Home Browse The effect of Vitamin D levels on the course of COVID-19 in hospitalized...
ALL Metrics
-
Views
Get PDF
Get XML
Cite
Export
Track
▬
✚
Research Article

The effect of Vitamin D levels on the course of COVID-19 in hospitalized patients – a 1-year prospective cohort study

[version 1; peer review: 1 approved with reservations]
Darko Siuka1, Rajko Saletinger2,3, Jure Uršič1, [...] Kristina Jevnikar4, Rado Janša1,2, David Štubljar
https://orcid.org/0000-0002-9653-9830
5, Joško Osredkar
https://orcid.org/0000-0002-1839-2415
6,7
Darko Siuka1, Rajko Saletinger2,3, [...] Jure Uršič1, Kristina Jevnikar4, Rado Janša1,2, David Štubljar
https://orcid.org/0000-0002-9653-9830
5, Joško Osredkar
https://orcid.org/0000-0002-1839-2415
6,7
PUBLISHED 09 Mar 2023
Author details Author details
OPEN PEER REVIEW
REVIEWER STATUS

This article is included in the Emerging Diseases and Outbreaks gateway.

Abstract

Background: The aim of the current study was to assess the patients with COVID-19 and the impact of vitamin D supplementation on the course of COVID-19. 
Methods: This prospective cohort study included patients hospitalized due to COVID-19 between December 2020 and December 2021. Patients' demographic, clinical, and laboratory parameters were analysed.  
Results: 301 participants were enrolled in the study. 46 (15,3%) had moderate, and 162 (53,8%) had severe COVID-19. 14 (4,7%) patients died, and 30 (10,0%) were admitted to the ICU due to disease worsening. The majority needed oxygen therapy (n=224; 74,4%). Average vitamin 25(OH)D3 levels were below optimal at the admittance, and vitamin D deficiency was detected in 205 individuals. More male patients were suffering from vitamin D deficiency. Patients with the more severe disease showed lower levels of vitamin 25(OH)D3 in their blood. The most severe group of patients had more symptoms that lasted significantly longer with progressing disease severity. This group of patients also suffered from more deaths, ICU admissions, and treatments with dexamethasone, remdesivir, and oxygen. 
Conclusion: Patients with the severe course of COVID-19 were shown to have increased inflammatory parameters, increased mortality, and higher incidence of vitamin D deficiency. The results suggest that the vitamin D deficiency might represent a significant risk factor for a severe course of COVID-19.

Keywords

vitamin D; COVID-19; severity; supplementation

Corresponding author: Joško Osredkar
Competing interests: No competing interests were disclosed.
Grant information: The author(s) declared that no grants were involved in supporting this work.
Copyright:  © 2023 Siuka D et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
How to cite: Siuka D, Saletinger R, Uršič J et al. The effect of Vitamin D levels on the course of COVID-19 in hospitalized patients – a 1-year prospective cohort study [version 1; peer review: 1 approved with reservations]. F1000Research 2023, 12:254 (https://doi.org/10.12688/f1000research.131730.1) First published: 09 Mar 2023, 12:254 (https://doi.org/10.12688/f1000research.131730.1) Latest published: 09 Mar 2023, 12:254 (https://doi.org/10.12688/f1000research.131730.1)

Introduction

Past pandemic waves of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) led to many critical cases and, consequently, deaths of high-risk patients. However, previous studies have shown fluctuations in coronavirus disease 2019 (COVID-19) severity throughout the year, especially during different seasons. Notably, seasons also play a role in immunity variation demonstrated by significant differences in the circulating immune cells such as lymphocytes and neutrophils.1,2 Moreover, studies have shown a strong correlation between low levels of serum vitamin D3 (25-hydroxyvitamin D3, 25(OH)D3) and the incidence of COVID-19,1,2 which coincides with most viral respiratory infections occurring during the winter season.3 Previous studies have shown a positive correlation between COVID-19 severity and vitamin D deficiency. Furthermore, vitamin D supplementation was shown to improve the clinical outcome of COVID-19 patients.4,5 Vitamin D deficiency is a global health problem as many healthy individuals have suboptimal serum vitamin D levels.1–3 Vitamin D has an immunomodulatory role as it decreases the proliferation of Th1 cells and stimulates the proliferation of Th2 cells, enables the secretion of anti-inflammatory cytokines, and thus lowers the production of pro-inflammatory cytokines.6 In addition to immunomodulatory and anti-inflammatory effects, vitamin D can also reduce the risk of respiratory tract infections, especially viral infections, such as COVID-19.7–17 Several studies confirmed the beneficial role of vitamin D in reducing the risk of susceptibility to acute respiratory infection, a protective effect of vitamin D against viral and bacterial respiratory pathogens in healthy, hospitalized, or critically ill patients.8,18–23 Moreover, a positive correlation was found between low levels of vitamin 25(OH)D3 and worse clinical outcomes (increased hospital stay, readmission to hospital, severity, sepsis, and mortality).22–37 Individuals with lower vitamin 25(OH)D3 levels were shown to have an increased risk of SARS-CoV-2 infection, admission to intensive care unit (ICUs), and increased mortality.38–40

Based on these studies, vitamin D supplementation during the period of respiratory infections and in individuals with COVID-19 was recommended by our group in October 2020, after the first wave of COVID-19. The ad hoc Slovenian recommendations for supplementation were as follows: for the healthy adult population, 800 IE to 2000 IE/day from October to the end of April; for high-risk individuals for vitamin D deficiency and respiratory infections 1000 to 2000 IE/day or 10 000 to 14 000/week. This group included patients with chronic diseases, individuals 70 years of age and older, individuals who live with COVID-19 patients in the same household, individuals with high-risk contact with COVID-19 patients, and healthcare workers. Pregnant women were recommended to take of 1500 IE to 2000 IE/day. Newly diagnosed COVID-19 patients were recommended a loading dose of 14 000 IE/day for four days followed by 2000 IE/day onwards. For hospitalized COVID-19 patients, the measurement of 25(OH)D3 was recommended and supplementation according to the measured serum levels was advised.41

Prior to the publication of Slovenian recommendations, many studies were published, where factors that contributed to low vitamin 25(OH)D3 levels and deficiency, including higher age, positive smoking status, obesity with higher body mass index (BMI), lack of sun exposure, and the presence of chronic illnesses (diabetes, malignancies, high blood pressure, gastrointestinal disorders, etc.) were identified. Most people with these risk factors have been shown to be at an increased risk regarding both severity of the disease and mortality from COVID-19.42 Thus, it was hypothesized that optimal levels of vitamin 25(OH)D3 in the early phase of SARS-CoV-2 infection could prevent progression to severe or critical COVID-19 and reduce mortality.3,43 Besides the recommendations, considerable public awareness campaigns and educational interventions have been conducted with the objective to increase individual vitamin D supplementation in Slovenia, especially during the second COVID-19 lockdown in December 2020.44 Therefore, the purpose of our study was to assess the severity of COVID-19 patients, who were admitted to our department and determine the impact of Vitamin D supplementation at the admittance on the clinical course of COVID-19.

Methods

We designed a prospective cohort study of COVID-19 patients, hospitalised in the COVID-19 unit of the University medical centre Ljubljana between December 2020 and December 2021. The study was approved by the Slovenian Medical Ethics Committee (Protocol ID: 0120-60/2021/5) and adhered to the tenets of the Declaration of Helsinki. Written informed consent was obtained from all participants enrolled in the study.

Study participants

Consecutive patients aged 18 or older, in the acute phase of COVID-19, with a PCR confirmed SARS-CoV-2 were included in the study, and their clinical charts were prospectively reviewed to collect the following relevant demographic, clinical, and laboratory parameters: age, sex, presence of comorbidities (diabetes, arterial hypertension, hyperlipidemia, coronary artery disease, history of stroke), history of smoking, alcohol consumption, the presence of COVID-19 related symptoms (fever, chest pain, cough, anosmia, dyspnoea, diarrhoea, and headache), time from the symptom’s onset or positive PCR to hospitalisation, laboratory parameters, COVID-19 related treatment and outcome. All patients underwent chest X-ray imaging in order to confirm the scale of COVID-19 infection and exclude or confirm COVID-19 associated pneumonia. Patients were divided into four groups based on the COVID-19 disease severity classification: (1) asymptomatic (positive PCR, no symptoms), (2) mild (the presence of symptoms but no shortness of breath, dyspnoea, or abnormal chest imaging), (3) moderate (evidence of lower respiratory disease during clinical assessment or imaging and who have an oxygen saturation (SpO2) ≥94% on room air at sea level) and (4) severe disease (SpO2 <94% on room air at sea level, a ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2) <300 mm Hg, respiratory frequency >30 breaths/min, or lung infiltrates >50%).

Laboratory parameters

COVID-19 infection was determined by RT-PCR during this initial visit. A nasopharyngeal swab specimen for the identification of SARS-CoV-2 was taken and sent to Institute of Microbiology and Immunology to confirm the infection. The patients’ blood pressure was measured at admission and 72 hours after admission. Blood samples were collected on a day of admission to the hospital and transported to the laboratory at the University Medical Centre in Ljubljana, where they were stored at minus 80 °C until analysis. Determination of inflammatory biomarkers, C-reactive-protein (CRP), interleukin-6 (IL-6), procalcitonin (PCT), D-dimer and 25(OH)D3 have been carried out according to a routine protocol using standard laboratory procedures. Patients received COVID-19 specific treatment consisting of oxygen supplementation, dexamethasone, and/or remdesivir according to the treatment guidelines.

Determination of serum vitamin D (25(OH)D3) concentration

Serum 25(OH)D3 concentration was measured in human serum with the chemiluminescence immunoassay vitamin D total (25-hydroxy-vitamin D). Vitamin D status was assigned with consideration of serum 25(OH)D3 concentration according to the literature: Deficient below 30 nmol/L, insufficient below 50 nmol/L, non-optimal between 50-75 nmol/L and optimal >75 nmol/L.43,45

Statistical analysis

The statistical analysis was performed using SPSS 21.0 (IBM Inc., Chicago, USA). Normally distributed variables were expressed as arithmetic mean and standard deviation, and One-Way ANOVA test was used for comparisons between variables. In case of abnormally distributed variables the differences between continuous variables were analysed by the nonparametric Mann-Whitney test. Binary logistic regression model was used to identify risk factors for moderate-to-severe COVID-19 course of the disease. Statistical significance for all tests was determined as p-value below 0.05.

Results

Overall, 301 participants were included in the analysis. The baseline demographic and clinical characteristics of patients are presented in Table 1. There was a similar distribution of female and male patients. The average age was 65 years. Laboratory parameters showed systemic inflammation with increased proinflammatory factors such as CRP, PCT, IL-6. Most patients (77%) had COVID-19 pneumonia detected by chest X-ray imaging. One case of acute respiratory insufficiency (ARI) was determined. 46 (15,3%) patients had moderate, and 162 (53,8%) patients had a severe course of COVID-19. Most patients were admitted to the hospital during winter season. 14 (4,7%) patients died during the follow-up, 30 (10,0%) were admitted to the ICU due to the disease worsening. A vast majority needed oxygen supplementation (n=224; 74,4%).

Table 1. Basic demographic and clinical characteristics.

N=301
Age [years]64,8±14,7
Sex
m/f165/136
Duration of symptoms [days]7,8±5,3
Systolic pressure at admission [mmHg]126,3±19,0
Diastolic pressure at admission [mmHg]74,8±11,6
Systolic pressure after 72h [mmHg]132,0±19,0
Diastolic pressure after 72h [mmHg]74,6±11,4
Laboratory parameters
HbA1c [%]6,6±1,8
Glucose [mmol/L]7,0±3,4
LDH [μkat/L]5,0±2,2
Ferritin [μg/L]864,6±748,9
CRP [mg/L]70,0±62,4
Procalcitonin [μg/L]0,4±3,6
Leucocytes [109/L]7,3±3,7
RDW [%]16,2±25,4
Thrombocytes [109/L]236,2±116,4
Lymphocytes [109/L]1,4±2,4
D-dimer [μg/L]1869,5±3555,9
IL-6 [ng/L]47,4±48,7
25-OH-D3 [nmol/L]63,4±33,2
Season
Jan-Feb96 (31,9%)
Mar-Apr61 (20,3%)
May-Jun19 (6,3%)
Jul-Aug41 (13,6%)
Sep-Oct60 (19,9%)
Nov-Dec22 (7,3%)
D3 deficiency205 (68,1%)
D3 deficiency level
<30 nmol/L deficient45 (15,0%)
30-50 nmol/L insufficient73 (24,3%)
50-75 nmol/L non-optimal87 (28,9%)
>75 nmol/L sufficient96 (31,9%)
Diabetes69 (22,9%)
Hyperlipidaemia95 (31,6%)
Coronary artery disease/stroke58 (19,3%)
Uncontrolled hypertension10 (3,3%)
Hypertension161 (53,5%)
ACEi103 (34,2%)
ACT41 (13,6%)
AAT51 (16,9)
Smoking22 (7,3%)
Alcohol1 (0,3%)
Diagnosis
ARI1 (0,3%)
SARS-CoV-2 with pneumonia (X-ray)233 (77,4%)
SARS-CoV-267 (22,3%)
COVID-19 severity
Asymptomatic37 (12,3%)
Mild55 (18,3%)
Moderate46 (15,3%)
Severe162 (53,8%)
SYMPTOMS
Fever227 (75,4%)
Chest pain78 (25,9%)
Cough196 (62,1%)
Anosmia/ageusia31 (10,3%)
Dyspnoea166 (55,1%)
Diarrhea52 (17,3%)
Headache42 (14,0%)
DVT/PE24 (8,0%)
Death14 (4,7%)
ICU admission30 (10,0%)
Dexamethasone203 (67,4%)
Remdesivir59 (19,6%)
Antibiotic71 (23,6%)
Oxygen224 (74,4%)

DVT, deep vein thrombosis; PE, pulmonary embolism; LDH, lactate dehydrogenase; CRP, C reactive protein, RDW, red cell distribution width.

Average vitamin 25(OH)D3 levels were below optimal, and vitamin D deficiency and insufficiency was detected in 205 (68.1%) individuals. Approximately one third of patients had optimal 25(OH)D3 levels above 75 nmol/L. Serum vitamin 25(OH)D3 levels were significantly lower in winter months (November-April) (p<0.001) (Figure 1). Higher levels of serum vitamin 25(OH)D3 were present in the summer months (Figure 2).

83696b14-f1a2-42fa-883f-97d17367e1dd_figure1.gif

Figure 1. The levels of vitamin 25(OH)D3 throughout the year.

83696b14-f1a2-42fa-883f-97d17367e1dd_figure2.gif

Figure 2. The levels of vitamin 25(OH)D3 between the summer and winter season.

Patients were divided into four groups based on their serum vitamin 25(OH)D3-deficient, insufficicient, sufficient and optimal. The difference is clinical characteristics between the groups are presented in Table 2. Vitamin D deficiency was more common in males. A shorter duration of symptoms before hospitalisation was seen in the most deficient group. Fever and cough were more frequent with the optimal group of patients. In addition, severe course of COVID-19 was more common in groups with higher levels of serum vitamin 25(OH)D3 Group of patients with optimal vitamin 25(OH)D3 levels have experienced more frequent pneumonia so they needed dexamethasone and oxygen therapy.

Table 2. Differences in clinical characteristics based on the level of 25(OH)D3 deficiency.

Vitamin 25(OH)D3 deficiency level
<30 nmol/L deficient (n=45)30-50 nmol/L insufficient (n=73)50-75 nmol/L non-optimal (n=87)>75 nmol/L sufficient (n=95)p-value
Age68,22±15,563,4±14,263,3±13,765,7±15,40,224
Sex0,176
m/f25/2043/3053/3444/52
Duration of symptoms6,2±±5,97,0±4,38,8±5,98,3±4,90,020
Systolic at admission128,5±23,1127,0±18,5127,8±17,3123,2±18,80,324
Diastolic at admission75,3±11,074,7±10,775,1±10,774,3±13,40,962
Systolic after 72h135,0±17,1132,3±20,2132,7±18,7129,8±19,20,519
Diastolic after 72h74,9±11,374,0±12,874,4±11,275,1±10,60,937
BLOOD TESTS
HbA1c6,6±1,96,9±2,36,8±1,76,1±1,10,060
Glucose7,0±3,17,6±4,97,2±3,06,4±2,30,179
LDH4,1±±1,25,0±2,74,9±2,05,5±2,10,008
Ferritin627,4±544,0861,3±697,91026,6±911,3837,8±686,50,047
CRP55,5±59,272,9±68,169,0±60,475,6±60,90,374
Procalcitonin0,19±0,481,03±7,360,18±0,530,15±0,340,377
Leucocytes7,8±3,47,5±4,07,7±4,36,7±2,70,316
RDW14,7±1,521,3±48,414,2±1,214,1±0,90,437
Thrombocytes249,6±99,8237,2±119,0228,9±115,3235,6±123,80,838
Lymphocytes1,3±0,71,3±1,21,7±4,01,2±1,60,546
D-dimer2332,3±2393,42015,7±3342,31450,1±2318,31911,3±4870,70,592
IL-664,4±51,042,7±56,248,4±48,133,2±36,90,449
25-OH-D321,7±6,240,4±6,062,9±7,8101,0±26,7<0,001
Season0,259
Jan-Feb20 (44,4%)26 (35,6%)26 (29,9%)24 (25,3%)
Mar-Apr11 (24,4%)14 (19,2%)19 (21,8%)17 (17,9%)
May-Jun2 (4,4%)4 (5,5%)7 (8,0%)6 (6,3%)
Jul-Aug3 (6,7%)10 (13,7%)10 (11,5%)18 (18,9%)
Sep-Oct6 (13,3%)9 (12,3%)21 (24,1%)24 (25,3%)
Nov-Dec3 (6,7%)9 (12,3%)4 (4,6%)6 (6,3%)
Diabetes13 (28,9%)21 (28,8%)17 (19,5%)18 (18,9%)0,291
Hyperlipidaemia20 (44,4%)23 (31,5%)23 (26,4%)29 (30,5%)0,204
Coronary artery disease/stroke13 (28,9%)14 (19,2%)13 (14,9%)18 (18,9%)0,295
Uncontrolled hypertension2 (4,4%)2 (2,7%)2 (2,3%)4 (4,2%)0,861
Hypertension31 (68,9%)38 (52,1%)48 (55,2%)44 (46,3%)0,082
ACEi24 (53,3%)23 (31,5%)27 (31,0%)29 (30,5%)0,035
ACT15 (33,3%)6 (8,2%)10 (11,5%)10 (10,5%)<0,001
AAT6 (13,3%)12 (16,4%)15 (17,2%)18 (18,9%)0,883
Smoking4 (8,9%)9 (12,3%)5 (5,7%)4 (4,2%)0,204
Alcohol001 (1,1%)00,481
Diagnosis<0,001
ARI0001 (1,1%)
SARS-CoV-2 with pneumonia (RTG)22 (48,9%)56 (76,7%)72 (82,8%)83 (87,4%)
SARS-CoV-223 (51,1%)17 (23,3%)15 (17,2%)12 (12,6%)
COVID-19 severity0,001
Asymptomatic13 (28,9%)12 (16,4%)8 (9,2%)4 (4,2%)
Mild9 (20,0%)7 (9,6%)15 (17,2%)24 (25,3%)
Moderate6 (13,3%)11 (15,1%)12 (13,8%)17 (17,9%)
Severe16 (35,6%)43 (58,9%)52 (59,8%)51 (53,7%)
SYMPTOMS
Fever25 (55,6%)52 (71,2%)73 (83,9%)77 (81,1%)0,002
Chest pain8 (17,8%)15 (20,5%)23 (26,4%)32 (33,7%)0,116
Cough19 (42,2%)47 (64,4%)59 (67,8%)71 (74,7%)0,008
Anosmia/ageusia1 (2,2%)6 (8,2%)11 (12,6%)13 (13,7%)0,156
Dyspnoea19 (42,2%)41 (56,2%)48 (55,2%)58 (61,1%)0,186
Diarrhoea5 (11,1%)14 (19,2%)14 (16,1%)19 (20,0%)0,595
Headache6 (13,3%)10 (13,7%)14 (16,1%)12 (12,6%)0,928
DVT/PE3 (6,7%)10 (13,7%)5 (5,7%)6 (6,3%)0,237
Death4 (8,9%)4 (5,5%)2 (2,3%)4 (4,2%)0,381
ICU admission3 (6,7%)9 (12,0%)8 (9,2%)10 (10,5%)0,782
Dexamethasone19 (42,2%)47 (64,4%)65 (74,7%)72 (75,8%)<0,001
Remdesivir6 (13,3%)16 (21,9%)19 (21,8%)18 (18,9%)0,639
Antibiotic8 (17,8%)15 (20,5%)24 (27,6%)24 (25,3%)0,553
Oxygen22 (48,9%)55 (75,3%)70 (80,5%)77 (81,1%)<0,001

Table 3 presents the distribution of patients according to the severity of COVID-19. There were notable differences in proinflammatory markers between the groups for LDH, ferritin, CRP, PCT. Patients with more severe disease had increased levels of proinflammatory markers, and significantly lower levels of serum vitamin 25(OH)D3. However, the lowest levels of vitamin 25(OH)D3 were detected in the asymptomatic group (Figure 3). Patients with severe COVID-19 exhibited more symptoms, had a higher rate of ICU admissions and mortality.

Table 3. Comparison of clinical characteristics based on COVID-19 severity level.

COVID-19 severity
Asymptomatic (n=37)Mild (n=55)Moderate (n=46)Severe (n=162)p-value
Age60,6±15,463,7±17,266,3±14,865,6±±13,40,241
Sex0,179
m/f20/1736/1920/2689/73
Duration of symptoms3,3±3,07,0±4,36,7±4,09,5±5,6<0,001
Systolic at admission132,0±24,1128,3±21,6122,8±16,8124,9±17,00,108
Diastolic at admission77,1±13,176,9±11,973,8±10,873,7±11,20,196
Systolic after 72h135,4±19,4128,0±18,9125,3±16,0134,1±19,30,018
Diastolic after 72h76,3±12,874,6±10,572,8±11,174,7±11,40,612
BLOOD TESTS
HbA1c6,2±1,16,7±2,36,3±1,16,7±1,90,449
Glucose6,4±2,96,8±2,86,6±1,87,3±4,00,355
LDH3,9±2,64,1±1,65,6±2,15,3±2,1<0,001
Ferritin449,3±385,3606,4±721,3793,6±815,31059,7±742,5<0,001
CRP39,9±46,372,1±69,180,1±58,073,7±63,30,020
Procalcitonin0,11±0,170,13±0,260,27±0,730,54±4,950,844
Leucocytes8,1±3,26,5±2,86,9±5,27,5±3,60,223
RDW14,9±1,313,9±1,214,2±0,917,0±30,80,934
Thrombocytes260,8±117,2207,8±97,8214,5±99,0244,5±123,90,097
Lymphocytes1,6±1,11,2±0,91,9±4,11,3±2,40,506
D-dimer2349,1±2573,91993,6±3244,31491,8±2303,31821,4±4080,60,770
IL-622,0±18,053,5±55,471,4±52,149,7±53,30,275
25-OH-D344,1±22,570,3±37,069,7±37,964,1±30,80,001
Season<0,001
Jan-Feb18 (48,6%)14 (25,5%)6 (13,0%)58 (35,8%)
Mar-Apr5 (13,5%)3 (5,5%)3 (6,5%)50 (30,9%)
May-Jun1 (2,7%)8 (14,5%)5 (10,9%)5 (3,1%)
Jul-Aug3 (8,1%)8 (14,5%)5 (10,9%)5 (3,1%)
Sep-Oct6 (16,2%)18 (32,7%)18 (11,1%)18 (11,1%)
Nov-Dec4 (10,8%93 (5,5%)1 (2,2%)14 (8,6%)
Extended season<0,001
Summer May-Oct10 (27,0%)34 (61,8%)36 (78,3%)39 (24,1%)
Winter Nov-Apr27 (73,0%)20 (36,4%)10 (21,7%)122 (75,3%)
D3 deficiency33 (89,2%)31 (56,4%)29 (63,0%)111 (68,5%)0,009
D3 deficiency level0,001
<30 nmol/L deficient13 (35,1%)9 (16,4%)6 (13,0%)16 (9,9%)
30-50 nmol/L insufficient12 (32,4%)7 (12,7%)11 (23,9%)43 (26,5%)
50-75 nmol/L non-optimal8 (21,6%)15 (27,3%)12 (26,1%)52 (32,1%)
>75 nmol/L sufficient4 (10,8%)24 (43,6%)17 (37,0%)51 (31,5%)
Diabetes9 (24,3%)13 (23,6%)10 (21,7%)36 (22,2%)0,991
Hyperlipidemia10 (27,0%)18 (32,7%)15 (32,6%)52 (32,1%)0,934
Coronary artery disease/stroke9 (24,3%)11 (20,0%)12 (26,1%)26 (16,0%)0,406
Uncontrolled hypertension2 (5,4%)3 (5,5%)1 (2,2%)3 (1,9%)0,437
Hypertension17 (45,9%)26 (47,3%)21 (45,7%)97 (59,9%)0,139
ACEi10 (27,0%)19 (34,5%)16 (34,8%)57 (35,2%)0,820
ACT7 (18,9%)8 (14,5%)11 (23,9%)15 (9,3%)0,054
AAT6 (16,2%)8 (14,5%)10 (21,7%)27 (16,7%)0,802
Smoking4 (10,8%)5 (9,1%)1 (2,2%)12 (7,4%)0,438
Alcohol01 (1,8%)000,215
Diagnosis<0,001
ARI001 (2,2%)0
SARS-CoV-2 with pneumonia (RTG)031 (56,4%)42 (91,3%)160 (98,8%)
SARS-CoV-237 (100%)24 (43,6%)3 (6,5%)2 (1,2%)
SYMPTOMS
Fever1 (2,7%)45 (81,8%)39 (84,8%)141 (87,0%)<0,001
Chest pain1 (2,7%)14 (25,5%)9 (19,6%)53 (32,7%)0,002
Cough4 (10,8%)32 (58,2%)32 (69,6%)128 (79,0%)<0,001
Anosmia/ageusia1 (2,7%)8 (14,5%)4 (8,7%)18 (11,1%)0,315
Dyspnoea1 (2,7%)19 (34,5%)26 (56,5%)119 (73,5%)<0,001
Diarrhea1 (2,7%)9 (16,4%)11 (23,9%)30 (18,5%)0,060
Headache05 (9,1%)13 (28,3%)24 (14,8%)0,001
DVT/PE1 (2,7%)2 (3,6%)2 (4,3%)19 (11,7%)0,087
Death1 (2,7%)01 (2,2%)11 (6,8%)0,133
ICU admission001 (2,2%)29 (17,9%)<0,001
Dexamethasone021 (38,2%)37 (80,4%)145 (89,5%)<0,001
Remdesivir02 (3,6%)9 (19,6%)48 (29,6%)<0,001
Antibiotic3 (8,1%)15 (27,3%)15 (32,6%)37 (22,8%)0,057
Oxygen024 (43,6%)38 (82,6%)161 (99,4%)<0,001
83696b14-f1a2-42fa-883f-97d17367e1dd_figure3.gif

Figure 3. Serum 25(OH)D3 levels based on COVID-19 severity.

Discussion

This study aimed to assess the severity of COVID-19 among our patients and potential effect of serum levels of vitamin D levels on the course of COVID-19. Previous studies have speculated about the role of vitamin D supplementation and COVID-19 but have been inconclusive. However, it is known that vitamin D plays an important role in immune system and can improve natural resistance to acute viral respiratory infections and moderate their course by inhibiting an excessive inflammatory response. A high prevalence of vitamin D deficiency especially pronounced in the autumn and winter months was reported in Slovenia, with up to 80% of adults exhibiting serum vitamin D levels <50 nmol/L, and severe deficiency with serum vitamin D levels <30 nmol/L was found in 40%.43 Therefore, our group advised vitamin D supplementation to mitigate the course of the COVID-19 disease, especially in patients at risk for a severe course. Our results show that most enrolled patients were still vitamin D deficient despite the recommendations which were published prior to the conduction of this study. It is noteworthy that vitamin D deficiency was predominantly observed during the winter months from November till April, which confirms our previous findings.43 These results could be explained by increased sun exposure in the summer, which is known to be an important source of natural vitamin D. It has been established that in the absence of UVB-induced vitamin D biosynthesis, vitamin D supply can be maintained in healthy adults with a dietary intake of between 600 and 800 IU of vitamin D.46,47 At the same time, it should be pointed out that this does not apply to individuals who already have vitamin D deficiency, and that such doses are sufficient to reach the threshold value for skeletal and muscle functions (50 nmol/L), but not to reach higher concentrations of serum level, e.g. 75 nmol/L. The results of our study show, that the Vitamin D deficiency is more prevalent in males. Interestingly, the duration of symptoms was the shortest in the most Vitamin D deficient group. Furthermore, fever and cough were more frequent within the group with optimal serum Vitamin D levels. In addition, the severe course of COVID-19 was also more common in groups with higher concentration of serum vitamin 25(OH)D3 levels. These results do not support the protective role of vitamin D in viral infections suggested in the previous studies, where vitamin D supplementation was shown to significantly lower the incidence of acute respiratory infections (ARIs) in subjects with severe vitamin D deficiency.48 Our results can be explained by several hypotheses. First, previous studies have shown that higher serum levels of vitamin D are required for beneficial effects on the immune system than for skeletal and muscle effects.49 This is further supported by a study in which patients with levels of vitamin D below 75 nmol/L were shown to 58% more likely to suffer from ARI.50 Most of our patients admitted they only started supplementing Vitamin D after they had already developed the symptoms, which could explain our results, as the immunomodulatory effects of Vitamin D have not yet started. Previous studies have shown a correlation between lower average vitamin D levels and a higher incidence of SARS-CoV-2 infections and higher mortality (Italy, France, Spain, Switzerland).51 For instance, in Chicago, those with vitamin 25(OH)D3 levels below 50 nmol/L had a 1.77 times greater risk of testing positive for the infection. Their vitamin 25(OH)D3 was determined up to a year before they fell ill or were tested.52 In our case unfortunately we did not measure levels of vitamin 25(OH)D3 at several time points. Similar differences in the vitamin D levels between positive and negative subjects was also noted in a Swiss study, where those with a positive test had an average level of only 27 nmol/L,53 and those with a negative test had an average level of 61 nmol/L. Also in Israel, it was shown that a lower level of vitamin D increases the risk of infection with SARS-CoV-2.54 In observational studies in Iran,55 Germany, and Italy, those patients with COVID who had lower levels of vitamin D had worse outcomes.56 Moreover, an almost 15-fold increased risk of death was observed in patients with vitamin D deficiency compared with those with higher vitamin 25(OH)D3 levels; similar relationships were also evident when the vitamin 25(OH)D3 cut-off was set at 50 nmol/L.56 Our results show that patients with more severe disease showed higher levels of inflammatory markers and significantly lower levels of serum vitamin 25(OH)D3. Interestingly however, again the lowest levels of vitamin 25(OH)D3 were detected in the asymptomatic group. This can be explained by the same reason as above those patients who had symptoms started taking high concentrations of vitamin D prior to their admission to the hospital as our recommendations were published over several media and in a public campaign. Patients with asymptomatic course of the disease were not aware of infection and were not supplementing vitamin D, which explains the lower levels. In addition, the majority of cases were detected during the winter months, during which the baseline serum Vitamin D levels are lower, which could have influenced the results. Nevertheless, the most severe group of patients exhibited more symptoms, a higher rate of ICU admission and a higher mortality rate which is in line with previous reports. The results of a previous study indicate that vitamin D supplementation decreases the rate of ICU admissions as well as mortality.57 The favourable outcome of vitamin D supplementation and increased serum levels can be explained by the fact that vitamin D moderates the excessive inflammation in the lungs (cytokine storm) that can have detrimental effects in some patients with COVID-19. Inconsistency in the effect of vitamin D supplementation has been shown previously and attributed to different dosing regimens, duration of supplementation, and methodology in published reports. Murai et al.58 did not detect differences in hospital stay of patients with COVID-19 who received vitamin D dose and those who did not receive vitamin D.

Our study had several limitations. No clear data about the length of vitamin D supplementation prior to hospitalisation could be obtained. Our largest limitation is that no follow-up was performed, as in the following period the severity of the disease might be lower due to higher level of serum vitamin 25(OH)D3. In addition, we did not measure the levels of vitamin 25(OH)D3 in several time points of hospitalisation to confirm its effect over time.

Conclusion

Vitamin D levels showed a reasonable effect in the prevention of SARS-CoV-2 morbidity and mortality. Our results show the association between lower levels of serum vitamin 25(OH)D3 and COVID-19 severity. Patients with the severe course of COVID-19 were shown to have increased inflammatory parameters, increased mortality, and higher incidence of vitamin D deficiency. The results suggest that the vitamin D deficiency might represent a significant risk factor for a severe course of COVID-19. Therefore, we recommend vitamin D supplementation in high-risk patients and hospitalised COVID-19 patients. Further, prospective longitudinal studies are warranted to assess the long-term effects of Vitamin D supplementation.

Author contribution

D.Si. and J.O. conceived of the idea for the project; D.Si. and J.O. wrote the draft version of the manuscript, R.S. supervised the patients invited to participate in the study; J.U. and K.J. compiled the clinical data on the patients involved; O.J. and D. St were responsible for completing laboratory data, and D.St. and R.J. performed the statistical calculations. All authors reviewed and agreed with the manuscript, and final approval was given by D.Si. and J.O. All authors have read and agreed to the published version of the manuscript.

Data availability

Zenodo: Siuka, Darko, Saletinger, Rajko, Uršič, Jure, Jevnikar, Kristina, Janša, Rado, Štubljar, David, & Osredkar, Joško. (2023). The effect of Vitamin D levels on the course of COVID-19 in hospitalized patients – a 1-year prospective cohort study (1.0) [Data set]. Zenodo. DOI: https://doi.org/10.5281/zenodo.7679129. 59

Data are available under the terms of the Creative Commons Attribution 2.0 Generic.

References

  • 1.  Siuka D, Fabjan T, Osredkar J: The COVID-19 Pandemic, Seasons and the Vitamin D Laboratory Strategy. International Journal of Sciences: Basic and Applied Research (IJSBAR). 2021; 56(2): 182–189.
  • 2.  Fares A: Factors influencing the seasonal patterns of infectious diseases. Int. J. Prev. Med. 2013; 4(2): 128–132. PubMed Abstract
  • 3.  Jordan T, Siuka D, Kozjek Rotovnik N, et al.: COVID-19 and Vitamin D- a Systematic Review. Zdr. Varst. 2022; 61(2): 124–132. PubMed Abstract | Publisher Full Text
  • 4.  Jolliffe DA, Griffiths CJ, Martineau AR: Vitamin D in the prevention of acute respiratory infection: Systematic review of clinical studies. J. Steroid Biochem. Mol. Biol. 2013; 136: 321–329. PubMed Abstract | Publisher Full Text
  • 5.  De Niet S, Trémège M, Coffiner M, et al.: Positive Effects of Vitamin D Supplementation in Patients Hospitalized for COVID-19: A Randomized, Double-Blind, Placebo-Controlled Trial. Nutrients. 2022; 14(15): 3048. PubMed Abstract | Publisher Full Text | Free Full Text
  • 6.  Vanherwegen AS, Gysemans C, Mathieu C: Regulation of immune function by vitamin D and its use in diseases of immunity. Endocrinol. Metab. Clin. N. Am. 2017; 46: 1061–1094. Publisher Full Text
  • 7.  Beard JA, Bearden A, Striker R: Vitamin D and the anti-viral state. J. Clin. Virol. 2011; 50: 194–200. PubMed Abstract | Publisher Full Text | Free Full Text
  • 8.  Greiller CL, Martineau AR: Modulation of the immune response to respiratory viruses by vitamin D. Nutrients. 2015; 7: 4240–4270. PubMed Abstract | Publisher Full Text | Free Full Text
  • 9.  Coussens AK: The role of UV radiation and vitamin D in the seasonality and outcomes of infectious disease. Photochem. Photobiol. Sci. 2017; 16: 314–338.
  • 10.  Lang PO, Aspinall R: Vitamin D Status and the Host Resistance to Infections: What It Is Currently (Not) Understood. Clin. Ther. 2017; 39: 930–945. PubMed Abstract | Publisher Full Text
  • 11.  Gruber-Bzura BM: Vitamin D and Influenza-Prevention or Therapy? Int. J. Mol. Sci. 2018; 19: 2419. PubMed Abstract | Publisher Full Text | Free Full Text
  • 12.  Rondanelli M, Miccono A, Lamburghini S, et al.: Self-Care for Common Colds: The Pivotal Role of Vitamin D, Vitamin C, Zinc, and Echinacea in Three Main Immune Interactive Clusters (Physical Barriers, Innate and Adaptive Immunity) Involved during an Episode of Common Colds-Practical Advice on Dosages and on the Time to Take These Nutrients/Botanicals in order to Prevent or Treat Common Colds. Evid.-Based Complement. Altern Med ECAM. 2018; 2018: 5813095.
  • 13.  Gombart AF, Pierre A, Maggini S: A Review of Micronutrients and the Immune System-Working in Harmony to Reduce the Risk of Infection. Nutrients. 2020; 12: 236. PubMed Abstract | Publisher Full Text | Free Full Text
  • 14.  Jolliffe DA, Camargo CA Jr, Sluyter JD, et al.: Vitamin D supplementation to prevent acute respiratory infections: A systematic review and meta-analysis of aggregate data from randomised controlled trials. Lancet Diabetes Endocrinol. 2021; 9: 276–292. PubMed Abstract | Publisher Full Text
  • 15.  Hewison M: Vitamin D and immune function: An overview. Proc. Nutr. Soc. 2012; 71: 50–61. Publisher Full Text
  • 16.  Wei R, Christakos S: Mechanisms Underlying the Regulation of Innate and Adaptive Immunity by Vitamin D. Nutrients. 2015; 7: 8251–8260. PubMed Abstract | Publisher Full Text | Free Full Text
  • 17.  Fabbri A, Infante M, Ricordi C: Editorial—Vitamin D status: A key modulator of innate immunity and natural defense from acute viral respiratory infections. Eur. Rev. Med. Pharmacol. Sci. 2020; 24: 4048–4052. PubMed Abstract | Publisher Full Text
  • 18.  Jolliffe DA, Griffiths CJ, Martineau AR: Vitamin D in the prevention of acute respiratory infection: Systematic review of clinical studies. J. Steroid Biochem. Mol. Biol. 2013; 136: 321–329. PubMed Abstract | Publisher Full Text
  • 19.  Hansdottir S, Monick MM, Hinde SL, et al.: Respiratory epithelial cells convert inactive vitamin D to its active form: Potential effects on host defense. J Immunol Baltim Md. 1950; 181: 7090–7099. Publisher Full Text
  • 20.  Olliver M, Spelmink L, Hiew J, et al.: Immunomodulatory effects of vitamin D on innate and adaptive immune responses to Streptococcus pneumoniae. J. Infect. Dis. 2013; 208: 1474–1481. PubMed Abstract | Publisher Full Text
  • 21.  Golpour A, Bereswill S, Heimesaat MM: Antimicrobial and Immune-Modulatory Effects of Vitamin D Provide Promising Antibiotics-Independent Approaches to Tackle Bacterial Infections—Lessons Learnt from a Literature Survey. Eur. J. Microbiol. Immunol. 2019; 9: 80–87. PubMed Abstract | Publisher Full Text | Free Full Text
  • 22.  Moromizato T, Litonjua AA, Braun AB, et al.: Association of low serum 25-hydroxyvitamin D levels and sepsis in the critically ill. Crit. Care Med. 2014; 42: 97–107. PubMed Abstract | Publisher Full Text
  • 23.  Thickett DR, Moromizato T, Litonjua AA, et al.: Association between prehospital vitamin D status and incident acute respiratory failure in critically ill patients: A retrospective cohort study. BMJ Open Respir. Res. 2015; 2: e000074. PubMed Abstract | Publisher Full Text | Free Full Text
  • 24.  Higgins DM, Wischmeyer PE, Queensland KM, et al.: Relationship of vitamin D deficiency to clinical outcomes in critically ill patients. JPEN J Parenter Enter Nutr. 2012; 36: 713–720. Publisher Full Text
  • 25.  Nair P, Lee P, Reynolds C, et al.: Significant perturbation of vitamin Dparathyroid-calcium axis and adverse clinical outcomes in critically ill patients. Intensive Care Med. 2013; 39: 267–274. PubMed Abstract | Publisher Full Text
  • 26.  Braun AB, Gibbons FK, Litonjua AA, et al.: Low serum 25-hydroxyvitamin D at critical care initiation is associated with increased mortality. Crit. Care Med. 2012; 40: 63–72. PubMed Abstract | Publisher Full Text | Free Full Text
  • 27.  Quraishi SA, Litonjua AA, Moromizato T, et al.: Association between prehospital vitamin D status and hospital-acquired Clostridium difficile infections. JPEN J. Parenter. Enter. Nutr. 2015; 39: 47–55. PubMed Abstract | Publisher Full Text | Free Full Text
  • 28.  Barnett N, Zhao Z, Koyama T, et al.: Vitamin D deficiency and risk of acute lung injury in severe sepsis and severe trauma: A case-control study. Ann. Intensive Care. 2014; 4: 5. PubMed Abstract | Publisher Full Text | Free Full Text
  • 29.  Amrein K, Schnedl C, Holl A, et al.: Effect of high-dose vitamin D3 on hospital length of stay in critically ill patients with vitamin D deficiency: The VITdAL-ICU randomized clinical trial. JAMA. 2014; 312: 1520–1530. Publisher Full Text
  • 30.  McNally JD, Menon K, Chakraborty P, et al.: The association of vitamin D status with pediatric critical illness. Pediatrics. 2012; 130: 429–436. Publisher Full Text
  • 31.  Kempker JA, West KG, Kempker RR, et al.: Vitamin D status and the risk for hospital-acquired infections in critically ill adults: A prospective cohort study. PLoS One. 2015; 10: e0122136. PubMed Abstract | Publisher Full Text | Free Full Text
  • 32.  Kaufman HW, Niles JK, Kroll MH, et al.: SARS-CoV-2 positivity rates associated with circulating 25-hydroxyvitamin D levels. PLoS One. 2020; 15: e0239252. eCollection 2020. PubMed Abstract | Publisher Full Text | Free Full Text
  • 33.  Ali N: Role of vitamin D in preventing COVID-19 infection, pro- gression and severity. J. Infect. Public Health. 2020; 13: 1373–1380. PubMed Abstract | Publisher Full Text | Free Full Text
  • 34.  Alguwaihes AM, Sabico S, Hasanato R, et al.: Severe vitamin D de- ficiency 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. 2021; 33: 1415–1422. PubMed Abstract | Publisher Full Text | Free Full Text
  • 35.  Al-Daghri NM, Amer OE, Alotaibi NH, et al.: Vitamin D status of Arab Gulf residents screened for SARS-CoV-2 and its association with COVID-19 infection: a multi-centre case-control study. J. Transl. Med. 2021; 19: 166. PubMed Abstract | Publisher Full Text | Free Full Text
  • 36.  Campi I, Gennari L, Merlotti D, et al.: Vitamin D and COVID-19 severity and related mortality: a prospective study in Italy. BMC Infect. Dis. 2021; 21: 566. PubMed Abstract | Publisher Full Text | Free Full Text
  • 37.  Chiodini I, Gatti D, Soranna D, et al.: Vitamin D Status and SARS- CoV-2 Infection and COVID-19 Clinical Outcomes. Front. Public Health. 2021; 9: 736665. PubMed Abstract | Publisher Full Text | Free Full Text
  • 38.  Petrelli F, Luciani A, Perego G, et al.: Therapeutic and prognostic role of vitamin D for COVID-19 infection: A systematic review and meta-analysis of 43 observational studies. J. Steroid Biochem. Mol. Biol. 2021; 211: 105883. PubMed Abstract | Publisher Full Text | Free Full Text
  • 39.  Liu N, Sun J, Wang X, et al.: Low vitamin D status is associated with coronavirus disease 2019 outcomes: a systematic review and meta-analysis. Int. J. Infect. Dis. 2021; 104: 58–64. PubMed Abstract | Publisher Full Text | Free Full Text
  • 40.  Ghasemian R, Shamshirian A, Heydari K, et al.: The role of vitamin D in the age of COVID-19: A systematic review and meta-analysis. Int. J. Clin. Pract. 2021; 75: e14675. Publisher Full Text
  • 41.  Pfeifer M, Siuka D, Pravst I: Recommendations for replacing cholecalciferol (vitamin D3) during periods respiratory infections and to replace cholecalciferol in individuals with COVID-19. [10th Nov 2022]. Reference Source
  • 42.  Zheng Z, Peng F, Xu B, et al.: Risk factors of critical & mortal COVID-19 cases: a systematic literature review and metaanalysis. J. Infect. 2020; 81(2): e16–e25. PubMed Abstract | Publisher Full Text | Free Full Text
  • 43.  Hribar M, Hristov H, Gregorič M, et al.: Nutrihealth Study: Seasonal Variation in Vitamin D Status Among the Slovenian Adult and Elderly Population. Nutrients. 2020; 12(6): 1838. Publisher Full Text
  • 44.  Žmitek K, Hribar M, Lavriša Ž, et al.: Socio-Demographic and Knowledge-Related Determinants of Vitamin D Supplementation in the Context of the COVID-19 Pandemic: Assessment of an Educational Intervention. Front. Nutr. 2021; 8: 648450. PubMed Abstract | Publisher Full Text | Free Full Text
  • 45.  Institute of Medicine Committee to Review Dietary Reference Intakes for Vitamin D and Calcium: The National Academies Collection: Reports funded by National Institutes of Health. Dietary Reference Intakes for Calcium and Vitamin DRoss AC, Taylor CL, et al., editors. Washington, DC, USA: National Academies Press (US), National Academy of Sciences; 2011.
  • 46.  EFSA NDA Panel (EFSA Panel on Dietetic Products, Nutrition and Allergies): Scientific opinion on dietary reference values for vitamin D. EFSA J. 2016; 14(10): 4547. Publisher Full Text
  • 47.  German Nutrition Society, New Reference Values for Vitamin D (D-A-CH). Ann. Nutr. Metab. 2012; 60: 241–246. Publisher Full Text
  • 48.  Martineau AR, et al.: Vitamin D supplementation to prevent acute respiratory infections: individual participant data meta-analysis. Health Technol. Assess. 2019; 23(2): 1–44. PubMed Abstract | Publisher Full Text | Free Full Text
  • 49.  Sabetta JR, DePetrillo P, Cipriani RJ, et al.: Serum 25-Hydroxyvitamin D and the Incidence of Acute Viral Respiratory Tract Infections in Healthy Adults. PLoS One. 2010; 5(6): e11088. PubMed Abstract | Publisher Full Text | Free Full Text
  • 50.  Monlezun DJ, Bittner EA, Christopher KB, et al.: Vitamin D status and acute respiratory infection: cross sectional results from the United States National\Health and Nutrition Examination Survey, 2001-2006. Nutrients. 2015; 7: 1933–1944. PubMed Abstract | Publisher Full Text | Free Full Text
  • 51.  Laird E, et al.: Vitamin D and Inflammation: Potential Implications for Severity of Covid-19. Ir. Med. J. 2020; 113(5): 81. PubMed Abstract
  • 52.  Meltzer DO, Best TJ, Zhang H, et al.: Association of Vitamin D Status and Other Clinical Characteristics With COVID-19 Test Results. JAMA Netw. Open. 2020; 3(9): e2019722. PubMed Abstract | Publisher Full Text | Free Full Text
  • 53.  D’Avolio A, Avataneo V, Manca A, et al.: 25-Hydroxyvitamin D concentrations are lower in patients with positive PCR for SARS-CoV-2. Nutrients. 2020; 12(5): 1359. PubMed Abstract | Publisher Full Text | Free Full Text
  • 54.  Merzon E, Tworowski D, Gorohovski A, et al.: Low plasma 25(OH) vitamin D level is associated with increased risk of COVID-19 infection: an Israeli population-based study.
  • 55.  Carpagnano GE, Di Lecce V, Quaranta VN, et al.: Vitamin D deficiency as a predictor of poor prognosis in patients with acute respiratory failure due to COVID-19. J. Endocrinol. Investig. 2020.
  • 56.  Radujkovic A, Hippchen T, Tiwari-Heckler S, et al.: Vitamin D Deficiency and Outcome of COVID-19 Patients. Nutrients. 2020; 12: 2757. PubMed Abstract | Publisher Full Text | Free Full Text
  • 57.  Entrenas Castillo M, Entrenas Costa LM, Vaquero Barrios JM, et al.: Effect of calcifediol treatment and best available therapy versus best available therapy on intensive care unit admission and mortality among patients hospitalized for COVID-19: A pilot randomized clinical study. J. Steroid Biochem. Mol. Biol. 2020; 203: 105751. PubMed Abstract | Publisher Full Text | Free Full Text
  • 58.  Murai IH, Fernandes AL, Sales LP, et al.: Effect of a single high dose of vitamin D3 on hospital length of stay in patients with moderate to severe COVID-19: A randomized clinical trial. JAMA. 2021; 325: 1053–1060. PubMed Abstract | Publisher Full Text | Free Full Text
  • 59.  Siuka D, Saletinger R, Uršič J, et al.: The effect of Vitamin D levels on the course of COVID-19 in hospitalized patients – a 1-year prospective cohort study (1.0). [Data set]. Zenodo. 2023. Publisher Full Text

Comments on this article Comments (0)

Version 1
VERSION 1 PUBLISHED 09 Mar 2023
Comment
Author details Author details
Competing interests
Grant information
Article Versions (1)
Copyright
Download
 
Export To
metrics
Views Downloads
F1000Research - -
PubMed Central
Data from PMC are received and updated monthly.
 - -
Citations
SEE MORE DETAILS
CITE
how to cite this article
Siuka D, Saletinger R, Uršič J et al. The effect of Vitamin D levels on the course of COVID-19 in hospitalized patients – a 1-year prospective cohort study [version 1; peer review: 1 approved with reservations] F1000Research 2023, 12:254 (https://doi.org/10.12688/f1000research.131730.1)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
track
receive updates on this article
Track an article to receive email alerts on any updates to this article.

Open Peer Review

Current Reviewer Status: ?
Key to Reviewer Statuses VIEW
ApprovedThe paper is scientifically sound in its current form and only minor, if any, improvements are suggested
Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.
Not approvedFundamental flaws in the paper seriously undermine the findings and conclusions
Version 1
VERSION 1
PUBLISHED 09 Mar 2023
Views
0
Cite
Reviewer Report 11 Oct 2023
Giulia Vivaldi, Queen Mary University of London, London, England, UK 
Approved with Reservations
VIEWS 0
https://doi.org/10.5256/f1000research.144599.r210758
Siuka and colleagues report findings from a prospective cohort study assessing the effect of vitamin D supplementation on people hospitalised with SARS-CoV-2 infection. The authors assessed vitamin D deficiency in 301 participants, who were hospitalised with varying levels of COVID-19 ... Continue reading
CITE
CITE
HOW TO CITE THIS REPORT
Vivaldi G. Reviewer Report For: The effect of Vitamin D levels on the course of COVID-19 in hospitalized patients – a 1-year prospective cohort study [version 1; peer review: 1 approved with reservations]. F1000Research 2023, 12:254 (https://doi.org/10.5256/f1000research.144599.r210758)
The direct URL for this report is:
https://f1000research.com/articles/12-254/v1#referee-response-210758
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
Report a concern

Comments on this article Comments (0)

Version 1
VERSION 1 PUBLISHED 09 Mar 2023
Comment

Open Peer Review

Reviewer Status

Alongside their report, reviewers assign a status to the article:

Approved
The paper is scientifically sound in its current form and only minor, if any, improvements are suggested
Approved with reservations
A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.
Not approved
Fundamental flaws in the paper seriously undermine the findings and conclusions

Reviewer Reports

Invited Reviewers
1
Version 1
09 Mar 23 		read
  1. Giulia Vivaldi, Queen Mary University of London, London, UK

Comments on this article

All Comments(0)

Add a comment
Sign up for content alerts

Browse by related subjects

    keyboard_arrow_left Back to all reports
    Alongside their report, reviewers assign a status to the article:
    Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested
    Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.
    Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions
    Sign In
    If you've forgotten your password, please enter your email address below and we'll send you instructions on how to reset your password.

    The email address should be the one you originally registered with F1000.
    Email address not valid, please try again

    You registered with F1000 via Google, so we cannot reset your password.

    To sign in, please click here.

    If you still need help with your Google account password, please click here.

    You registered with F1000 via Facebook, so we cannot reset your password.

    To sign in, please click here.

    If you still need help with your Facebook account password, please click here.

    Code not correct, please try again
    Email us for further assistance.
    Server error, please try again.