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Article

Is Serum 25-Hydroxyvitamin D Level Associated with Severity of COVID-19? A Retrospective Study

by
Munachimso Kizito Mbata
1,2,†,
Mireille Hunziker
1,3,†,
Anja Makhdoomi
1,
Giorgia Lüthi-Corridori
1,2,
Maria Boesing
1,2,
Stéphanie Giezendanner
1,
Jürgen Muser
4,
Anne B. Leuppi-Taegtmeyer
2,5,6 and
Jörg D. Leuppi
1,2,*
1
Cantonal Hospital Baselland, University Center of Internal Medicine, Rheinstrasse 26, 4410 Liestal, Switzerland
2
Faculty of Medicine, University of Basel, Klingelbergstrasse 61, 4056 Basel, Switzerland
3
Center for Rehabilitation and Geriatrics, Cantonal Hospital Baselland, Gemeindeholzweg, 4101 Bruderholz, Switzerland
4
Central Laboratories, Cantonal Hospital Baselland, Rheinstrasse 26, 4410 Liestal, Switzerland
5
Hospital Pharmacy, Cantonal Hospital Baselland, Rheinstrasse 26, 4410 Liestal, Switzerland
6
Department of Patient Safety, Medical Directorate, University Hospital Basel, Schanzenstrasse 55, 4056 Basel, Switzerland
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
J. Clin. Med. 2023, 12(17), 5520; https://doi.org/10.3390/jcm12175520
Submission received: 17 July 2023 / Revised: 19 August 2023 / Accepted: 23 August 2023 / Published: 25 August 2023
(This article belongs to the Section Infectious Diseases)
Browse Figures
Review Reports Versions Notes

Abstract

:
(1) Background: SARS-COV2 infection has a clinical spectrum ranging from asymptomatic infection to COVID-19 with acute respiratory distress syndrome (ARDS). Although vitamin D deficiency is often found in patients with ARDS, its role in COVID-19 is not clear. The aim of this study was to explore a possible association between serum 25-hydroxyvitamin D levels and the severity of COVID-19 in hospitalised patients. (2) Methods: In this retrospective observational study, we analysed data from 763 patients hospitalised for COVID-19 in 2020 and 2021. Patients were included in the study if serum 25-hydroxyvitamin D was assessed 30 days before or after hospital admission. Vitamin D deficiency was defined as <50 nmol/L (<20 ng/mL). The primary outcome was COVID-19 severity. (3) Results: The overall median serum 25-hydroxyvitamin D level was 54 nmol/L (IQR 35–76); 47% of the patients were vitamin D deficient. Most patients had mild to moderate COVID-19 and no differences were observed between vitamin D deficient and non-deficient patients (81% vs. 84% of patients, respectively p = 0.829). (4) Conclusion: No association was found between serum 25-hydroxyvitamin D levels and COVID-19 severity in this large observational study conducted over 2 years of the pandemic.

1. Introduction

On 11 March 2020, the World Health Organization (WHO) declared an outbreak of the novel coronavirus 2019 (2019-nCoV) a global pandemic [1]. It originally started in late 2019 in Wuhan, Hubei, China and was renamed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in February 2020 [2,3]. The clinical spectrum of the associated disease, COVID-19, is broad and ranges from asymptomatic and mild upper respiratory infections to potentially lethal acute respiratory distress syndrome (ARDS) [4] and multi-organ failure [5]. Other COVID-19 manifestations, such as uni- or bilateral pulmonary infiltrates in chest imaging like X-ray or computed tomography (CT), can be observed [6].
The mortality of COVID-19 is determined by various factors, including country of residence, patients’ comorbidities, the treatment setting and time of infection [7,8,9]. In Switzerland, the in-hospital mortality was 9.3% [8], while the overall mortality was 1.0% [7] between January 2020 and December 2021. During the two years of the pandemic, patient numbers, symptoms and especially therapeutic guidelines changed rapidly because the virus and its mutations were initially unknown.
Vitamin D is a fat-soluble vitamin, which needs to be introduced into the body by diet or supplementation (in the form of vitamin D2 (ergocalciferol) or vitamin D3 (cholecalciferol)) or produced in the skin from precursors that are converted by sunlight (specifically via ultraviolet B rays) into vitamin D3 [10]. Further, 25-hydroxyvitamin D is the major circulating form of vitamin D; it has a halflife of approximately 2–3 weeks. Additionally, 25-hydroxyvitamin D is a summation of both vitamin D intake and vitamin D that is produced from sun exposure and is the only vitamin D metabolite that is used to determine whether a patient is vitamin D deficient or sufficient.
It has been shown that vitamin D deficiency is associated with various diseases, such as diabetes, viral infections, immune dysregulation, inflammation, cardiovascular disease, cognitive decline and others [11,12,13]. This knowledge has led to studies about vitamin D and COVID-19, which showed contradictory results, especially when differentiating between randomised controlled trials (RCTs) and observational studies [14]. In a meta-analysis of eleven cohort studies and two RCTs, Chen et al. (2021) highlighted no significant association between increased risk of COVID-19 infection or in-hospital death with vitamin D deficiency or insufficiency [15]. However, within the different studies of the meta-analysis, associations between low serum 25-hydroxyvitamin D levels and increased COVID-19 infection rates and worse outcomes were shown [16,17,18], as well as associations between low serum 25-hydroxyvitamin D levels and death [18,19,20,21,22,23,24,25]. On the other hand, other studies found no association between serum 25-hydroxyvitamin D levels and COVID-19 infection [19,26,27]. Dancer et al. (2015) also suggested that a lack of vitamin D contributes to ARDS development because patients with ARDS more often showed a vitamin D deficiency [28]. As ARDS is common in patients with COVID-19, there may be a link between the serum 25-hydroxyvitamin D level and the development of worse outcomes, and several randomised controlled trials have been initiated to investigate this further [29,30,31,32]. However, to date, study results remain inconclusive.
With the current study, we therefore wanted to test retrospectively the hypothesis that vitamin D deficiency is more often associated with a severe outcome in patients hospitalised with COVID-19.

2. Materials and Methods

2.1. Study Design and Setting

This cross-sectional retrospective observational study was performed at the Cantonal Hospital Baselland (dt. Kantonsspital Baselland (KSBL)), a tertiary teaching hospital in Switzerland located on two sites (Liestal and Bruderholz).

2.2. Study Outcomes

The primary study outcome was COVID-19 severity during the course of hospitalisation according to vitamin D status. COVID-19 severity was categorized according to the WHO Ordinal Scale for Clinical Improvement (OSCI) in an adapted version as follows (Table 1):
Secondary exploratory outcomes included the need for oxygen supplementation, in-hospital death, 30 days all-cause rehospitalisation, length of hospital stay alive (LOS), vitamin D supplementation as well as other medications administered, COVID-19-related complications, such as bacterial superinfection, acute kidney failure, gastrointestinal, cardiac and neurologic complications, thromboembolic complications, ventilator-associated pneumonia and multi-organ failure. The COVID-19 wave was also noted and defined as follows (Table 2):

2.3. Patient Population: Inclusion and Exclusion Criteria

All adult patients who were hospitalised in the Cantonal Hospital Baselland due to symptomatic, laboratory-confirmed COVID-19 disease with a current available 25-hydroxyvitamin D level (within 30 days before or after hospital admission) between January 2020 and December 2021 were included in the study. COVID-19 needed to be the main diagnosis, which we defined as hospitalisation for COVID-19 or its complications. Complications had to occur within 14 days after testing positive for SARS-CoV-2 (polymerase chain reaction or antigen tests) (see Figure 1). Patients who had declined general consent for the use of health-related data and samples for research purposes were excluded.

2.4. Data Collection Process

Patients were selected according to the above-defined criteria. In a case where there was multiple COVID-19 hospitalisation of a particular patient recorded in the defined time period, only the initial COVID-19 hospitalisation of that patient was considered and included in order to avoid bias. Patients’ medical data were collected manually from the in-house electronic patient records and entered into the Research electronic data capture database (REDCap®) [34,35].

2.5. Defining Vitamin D Deficiency

Serum 25-hydroxyvitamin D levels were measured by liquid chromatography/tandem mass spectrometry (MassChrom® assay from Chromsystems) and were expressed in nmol/L [36]. The serum 25-hydroxyvitamin D level was displayed as a continuous variable as well as a categorical variable. Vitamin deficiency was defined as 25-hydroxyvitamin D level: <50 nmol/L (<20 ng/mL) [37].
Vitamin D supplementation was defined as any dose of vitamin D taken during or after hospitalisation with the intention to increase the levels of 25-hydroxyvitamin D in the body [38].

2.6. Statistical Analysis

All statistical analyses were conducted using R statistical software, version 3.4.3 (R Foundation for Statistical Computing) or Statistical Package for the Social Sciences software (SPSS Statistics), Version 24 (IBM).
Categorical variables were shown in absolute and relative frequencies. Continuous variables were shown as mean +/− standard deviation (SD) when normally distributed, or median and interquartile range (IQR) when not normally distributed. Normal distribution was verified using histograms and Q–Q plots.
Categorical variables were analysed with the chi-squared test or Fisher’s exact test. To compare categories of COVID-19 severity and the LOS, which were normally distributed, we used the one-way analysis of variance (ANOVA). For the remaining continuous variables (not normally distributed), we used the Kruskal–Wallis test. For hypothesis testing, we considered p-values < 0.05 as statistically significant.
A multivariable logistic regression was performed to assess the relationship between 25-hydroxyvitamin D levels and COVID-19 severity, the need for oxygen supplementation, death and rehospitalisation. A negative binomial regression was performed to assess the relationship between 25-hydroxyvitamin D and LOS. The results of the regression models were presented as odds ratios (OR) or incident rate ratios (IRR) and 95% confidential intervals (CI), with p < 0.05 considered statistically significant. To assess the relationship between 25-hydroxyvitamin D level and COVID-19 severity in the multivariable analyses, we categorised severity in two different ways as follows:
Using the ordinal classification mild, moderate, severe, critical and death, using a dichotomised severity variable, whereby mild = mild or moderate and severe = severe, critical or dead.

2.7. Ethical Approval

The study was approved by the Ethics Committee of Northwestern and Central Switzerland (EKNZ, BASEC-Number 2021-02479).

3. Results

3.1. Patient-Based Baseline Characteristics

The study population included 763 patients hospitalised for COVID-19 with a current 25-hydroxyvitamin D status available (Figure 1). Out of 1480 patients, 763 patients were included, whereas 717 patients were excluded due to several reasons (see Figure 1).
The patients’ baseline characteristics are shown in Table 3, which also provides a comparison between the vitamin D deficient and non-deficient groups. The overall median serum 25-hydroxyvitamin D level was 54 nmol/L (IQR 35.00–76.00), and 47% of the patients were vitamin D deficient. All measurements were carried out within 30 days before or after hospital admission, and over 98% were carried out between 5 days before or during hospitalisation.

3.2. Primary Study Outcome: COVID-19 Severity According to Vitamin D Status

In both deficient and non-deficient patients, most individuals had mild to moderate COVID-19 severity (81% vs. 84%, p = 0.829) (Table 4). Cases of severe and critical COVID-19 were present in both groups, and there was no difference in their distribution. Median serum 25-hydroxyvitamin D levels were similar in patients with mild, moderate, severe, critical and fatal COVID-19 (Table 5).

3.3. Secondary Study Outcomes: COVID-19 Clinical Outcome According to Vitamin D Status

Rates of oxygen supplementation, death, rehospitalisation and LOS also did not differ significantly between vitamin D deficient and non-deficient patients (Table 4 and Table 5).
COVID-19-related complications were more common in vitamin D deficient patients than in non-deficient patients (89% vs. 81%, p = 0.003) (Table 4). The most common complication was bacterial superinfection (78% in vitamin D deficient patients vs. 74% in non-deficient patients, p = 0.178), followed by acute kidney failure (21% in both groups, p = 1.0). Gastrointestinal complications were significantly more common in the vitamin D deficient group (26% vs. 18%, p = 0.005) (Figure 2).
Vitamin D supplementation was provided in 37% (Table 6). The supplementation dose of vitamin D recommended and used for most of the deficient patients for correction was 800 IU oral vitamin D3 per day. Fifteen percent of patients were supplemented already before hospitalisation and 22% were started with vitamin D supplementation during the hospitalisation. Vitamin D supplementation was more commonly provided to patients with vitamin D deficiency than to patients without. Furthermore, vitamin D deficient patients were more often supplemented during hospitalisation than non-deficient patients. This finding suggests that measuring vitamin D had an influence on the prescription of vitamin D supplementation during hospitalisation. Nevertheless, more than half (56%) of the vitamin D deficient patients were not supplemented with vitamin D before or during the hospitalisation (Table 6).
Additional organ support, such as vasoactive drugs, dialysis or extracorporeal membrane oxygenation, was provided in 59 patients (8%) (Table 6). All other therapies received are provided in Table 6. According to internal guidelines of the Cantonal Hospital Baselland, based on the Brigham and Women’s Hospital [39] and National Institute of Health (NIH) guidelines [40], different standard COVID-19 treatments were recommended at different time points of this pandemic (Figure 3).

3.4. Multivariable Analysis of Primary and Secondary Study Outcome Measures

After adjusting for covariates age, sex, vitamin D supplementation, smoking status, comorbidities, COVID-19 vaccination status and COVID-19 wave, there was no significant association between 25-hydroxyvitamin D level and COVID-19 severity, oxygen supplementation rate, death, rehospitalisation rate, LOS and complication rate (Figure 4).

4. Discussion

In this real-life observational study, we found no association of 25-hydroxyvitamin D levels or vitamin D deficiency with the severity of COVID-19, need for oxygen supplementation, rehospitalisation, LOS and in-hospital mortality after adjusting for covariates age, sex, vitamin D supplementation, smoking status, comorbidities, COVID-19 vaccination status and COVID-19 wave. COVID-19-related complications were more common in the vitamin D deficient group.
Our findings correspond to Hernández et al.’s study conducted in 2021, which showed no association between 25-hydroxyvitamin D levels or vitamin D deficiency and COVID-19 severity [41]. Similarly, our study and Im et al. [42] observed non-statistically significant trends for more vitamin D deficient patients in the critical COVID-19 group compared to the other severity groups. Our study and Georgoulis et al. included similar patients, with more than 80% having at least one comorbidity and one-third being obese. In the vitamin D deficient groups, there were more obese patients than in the non-deficient groups, which corresponds to obesity being a risk factor for vitamin D deficiency [43].
Our findings do not correspond to a systematic review where aged (mean > 60 years) vitamin D deficient patients had greater risk of adverse outcomes compared to vitamin D non-deficient patients [44]. However, the studies analysed in the review only investigated small cohorts ranging from 20 to 185 patients, which may not have been representative for all COVID-19 waves [44]. In our study, no statistically significant association was found between vitamin D levels and in-hospital death; this corresponds to the findings of Kazemi et al. [45]. Our study also found no statistically significant association between 30-day all-cause rehospitalisation and 25-hydroxyvitamin D levels. Our study and Reis et al. found no association of 25-hydroxyvitamin D levels with the LOS. However, in their study, a statistically non-significant trend for longer LOS was observed in patients with vitamin D deficiency, a finding that our study did not corroborate [46]. It is important to note that, in this study, we used the cutoff of 50 nmol/L (20 ng/mL) for defining vitamin D deficiency, in line with the definition provided by Holick et al. [37]. However, levels below 75 nmol/L (30 ng/mL) might already affect certain health risks, including the risk for infection, and the goal should be to maintain the level above this value [47,48,49].
Vitamin D supplementation was provided in 37% (15% were supplemented already before hospitalisation, while 22% started with the supplementation during the hospitalisation). Concerning COVID-19 treatment, the majority of the patients were treated with Remdesivir and antibiotics throughout the COVID-19 period.
Our study included patients whose serum 25-hydroxyvitamin D levels were measured 30 days before or after hospital admission, which might have resulted in vitamin D supplementation prior to infection in certain patients and effectively higher levels at the time of admission. However, the vast majority (98%) had the 25-hydroxyvitamin D assessment up to 5 days before admission or during admission, indicating that the measurements were most often taken during acute infection. Furthermore, only 21 of the vitamin D deficient patients (6%) had received vitamin D supplementation before admission. Vitamin D supplementation was evenly distributed between the two groups, but vitamin D deficient patients were less often supplemented with vitamin D before the hospitalisation but more often started supplementation during the hospitalisation. However, we did not consider the exact dosage, which might have provided a better understanding of the role of supplementation.
More than 80% of our patients suffered from a COVID-19-related complication, mostly bacterial superinfection. There were significantly more vitamin D deficient patients suffering from a complication compared to the non-deficient patients. Previous research has led to the assumption that a non-deficient vitamin D status could play an immunoprotective role in respiratory infections by promoting the recruitment of immune cells to the infection site and the induction of infected cell apoptosis, leading to clearance of respiratory pathogens [50,51,52]. Furthermore, vitamin D has been shown to reduce inflammatory activity by suppressing cytokine production, which may lead to fewer thromboembolic complications due to a less procoagulatory setting [53]. However, the model using continuous 25-hydroxyvitamin D values as a potential predictor for complications did not confirm this association. When looking at the complications in detail, a significant difference between vitamin D deficient and non-deficient patients was found in gastrointestinal complications. This finding adds to the other research, suggesting that vitamin D may play a role in intestinal health as it might alter the gut immune function, predisposing deficient patients to gastrointestinal complications [54,55,56]. COVID-19, on the other hand, is known to be associated with gastrointestinal complications, such as ulcerative colitis and acute pancreatitis [57,58].

Strengths and Limitations

In this study, we included COVID-19 confirmed hospitalised cases over 2 years of the pandemic, enabling us to study a large and heterogeneous COVID-19 cohort. In addition to categories of vitamin D deficiency/non-deficiency, we assessed continuous 25-hydroxyvitamin D values as a potential predictor for different outcomes. Models were adjusted for covariates, minimising any bias effect, resulting in robust models. We also used an established classification for disease severity with the OSCI, enabling us to compare our findings with other studies in the field. Our study only included patients with an available 25-hydroxyvitamin D measurement, which might have resulted in a selection bias and limited comprehensive understanding of all hospitalised COVID-19 patients. Variables such as vital signs for more detailed COVID-19 severity definition, osteoporosis and hyperparathyroidism as comorbidities and risk factors in vitamin D deficiency were not assessed. As a retrospective study, one potential limitation is that patients were included if they had a 25-hydroxyvitamin D level taken before, during or after COVID-19. This could introduce confounding elements to the study design as 25-hydroxyvitamin D levels are likely to fluctuate throughout the disease and may be influenced by various factors, such as disease severity, medications and comorbidities. Additionally, the timing of serum 25-hydroxyvitamin D level measurement may vary between the included patients (in our case, measured in 98% of the patients before or during admission), which could affect the comparability of the data collected. Also, vitamin D supplementation was investigated in a general manner without considering the exact dosage.

5. Conclusions

In this retrospective study, we found no association of vitamin D deficiency or 25-hydroxyvitamin D levels with COVID-19 severity, oxygen supplementation, mortality, rehospitalisation or LOS after adjusting for covariates. Vitamin D deficient patients seem to be more at risk for COVID-19-related complications, especially gastrointestinal ones. Since we analysed data from a large and heterogeneous cohort over the course of two years of the pandemic, these results present an important contribution to the controversially discussed role of vitamin D in COVID-19.

Author Contributions

Conceptualization, M.H., A.M., M.B., G.L.-C. and J.D.L.; Methodology, M.H., M.B. and S.G.; Software, M.B. and S.G.; Validation, M.K.M., M.H. and G.L.-C.; Formal analysis, M.H., M.B. and S.G.; Investigation, M.K.M., A.M. and M.H.; Resources, M.K.M., M.H. and J.M.; Data curation, M.K.M., M.H., G.L.-C. and M.B.; Writing—original draft preparation, M.K.M., M.H. and A.B.L.-T.; Writing—review and editing, M.K.M., M.H., A.M., M.B, G.L.-C., J.M., A.B.L.-T. and J.D.L.; Supervision, G.L.-C., M.B. and J.D.L.; Project administration, J.D.L.; Funding acquisition, J.D.L. All authors have read and agreed to the published version of the manuscript.

Funding

This project was financed by the research fund of sponsor–investigator Jörg D. Leuppi, who is supported by grants from the Swiss National Science Foundation (SNF 160072 and 185592) as well as by Swiss Personalized Health Network (SPHN 2018DR108).

Institutional Review Board Statement

The study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of northwestern Switzerland (EKNZ, BASEC-Number 2021-02479). Approved on 13 January 2022.

Informed Consent Statement

All patients whose written informed consent was obtained and those whose consent exception was permitted by the ethics committee were included in the study. Patients who had declined general consent for the use of health-related data and samples for research purposes were excluded.

Data Availability Statement

The data presented in this study are available on request from the corresponding author. The data are not publicly available due to data privacy restrictions.

Acknowledgments

The authors express appreciation to Zahra Pasha for linguistic writing assistance. We also wish to thank Stefan Tschopp for the database setup, Philipp Kreutzinger for the list of patients with COVID-19 diagnosis, Sandra Mitrovic for providing the description of the method used in measuring 25-hydroxyvitamin D level and Philip Tarr for the help with the internal COVID-19 guidelines.

Conflicts of Interest

Jörg D. Leuppi has received unrestricted grant money unrelated to the project from AstraZeneca AG Switzerland, Boehringer GmbH Switzerland, GSK AG Switzerland and Merck Sharp & Dohme AG Switzerland. All authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

References

  1. World Health Organization. Coronavirus Disease 2019 (COVID-19) Situation Report—51; World Health Organization: Geneva, Switzerland, 2020. [Google Scholar]
  2. Zhu, N.; Zhang, D.; Wang, W.; Li, X.; Yang, B.; Song, J.; Zhao, X.; Huang, B.; Shi, W.; Lu, R.; et al. A Novel Coronavirus from Patients with Pneumonia in China, 2019. N. Engl. J. Med. 2020, 382, 727–733. [Google Scholar] [CrossRef] [PubMed]
  3. Gorbalenya, A.E.; Baker, S.C.; Baric, R.S.; de Groot, R.J.; Drosten, C.; Gulyaeva, A.A.; Haagmans, B.L.; Lauber, C.; Leontovich, A.M.; Neuman, B.W.; et al. Severe acute respiratory syndrome-related coronavirus: The species and its viruses—A statement of the Coronavirus Study Group. bioRxiv 2020. [Google Scholar] [CrossRef]
  4. Notz, Q.; Herrmann, J.; Schlesinger, T.; Kranke, P.; Sitter, M.; Helmer, P.; Stumpner, J.; Roeder, D.; Amrein, K.; Stoppe, C.; et al. Vitamin D deficiency in critically ill COVID-19 ARDS patients. Clin. Nutr. 2021, 41, 3089–3095. [Google Scholar] [CrossRef] [PubMed]
  5. Chen, N.; Zhou, M.; Dong, X.; Qu, J.; Gong, F.; Han, Y.; Qiu, Y.; Wang, J.; Liu, Y.; Wei, Y.; et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: A descriptive study. Lancet 2020, 395, 507–513. [Google Scholar] [CrossRef]
  6. Abbas, M.; Robalo Nunes, T.; Martischang, R.; Zingg, W.; Iten, A.; Pittet, D.; Harbarth, S. Nosocomial transmission and outbreaks of coronavirus disease 2019: The need to protect both patients and healthcare workers. Antimicrob. Resist. Infect. Control 2021, 10, 7. [Google Scholar] [CrossRef]
  7. John Hopkins University & Medicine. Mortality Analysis. Available online: https://coronavirus.jhu.edu/data/mortality (accessed on 16 December 2021).
  8. Diebold, M.; Martinez, A.E.; Adam, K.M.; Bassetti, S.; Osthoff, M.; Kassi, E.; Steiger, J.; Pargger, H.; Siegemund, M.; Battegay, M.; et al. Temporal trends of COVID-19 related in-hospital mortality and demographics in Switzerland—A retrospective single centre cohort study. Swiss Med. Wkly. 2021, 151, w20572. [Google Scholar] [CrossRef]
  9. Federal Office of Public Health FOPH. COVID-19 Switzerland, Information on the Current Situation, as of 4 June 2021. Available online: https://www.covid19.admin.ch/de/epidemiologic/case?demoView=graph (accessed on 17 December 2021).
  10. Holick, M.F. Resurrection of vitamin D deficiency and rickets. J. Clin. Investig. 2006, 116, 2062–2072. [Google Scholar] [CrossRef]
  11. Holick, M.F. Vitamin D deficiency. N. Engl. J. Med. 2007, 357, 266–281. [Google Scholar] [CrossRef]
  12. Hribar, C.A.; Cobbold, P.H.; Church, F.C. Potential Role of Vitamin D in the Elderly to Resist COVID-19 and to Slow Progression of Parkinson’s Disease. Brain. Sci. 2020, 10, 284. [Google Scholar] [CrossRef]
  13. Teymoori-Rad, M.; Shokri, F.; Salimi, V.; Marashi, S.M. The interplay between vitamin D and viral infections. Rev. Med. Virol. 2019, 29, e2032. [Google Scholar] [CrossRef]
  14. Grant, W.B.; Lahore, H.; McDonnell, S.L.; Baggerly, C.A.; French, C.B.; Aliano, J.L.; Bhattoa, H.P. Evidence that Vitamin D Supplementation Could Reduce Risk of Influenza and COVID-19 Infections and Deaths. Nutrients 2020, 12, 988. [Google Scholar] [CrossRef] [PubMed]
  15. Chen, J.; Mei, K.; Xie, L.; Yuan, P.; Ma, J.; Yu, P.; Zhu, W.; Zheng, C.; Liu, X. Low vitamin D levels do not aggravate COVID-19 risk or death, and vitamin D supplementation does not improve outcomes in hospitalized patients with COVID-19: A meta-analysis and GRADE assessment of cohort studies and RCTs. Nutr. J. 2021, 20, 89. [Google Scholar] [CrossRef] [PubMed]
  16. Meltzer, D.O.; Best, T.J.; Zhang, H.; Vokes, T.; Arora, V.; Solway, J. Association of Vitamin D Status and Other Clinical Characteristics with COVID-19 Test Results. JAMA Netw. Open 2020, 3, e2019722. [Google Scholar] [CrossRef]
  17. Mendy, A.; Apewokin, S.; Wells, A.A.; Morrow, A.L. Factors Associated with Hospitalization and Disease Severity in a Racially and Ethnically Diverse Population of COVID-19 Patients. medRxiv 2020. [Google Scholar] [CrossRef]
  18. Radujkovic, A.; Hippchen, T.; Tiwari-Heckler, S.; Dreher, S.; Boxberger, M.; Merle, U. Vitamin D Deficiency and Outcome of COVID-19 Patients. Nutrients 2020, 12, 2757. [Google Scholar] [CrossRef]
  19. Hastie, C.E.; Pell, J.P.; Sattar, N. Vitamin D and COVID-19 infection and mortality in UK Biobank. Eur. J. Nutr. 2021, 60, 545–548. [Google Scholar] [CrossRef]
  20. Angelidi, A.M.; Belanger, M.J.; Lorinsky, M.K.; Karamanis, D.; Chamorro-Pareja, N.; Ognibene, J.; Palaiodimos, L.; Mantzoros, C.S. Vitamin D Status Is Associated with In-Hospital Mortality and Mechanical Ventilation: A Cohort of COVID-19 Hospitalized Patients. Mayo Clin. Proc. 2021, 96, 875–886. [Google Scholar] [CrossRef]
  21. Karahan, S.; Katkat, F. Impact of Serum 25(OH) Vitamin D Level on Mortality in Patients with COVID-19 in Turkey. J. Nutr. Health Aging 2021, 25, 189–196. [Google Scholar] [CrossRef]
  22. Charoenngam, N.; Shirvani, A.; Reddy, N.; Vodopivec, D.M.; Apovian, C.M.; Holick, M.F. Association of Vitamin D Status with Hospital Morbidity and Mortality in Adult Hospitalized Patients with COVID-19. Endocr. Pract. 2021, 27, 271–278. [Google Scholar] [CrossRef]
  23. AlSafar, H.; Grant, W.B.; Hijazi, R.; Uddin, M.; Alkaabi, N.; Tay, G.; Mahboub, B.; Al Anouti, F. COVID-19 Disease Severity and Death in Relation to Vitamin D Status among SARS-CoV-2-Positive UAE Residents. Nutrients 2021, 13, 1714. [Google Scholar] [CrossRef]
  24. Carpagnano, G.E.; Di Lecce, V.; Quaranta, V.N.; Zito, A.; Buonamico, E.; Capozza, E.; Palumbo, A.; Di Gioia, G.; Valerio, V.N.; Resta, O. Vitamin D deficiency as a predictor of poor prognosis in patients with acute respiratory failure due to COVID-19. J. Endocrinol. Investig. 2021, 44, 765–771. [Google Scholar] [CrossRef] [PubMed]
  25. De Smet, D.; De Smet, K.; Herroelen, P.; Gryspeerdt, S.; Martens, G.A. Serum 25(OH)D Level on Hospital Admission Associated with COVID-19 Stage and Mortality. Am. J. Clin. Pathol. 2021, 155, 381–388. [Google Scholar] [CrossRef]
  26. Hastie, C.E.; Mackay, D.F.; Ho, F.; Celis-Morales, C.A.; Katikireddi, S.V.; Niedzwiedz, C.L.; Jani, B.D.; Welsh, P.; Mair, F.S.; Gray, S.R.; et al. Corrigendum to “Vitamin D concentrations and COVID-19 infection in UK Biobank” [Diabetes Metabol Syndr: Clin Res Rev 2020 14 (4) 561–5]. Diabetes Metab. Syndr. 2020, 14, 1315–1316. [Google Scholar] [CrossRef] [PubMed]
  27. Raisi-Estabragh, Z.; McCracken, C.; Bethell, M.S.; Cooper, J.; Cooper, C.; Caulfield, M.J.; Munroe, P.B.; Harvey, N.C.; Petersen, S.E. Greater risk of severe COVID-19 in Black, Asian and Minority Ethnic populations is not explained by cardiometabolic, socioeconomic or behavioural factors, or by 25(OH)-vitamin D status: Study of 1326 cases from the UK Biobank. J. Public Health 2020, 42, 451–460. [Google Scholar] [CrossRef]
  28. Dancer, R.C.; Parekh, D.; Lax, S.; D’Souza, V.; Zheng, S.; Bassford, C.R.; Park, D.; Bartis, D.G.; Mahida, R.; Turner, A.M.; et al. Vitamin D deficiency contributes directly to the acute respiratory distress syndrome (ARDS). Thorax 2015, 70, 617–624. [Google Scholar] [CrossRef]
  29. Jaun, F.; Boesing, M.; Luthi-Corridori, G.; Abig, K.; Makhdoomi, A.; Bloch, N.; Lins, C.; Raess, A.; Grillmayr, V.; Haas, P.; et al. High-dose vitamin D substitution in patients with COVID-19: Study protocol for a randomized, double-blind, placebo-controlled, multi-center study-VitCov Trial. Trials 2022, 23, 114. [Google Scholar] [CrossRef]
  30. Bergman, P.; Lindh, A.U.; Bjorkhem-Bergman, L.; Lindh, J.D. Vitamin D and Respiratory Tract Infections: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. PLoS ONE 2013, 8, e65835. [Google Scholar] [CrossRef]
  31. Sabico, S.; Enani, M.A.; Sheshah, E.; Aljohani, N.J.; Aldisi, D.A.; Alotaibi, N.H.; Alshingetti, N.; Alomar, S.Y.; Alnaami, A.M.; Amer, O.E.; et al. Effects of a 2-Week 5000 IU versus 1000 IU Vitamin D3 Supplementation on Recovery of Symptoms in Patients with Mild to Moderate Covid-19: A Randomized Clinical Trial. Nutrients 2021, 13, 2170. [Google Scholar] [CrossRef]
  32. Amrein, K.; Schnedl, C.; Holl, A.; Riedl, R.; Christopher, K.B.; Pachler, C.; Urbanic Purkart, T.; Waltensdorfer, A.; Munch, A.; Warnkross, H.; 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. [Google Scholar] [CrossRef]
  33. Marshall, J.C.; Murthy, S.; Diaz, J.; Adhikari, N.K.; Angus, D.C.; Arabi, Y.M.; Baillie, K.; Bauer, M.; Berry, S.; Blackwood, B.; et al. A minimal common outcome measure set for COVID-19 clinical research. Lancet Infect. Dis. 2020, 20, e192–e197. [Google Scholar] [CrossRef]
  34. Harris, P.A.; Taylor, R.; Minor, B.L.; Elliott, V.; Fernandez, M.; O’Neal, L.; McLeod, L.; Delacqua, G.; Delacqua, F.; Kirby, J.; et al. The REDCap consortium: Building an international community of software platform partners. J. Biomed. Inform. 2019, 95, 103208. [Google Scholar] [CrossRef] [PubMed]
  35. Harris, P.A.; Taylor, R.; Thielke, R.; Payne, J.; Gonzalez, N.; Conde, J.G. Research electronic data capture (REDCap)—A metadata-driven methodology and workflow process for providing translational research informatics support. J. Biomed. Inform. 2009, 42, 377–381. [Google Scholar] [CrossRef] [PubMed]
  36. Mineva, E.M.; Schleicher, R.L.; Chaudhary-Webb, M.; Maw, K.L.; Botelho, J.C.; Vesper, H.W.; Pfeiffer, C.M. A candidate reference measurement procedure for quantifying serum concentrations of 25-hydroxyvitamin D(3) and 25-hydroxyvitamin D(2) using isotope-dilution liquid chromatography-tandem mass spectrometry. Anal. Bioanal. Chem. 2015, 407, 5615–5624. [Google Scholar] [CrossRef] [PubMed]
  37. Holick, M.F. Vitamin D status: Measurement, interpretation, and clinical application. Ann. Epidemiol. 2009, 19, 73–78. [Google Scholar] [CrossRef] [PubMed]
  38. Bess Dawson-Hughes, M. Patient Education: Vitamin D Deficiency (Beyond the Basics). Available online: https://www.uptodate.com/contents/vitamin-d-deficiency-beyond-the-basics (accessed on 16 August 2023).
  39. Brigham and Women’s Hospital. COVID Protocols—Treatments. Available online: https://covidprotocols.org/en/chapters/treatments/ (accessed on 15 June 2022).
  40. National Institutes of Health. COVID-19 Treatment Guidelines—Therapies. Available online: https://www.covid19treatmentguidelines.nih.gov/therapies/ (accessed on 15 June 2022).
  41. Hernandez, J.L.; Nan, D.; Fernandez-Ayala, M.; Garcia-Unzueta, M.; Hernandez-Hernandez, M.A.; Lopez-Hoyos, M.; Munoz-Cacho, P.; Olmos, J.M.; Gutierrez-Cuadra, M.; Ruiz-Cubillan, J.J.; et al. Vitamin D Status in Hospitalized Patients with SARS-CoV-2 Infection. J. Clin. Endocrinol. Metab. 2021, 106, e1343–e1353. [Google Scholar] [CrossRef]
  42. Im, J.H.; Je, Y.S.; Baek, J.; Chung, M.H.; Kwon, H.Y.; Lee, J.S. Nutritional status of patients with COVID-19. Int. J. Infect. Dis. 2020, 100, 390–393. [Google Scholar] [CrossRef]
  43. Georgoulis, M.; Kontogianni, M.D.; Kechribari, I.; Tenta, R.; Fragopoulou, E.; Lamprou, K.; Perraki, E.; Vagiakis, E.; Yiannakouris, N. Associations between serum vitamin D status and the cardiometabolic profile of patients with obstructive sleep apnea. Hormones 2023. [Google Scholar] [CrossRef]
  44. Drame, M.; Cofais, C.; Hentzien, M.; Proye, E.; Coulibaly, P.S.; Demoustier-Tampere, D.; Destailleur, M.H.; Lotin, M.; Cantagrit, E.; Cebille, A.; et al. Relation between Vitamin D and COVID-19 in Aged People: A Systematic Review. Nutrients 2021, 13, 1339. [Google Scholar] [CrossRef]
  45. Kazemi, A.; Mohammadi, V.; Aghababaee, S.K.; Golzarand, M.; Clark, C.C.T.; Babajafari, S. Association of Vitamin D Status with SARS-CoV-2 Infection or COVID-19 Severity: A Systematic Review and Meta-analysis. Adv. Nutr. 2021, 12, 1636–1658. [Google Scholar] [CrossRef]
  46. Reis, B.Z.; Fernandes, A.L.; Sales, L.P.; Santos, M.D.; Dos Santos, C.C.; Pinto, A.J.; Goessler, K.F.; Franco, A.S.; Duran, C.S.C.; Silva, C.B.R.; et al. Influence of vitamin D status on hospital length of stay and prognosis in hospitalized patients with moderate to severe COVID-19: A multicenter prospective cohort study. Am. J. Clin. Nutr. 2021, 114, 598–604. [Google Scholar] [CrossRef]
  47. Amrein, K.; Scherkl, M.; Hoffmann, M.; Neuwersch-Sommeregger, S.; Kostenberger, M.; Tmava Berisha, A.; Martucci, G.; Pilz, S.; Malle, O. Vitamin D deficiency 2.0: An update on the current status worldwide. Eur. J. Clin. Nutr. 2020, 74, 1498–1513. [Google Scholar] [CrossRef] [PubMed]
  48. Andrade, J.M.; Grandoff, P.G.; Schneider, S.T. Vitamin D Intake and Factors Associated with Self-Reported Vitamin D Deficiency Among US Adults: A 2021 Cross-Sectional Study. Front. Nutr. 2022, 9, 899300. [Google Scholar] [CrossRef] [PubMed]
  49. Gallagher, J.C.; Jindal, P.S.; Smith, L.M. Vitamin D supplementation in young White and African American women. J. Bone Miner. Res. 2014, 29, 173–181. [Google Scholar] [CrossRef]
  50. Bahar-Shany, K.; Ravid, A.; Koren, R. Upregulation of MMP-9 production by TNFalpha in keratinocytes and its attenuation by vitamin D. J. Cell Physiol. 2010, 222, 729–737. [Google Scholar] [CrossRef] [PubMed]
  51. Barlow, P.G.; Beaumont, P.E.; Cosseau, C.; Mackellar, A.; Wilkinson, T.S.; Hancock, R.E.; Haslett, C.; Govan, J.R.; Simpson, A.J.; Davidson, D.J. The human cathelicidin LL-37 preferentially promotes apoptosis of infected airway epithelium. Am. J. Respir. Cell Mol. Biol. 2010, 43, 692–702. [Google Scholar] [CrossRef] [PubMed]
  52. Yang, D.; Chen, Q.; Schmidt, A.P.; Anderson, G.M.; Wang, J.M.; Wooters, J.; Oppenheim, J.J.; Chertov, O. Ll-37, the Neutrophil Granule–And Epithelial Cell–Derived Cathelicidin, Utilizes Formyl Peptide Receptor–Like 1 (Fprl1) as a Receptor to Chemoattract Human Peripheral Blood Neutrophils, Monocytes, and T Cells. J. Exp. Med. 2000, 192, 1069–1074. [Google Scholar] [CrossRef]
  53. Syed Mohd, S.S.; Mishra, A.; Ashraf, M.Z. Vitamin D and Its Relationship with the Pathways Related to Thrombosis and Various Diseases. In Vitamin D; IntechOpen: London, UK, 2021. [Google Scholar]
  54. Wu, Z.; Liu, D.; Deng, F. The Role of Vitamin D in Immune System and Inflammatory Bowel Disease. J. Inflamm. Res. 2022, 15, 3167–3185. [Google Scholar] [CrossRef]
  55. Ko, K.H.; Kim, Y.S.; Lee, B.K.; Choi, J.H.; Woo, Y.M.; Kim, J.Y.; Moon, J.S. Vitamin D deficiency is associated with disease activity in patients with Crohn’s disease. Intest. Res. 2019, 17, 70–77. [Google Scholar] [CrossRef]
  56. Ulitsky, A.; Ananthakrishnan, A.N.; Naik, A.; Skaros, S.; Zadvornova, Y.; Binion, D.G.; Issa, M. Vitamin D deficiency in patients with inflammatory bowel disease: Association with disease activity and quality of life. J. Parenter. Enteral. Nutr. 2011, 35, 308–316. [Google Scholar] [CrossRef]
  57. Calabrese, E.; Zorzi, F.; Monteleone, G.; Del Vecchio Blanco, G. Onset of ulcerative colitis during SARS-CoV-2 infection. Dig. Liver Dis. 2020, 52, 1228–1229. [Google Scholar] [CrossRef]
  58. de-Madaria, E.; Capurso, G. COVID-19 and acute pancreatitis: Examining the causality. Nat. Rev. Gastroenterol. Hepatol. 2021, 18, 3–4. [Google Scholar] [CrossRef] [PubMed]
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Figure 1. Flowchart diagram for patient selection process. Fields with a white background: number of excluded patients due to this reason for exclusion.
Figure 1. Flowchart diagram for patient selection process. Fields with a white background: number of excluded patients due to this reason for exclusion.
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Figure 2. COVID-19-related complications in vitamin D deficient vs. non-deficient patients (shown in % per category, logarithmic scale).
Figure 2. COVID-19-related complications in vitamin D deficient vs. non-deficient patients (shown in % per category, logarithmic scale).
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Figure 3. Overview timeline of COVID-19 therapies adapted according to the KSBL guidelines. * Dexamethasone and aggravation of O2 need within 3 days or need of NIV/HFNO/intubation. ** O2 and within the first 8 days since the beginning of symptoms. *** within 10 days since the beginning of symptoms and negative SARS-CoV-2 N and S antibody or only S after vaccination. **** When Omicron was dominant, replaced Casirivimab/Imdevimab.
Figure 3. Overview timeline of COVID-19 therapies adapted according to the KSBL guidelines. * Dexamethasone and aggravation of O2 need within 3 days or need of NIV/HFNO/intubation. ** O2 and within the first 8 days since the beginning of symptoms. *** within 10 days since the beginning of symptoms and negative SARS-CoV-2 N and S antibody or only S after vaccination. **** When Omicron was dominant, replaced Casirivimab/Imdevimab.
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Figure 4. Odds ratio (or incident rate ratio 1) with 95% confidence intervals for different outcomes depending on serum vitamin D level (per 25 nmol/L increase), adjusted for age, sex, vitamin D supplementation, smoking status, comorbidities, vaccination status, and COVID-19 wave. Severe course of COVID-19 was defined as WHO category severe, critical or death. 1 Incident rate ratio for outcome length of hospital stay.
Figure 4. Odds ratio (or incident rate ratio 1) with 95% confidence intervals for different outcomes depending on serum vitamin D level (per 25 nmol/L increase), adjusted for age, sex, vitamin D supplementation, smoking status, comorbidities, vaccination status, and COVID-19 wave. Severe course of COVID-19 was defined as WHO category severe, critical or death. 1 Incident rate ratio for outcome length of hospital stay.
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Table 1. Definition of COVID-19 severity.
Table 1. Definition of COVID-19 severity.
MildHospitalised without oxygen therapy
ModerateHospitalised with oxygen by a nasal prong or mask
SevereHospitalised with oxygen by non-invasive ventilation (NIV) or high-flow nasal oxygen (HFNO)
CriticalHospitalised and intubated, incl. patients with additional organ support (dialysis, extracorporeal membrane oxygenation (ECMO), vasoactive drugs)
Dead
Modified from the WHO Ordinal Scale for Clinical Improvement [33].
Table 2. Definition of COVID-19 waves.
Table 2. Definition of COVID-19 waves.
First wave27 February 2020 to 30 June 2020
Second wave1 July 2020 to 28 February 2021
Third wave1 March 2021 to 30 June 2021
Fourth wave1 July 2021 to 15 October 2022
Fifth wave16 October 2021 to 31 December 2021
Table 3. Patient baseline characteristics by vitamin D status.
Table 3. Patient baseline characteristics by vitamin D status.
Total Study PopulationVitamin D Deficient (<50 nmol/L)Vitamin D
Non-Deficient
(≥50 nmol/L)		p-Value
n (%)763 (100)343 (47)420 (53)
Age (years), mean ± SD65.28 ± 16.3664.09 ± 17.2766.26 ± 15.530.068
Sex female, n (%)329 (43.1)121 (35.3)208 (49.5)<0.001 ***
BMI (kg/m2) mean ± SD28.18 ± 5.4528.95 ± 5.7227.56 ± 5.140.002 **
Smoking status 0.409
Non-smoker, n (%)107 (14.0)50 (14.6)57 (13.6)
Smoker, n (%)28 (3.7)11 (3.2)17 (4.0)
Former smoker, n (%)98 (12.8)51 (14.9)47 (11.2)
Unknown, n (%)530 (69.5)231 (67.3)299 (71.2)
Pack years, median (IQR)40 (23.5–52.3)40 (25–52.5)37.5 (20.8–52.3)0.504 ‡
Patients with comorbidity, n (%)642 (84.1)295 (86)347 (82.6)0.240
Number of comorbidities, median (IQR)3 (2–4)3 (2–4)3 (2–4)0.212 ‡
Arterial hypertension, n (%)360 (47.2)160 (46.6)200 (47.6)0.846
Cardiac diseases, n (%)231 (30.3)112 (32.7)119 (28.3)0.225
Obesity, n (%)225 (29.7)116 (34.2)109 (26.1)0.018 *
Diabetes, n (%)166 (21.8)83 (24.2)83 (19.8)0.165
Chronic respiratory diseases, n (%)172 (22.5)83 (24.2)89 (21.2)0.367
Immunosuppression, n (%)60 (7.9)18 (5.2)42 (10)0.022 *
Chronic kidney diseases, n (%)161 (21.1)74 (21.6)87 (20.7)0.825
Thyroid diseases, n (%)93 (12.2)33 (9.6)60 (14.3)0.065
Malignant diseases, n (%)100 (13.1)40 (11.7)60 (14.3)0.337
Active Cancer, n (%)32 (4.2)11 (3.2)21 (5)0.295
Chronic liver diseases, n (%)58 (7.6)27 (7.9)31 (7.4)0.907
Neurological disorders, n (%)196 (25.7)73 (21.3)123 (29.3)0.015 *
Electrolyte imbalance, n (%)181 (23.7)75 (21.9)106 (25.2)0.315
COVID-19 vaccination status661 (87) 0.156
Negative (unvaccinated), n (%)616 (81)262 (76)354 (84)
Positive (vaccinated), n (%)45 (6.8)23 (8.1)22 (5.9)
Time between vaccination and admission (days), median (IQR)63 (12.5–200.5)95.5 (10–214.5)46 (13–183)0.978 ‡
25-hydroxy vitamin D measured 5 days before admission or during admission, n (%), mean751 (98.4)339 (98.8)412 (98.1)0.601
BMI = body mass index (kg/m2), SD = standard deviation, IQR = interquartile range. Number of comorbidities summed the presence of the following comorbidities: arterial hypertension, cardiac diseases, obesity (BMI ≥ 30 kg/m2), diabetes, chronic respiratory disease, immunosuppression, chronic kidney disease, thyroid disease, malignant disease, chronic liver disease, neurological disorder and electrolyte imbalance. Continuous variables are shown as mean ± SD and a t-test was applied when normally distributed, or as median with IQR and a Mann–Whitney U test (‡) was applied when not normally distributed. Categorial variables are shown as absolute and relative frequencies and a chi-squared test was used for the analyses. p-values < 0.05 were considered statistically significant. Significance codes: * <0.05, ** <0.01, *** <0.001.
Table 4. COVID-19 severity and outcome by vitamin D status.
Table 4. COVID-19 severity and outcome by vitamin D status.
TotalVitamin D Deficient (<50 nmol/L)Vitamin D
Non-Deficient
(≥50 nmol/L)		p-Value
n (%)763 (100)343 (45)420 (55)
COVID-19 severity category763 (100) 0.561 a
Mild, n (%)255 (33.4)112 (32.7)143 (34)
Moderate, n (%)374 (49)166 (48.4)208 (49.5)
Severe, n (%)27 (3.5)11 (3.2)16 (3.8)
Critical, n (%)38 (5)22 (6.4)16 (3.8)
Death, n (%)69 (9)32 (9.3)37 (8.8)
Oxygen supplementation, n (%)508 (66.6)231 (67.3)277 (66)0.742 a
Death, n (%)69 (9)32 (9.3)37 (8.8)0.903 a
COVID-19-related complications647 (84.8)306 (89.2)341 (81.2)0.003 a
Length of hospital stay alive (LOS) (days), median (IQR)7 (4–11)7 (4–11)7 (4–11)0.865 b
Rehospitalised at KSBL within 30 days, n (%)32 (4.2)17 (5)15 (3.6)0.443 a
LOS = length of hospital stay (days), SD = standard deviation, IQR = interquartile range. a Chi-squared test. b Mann–Whitney U test. Most of the cases had a mild to moderate COVID-19 course throughout all the waves, and oxygen supplementation was used more or less the same over the COVID-19 waves.
Table 5. Median serum vitamin D values for population sub-groups.
Table 5. Median serum vitamin D values for population sub-groups.
Serum Vitamin D (nmol/L), Median (IQR)p-Value
COVID-19 severity
Mild55 (36–76)
Moderate54 (36–76)
Severe55 (36–73)0.649 ₤
Critical45 (34–71)
Dead51 (29–82)
Oxygen supplementation
Yes53 (36–76)0.837 ‡
No55 (35–76)
Death
Yes51 (29–82)0.836 ‡
No54 (35–74)
Rehospitalisation at KSBL within 30 days
Yes45 (32–73)0.402 ‡
No54 (36–76)
Length of hospital stay
1–3 days52 (38–79)0.942 ₤
4–7 days56 (37–74)
8–13 days52 (34–71)
14–21 days55 (36–78)
22–28 days52 (36–86)
>28 days50 (38–70)
COVID-19-related complications
Yes52 (43–82)0.016 ‡*
No64 (35–74)
IQR = interquartile range. Continuous variables are shown as mean ± SD when normally distributed or as median with IQR when not normally distributed, and a Mann–Whitney U test (‡) was applied for analyses between two groups or a Kruskal–Wallis test (₤) between several groups. p-values < 0.05 were considered statistically significant. Significant codes: * <0.05.
Table 6. Analysis of COVID-19 therapies according to vitamin D status.
Table 6. Analysis of COVID-19 therapies according to vitamin D status.
TotalVitamin D Deficient
(<50 nmol/L)		Vitamin D
Non-Deficient
(≥50 nmol/L)
n (%)763 (100)343 (45)420 (55)
Antibiotics, n (%)592 (78)264 (77)328 (78)
Specific COVID-19 therapy, n (%)513 (67)236 (69)277 (66)
Anticoagulants and platelet aggregation inhibitors, n (%)750 (98)336 (98)414 (98)
Antihypertensive therapy, n (%)407 (53)167 (49)240 (57)
Inhalation therapy, n (%)239 (31)102 (30)137 (33)
Vitamin D supplementation, n (%)279 (37)150 (44)129 (31)
Only before hospitalization, n (%)111 (15)21 (14)90 (70)
Only during hospitalization, n (%)168 (22)129 (86)39 (30)
No vitamin D supplementation, n (%)484 (63)193 (56)291 (69)
Additional Organ Support59 (8)27 (8)32 (8)
Dialysis, n (%)5 (1)1 (4)4 (1)
Vasoactive drugs, n (%)45 (6)21 (6)24 (6)
ECMO, n (%)9 (1)5 (19)4 (1)
Vitamin D deficient patients had less antihypertensive therapy (supplemented: 49% vs. non-supplemented: 57%) and less inhalation therapy (supplemented: 30% vs. non-supplemented: 33%). Antibiotics were provided in 78%, whilst specific COVID-19 therapies were only provided in 67%, with dexamethasone being the most frequent.
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Mbata, M.K.; Hunziker, M.; Makhdoomi, A.; Lüthi-Corridori, G.; Boesing, M.; Giezendanner, S.; Muser, J.; Leuppi-Taegtmeyer, A.B.; Leuppi, J.D. Is Serum 25-Hydroxyvitamin D Level Associated with Severity of COVID-19? A Retrospective Study. J. Clin. Med. 2023, 12, 5520. https://doi.org/10.3390/jcm12175520

AMA Style

Mbata MK, Hunziker M, Makhdoomi A, Lüthi-Corridori G, Boesing M, Giezendanner S, Muser J, Leuppi-Taegtmeyer AB, Leuppi JD. Is Serum 25-Hydroxyvitamin D Level Associated with Severity of COVID-19? A Retrospective Study. Journal of Clinical Medicine. 2023; 12(17):5520. https://doi.org/10.3390/jcm12175520

Chicago/Turabian Style

Mbata, Munachimso Kizito, Mireille Hunziker, Anja Makhdoomi, Giorgia Lüthi-Corridori, Maria Boesing, Stéphanie Giezendanner, Jürgen Muser, Anne B. Leuppi-Taegtmeyer, and Jörg D. Leuppi. 2023. "Is Serum 25-Hydroxyvitamin D Level Associated with Severity of COVID-19? A Retrospective Study" Journal of Clinical Medicine 12, no. 17: 5520. https://doi.org/10.3390/jcm12175520

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