Reference
Karonova TL, Golovatyuk KA, Kudryavtsev IV, et al. Effect of cholecalciferol supplementation on the clinical features and inflammatory markers in hospitalized COVID-19 patients: a randomized, open-label, single-center study. Nutrients. 2022;14(13):2602.
Study Objective
To evaluate the impact vitamin D3 supplementation has on clinical features and inflammatory markers in Covid-19 patients
Key Takeaway
Supplementing with 10,000 IU/day of vitamin D3 in patients with vitamin D insufficiency or deficiency improved C-reactive protein (CRP) and white blood cell counts compared to controls.
Design
Randomized, single-center open-label study
Participants
The study included 129 hospitalized patients in St Petersburg, Russia, aged 18 to 75 years (49% female, 51% male), with Covid-19 diagnosed by polymerase chain reaction (PCR) and/or chest computed tomography (CT).
Excluded from the study were patients taking 1,000 IU vitamin D or higher, those for whom taking vitamin D was contraindicated, and patients with estimated glomerular filtration rate (eGFR) <40 mL/min/1.73 m2, gastrointestinal and liver diseases, granulomatous diseases, cancer (less than 5 years), immunodeficiency, and drug or alcohol addiction.
Intervention
Vitamin D3 10,000 IU/day for 9 days or no supplementation
Study Parameters Assessed
Investigators assessed the following parameters:
- Changes in serum 25(OH)D levels
- Complete blood count (CBC)
- C-reactive protein (CRP)
- B cell subsets on the 9th day of hospitalization compared to 1st day
- Disease severity
- Oxygen supplementation
- Intensive care unit (ICU) admission rate
- Clinical outcomes
- Duration of hospitalization
Primary Outcomes
Investigators evaluated the following measurements:
- Changes in serum 25(OH)D levels
- CBC
- CRP
- B cell subsets on the 9th day of hospitalization compared to 1st day
Key Findings
Changes in serum 25(OH)D levels
At day 9, significantly fewer patients in the intervention group had vitamin D deficiency (P<0.01).
After 9 days, supplementation with vitamin D3 increased the median 25(OH)D level from 16.4 ng/mL to 22.8 ng/mL (P<0.001). In contrast, the control group saw a median decrease of 2.6 ng/mL in their 25(OH)D levels (13.9 ng/mL to 10.6 ng/mL), or –18.2% over this same time period.
Additionally, after supplementation, the median serum 25(OH)D level in the treatment group was significantly higher compared to the control group: 22.8 ng/mL vs 10.6 ng/mL, respectively (P<0.001)
CBC
After 9 days of supplementation with vitamin D, neutrophils and lymphocyte counts were significantly higher compared to controls.
The median neutrophil count in the intervention group was 8.6 x 109/L compared to 6.4 x 109/L in the control group (P=0.04).
The median lymphocyte count in the intervention group was 1.8 x 109/L compared to 1.58 x 109/L in the control group (P=0.02).
The median neutrophil-to-lymphocyte ratio (NLR), however, was not significantly different between the 2 groups: 4.5 in the treatment group vs 4.4 in the control group (P=0.71).
CRP
After 9 days of supplementation with vitamin D, CRP was significantly lower compared to controls (P=0.02). Additionally, CRP was negatively associated with CRP levels (r= –0.28, P=0.02).
The median CRP in the intervention group was 2 mg/L vs 3 ng/mL in the control group (P=0.02).
B cell subsets
On the 9th day of hospitalization compared to the 1st day:
- Frequency of CD38++CD27 transitional cells was significantly lower in the treatment group compared to the control group (1.43% vs 2.74%, respectively; P=0.006).
- Frequency of mature naive CD27−CD38+ B cells was significantly lower in the treatment group compared to the control group (57.57% vs 67.03%, respectively; P=0.02)
- CD27−CD38− double-negative (DN) B cells were significantly higher in the treatment group compared to the control group (6.21% vs 4.19%, respectively; P=0.02)
Bed days
In the intervention group, there was a negative association between serum 25(OH)D on the 9th day and the number of bed days (r= −0.23, P=0.006); however, there were no significant differences between the groups in the number of bed days or the percentage of patients who were discharged (P=0.87 and P=0.93, respectively).
Transparency
The other authors declared no conflict of interest; however, Bio-Tech Pharmacal, Inc (Fayetteville, AR) funds the Sunlight, Nutrition and Health Research Center, which employs the co-author, William A. Grant.
Practice Implications & Limitations
The pandemic caused by the severe acute respiratory syndrome (SARS) associated with the coronavirus (SARS-CoV) and discovered in 2019 (Covid-19) ushered in a global search for risk factors and ways to prevent and treat the infection and its sequelae.
Studies have consistently shown an inverse correlation between low serum levels of vitamin D and Covid-19 severity and mortality risk.1 They’ve also shown an inverse association with Covid-19 positivity rates. In a large, retrospective, observational analysis of 191,779 patients whose specimens were processed by Quest Diagnostics, each 1 ng/mL increase in serum 25(OH)D was associated with an unadjusted odds ratio of 0.97 (95% CI, 0.977–0.980) for a positive SARS-CoV-2 PCR test result. The decrease in positivity rate associated with serum 25(OH)D plateaued at 55 ng/mL.2
While the current study showed improvement in laboratory markers, the lack of significant improvement in clinical outcomes may be due to (1) providing too low of a dose or (2) using the wrong form of vitamin D.
The current study achieved a mean serum 25(OH)D of 22.8 ng/mL in the intervention group; however, that level may be too low to achieve clinical benefit.
Additionally, receiving vitamin D3 was associated with a 2.14 times lower risk of dying compared to not receiving vitamin D3.
A prior, prospective study gave vitamin D3 to 95 hospitalized Covid patients for up to 14 days.3 All patients in the treatment group had serum 25(0H)D levels <30 ng/mL at baseline. The researchers then developed an acute bolus treatment protocol that customized the dose and duration of vitamin D supplementation to increase serum 25(OH)D levels >30 ng/mL. The total vitamin D3 received during the treatment period varied from 224,000 IU to 320,000 IU.
Compared to those with serum 25(OH)D > 30 ng/mL, having serum 25(OH)D <30 ng/mL was associated with a 1.9 times greater risk of staying in the hospital for more than 8 days (P=0.02). Additionally, receiving vitamin D3 was associated with a 2.14 times lower risk of dying compared to not receiving vitamin D3 (P=0.03, 95% CI: 1.0585 to 4.3327).
The form of vitamin D may also be an important consideration. In acute hospital settings, research may eventually confirm that administering calcifediol (vitamin D2) instead of cholecalciferol (vitamin D3) is superior. Vitamin D2 increases serum 25(OH)D faster than vitamin D3. In one pharmacokinetic study involving 35 healthy women aged 50 to 70 years, serum 25(OH)D was 28% higher after the 1st dose of vitamin D2 compared to vitamin D3 and 123% higher after 15 weeks.4
Vitamin D2 was evaluated in Covid patients in a retrospective, multicenter cohort study. Oral vitamin D2 (532 mcg) was administered upon hospital admission, then 266 mcg on days 3 and 7, then 266 mcg weekly until discharge or ICU admission. A total of 73 patients (mean age 69 years, 53% male) received vitamin D2. After 30 days, the risk of dying was significantly lower for those who took vitamin D2 (OR 0.22 [95% CI, 0.08–0.61], P<0.01) compared to patients who did not receive vitamin D2.5 Unfortunately, serum vitamin concentrations were not available at baseline or any time period during this study. But based on previous studies, the authors speculate that the dose they administered was sufficient to raise serum 25(OH)D levels above 30 to 40 ng/mL from the 3rd day of treatment.
Positive clinical outcomes have been obtained by supplementing Covid-19 patients with vitamin D (as D2 or D3). While it appears that a serum concentration above 30 ng/mL may be the threshold for obtaining clinical results, the optimal form, dosing regime, and target serum concentration for the best outcomes are still unknown.
