Coronavirus Workup Vitamin D
By Ronald Steriti, ND, PhD
Serum Vitamin D and Mortality Rate in Hospitalized Patients
A study assessed Vitamin D levels in individuals with severe acute respiratory syndrome coronavirus-19 infection and its potential as a predictive marker.
All patients, diagnosed with COVID-19 infection from February 16 to March 21, 2020, and referred to Firoozgar Hospital, Tehran, Iran, were enrolled in this study. Vitamin D analysis was undertaken on patient serum samples using a commercial kit (Pars Azmoon Co., Tehran, Iran). SPSS v. 22 was used for statistical analysis.
Vitamin D serum concentration was analyzed in a total of 317 patients whose mean age ± standard deviation was 62.05 ± 15 years and with 62.5% being male. A significant association of Vitamin D level and death was observed. Higher levels of serum Vitamin D had protection against death (odds ratio = 0.955 [95% confidence interval = 0.923-0.988], P = 0.008).
Vitamin D deficiency was associated with a higher death rate and intensive care unit admission. (Ranjbar et al., 2021)
Pre-Infection 25-Hydroxyvitamin D3 Levels
A retrospective study examined if, and to what degree, a relationship exists between pre-infection serum 25-hydroxyvitamin D (25(OH)D) level and disease severity and mortality due to SARS-CoV-2.
The records of individuals admitted between April 7th, 2020 and February 4th, 2021 to the Galilee Medical Center (GMC) in Nahariya, Israel, with positive polymerase chain reaction (PCR) tests for SARS-CoV-2 (COVID-19) were searched for historical 25(OH)D levels measured 14 to 730 days prior to the positive PCR test.
Patients admitted to GMC with COVID-19 were categorized according to disease severity and level of 25(OH)D. An association between pre-infection 25(OH)D levels, divided between four categories (deficient, insufficient, adequate, and high-normal), and COVID-19 severity was ascertained utilizing a multivariable regression analysis. To isolate the possible influence of the sinusoidal pattern of seasonal 25(OH)D changes throughout the year, a cosinor model was used.
Of 1176 patients admitted, 253 had records of a 25(OH)D level prior to COVID-19 infection. A lower vitamin D status was more common in patients with the severe or critical disease (<20 ng/mL [87.4%]) than in individuals with mild or moderate disease (<20 ng/mL [34.3%] p < 0.001). Patients with vitamin D deficiency (<20 ng/mL) were 14 times more likely to have severe or critical disease than patients with 25(OH)D ≥40 ng/mL (odds ratio [OR], 14; 95% confidence interval [CI], 4 to 51; p < 0.001).
Among hospitalized COVID-19 patients, pre-infection deficiency of vitamin D was associated with increased disease severity and mortality. (Dror et al., 2022)
Vitamin D Level in Hospitalized Patients
A study investigated the association between vitamin D levels and the severity or outcomes of COVID-19 disease.
A cross-sectional observational study was conducted in the Eastern province of Saudi Arabia from January to August 2021. All the admitted patients who were diagnosed with COVID-19 infection were distributed into three groups depending on their vitamin D levels: normal, insufficiency, and deficiency. For the three groups, demographic data, and laboratory investigations as well as data regarding the severity of COVID-19 were collected and analyzed.
A total of 203 diagnosed cases of COVID-19 were included in this study.
The vitamin D level was normal (>30) in 31 (15.3%) cases, insufficient in 45 (22.2%) cases and deficient in 127 (62.6%) cases. Among the included cases, 58 (28.6%) were critical cases, 109 (53.7%) were severe and 36 (17.7%) had a mild-moderate COVID-19 infection.
The most prevalent comorbidity of patients was diabetes mellitus 117 (57.6%), followed by hypertension 70 (34.5%), cardiac disease 24 (11.8%), chronic kidney disease 19 (9.4%) and chronic respiratory disease in 17 (8.4%) cases.
Importantly, the current study did not detect any significant association between vitaminD status and COVID-19 severity (p-value=0.371) or outcomes (hospital stay, intensive care units admission, ventilation, and mortality rate) (p-value > 0.05), even after adjusting the statistical model for the confounders.
In hospital settings, vitamin D levels are not associated with the severity or outcomes of COVID-19 disease. (AlKhafaji et al., 2022)
Vitamin D Deficiency is Associated with Higher Risks
A study published in Internal and Emergency Medicine evaluated the association between vitamin D levels and the risks of SARS-CoV-2 infection and severe disease in those infected.
A retrospective study was carried out among members of Clalit Health Services (CHS), the largest healthcare organization in Israel, between March 1 and October 31, 2020. Two matched case-control groups were created of individuals for which vitamin D levels and body mass index (BMI) were available before the pandemic: group (A), in which 41,757 individuals with positive SARS-CoV-2 PCR tests were matched with 417,570 control individuals without evidence of infection, and group (B), in which 2533 patients hospitalized in severe condition for COVID-19 were matched with 2533 patients who were tested positive for SARS-CoV-2, but were not hospitalized.
An inverse correlation was demonstrated between the level of vitamin D and the risks of SARS-CoV-2 infection and of severe disease in those infected.
Patients with very low vitamin D levels (< 30 nmol/L) had the highest risks for SARS-CoV-2 infection and also for severe COVID-19 when infected-OR 1.246 [95% CI 1.210-1.304] and 1.513 [95% CI 1.230-1.861], respectively.
In this large observational population study, a significant association between vitamin D deficiency was found with the risks of SARS-CoV-2 infection and of severe disease in those infected. (Israel et al., 2022)
Vitamin D Status and COVID Hospitalization and Mortality.
A study published in the Journal of General Internal Medicine evaluated the dose-response relationship between continuous 25(OH)D and risk for COVID-19-related hospitalization and mortality after adjusting for covariates associated with both vitamin D deficiency and COVID-19 outcomes.
A retrospective cohort study included veteran patients receiving care in US Department of Veteran Affairs (VA) health care facilities with a positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test and a blood 25(OH)D test between February 20, 2020, and November 8, 2020, followed for up to 60 days.
Exposure was blood 25(OH)D concentration ascertained closest to and within 15 to 90 days preceding an index positive SARS-CoV-2 test. Co-primary study outcomes were COVID-19-related inpatient hospitalization requiring airborne, droplet, contact, or other isolation and mortality ascertained within 60 days of an index positive SARS-CoV-2 test.
Of 4,599 veterans with a positive SARS-CoV-2 test, vitamin D deficiency (< 20 ng/mL) was identified in 665 (14.5%); 964 (21.0%) were hospitalized; and 340 (7.4%) died.
After adjusting for all covariates, including race/ethnicity and poverty, there was a significant independent inverse dose-response relationship between increasing continuous 25(OH)D concentrations (from 15 to 60 ng/mL) and decreasing probability of COVID-19-related hospitalization (from 24.1 to 18.7%, p=0.009) and mortality (from 10.4 to 5.7%, p=0.001).
In modeling 25(OH)D as a log-transformed continuous variable, the greatest risk for hospitalization and death was observed at lower 25(OH)D concentrations.
Continuous blood 25(OH)D concentrations are independently associated with COVID-19-related hospitalization and mortality in an inverse dose-response relationship in this large racially and ethnically diverse cohort of VA patients. (Seal et al., 2022)
25-Hydroxyvitamin D Levels in Mexico City
A study determined 25-hydroxyvitamin D (25[OH]D) levels and its association with mortality in patients with critical COVID-19.
This was a prospective observational study including adult patients with critical COVID-19. Data, including clinical characteristics and 25(OH)D levels measured at the time of intensive care unit admission, were collected. All patients were followed until hospital discharge or in-hospital death.
The entire cohort comprised 94 patients with critical COVID-19 (males, 59.6%; median age, 61.5 years). The median 25(OH)D level was 12.7 ng/mL, and 15 (16%) and 79 (84%) patients had vitamin D insufficiency and vitamin D deficiency, respectively. The median serum 25(OH)D level was significantly lower in deceased patients compared with surviving (12.1 vs. 18.7 ng/mL, P < 0.001). Vitamin D deficiency was present in 100% of the deceased patients. Multivariate logistic regression analysis revealed that age, body mass index, other risk factors, and 25(OH)D level were independent predictors of mortality.
Vitamin D deficiency was present in 84% of critical COVID-19 patients. Serum 25(OH)D was independently associated with mortality in critical patients with COVID-19. (Parra-Ortega et al., 2021)
Vitamin D Serum Levels
A study published in Nutrients determined vitamin D serum levels among acute, healed, and negative COVID-19 patients.
A multicenter real-practice study evaluated the differences of 25(OH)D3 serum levels in adults tested for SARS-CoV-2 (acute COVID-19 patients, subjects healed from COVID-19, and non-infected ones) recruited over a 6-month period (March-September 2021).
In a sample of 117 subjects, a statistically significant difference was found, with acute COVID-19 patients demonstrating the lowest levels of serum 25(OH)D3 (9.63 ± 8.70 ng/mL), significantly lower than values reported by no-COVID-19 patients (15.96 ± 5.99 ng/mL, p = 0.0091) and healed COVID-19 patients (11.52 ± 4.90 ng/mL, p > 0.05).
Male gender across the three groups displayed unfluctuating 25(OH)D3 levels, hinting at an inability to ensure adequate levels of the active vitamin D3 form (1α,25(OH)2D3).
A secondary endpoint assessed the correlation between serum 25(OH)D3 levels and pro-inflammatory cytokine interleukin-6 (IL-6) in patients with extremely low serum 25(OH)D3 levels (<1 ng/mL) and in a subset supplemented with 1α,25(OH)2D3.
Although patients with severe hypovitaminosis-D showed no significant increase in IL-6 levels, acute COVID-19 patients manifested high circulating IL-6 at admission (females = 127.64 ± 22.24 pg/mL, males = 139.28 ± 48.95 ng/mL) which dropped drastically after the administration of 1α,25(OH)2D3 (1.84 ± 0.77 pg/mL and 2.65 ± 0.92 ng/mL, respectively).
Taken together, these findings suggest that an administration of 1α,25(OH)2D3 might be helpful for treating male patients with an acute COVID-19 infection. (Gallelli et al., 2021)
Vitamin-D Status and Clinical Outcomes
A study evaluated the 25(OH)D status in COVID-19 patients admitted in Karachi, Pakistan, and associated vitamin D deficiency with primary outcomes of mortality, length of stay, intubation, and frequency of COVID-19 symptoms.
A total of 91 patients were evaluated for 25(OH)D status during their COVID-19 disease course. 25-hydroxyvitamin D levels were classified as deficient (< 10 ng/mL), insufficient (10-30 ng/mL), or sufficient (> 30 ng/mL). The study population comprised 68.1% males (N = 62). The mean age was 52.6 ± 15.7 years.
Vitamin D deficiency was significantly associated with intensive care unit (ICU) admission (RR: 3.20; P = 0.048), invasive ventilation (RR: 2.78; P = 0.043), persistent pulmonary infiltrates (RR: 7.58; P < 0.001), and death (RR: 2.98; P < 0.001) on univariate Cox regression. On multivariate Cox regression, only death (RR: 2.13; P = 0.046) and persistent pulmonary infiltrates (RR: 6.78; P = 0.009) remained significant after adjustment for confounding factors.
On Kaplan Meier curves, vitamin D deficient patients had persistent pulmonary infiltrates and a greater probability of requiring mechanical ventilation than patients with 25(OH)D ≥ 10 ng/mL. Mechanical ventilation had to be initiated early in the deficient group during the 30-day hospital stay (Chi-square: 4.565, P = 0.033).
Patients with 25(OH)D ≥ 10 ng/mL also demonstrated a higher probability of survival than those with 25(OH)D concentrations < 10 ng/mL. 25-hydroxyvitamin D deficient population had longer hospital stays and worse outcomes. (Asghar et al., 2021)
Low Levels of Vitamin D Associated with Coagulopathy
A study explored the association of vitamin D in the risk of coagulopathy in coronavirus disease-19 (COVID-19).
Clinical and laboratory findings were obtained from 50 confirmed COVID-19 patients hospitalized in Saiful Anwar General Hospital, Malang, Indonesia, from September to November 2020. Thrombotic events during hospitalization were recorded, and the ISTH disseminated intravascular coagulation (DIC) score was used to classify overt DIC.
Hypovitaminosis D was defined by serum vitamin D level <49.92 nmol/L.
Among 50 patients, 42 (84%) had hypovitaminosis D, and 6 (12%) developed thrombotic events. Vitamin D levels were lower in patients with thrombotic events (p=0.015), D-dimer >2 mg/L (p=0.006), ISTH DIC score 5 (p=0.020), admitted on ICU (p=0.002), and non-survivor groups (p=0.007).
Multivariate analysis for the risk in increased D-dimer levels showed low vitamin D as the only significant risk factor with OR 1.8 (1.2-4.4), p=0.034. Low vitamin D also increased the risk for developing overt DIC with OR. 5.4 (1.0-30.2), p=0.039.
Vitamin D level had negative correlations with ferritin (R=-0.316, p=0.044) and CRP (R=-0.530, p=0.000).
In conclusion, a low level of vitamin D was found in most hospitalized COVID-19 patients and might be associated with the development of coagulopathy. (Susianti et al., 2021)
Very Low Vitamin D Levels are a Strong Independent Predictor of Mortality
A study assessed the association between 25-hydroxyvitamin D levels and COVID-19 outcomes in hospitalized subjects with severe SARS-CoV-2 infection.
This retrospective cohort study measured serum 25-hydroxyvitamin D levels in subjects with severe COVID-19 pneumonia were measured at hospital admission, between March 17, 2020, and March 1, 2021.
Out of 2,908 patients, 571 (19.6%) had vitamin D deficiency (defined as a serum 25-hydroxyvitamin D level <12.5 ng/mL [<31.25 nmol/L]), and 1069 (36.7%) had levels between 12.5 ng/mL (31.25 nmol/L) and 20 ng/mL 850 nmol/L).
Compared to subjects without vitamin D deficiency, those with 25-hydroxyvitamin D level <12.5 ng/mL had higher rates of in-hospital mortality at 30 d (28.0 vs. 17.3%; p <0.001), global mortality (31.9 vs. 20.8%; p <0.001), mechanical ventilation requirement (23.8 vs. 17.2%; p <0.001), and significantly longer hospital stay (median [interquartile range] of 9 [6-17 d] vs. 7 [5-12 d], p <0.001).
In the unadjusted analysis, the risk of in-hospital death was greater for patients with vitamin D deficiency (HR 1.43; 95% CI, 1.20-1.70; p <0.001). After adjusting for confounders, the risk of in-hospital death within 30 d remained significantly greater in patients with vitamin D deficiency (HR 1.46; 95% CI, 1.21-1.76; p <0.001).
The risk was reduced but remained significant with 25-hydroxyvitamin D levels between 12.5 ng/mL and 20 ng/mL (HR 1.31; 95% CI 1.10-1.55, p = 0.02).
In comparison with other clinical biomarkers, vitamin D deficiency was an independent predictive marker of in-hospital mortality after adjusting for confounders.
Very low 25-hydroxyvitamin D levels measured at hospital admission were significantly associated with in-hospital mortality and are a useful prognostic biomarker in severe COVID-19 patients. (Ramirez-Sandoval et al., 2021)
Vitamin D Insufficiency in COVID-19 and Influenza A
A study reported 25-hydroxy vitamin D (25(OH)D) measurements in hospitalised people with COVID-19 and influenza A and in survivors of critical illness to test the hypotheses that vitamin D insufficiency scales with illness severity and persists in survivors.
A cross-sectional study obtained plasma from 295 hospitalised people with COVID-19 (International Severe Acute Respiratory and emerging Infections Consortium (ISARIC)/WHO Clinical Characterization Protocol for Severe Emerging Infections UK study), 93 with influenza A (Mechanisms of Severe Acute Influenza Consortium (MOSAIC) study, during the 2009-2010 H1N1 pandemic) and 139 survivors of non-selected critical illness (prior to the COVID-19 pandemic). Total 25(OH)D was measured by liquid chromatography-tandem mass spectrometry. Free 25(OH)D was measured by ELISA in COVID-19 samples. Outcome measures were the receipt of invasive mechanical ventilation (IMV) and in-hospital mortality.
Vitamin D insufficiency (total 25(OH)D 25-50 nmol/L) and deficiency (<25 nmol/L) were prevalent in COVID-19 (29.3% and 44.4%, respectively), influenza A (47.3% and 37.6%) and critical illness survivors (30.2% and 56.8%). In COVID-19 and influenza A, total 25(OH)D measured early in illness was lower in patients who received IMV (19.6 vs 31.9 nmol/L (p<0.0001) and 22.9 vs 31.1 nmol/L (p=0.0009), respectively). In COVID-19, biologically active free 25(OH)D correlated with total 25(OH)D and was lower in patients who received IMV, but was not associated with selected circulating inflammatory mediators.
Vitamin D deficiency/insufficiency was present in majority of hospitalised patients with COVID-19 or influenza A and correlated with severity and persisted in critical illness survivors at concentrations expected to disrupt bone metabolism. (Hurst et al., 2021)
Vitamin D and Zinc Status among Outpatients
A study compared the serum concentrations of 25-hydroxyvitamin D (25(OH)D) and zinc in COVID-19 outpatients with those of potentially non-infected participants. The association of clinical symptoms with vitamin D and zinc status was also examined.
A checklist and laboratory examination were applied to collect data in a cross-sectional study conducted on 53 infected outpatients with COVID-19 and 53 potentially non-infected participants.
Serum concentration of 25(OH)D were not significantly lower in patients with moderate illness (19 ± 12 ng/mL) than patients with asymptomatic or mild illness (29 ± 18 ng/mL), with a trend noted for a lower serum concentration of 25(OH)D in moderate than asymptomatic or mild illness patients (p = 0.054).
Infected patients (101 ± 18 µg/dL) showed a lower serum concentration of zinc than potentially non-infected participants (114 ± 13 µg/dL) (p = 0.01).
Patients with normal (odds ratio (OR), 0.19; p ≤ 0.001) and insufficient (OR, 0.3; p = 0.007) vitamin D status at the second to seventh days of disease had decreased OR of general symptoms compared to patients with vitamin D deficiency.
This study revealed the importance of 25(OH)D measurement to predict the progression of general and pulmonary symptoms and showed that infected patients had significantly lower zinc concentrations than potentially non-infected participants. (Golabi et al., 2021)
Serum 25(OH)D Deficiency and High D-Dimer
A study identified the risk factors for COVID-19 pneumonia and to characterized the epidemiology of the disease.
This was a prospective study of consecutive patients with SARS-CoV-2 infection and respiratory symptoms, enrolled between April 12 and April 30 of 2020. Pneumonia was diagnosed on the basis of abnormal chest CT findings. At admission, we performed a complete blood count, as well as determining serum levels of CRP, procalcitonin, D-dimer, ferritin, LDH, and 25-hydroxyvitamin D (25[OH]D). Comorbidities, body mass index (BMI), and smoking habits were noted. We also analyzed the risk factors for development of COVID-19 pneumonia.
The study evaluated 124 patients (79 males) with a mean age of 38 ± 16.6 years. Fever was observed in 67 patients (54.0%), fatigue, cough, and dyspnea being observed in 94 (75.8%), 86 (69.3%), and 37 (29.8%), respectively. Of the 124 patients, 77 (62.1%) developed pneumonia.
Common comorbidities in the patients with pneumonia were hypertension, diabetes, and cardiovascular disease. D-dimer > 0.5 µg/mL (OR = 8.6; 95% CI: 3.32 - 22.26, p < 0.001); 25(OH)D < 20 µg/dL (OR = 6.75; 95% CI: 2.81 - 16.21, p < 0.001); and age > 60 years (OR = 15.66; 95% CI: 2.02 - 121.40, p < 0.001) were variables showing significant correlation with COVID-19 pneumonia.
Serum 25(OH)D deficiency, high D-dimer levels, and advanced age are associated with a greater risk of developing COVID-19 pneumonia. (Sunnetcioglu et al., 2021)
Vitamin D Deficiency Is Associated With Higher Hospitalization Risk
A study examined whether hospitalization with COVID-19 is more prevalent in individuals with lower vitamin D levels.
The study included individuals with test results for serum 25-hydroxyvitamin D (25[OH]D) between April 1, 2020, and January 29, 2021, from 2 districts in North West England. The last 25(OH)D level in the previous 12 months was categorized as "deficient" if less than 25 nmol/L and "insufficient" if 25 to 50 nmol/L.
The study included 80 670 participants. Of these, 1808 were admitted to the hospital with COVID-19, of whom 670 died. In a primary cohort, median serum 25(OH)D in nonhospitalized participants with COVID-19 was 50.0 nmol/L (interquartile range [IQR], 34.0-66.7) vs 35.0 nmol/L (IQR, 21.0-57.0) in those admitted with COVID-19 (P < 0.005).
In a validation cohort, median serum 25(OH)D was 47.1 nmol/L (IQR, 31.8-64.7) in non-hospitalized vs 33.0 nmol/L (IQR, 19.4-54.1) in hospitalized patients. Age-, sex-, and season-adjusted odds ratios for hospital admission were 2.3 to 2.4 times higher among participants with serum 25(OH)D <50 nmol/L compared with those with normal serum 25(OH)D levels, without excess mortality risk.
Age-, sex-, and season-adjusted odds ratios for hospital admission were 2.3 to 2.4 times higher among participants with serum 25(OH)D <50 nmol/L compared with those with normal serum 25(OH)D levels, without excess mortality risk.
Vitamin D deficiency is associated with higher risk of COVID-19 hospitalization. Widespread measurement of serum 25(OH)D and treatment of insufficiency or deficiency may reduce this risk. (Jude et al., 2021)
Severe Vitamin D Deficiency
A retrospective case-control study identified differences in vitamin D status and clinical characteristics of hospitalized patients screened for SARS-CoV-2, and determined associations of vitamin D levels with increased COVID-19 risk and mortality.
A total of 222 [SARS-CoV-2 (+) N = 150 (97 males; 53 females); SARS-CoV-2 (-) N = 72 (38 males, 34 females)] out of 550 hospitalized adult patients screened for SARS-CoV-2 and admitted at King Saud University Medical City-King Khalid University Hospital (KSUMC-KKUH) in Riyadh, Saudi Arabia from May-July 2020 were included. Clinical, radiologic and serologic data, including 25(OH)D levels were analyzed.
Vitamin D deficiency (25(OH)D < 50 nmol/l) was present in 75% of all patients.
Serum 25(OH)D levels were significantly lower among SARS-CoV-2 (+) than SARS-CoV-2 (-) patients after adjusting for age, sex and body mass index (BMI) (35.8 ± 1.5 nmol/l vs. 42.5 ± 3.0 nmol/l; p = 0.037). Multivariate regression analysis revealed that significant predictors for SARS-CoV-2 include age > 60 years and pre-existing conditions (p < 0.05). Statistically significant predictors for mortality adjusted for covariates include male sex [Odds ratio, OR 3.3 (95% confidence interval, CI 1.2-9.2); p = 0.02], chronic kidney disease [OR 3.5 (95% CI 1.4-8.7); p = 0.008] and severe 25(OH)D deficiency (< 12.5 nmol/l), but at borderline significance [OR 4.9 (95% CI (0.9-25.8); p = 0.06].
In hospital settings, 25(OH)D deficiency is not associated with SARS-CoV-2 infection, but may increase risk for mortality in severely deficient cases. (Alguwaihes et al., 2021)
Vitamin D Deficiency in Critically Ill COVID-19 ARDS Patients
A study analyzed clinical and immunologic effects of vitamin D levels in patients suffering from coronavirus disease 2019 (COVID-19) induced acute respiratory distress syndrome (ARDS).
This was a single-center retrospective study in patients receiving intensive care with a confirmed SARS-CoV-2 infection and COVID-19 ARDS. 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D serum levels, pro- and anti-inflammatory cytokines and immune cell subsets were measured on admission as well as after 10-15 days. Clinical parameters were extracted from the patient data management system. Standard operating procedures included the daily administration of vitamin D|3| via enteral feeding.
A total of 39 patients with COVID-19 ARDS were eligible, of which 26 were included in this study as data on vitamin D status was available. 96% suffered from severe COVID-19 ARDS.
All patients without prior vitamin D supplementation (n = 22) had deficient serum levels of 25-hydroxyvitamin D. Vitamin D supplementation resulted in higher serum levels of 25-hydroxyvitamin D but not did not increase 1,25-dihydroxyvitamin D levels after 10-15 days.
Clinical parameters did not differ between patients with sufficient or deficient levels of 25-hydroxyvitamin D. Only circulating plasmablasts were higher in patients with 25-hydroxyvitamin D levels ≥30 ng/ml (p = 0.029). Patients with 1,25-dihydroxyvitamin D levels below 20 pg/ml required longer mechanical ventilation (p = 0.045) and had a worse acute physiology and chronic health evaluation (APACHE) II score (p = 0.048).
The vast majority of COVID-19 ARDS patients had vitamin D deficiency. 25-hydroxyvitamin D status was not related to changes in clinical course, whereas low levels of 1,25-dihydroxyvitamin D were associated with prolonged mechanical ventilation and a worse APACHE II score. (Notz et al., 2021)
A Retrospective Single-Center Analysis
A study published in the Tohoku Journal of Experimental Medicine evaluated the complications and mortality in different vitamin D status groups in COVID-19 hospitalized patients. The, Shahid Modarres Hospital, Shahid Beheshti University of Medical Sciences conducted the study.
This retrospective study was conducted on 646 laboratory-confirmed COVID-19 patients who were hospitalized in Shahid Modarres Hospital, Tehran, Iran from 16th March 2020 until 25th February 2021.
Overall, patients with vitamin D deficiency, insufficiency and sufficiency were 16.9%, 43.6% and 39.5%, respectively. The presence of comorbidity, length of hospitalization, ICU admission, and invasive mechanical ventilation requirement and overall complications were significantly more in patients with vitamin D deficiency (p-value < 0.001). 46.8% (51/109) of vitamin D deficient patients died due to the disease, whilst the mortality rate among insufficient and sufficient vitamin D groups was 29.4% (83/282) and 5.5% (14/255), respectively.
In univariate analysis, age > 60 years (odds ratio (OR) = 6.1), presence of comorbidity (OR = 10.7), insufficient vitamin D status (OR = 7.2), and deficient vitamin D status (OR = 15.1) were associated with increase in COVID-19 mortality (p-value < 0.001). Finally, the multivariate analysis adjusted for age, sex, and comorbidities indicated vitamin D deficiency as an independent risk factor for mortality (OR = 3.3, p-value = 0.002).
Vitamin D deficiency is a strong risk factor for mortality and severity of SARS-CoV-2 infection. Vitamin D supplementation may be able to prevent or improve the prognosis of COVID-19 during this pandemic. (Afaghi et al., 2021)
Increased Risk for COVID-19 in Patients with Vitamin D Deficiency
A study used the i2b2 patient's registry platform at the University of Florida Health Center to generate a count of patients using the international classification of diseases (ICD)-10 diagnosis codes for the period of October 1, 2015, through June 30, 2020. Logistic regression of the aggregates was used for the analysis.
Patients with vitamin D deficiency were 4.6 times more likely to be positive for COVID-19 (indicated by the ICD-10 diagnostic code COVID19) than patients with no deficiency (P < 0.001).
The association decreased slightly after adjusting for sex (odds ratio [OR] = 4.58; P < 0.001) and malabsorption (OR = 4.46; P < 0.001), respectively. The association decreased significantly but remained robust (P < 0.001) after adjusting for race (OR = 3.76; P < 0.001), periodontal disease status (OR = 3.64; P < 0.001), diabetes (OR = 3.28; P < 0.001), and obesity (OR = 2.27; P < 0.001), respectively.
In addition, patients with vitamin D deficiency were 5 times more likely to be infected with COVID-19 than patients with no deficiency after adjusting for age groups (OR = 5.155; P < 0.001).
Vitamin D deficiency is significantly associated with increased risk for COVID-19. (Katz et al., 2021)
Strong Correlation Between Severe Vitamin D Deficiency in Europe
A study analyzed the vitamin D European population data compiled by 2019 European Calcified Tissue Society (ECTS) statement on vitamin D status published in the European Journal of Endocrinology. For the data set to be used for analysis, only recently published data that included general adult population of both genders aged 40-65 years or wider and must have included the prevalence of vitamin D deficiency.
There were data sets from 10 countries that fitted the criteria and were analyzed. Severe vitamin D deficiency was defined as 25(OH)D less than 25 nmol/L (10 ng/dL). Pearson correlation analysis between death rate per million of population from coronavirus disease 2019 (COVID-19) and prevalence of severe vitamin D deficiency showed a strong correlation with r = 0.79, p = 0.007.
Over time, correlation strengthened, and r coefficient asymptotically increased. After adjusting for countries' age structure and per capita health expenditures, multiple linear regression analysis showed that higher prevalence of severe vitamin D deficiency is associated with increased mortality. Each 1% increase in prevalence increased deaths by 55 per million (95% confidence interval, CI 8-102), p = 0.03.
The authors recommend universal screening for vitamin D deficiency. (Pugach and Pugach, 2021)
Vitamin D Metabolites, Negative
A retrospective study investigated vitamin D status markers and vitamin D degradation products in a mixed cohort of 148 hospitalized COVID-19 patients with various clinical courses of COVID-19.
The serum concentrations of 25(OH)D|3|, 25(OH)D|2|, 24,25(OH)|2|D|3|, and 25,26(OH)|2|D|3| were determined by a validated liquid-chromatography tandem mass-spectrometry method in leftover serum samples from 148 COVID-19 patients that were admitted to the University Hospital of the Medical University of Graz between April and November 2020. Anthropometric and clinical data, as well as outcomes were obtained from the laboratory and hospital information systems.
From the 148 patients, 34 (23%) died within 30 days after admission. The frequency of fatal outcomes did not differ between males and females. Non-survivors were significantly older than survivors, had higher peak concentrations of IL-6 and CRP, and required mechanical ventilation more frequently.
The serum concentrations of all vitamin D metabolites and the vitamin D metabolite ratio (VMR) did not differ significantly between survivors and non-survivors. Additionally, the need for respiratory support was unrelated to the serum concentrations of 25(OH)D vitamin D and the two vitamin D catabolites, as well as the VMR. (4)
The results do not support a relevant role of vitamin D for the course and outcome of COVID-19. (Zelzer et al., 2021)
Vitamin D Deficiency, A Case Series
This study is a case series from confirmed cases of COVID-19 in Bethesda Hospital Yogyakarta Indonesia. The data of clinical symptoms, signs and laboratory examinations were obtained from the electronic medical records. The vitamin D status was measured by Enzyme-Linked Fluorescent Assay (ELFA) method.
The data were obtained from 10 participants consisting of 50% male and 50% female. The mean age was 49.6 years. The prevalence of vitamin D deficiency in this study was 90% (vitamin D levels < 20 ng/mL) and 10% of insufficiency (vitamin D levels < 30 ng/mL).
Patients in this study had various symptoms such as fatigue (60%), fever (50%), dry cough (40%), non-specific headache (10%), and diarrhea (10%); have no symptoms (20%); and also had the various chronic diseases as comorbidity such as hypertension (40%), diabetes (10%), COPD (10%), and post stroke (10%).
All of the COVID-19 patients in this study had hypovitaminosis D. The prevalence of vitamin D deficiency in this case series is 90% and only 1 patient (10%) had vitamin D insufficiency. (Pinzon et al., 2020)
Low 25-Hydroxyvitamin D Levels on Admission
This was a prospective observational study of SARS-CoV2 positive critically ill patients treated in a multidisciplinary ICU. Thirty (30) Greek patients were included, in whom 25(OH)D was measured on ICU admission.
Eighty (80%) percent of patients had vitamin D deficiency, and the remaining insufficiency. Based on 25(OH)D levels, patients were stratified in two groups: higher and lower than the median value of the cohort (15.2 ng/mL). The two groups did not differ in their demographic or clinical characteristics.
All patients who died within 28 days belonged to the low vitamin D group. Survival analysis showed that the low vitamin D group had a higher 28-day survival absence probability (log-rank test, p = 0.01). Critically ill COVID-19 patients who died in the ICU within 28 days appeared to have lower ICU admission 25(OH)D levels compared to survivors. When the cohort was divided at the median 25(OH)D value, the low vitamin D group had an increased risk of 28-day mortality.
Low 25-hydroxyvitamin D levels on admission to the intensive care unit may predispose COVID-19 pneumonia patients to a higher 28-day mortality risk. (Vassiliou et al., 2020)
Vitamin D Deficiency as a Predictor of Poor Prognosis
A study analyzed vitamin D levels in patients with acute respiratory failure due to COVID-19 and to assess any correlations with disease severity and prognosis.
In this retrospective, observational study, we analysed demographic, clinical and laboratory data of 42 patients with acute respiratory failure due to COVID-19, treated in Respiratory Intermediate Care Unit (RICU) of the Policlinic of Bari from March, 11 to April 30, 2020.
Eighty one percent of patients had hypovitaminosis D. Based on vitamin D levels, the population was stratified into four groups: no hypovitaminosis D, insufficiency, moderate deficiency, and severe deficiency. No differences regarding demographic and clinical characteristics were found. A survival analysis highlighted that, after 10 days of hospitalization, severe vitamin D deficiency patients had a 50% mortality probability, while those with vitamin D ≥ 10 ng/mL had a 5% mortality risk (p = 0.019).
High prevalence of hypovitaminosis D was found in COVID-19 patients with acute respiratory failure, treated in a RICU. Patients with severe vitamin D deficiency had a significantly higher mortality risk. Severe vitamin D deficiency may be a marker of poor prognosis in these patients, suggesting that adjunctive treatment might improve disease outcomes. (Carpagnano et al., 2020)
Vitamin D and Seroconversion in UK Healthcare Workers
A study of vitamin D status and seroconversion for COVID-19 in UK healthcare workers found that NHS staff with vitamin D deficiency were more likely to have developed COVID-19, with staff from BAME ethnicity being the most vitamin D deficient. (Faniyi et al., 2020)
Vitamin D Deficiency Is Inversely Associated in Chinese People
A study investigated whether vitamin D deficiency is associated with COVID-19 incidence and disease severity in Chinese people.
In a cross-sectional study we retrospectively analyzed 335 COVID-19 patients (median: 56.0; IQR: 43.0-64.0 y) who were admitted to the Wuhan Tongji Hospital between 27 February and 21 March 2020. We also included an age- and sex-matched population of 560 individuals (median: 55; IQR: 49.0-60.0 y) who underwent the physical examination program. Their serum 25-hydroxyvitamin D [25(OH)D] concentrations were measured during the same period from 2018-2019. Serum 25(OH)D concentrations were measured for all COVID-19 patients on admission. Severity of COVID-19 was determined based on the level of respiratory involvement. A general linear model with adjustment for covariates was used to compare 25(OH)D concentrations between the COVID-19 and 2018-2019 control groups. Adjusted ORs with 95% CIs for associations between vitamin D status and COVID-19 severity were estimated via multivariable logistic regression.
In the general linear model adjusted for age, sex, comorbidities, and BMI, serum 25(OH)D concentrations were significantly lower among COVID-19 patients than the 2018-2019 controls [ln transformed values of 3.32 ± 0.04 vs. 3.46 ± 0.022 ln (nmol/L), P = 0.014]. Multivariable logistic regression showed that male sex (OR: 2.26; 95% CI: 1.06, 4.82), advanced age (≥65 y) (OR: 4.93; 95% CI: 1.44, 16.9), and vitamin D deficiency (<30 nmol/L) (OR: 2.72; 95% CI: 1.23, 6.01) were significantly associated with COVID-19 severity (all P < 0.05).
These findings suggested that vitamin D deficiency impacts COVID-19 hospitalization and severity in the Chinese population. (Luo et al., 2020)
Afaghi, S, et al. (2021), ‘Prevalence and Clinical Outcomes of Vitamin D Deficiency in COVID-19 Hospitalized Patients: A Retrospective Single-Center Analysis.’, Tohoku J Exp Med, 255 (2), 127-34. PubMed: 34645738
Alguwaihes, AM, et al. (2021), ‘Severe vitamin D deficiency is not related to SARS-CoV-2 infection but may increase mortality risk in hospitalized adults: a retrospective case-control study in an Arab Gulf country.’, Aging Clin Exp Res, 33 (5), 1415-22. PubMed: 33788172
AlKhafaji, D, et al. (2022), ‘The Impact of Vitamin D Level on the Severity and Outcome of Hospitalized Patients with COVID-19 Disease.’, Int J Gen Med, 15 343-52. PubMed: 35027842
Asghar, MS, et al. (2021), ‘Evaluation of Vitamin-D Status and Its Association with Clinical Outcomes Among COVID-19 Patients in Pakistan.’, Am J Trop Med Hyg, tpmd210577. PubMed: 34758449
Carpagnano, GE, et al. (2020), ‘Vitamin D deficiency as a predictor of poor prognosis in patients with acute respiratory failure due to COVID-19.’, J Endocrinol Invest, PubMed: 32772324
Dror, AA, et al. (2022), ‘Pre-infection 25-hydroxyvitamin D3 levels and association with severity of COVID-19 illness.’, PLoS One, 17 (2), e0263069. PubMed: 35113901
Faniyi, AA, et al. (2020), ‘Vitamin D status and seroconversion for COVID-19 in UK healthcare workers.’, Eur Respir J, PubMed: 33303541
Gallelli, L, et al. (2021), ‘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, 13 (11), 3932. PubMed: 34836187
Golabi, S, et al. (2021), ‘The Association between Vitamin D and Zinc Status and the Progression of Clinical Symptoms among Outpatients Infected with SARS-CoV-2 and Potentially Non-Infected Participants: A Cross-Sectional Study.’, Nutrients, 13 (10), PubMed: 34684369
Hurst, EA, et al. (2021), ‘Vitamin D insufficiency in COVID-19 and influenza A, and critical illness survivors: a cross-sectional study.’, BMJ Open, 11 (10), e055435. PubMed: 34686560
Israel, A, et al. (2022), ‘Vitamin D deficiency is associated with higher risks for SARS-CoV-2 infection and COVID-19 severity: a retrospective case-control study.’, Intern Emerg Med, PubMed: 35000118
Jude, EB, et al. (2021), ‘Vitamin D Deficiency Is Associated With Higher Hospitalization Risk From COVID-19: A Retrospective Case-control Study.’, J Clin Endocrinol Metab, 106 (11), e4708-15. PubMed: 34139758
Katz, J, S Yue, and W Xue (2021), ‘Increased risk for COVID-19 in patients with vitamin D deficiency.’, Nutrition, 84 111106. PubMed: 33418230
Luo, X, et al. (2020), ‘Vitamin D Deficiency Is Inversely Associated with COVID-19 Incidence and Disease Severity in Chinese People.’, J Nutr, PubMed: 33188401
Notz, Q, et al. (2021), ‘Vitamin D deficiency in critically ill COVID-19 ARDS patients.’, Clin Nutr, PubMed: 33745749
Parra-Ortega, I, et al. (2021), ‘25-Hydroxyvitamin D level is associated with mortality in patients with critical COVID-19: a prospective observational study in Mexico City.’, Nutr Res Pract, 15 (Suppl 1), S32-40. PubMed: 34909131
Pinzon, RT, Angela, and AW Pradana (2020), ‘Vitamin D deficiency among patients with COVID-19: case series and recent literature review.’, Trop Med Health, 48 (1), 102. PubMed: 33342439
Pugach, IZ and S Pugach (2021), ‘Strong correlation between prevalence of severe vitamin D deficiency and population mortality rate from COVID-19 in Europe.’, Wien Klin Wochenschr, PubMed: 33721102
Ramirez-Sandoval, JC, et al. (2021), ‘Very Low Vitamin D Levels are a Strong Independent Predictor of Mortality in Hospitalized Patients with Severe COVID-19.’, Arch Med Res, PubMed: 34711432
Ranjbar, M, et al. (2021), ‘Serum level of Vitamin D is associated with COVID-19 mortality rate in hospitalized patients.’, J Res Med Sci, 26 112. PubMed: 35126575
Seal, KH, et al. (2022), ‘Association of Vitamin D Status and COVID-19-Related Hospitalization and Mortality.’, J Gen Intern Med, PubMed: 34981368
Sunnetcioglu, A, et al. (2021), ‘Serum 25(OH)D Deficiency and High D-Dimer Levels are Associated with COVID-19 Pneumonia.’, Clin Lab, 67 (7), PubMed: 34258973
Susianti, H, et al. (2021), ‘Low levels of vitamin D were associated with coagulopathy among hospitalized coronavirus disease-19 (COVID-19) patients: A single-centered study in Indonesia.’, J Med Biochem, 40 (4), 341-50. PubMed: 34744508
Vassiliou, AG, et al. (2020), ‘Low 25-Hydroxyvitamin D Levels on Admission to the Intensive Care Unit May Predispose COVID-19 Pneumonia Patients to a Higher 28-Day Mortality Risk: A Pilot Study on a Greek ICU Cohort.’, Nutrients, 12 PubMed: 33316914
Zelzer, S, et al. (2021), ‘Vitamin D Metabolites and Clinical Outcome in Hospitalized COVID-19 Patients.’, Nutrients, 13 (7), PubMed: 34206219