25(OH)D2). The assay was done at SSI and is highly sensitive using minimal sample cleanup to reduce sample loss during extraction, chemical derivatization to enhance 25(OH)D2 and 25(OH)D3 ionization, and liquid chromatography tandem mass spectroscopy coupled with multiple reaction monitoring34. Vitamin D level was calculated as the sum of 25(OH)D3 and 25(OH)D2.\n\nInformation on SARS-CoV-2 test results\nTo confirm the diagnosis of COVID-19, the study cohort was linked to the SSI COVID-19 surveillance database, which includes results for every SARS-CoV-2 PCR test carried out in Denmark since February 2020. The database is based on information from the Departments of Clinical Microbiology and Test Center Denmark and is updated daily. In addition to test results, it also contains information on hospitalizations, admissions to ICU, and COVID-19 related death35.\n\nSeverity of COVID-19\nWe defined onset of COVID-19 as date of a positive SARS-CoV-2 test and not as date of a hospital contact as we consider date of test to be closest to onset of first symptoms. A hospital contact related to COVID-19 was defined as a registration in the NPR with a diagnosis of COVID-19 (ICD-10 code; DB342A or DB972A) as primary or secondary diagnosis within 14 days after a positive test. However, if a hospitalized person with the above diagnostic codes tested positive within 2 days after admission, this hospitalization was also considered related to COVID-19. We defined four categories of increasing severity: (1) no hospital admission (incl. hospital contacts \u003c 12 h), (2) hospitalized (≥ 12 h), but not admitted to ICU, (3) admitted to ICU, regardless of duration of hospital contact and (4) death within 30 days after a positive SARS-CoV-2 test.\n\nPotential confounders\nAs older age, male sex, chronic diseases, obesity, and non-white race have been associated with vitamin D deficiency36,37, as well as with an increased risk of severe COVID-192, we consider those covariates as potential confounders. For each cohort member we therefore obtained detailed information on pre-existing diseases registered 5 years to 1 month prior to the positive SARS-CoV-2 test using information from the NPR32,33 and Cancer Registry32,38. The categories of pre-existing diseases were defined according to a modified version of the Charlson comorbidity index39 and we used the updated weights40 (Supplementary Table 1). Obesity was defined as any registration of clinical obesity in the NPR (ICD-10 codes: E65 or E66). We have no specific information on race/ethnicity, accordingly we used country of origin as proxy of race. Country of origin was defined using data from CPR on family relations and place of birth according to an algorithm developed by Statistics Denmark41.\n\nStatistical methods\n25(OH)D levels were modelled in predefined categories, (\u003c 25 nmol/L (deficient), 25 to \u003c 50 nmol/L (insufficient), and ≥ 50 nmol/L (sufficient)) and as a continuous variable. We a posteriori divided the category of sufficient 25(OH)D levels into two levels; 50 to \u003c 75 nmol/L and ≥ 75 nmol/L.\nAssuming proportionality between the 4 categories of severity we used ordinal logistic regression to calculate proportional odds ratios (POR) to evaluate the possible association between severity of COVID-19 and vitamin D levels. We calculated profile likelihood based 95% confidence intervals to account for the non-normal distribution of the POR. We furthermore stratified the analyses according to age at SARS-CoV-2 test (\u003c 65 and ≥ 65 years) and sex.\nTo adjust for variation in 25(OH)D due to seasonality during blood sample collection, we regressed the 25(OH)D levels on the periodic function βsine sin(2ΠMi/12) + βcosinus cos(2ΠMi /12), where Mi is month of sample collection. The residuals from this model were added to the specific 25-hydroxyvitamin D means derived from the model to create an adjusted 25(OH)D as described by Munger et al.42. Besides adjusting for seasonality in vitamin D, we a priori included age, sex, Charlson comorbidity index, obesity and country of origin in the model.\n\nSupplementary analyses\nWe evaluated the validity of the proportional odds assumption, by estimating odds ratios of the pairwise comparisons of COVID-19 hospitalization, ICU and fatal COVID-19 vs no hospitalization, respectively.\n\nSensitivity analyses\nTo further account for possible variations in vitamin D levels over calendar periods in 2018, 2019 and 2020 we restricted cohort members to those who had their blood samples drawn from the 1st of February 2020 to the 1st of May 2020. In a second sensitivity analysis we restricted cohort members to those who had a blood sample drawn 1–30 days before the positive SARS-CoV-2 test. We did this in order to minimize the risk of reverse causality i.e. that the COVID-19 illness would affect the person’s vitamin D level, and in order to eliminate the possibility of changes in vitamin D related behaviors after the blood sample was drawn e.g. beginning vitamin D supplementation.\n\nA posteriori analysis\nVitamin D levels appeared surprisingly high among the deceased COVID-19 cases. We speculate that this could reflect prescribed vitamin D supplementation to frail older persons. We therefore omitted death from the four categories of COVID-19 severity and estimated the odds of experiencing a more severe outcome of COVID-19 among individuals who survived the COVID-19.\n\nEthics\nThis study was approved by the Danish National Committee on Health Research Ethics (H-20028195) and the Statens Serum Institut’s compliance department. We used already stored blood samples originally collected for other purposes. These blood samples were routinely sent to and stored by the National Biobank in Denmark. As the study was carried out (1) without active participation, (2) with no contact with any of the study participants, (3) without any health risks or other burdens for the persons whose data were used, and (4) including a large number of participants (originally approx. 2000), the Danish National Committee on Health Research Ethics granted us a dispensation from for the rule of obtaining consent in accordance with the Committee Act, section 16, subsection 3. All the analyses and the reporting of results have been done completely anonymously. The project group ensured that none of the blood sample owners had actively refused that their biological material could be used for research—this information is available in the Danish national “Tissue Use Register”.\n\nResults\nOverall, 587 individuals with a least one blood sample in the DNB were registered with COVID-19 in the Danish Biobank Register. 120 persons did not have a blood sample drawn within the accepted time interval and 9 did not have a physical blood sample in the DNB, reducing the number of COVID-19 cases to 458. After linkage with the COVID-19 surveillance database 8 out the 458 did not have a positive SARS-CoV-2 test, and finally 3 persons were excluded as they had no address in Denmark at the time of the test (Fig. 1). The distribution of sex, mean age and vitamin D level of the 8 patients who did not have a positive SARS-CoV-2 test despite a COVID-19 registration did not differ from that among the 447 patients included in the study (data not shown).\nFigure 1 Flowchart showing the identification of the study participants.\nTable 1 shows the characteristics of the 447 cohort members according to predefined categories of vitamin D levels. Overall, 11%, 30% and 59% of the cohort members had vitamin D deficiency, insufficiency or sufficiency, respectively (Table 1). Vitamin D level was statistically significantly associated with sex, age, country of origin and comorbidity, but not with obesity or time interval between date of blood sample drawn and SARS-CoV-2 test. Against expectations, we observed that 68% (145/212) of the cohort members ≥ 70 years had sufficient vitamin D levels versus 50% among individuals \u003c 70 years (118/235), and that vitamin D sufficiency was more common among individuals with comorbidities than among individuals without comorbidities (68% (115/168) versus 53% (148/279), respectively).\nTable 1 Summary of baseline characteristics of the study cohort.\nThe total cohort N (%) Vitamin D level Homogeneity test\n\u003c 25 nmol/L (Deficient) N (%) 25 to \u003c 50 nmol/L (Insufficient) N (%) ≥ 50 nmol/L (Sufficient) N (%)\nTotal 447 (100%) 49 (100%) 135 (100%) 263 (100%)\nSex\nMale 219 (49.0) 31 (63.3) 78 (57.8) 110 (41.8)\nFemale 228 (51.0) 18 (36.7) 57 (42.2) 153 (58.2) P = 0.0011\nAge (years)\n\u003c 30 30 (6.7) – 11 (8.2) 16 (6.1)\n30–39 31 (6.9) 6 (12.2)a 15 (11.1) 13 (4.9)\n40–49 43 (9.6) 8 (16.3) 19 (14.1) 16 (6.1)\n50–59 71 (15.9) 5 (10.2) 33 (24.4) 33 (12.6)\n60–69 60 (13.4) 5 (10.2) 15 (11.1) 40 (15.2)\n70–79 117 (26.2) 12 (24.5) 25 (18.5) 80 (30.4)\n≥ 80 95 (21.3) 13 (26.5) 17 (12.6) 65 (24.7) P \u003c 0.0001b\nCountry-of-origin\nDenmark 337 (75.4) 34 (69.4) 87 (64.4) 216 (82.1)\nNon-Westernc 88 (19.7) 15 (30.6)d 43 (31.9) 33 (12.6)\nWesterne 22 (4.9) – 5 (3.7) 14 (5.3) P \u003c 0.0001\nCharlson comorbidity index\n0 279 (62.4) 32 (65.3) 99 (73.3) 148 (56.3)\n1–2 140 (31.3) 17 (34.7)f 28 (20.7) 96 (36.5)\n≥ 3 28 (6.3) – 8 (5.9) 19 (7.2) P = 0.011\nObesity\nYes 48 (10.7) 5 (10.2) 13 (9.6) 30 (11.4)\nNo 399 (89.3) 44 (89.8) 122 (90.4) 233 (88.6) P = 0.86\nTiming of blood collection in relation to SARS-CoV-2 test\n1 year–2 years before test 104 (23.3) – 37 (27.4) 63 (24.0)\n6 months–1 year before test 46 (10.3) – 16 (11.9) 25 (9.5)\n1–6 months before test 27 (6.0) 11g (22.4) 8 (5.9) 17 (6.5)\n1 day–1 month before test 79 (17.7) 8 (16.3) 20 (14.8) 51 (19.4)\n0 day–2 days after test 153 (34.2) 22 (44.9) 45 (33.3) 86 (32.7)\nMore than 2 days after test 37 (8.3) 8 (16.3) 9 (6.7) 20 (7.6) P = 0.17\naDue to few numbers the age groups \u003c 30 and 30–39 years are grouped together in this table.\nbKruskal–Wallis test.\ncAlbania, Bosnia and Hercegovina, Belarus, Yugoslavia, Kosovo, Macedonia, Moldovia, Montenegro, Russia, Serbia, Soviet Union, Turkey, Ukraine, Africa, Asia, South and Central America, the Oceania (excl. Australia and New Zealand) and stateless people.\ndDue to few numbers Non-Western and Western countries are grouped together in this table.\neEU, Andorra, Australia, Canada, Iceland, Liechtenstein, Monaco, New Zealand, Norway, San Marino, Switzerland, UK, US, The Vatican.\nfDue to few number the categories of Charlson comorbidity index; 1–2 and ≥ 3 are grouped together.\ngDue to few number the 3 periods covering the interval 1 month to 2 years are grouped together.\nAmong the 447 cohort members, 126 (28%) were not hospitalized, 205 (46%) were hospitalized for COVID-19, but not admitted to an ICU, 34 (8%) were admitted to an ICU and 82 (18%) died from COVID-19. Figure 2 shows individual vitamin D levels in a boxplot according to COVID-19 severity, age (\u003c 65 year and ≥ 65 years) and sex. Lower levels of vitamin D were associated with higher COVID-19 severity among males younger than 65 years of age but not among women of same age. Among the older men and women, the relationship between vitamin D levels and severity of COVID-19 resembled a U-formed association i.e. highest vitamin D levels were observed among those who were not hospitalized and among those who did not survive COVID-19 (Fig. 2).\nFigure 2 Boxplot with jitter showing the individual vitamin D levels (grey) according to degree of severity, age and sex.\nIn the main analysis, the odds of experiencing a more severe outcome of COVID-19 (progressing to the next severity category), among individuals with insufficient and sufficient levels of 25(OH)D were approximately 50% of that among individuals with deficient levels (POR = 0.49 (95% CI 0.25–0.94) and POR = 0.51 (95% CI 0.27–0.96), respectively) adjusted for age, sex, comorbidity, seasonality, obesity and country of origin (hereinafter referred to as aPOR). Treating vitamin D levels as a continuous variable, the odds of experiencing a more severe outcome of COVID-19 was reduced by 3% per 5 nmol/L increase in vitamin D level (aPOR = 0.97 (95% CI 0.93–1.01)). However, this estimate did not reach statistically significance. No beneficial effect of increasing levels of vitamin D was observed in the analysis dividing the category of vitamin sufficiency into 50 to \u003c 75 nmol/L and ≥ 75 nmol/L (Table 2).\nTable 2 Proportional Odds Ratios of developing more severe COVID-19 according to 25(OH)D levels, sex and age.\nTotal Age\nN POR (95% CI) aPOR (95% CI)  \u003c 65 yearsb  ≥ 65 years\nN aPOR (95% CI) N aPOR (95% CI)\nTotal\nPredefined cutpoints of 25(OH)D levels\n \u003c 25 nmol/L (Deficient) 49 1 (ref) 1 (ref) 23 1 (ref) 26 1 (ref)\n 25 to \u003c 50 nmol/L (Insufficient) 135 0.36 (0.20–0.66) 0.49 (0.25–0.94) 86 0.43 (0.16–1.13) 49 0.49 (0.19–1.24)\n ≥ 50 nmol/L (Sufficient) 263 0.56 (0.32–0.98) 0.51 (0.27–0.96) 99 0.38 (0.14–1.05) 164 0.60 (0.26–1.36)\n  50 to \u003c 75 nmol/La 167 0.58 (0.32–1.03) 0.50 (0.26–0.96) 64 0.39 (0.13–1.10) 103 0.58 (0.24–1.36)\n  ≥ 75 nmol/La 96 0.54 (0.29–1.03) 0.53 (0.26–1.08) 35 0.38 (0.11–1.27) 61 0.64 (0.25–1.60)\nContinuous levels of 25(OH)D\n Per 5 nmol/L 447 0.99 (0.96–1.02) 0.97 (0.93–1.01) 208 0.94 (0.88–1.01) 239 0.98 (0.93–1.04)\nMales\nPredefined cutpoints of 25(OH)D levels\n \u003c 25 nmol/L (Deficient) 31 1 (ref) 1 (ref) 17 1 (ref) 14 1 (ref)\n 25 to \u003c 50 nmol/L (Insufficient) 78 0.32 (0.15–0.69) 0.35 (0.15–0.80) 46 0.44 (0.13–1.48) 32 0.26 (0.07–0.91)\n ≥ 50 nmol/L (Sufficient) 110 0.54 (0.26–1.12) 0.38 (0.17–0.87) 36 0.40 (0.11–1.44) 74 0.33 (0.09–1.08)\nContinuous levels of 25(OH)D\n Per 5 nmol/L 219 0.99 (0.94–1.04) 0.97 (0.92–1.03) 99 0.92 (0.84–1.01) 120 1.00 (0.93–1.08)\nFemales\nPredefined cutpoints of 25(OH)D levels\n \u003c 25 nmol/L (Deficient) 18 1 (ref) 1 (ref) 6 1 (ref) 12 1 (ref)\n 25 to \u003c 50 nmol/L (Insufficient) 57 0.44 (0.17–1.15) 0.88 (0.28–2.80) 40 0.53 (0.09–3.42) 17 1.14 (0.24–5.34)\n ≥ 50 nmol/L (Sufficient) 153 0.82 (0.34–1.98) 0.84 (0.30–2.40) 63 0.37 (0.06–2.52) 90 1.20 (0.33–4.42)\nContinuous levels of 25(OH)D\n Per 5 nmol/L 228 1.01 (0.96–1.06) 0.96 (0.90–1.02) 109 0.94 (0.83–1.04) 119 0.97 (0.89–1.05)\nPOR Proportional Odds Ratio, CI Confidence Interval, aPOR Proportional Odds Ratio adjusted for age, seasonal variation in vitamin D level, country of origin, Charlson comorbidity index, obesity and sex\naReference group is still the group of individuals with deficient 25(OH)D levels.\nbDue to few numbers the two highest comorbidity indices are grouped when adjusting.\nAnalyses stratified according to age (\u003c 65 years, ≥ 65 years) and sex revealed estimates compatible with a higher severity of COVID-19 among vitamin D deficient males in all age groups and among women less than 65 years of age, whereas no such association was seen among women 65 years of age or older (Table 2). Numbers were few in the stratified analyses, as reflected by the rather wide confidence intervals surrounding the aPOR estimates, of which many did not reach statistically significance.\n\nSupplementary analyses\nTo evaluate the validity of the proportional odds assumption, we estimated the odds of progression in COVID-19 disease severity from non-hospitalized to hospitalized, non-hospitalized to ICU treatment and finally from non-hospitalized to death, according to vitamin D level. Overall, these results supported the validity of the main analysis based on proportional odds regression in that sufficient and insufficient levels protected against severe COVID-19 vs no hospitalization in pairwise comparisons (Supplementary Table 2).\n\nSensitivity and a posteriori analyses\nIn the sensitivity analyses restricting cohort members to those with blood samples drawn in the spring of 2020 (n = 276) or to those with blood samples drawn within 1–30 days before positive test (n = 76), estimates remained supportive of a higher severity of COVID-19 among vitamin D deficient persons (Supplementary Table 3). Similar findings were observed in the a posteriori analyses in which we reduced the four severity levels to three levels by excluding cohort members who died within 30 days of a positive test (Supplementary Table 4).\n\nDiscussion\nWe studied the association between vitamin D level and severity of COVID-19 among 447 individuals who tested positive within the first 3 months of the SARS-CoV-2 epidemic in Denmark. Overall, we found that individuals with vitamin D deficiency were at a higher risk of progressing to a more severe clinical outcome of COVID-19.\nMost of the previous hospital-based studies observed an association between vitamin D deficiency and a more critical outcome of COVID-19. Vitamin D deficiency has been associated with elevated risk of oxygen support43, ICU admission24, invasive mechanical ventilation11, severe sepsis/septic shock24, lung damage15, hypoxia13, death11,14,15, higher level of the inflammatory marker CRP13 and severe/critical COVID-19 illness defined according to severity scales developed by WHO or CDC13,14. However, other studies observed no association between vitamin D deficiency and clinical outcome of COVID-19, such as ICU treatment19, requirement for mechanical ventilation16,19, mortality16,19,25, length of hospitalization17,19 and severe/critical COVID-1917 (WHO definitions).\nAlthough some previous studious found no effect, a recent meta-analysis carried out by Dissanayake et al. including nearly 2 million adults and 76 studies concluded that vitamin D deficiency/insufficiency probably increases susceptibility to COVID-19 and severe COVID-19, although with a high risk of bias and heterogeneity, whereas association with mortality is less robust22. Future rigorous prospective studies, using a standardized definition of vitamin D deficiency, insufficiency and sufficiency will be essential.\nHeterogeneity could be due to different definitions of vitamin D deficiency and of COVID-19 severity. We followed the definition given by the Danish National Board of Health claiming that vitamin D levels less than 25 nmol/L are considered deficient and levels ≥ 50 nmol/L as sufficient44, but in other studies vitamin D deficiency was defined as \u003c 30 nmol/L12 or \u003c 50 nmol/L14,15 and sufficient vitamin D levels as ≥ 75 nmol/L17. We did, however, a posteriori divide the highest level of vitamin D into 50 nmol/L to \u003c 75 nmol/L and ≥ 75 nmol/L and found no evidence of an increasing beneficial effect of higher vitamin D levels on COVID-19 severity.\nWe defined severity of COVID-19 according to data routinely recorded in Danish Nationwide Health and administrative registers which facilitates a uniform and easy replicable rating of severity. In contrast to many of the other studies on COVID-19 we included non-hospitalized COVID-19 patients, which could have caused bias. However, to get a SARS-CoV-2 test in Denmark in the spring of 2020, a person had to be referred by a physician who had to assess whether a clinical evaluation at a hospital was required. If this was not the case the person was referred to a regional test center45. We therefore consider the majority of non-hospitalized in our study as representative of those referred to a hospital for clinical evaluation, but due to milder symptoms the assessing hospital physician did not considered inpatient admission necessary45. Certain discrepancies in the procedures of COVID-19 testing and registrations in the Danish health care system may however have existed at the beginning of the epidemic.\nWe are aware of the fact that by defining COVID-19 mortality as deceased within 30 days after a positive SARS-CoV-2 test, we may have included individuals who did not die due to COVID-19, but due to unrelated conditions. However, the proportion of deceased individuals infected with SARS-CoV-2 who died due to other causes than COVID-19 within 30 days after the test is considered to be low in Denmark until December 2021, the appearance of the omicron variant46.\nA rather high proportion of the deceased COVID-19 patients in the present study had sufficient vitamin D levels i.e. ≥ 50 nmol/L. We speculate that this could be due to vitamin supplementation among the more vulnerable and elderly population. To evaluate the influence of confounding by indication we a posteriori repeated our analysis omitting study cohort members who did not survive COVID-19 and found compatible estimates.\nAnother important source to heterogeneity is timing of vitamin D measurements in relation to the test. Previous studies have tested vitamin D levels at time of admission, some during admission and few within the preceding 10 years22. Due to risk of reverse causality and possible vitamin D modifying conditions after the blood samples were drawn, e.g. use of vitamin D supplementation, we would have preferred to measure vitamin D in blood samples drawn 1–30 days before start of symptoms. This criterion could only be met for 18% of the COVID-19 patients in the present study. Although estimates lost statistical significance and confidence intervals were broad, we consider the results based on this smaller group of participants compatible with vitamin D deficiency being associated with an elevated risk of a more severe outcome of COVID-19.\nWe addressed the association between vitamin D status and COVID-19 severity among individuals infected in the spring of 2020 i.e. at the beginning of the epidemic. Several different variants of SARS-CoV-2 have appeared since then, with different patterns of severity and contagiousness, thus our findings may not be applicable to all SARS-CoV-2 infected individuals. Furthermore, COVID-19 vaccinations was initiated in Denmark in December 2020. The association between vitamin D status and severity of COVID-19 in the present study is therefore observed in a group of non-vaccinated persons.\nWe defined a COVID-19 related hospital contact as a registration in the NPR with a diagnosis of COVID-19 (ICD-10 code; DB342A or DB972A) as primary or secondary diagnosis within 14 days after a positive test or 2 days before a positive test. In situations where COVID-19 is recorded as a secondary diagnosis, we may have included some individuals hospitalized due to other causes than COVID-19, who was incidentally found SARS-CoV-2 positive. However, 87% of the COVID-19 hospitalizations in the present study were hospital contacts with a primary diagnosis of DB342A or DB972A. Another limitation could be false positive PCR test results. The specificity of the PCR test in Denmark has, however, been estimated as 99.85%, and accordingly we do not consider false positive PCR tests to have any influence on our results47.\nChronic health conditions have been shown to affect vitamin D levels and COVID-19 severity. We therefore adjusted for pre-existing diseases and obesity, however we cannot rule out the existence of residual confounding due to other health conditions not included in the Charlson comorbidity index.\n\nConclusion\nIn this Danish observational study of 447 COVID-19 patients, we observed that deficient vitamin D levels were associated with an elevated risk of progressing to a more severe COVID-19 outcome.\nThe possible role of vitamin D supplementation in the treatment of COVID-19 has already been assessed in randomized controlled trials, but as pointed out in recent meta-analyses, large variations in vitamin D supplementation schemes in the hitherto published studies means that no definitive conclusion can be drawn on the therapeutic effect of vitamin D, until larger well-designed interventional studies addressing issues such as the appropriate dose, duration and mode of vitamin D administration have been completed48–50.\n\nSupplementary Information\n\nSupplementary Tables.\n\nThe original online version of this Article was revised: Sanne Grundvald Boelt was omitted from the author list in the original version of this Article. The Author Contributions section now reads: “A.A. contributed to the conception and idea of the work. N.M.N., A.S.C., L.B. and A.A. contributed to the design of the study. N.M.N., A.S.C., L.B., S.G.B. contributed to the acquisition of data. N.M.N., A.H., L.B., S.G.B. and T.G.J. contributed to the analyses of the data. All authors contributed to the interpretation of the data and the results in the manuscript. N.M.N. drafted the manuscript, made Fig. 1, T.G.J. made Fig. 2. All the authors revised the manuscript critically and has approved the final version.”\nPublisher's note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\nChange history\n1/31/2023\nA Correction to this paper has been published: 10.1038/s41598-023-28993-3\n\nSupplementary Information\nThe online version contains supplementary material available at 10.1038/s41598-022-21513-9.\n\nAcknowledgements\nThe Danish Departments of Clinical Microbiology (KMA) and Statens Serum Institut carried out laboratory analyses, registration, and release of the national SARS-CoV-2 surveillance data for the present study.\n\nAuthor contributions\nA.A. contributed to the conception and idea of the work. N.M.N., A.S.C., L.B. and A.A. contributed to the design of the study. N.M.N., A.S.C., L.B., S.G.B. contributed to the acquisition of data. N.M.N., A.H., L.B., S.G.B. and T.G.J. contributed to the analyses of the data. All authors contributed to the interpretation of the data and the results in the manuscript. N.M.N. drafted the manuscript, made Fig. 1, T.G.J. made Fig. 2. All the authors revised the manuscript critically and has approved the final version.\n\nFunding\nCOVID-19 research at the Danish National Biobank has been supported by a grant from Novo Nordisk Foundation NNF20SA0062871.\n\nData availability\nThe data in the present study are considered person-sensitive, and cannot be shared due to data protection regulations.\n\nCompeting interests\nThe authors declare no competing 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