Next Article in Journal
Verapamil Attenuates the Severity of Tendinopathy by Mitigating Mitochondrial Dysfunction through the Activation of the Nrf2/HO-1 Pathway
Previous Article in Journal
The Role of Pretreatment Serum Interleukin 6 in Predicting Short-Term Mortality in Patients with Advanced Pancreatic Cancer
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Biomedicines
Volume 12
Issue 4
10.3390/biomedicines12040905
biomedicines-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

Vitamin D Levels in COVID-19 and NonCOVID-19 Pediatric Patients and Its Relationship with Clinical and Laboratory Characteristics

by
Maria Totan
1,2,
Ioana-Octavia Matacuta-Bogdan
1,*,
Adrian Hasegan
1 and
Ionela Maniu
3,4,*
1
Faculty of Medicine, Lucian Blaga University of Sibiu, 2A Lucian Blaga Str., 550169 Sibiu, Romania
2
Clinical Laboratory, Pediatric Clinical Hospital Sibiu, 2-4 Pompeiu Onofreiu Str., 550166 Sibiu, Romania
3
Research Team, Pediatric Clinical Hospital Sibiu, 550166 Sibiu, Romania
4
Research Center in Informatics and Information Technology, Mathematics and Informatics Department, Faculty of Sciences, Lucian Blaga University of Sibiu, 550025 Sibiu, Romania
*
Authors to whom correspondence should be addressed.
Biomedicines 2024, 12(4), 905; https://doi.org/10.3390/biomedicines12040905
Submission received: 26 March 2024 / Revised: 14 April 2024 / Accepted: 16 April 2024 / Published: 18 April 2024
(This article belongs to the Section Molecular and Translational Medicine)
Versions Notes

Abstract

:
25-hydroxyvitamin D [25(OH)D] is a marker with an important role in regulating the inflammatory response. Low concentrations of this vitamin are often found among the population, correlated with increased risk of respiratory tract infections. The aim of the study is to evaluate the relationship between vitamin D levels and clinical and laboratory markers in children and adolescents hospitalized with and without COVID-19. A retrospective study, including all patients tested for SARS-CoV-2 and having vitamin D measured, was performed. All included hospitalized cases, 78 COVID-19 patients and 162 NonCOVID-19 patients, were divided into subgroups according to their 25(OH)D serum levels (<20 ng/mL—deficiency, 20–30 ng/mL—insufficiency, ≥30 ng/mL—normal or <30 ng/mL, ≥30 ng/mL) and age (≤2 years, >2 years). Vitamin D deficiency and insufficiency increased with age, in both COVID-19 and NonCOVID-19 groups. All symptoms were encountered more frequently in cases of pediatric patients with COVID-19 in comparison with NonCOVID-19 cases. The most frequently encountered symptoms in the COVID-19 group were fever, loss of appetite, and nasal congestion. In the NonCOVID-19 group, serum 25(OH)D concentrations were positively correlated with leukocytes, lymphocytes, and LMR and negatively correlated with neutrophils, NLR, and PLR while no significant correlation was observed in the case of COVID-19 group. Differences between vitamin D status and clinical and laboratory parameters were observed, but their clinical significance should be interpreted with caution. The results of this study may offer further support for future studies exploring the mechanisms of the relationship between vitamin D and clinical and laboratory markers as well as for studies investigating the implications of vitamin D deficiency/supplementation on overall health/clinical outcomes of patients with/without COVID-19.

1. Introduction

Vitamin D (sunshine vitamin) is synthesized from 7-dehydrocholesterol at the dermis level (under the action of UVB light of 290–315 nm wavelength) or from the diet/supplements [1]. To obtain a biologically active form, vitamin D3 requires two hydroxylation steps (first in the liver under the action of 24,25-hydroxylase enzyme, second in the kidneys under the action of renal 1-α-hydroxylase enzyme). The resulting active forms 1.25(OH)2 vitamin D which has limited clinical significance and a short half-life in circulation (approximately 4–8 h). Of the two resulting forms, 25(OH)D and 1.25(OH)2D, the first reflects more accurately the vitamin D status because it is more easily measurable (concentration pmol vs. nmol levels), and its half-life circulation (2–3 weeks vs. 4–8 h) [2], 1.25(OH)2D, could be influenced by PTH (parathyroid hormone) [2]. Vitamin D has a role in calcium and phosphorus homeostasis, bone metabolism, and immune response modulation (through several mechanisms) [3]. The implications of vitamin D in immunity has been analyzed more and more in recent years. The presence of vitamin D receptors in a vast majority of immune cells suggests that vitamin D has regulatory functions of both the innate and adaptive immune system [4]. Many studies showed that supplementation of vitamin D exerts a protective role against respiratory infections [5,6]. Previous studies analyzed the relationship/role of vitamin D levels/supplementation in incidence/severity of respiratory tract infections, including COVID-19 [7,8,9]. Studies regarding the relationship between vitamin D and COVID-19 clinical and laboratory profile or disease outcomes, mainly focused on adult patients and often showed conflicting results [10,11,12,13,14,15,16,17,18,19,20,21,22]. A series of studies identified a negative correlation between vitamin D and NLR and CRP [12,13], while other studies did not identify any correlation between them [14,15,16,17]. The study of Yarali et al. [18] reported that in SARS-CoV-2 infection in children, the leukocytes count was normal, while the study of Yamada et al. [19] reported the association between leukocytosis and a poor outcome. The magnesium levels were reported as low and correlated with disease severity by studies [20,21], while the study [22] showed that hypomagnesemia is related with moderate cases. This study aimed to describe and evaluate the vitamin D levels and its association with clinical and laboratory markers in children hospitalized with and without COVID-19 from our geographic area.

2. Materials and Methods

We retrospectively evaluated the electronic medical records for patients (aged under 18 years) who were tested for SARS-CoV-2 by nasopharyngeal swab RT-PCR analysis and had measured serum 25(OH)D concentration at admission for hospitalization in any ward of the Pediatric Clinical Hospital of Sibiu in the period from July 2022 to May 2023. Informed consent was obtained from all patients’ guardians for all subjects included in this study in accordance with the Declaration of Helsinki. The study was approved by the Institutional Review Board of Pediatric Clinical Hospital of Sibiu (No. 2218). Retrospective data including demographic, clinical, and laboratory results were analyzed.
Laboratory examinations included serum biomarkers (calcium (mmol/L), magnesium (mmol/L), urea (mg/dL), creatinine (mg/dL), iron (µmol/L), AST—asparate aminotransferase (U/L), ALT—alanine aminotransferase (U/L), CRP—C-reactive protein (mg/L); hematological parameters (hemoglobin (g/dL), leukocyte (×103/µL), neutrophil (%), lymphocytes (%), monocytes (%), basophils (%), platelet (×103/µL), NLR—neutrophil lymphocyte ratio, PLR—platelet lymphocytes ratio, LMR—lymphocytes monocytes ratio, RBC—erythrocite (×106/µL), MCV—erythrocite mean cell volume (fL), MCH—mean cell hemoglobin (pg), MCHC—mean cell hemoglobin concentration (g/dL)), and immunological tests (25(OH)D (ng/mL)). We considered normal range references, adjusted to age and gender, according to the laboratory guidelines where the study took place [23].
Serum 25(OH)D concentration was measured by chemiluminescence immunoassay method using a Biomerieux kit (Craponne, France). Vitamin D deficiency, insufficiency, and normal values were defined as 25(OH)D levels: <20 ng/mL—deficiency, 20–30 ng/mL—insufficiency, >30 ng/mL—normal [24]. Serum biomarkers were measured using an automated biochemical analyzer, Abbott, C 4000 (Abbott Park, IL, USA). Hematological parameters were measured using an automated hematological analyzer Sysmex XS-1000i (Burladingen, Germany). A confirmed case of COVID-19 was defined as a positive result real-time reverse transcriptase-polymerase-chain reaction (RT-PCR) assay of nasal and pharyngeal swab specimen, using automatic extraction, on a 24-position extractor Lab-Aid 824-Zeesan, and the amplification is done on a BIORAD CFX2s device (Hercules, CA, USA).
Data were analyzed using descriptive statistics. Categorical variables were expressed as counts and percentages and continuous variables were expressed as medians and interquartile range (IQR: 25th percentile–75th percentile). The Shapiro–Wilk test was used to assess the normal distribution of continuous variables. Comparisons across different groups were conducted using the Mann–Whitney U test or Kruskal–Wallis test to determine differences in medians and the Chi-Square test or Fischer exact test to determine differences in proportions. Correlations between vitamin D levels and laboratory variables were analyzed using Spearman’s rank correlation coefficient. Statistical analyses were performed using SPSS v.20 and R v.4.0.5 software.

3. Results

A total of 240 patients tested for SARS-CoV-2 and having vitamin D measured were included in this study. Of this, 78 were hospitalized for COVID-19 and 162 were NonCOVID-19 patients, hospitalized for other pathologies. Regarding gender, the COVID-19 group had 52.56% males (n = 41), and a similar percentage was encountered in the NonCOVID-19 group (56.79%, n = 92). The median age in the COVID-19 group was 10 months while in the NonCOVID-19 group the median age was higher (90.50 months). We divided each group of patients into three subgroups according to their 25 (OH) D serum levels. The number of cases with vitamin D deficiency and insufficiency increased with age, in both COVID-19 and NonCOVID-19 groups, and the percentages were higher in COVID-19 patients compared to NonCOVID-19 patients (COVID-19 vs. NonCOVID-19: <1 year—15.55% vs. 8.70%; 1–2 years—20.00 % vs. 7.69%; 2–6 years—33.34% vs. 15.62%, >6 years—87.5% vs. 63.8%). There were no statistical differences between gender and vitamin D levels. All symptoms were encountered more frequently in cases of pediatric patients with COVID-19 in comparison with NonCOVID-19 cases (p < 0.000). The most frequently encountered symptoms in the COVID-19 group were fever (87.18%), loss of appetite (57.69%), and nasal congestion (50%). Comparison of demographic features and clinical symptoms of patients between children with and without COVID-19 who had deficient, insufficient and normal levels of vitamin D are shown in Table 1.
We analyzed the correlation between vitamin D and various inflammatory and hematological parameters. We divided each group of patients into two subgroups according to their age (age ≤ 2 years, age > 2 years) and the results are presented in Table 2. We also performed a comparative analysis of median values of laboratory characteristics according to vitamin D status and age and the results are presented in Table 3.
It can be observed that, in the case of both age groups, calcium levels and serum magnesium concentration were lower for children with COVID-19 infection and vitamin D < 30 ng/mL compared to the other subgroups. Creatinine levels in children over 2 years old are higher in patients with COVID-19 and vitamin D < 30 ng/mL (median: 0.60, IQR: 0.50–0.72) compared to patients with COVID-19 and vitamin D ≥ 30 ng/mL (median: 0.48, IQR: 0.45–0.55). This trend is also observed in NonCOVID-19 patients (over 2 years old). Regardless of age, iron levels are lower in COVID-19 compared to NonCOVID-19 patients. In children under 2 years old, iron was lower in patients with COVID-19 and vitamin D < 30 ng/mL compared to other subgroups. In both age groups, in the case of COVID-19 patients, a positive association was observed between neutrophils and vitamin D (age ≤ 2 years: 37.10 vs. 41.10; age > 2 years: 64.60 vs. 69.20), and in the case of NonCOVID-19 patients a negative association was observed between neutrophils and vitamin D (age ≤ 2 years: 18.60 vs. 16.70; age > 2 years: 48.80 vs. 40.90). In the NonCOVID-19 group, serum 25(OH)D concentrations were positively correlated with leukocytes (r = 0.203, p = 0.010), lymphocytes (r = 0.428, p = 0.000), and LMR (r = 0.332, p = 0.000) and negatively correlated with neutrophils (r = −0.435, p = 0.000), NLR (r = −0.439, p = 0.000), and PLR (r = −0.267, p = 0.001), while no significant correlation was observed in the case of the COVID-19 group. In both COVID-19 and NonCOVID-19 groups, positive correlations were encountered with AST (COVID-19: r = 0.247, p = 0.041; NonCOVID-19: r = 0.466, p = 0.000) and magnesium (COVID-19: r = 0.470, p = 0.036; NonCOVID-19: r = 0.350, p = 0.000), while negative correlations were encountered with MCV (COVID-19: r = −0.330, p = 0.003; NonCOVID-19: r = −0.355, p = 0.000) and MCH (COVID-19: r = −0.270, p = 0.017; NonCOVID-19: r = −0.183, p = 0.020).

4. Discussion

Recent studies on vitamin D investigated its association in multiple metabolic, physiological, and immunological processes. Its effects on both innate and acquired immunity, cellular and humoral, have been extensively analyzed [8,25,26,27]. Our study evaluated both clinical and laboratory parameters in correlation with the level of vitamin D in children hospitalized with COVID-19 compared to those without this infectious pathology.
The most frequently encountered symptoms in the COVID-19 group were fever, loss of appetite, and respiratory symptoms. Fever was more common in COVID-19 patients (87.18% vs. 8.33%) with normal vitamin D levels in both studied groups (73.52% vs. 63.63%). The next most frequent symptom in the COVID-19 group was decreased appetite followed by respiratory symptoms, including cough (COVID-19: 83.78% vs. Non COVID-19: 71.42%), rhinorrhea (COVID-19: 80% vs. Non COVID-19:57.14%), nasal congestion (COVID-19: 71.79% vs. Non COVID-19: 70%), and breathing difficulties occurring only in COVID-19-positive patients. Fever as a symptom of SARS-CoV-2 infection was reported with varying frequency in pediatric patients, ranging from 43.5% to 90.9% [7,14,28,29,30,31,32,33,34]. The results obtained are similar to those reported by Alpcan et al. [14], who identified fever as the most frequent symptom (61.3%) in patients infected with SARS-CoV-2. They also found that patients with low levels of vitamin D had a lower incidence of fever. Moreover, they note that among respiratory symptoms, cough is the most frequent, followed by dyspnea and rhinorrhea. Heidari et al. reported a higher rate in patients with normal vitamin D levels [35]. In their study, Yilmaz and colleagues [7] identified fever as a symptom in one-third of COVID-19 patients and also a negative correlation between fever and vitamin D, a conclusion similar to that of the study conducted by Shah et al. [36]. Fever correlates with inflammation and cytokines released during SARS-CoV-2 infection. A special role is played by prostaglandin E, which modulates fever but is also correlated with cough. Headache occurs in nearly a quarter of children infected with SARS-CoV-2 included in the study, and in half of the cases, it occurs in subjects with normal serum levels of vitamin D. Alpcan et al. reported a frequency of 12% for this symptom [14].
Hematological parameters are affected in the context of infections, including SARS-CoV-2 infection. Our study showed that, in the case of children under 2 years old, hemoglobin levels were lower in patients with vitamin D < 30 ng/mL, compared to those with vitamin D ≥ 30 ng/mL, in both groups. In our population, iron-deficient anemia is the most common nutritional disease in children under 2 years of age due to the lack of iron supplementation and nutritional habits. Studies showed controversial results. Some reported that lower hemoglobin levels are associated with the severity of COVID-19, especially multiple system inflammatory syndrome [37], while other studies showed no abnormalities in red blood cell count or level of hemoglobin even in severe disease [38,39,40,41].
The current study shows that leukocyte and lymphocyte levels (regardless of age) are lower in COVID-19 patients compared to NonCOVID-19 patients. Serum 25(OH)D concentrations were positively correlated with leukocytes and lymphocytes in the NonCOVID-19 group. Studies [42,43] reported a positive correlation between serum concentrations of vitamin D and lymphocyte count. This finding is consistent with other studies that show that low leukocyte count is one of the hematological modified parameters. The reported percentages vary in wide ranges, from 19% to 47% for different studies [44,45,46]. In the study conducted by Yarali et al., it was shown that most children with COVID-19 had a normal leukocyte count [18]. In the meta-analysis of Yamada et al. on 18 studies that included 3278 patients, leukocytosis was associated with poor outcomes while leukopenia was associated with a better prognosis [19]. Other authors concluded that, for children, leukocyte count may not be a reliable laboratory marker to assess the severity of the disease [46]. Many mechanisms are responsible for lymphopenia found in COVID-19. SARS-CoV-2 virus binds to ACE-2 receptors on the surface of the lymphocytes, invades them and causes them to decompose. The cytokines released during inflammation may induce lymphocyte apoptosis and a disruption in their turnover, contributing to the low lymphocyte count [42,47]. Compared to adults with COVID-19, lymphopenia is rare in children and correlated to more severe forms of the disease. Children naturally have more natural killer cells and therefore lymphopenia is not so frequent [37,38,41,46,48,49].
In terms of neutrophils, we encountered elevated levels in COVID-19 compared to NonCOVID-19 patients, regardless of age. Moreover, in the COVID-19 group, there is a positive association between neutrophils and vitamin D, and for the NonCOVID-19 group we found a negative association between neutrophils and vitamin D in both age groups. The results of the various studies we refer to are contradictory. Some of them report neutropenia to be more prevalent compared to neutrophilia. In the study of Yarali et al. [18], neutropenia was noted in 23.3%, compared to neutrophilia (13.3%), and over 14% from the children with COVID-19 included in the study of Guner Ozenen et al. [50] had neutropenia. Similar results were reported by Argun et al. [45], but his study only included 33 children. In studies [12,18,44,45,50], neutrophilia was associated with the severity and the prognosis of the SARS-CoV-2 infection, especially in those children who developed multi-system inflammatory syndrome (MIS-C). In his study on 26 patients, Pimentel et al. found a higher neutrophil count in the low vitamin D group, but no correlations between vitamin D concentration in the serum and neutrophil count were identified [51].
Our study revealed that, regardless of age, the NLR ratio is higher in COVID-19 when compared to NonCOVID-19 patients. In COVID-19, the neutrophil to lymphocyte ratio was associated with the extent of symptoms, disease severity, and poor outcome for both adults and children [13,37,52,53,54,55,56,57]. The association between NLR and vitamin D is not yet fully understood. The study of Renieris et al. [15] and Pimentel et al. [51] showed that NLR was inversely associated to vitamin D levels, while Gulcan et al. [58] did not identify any correlation between the two parameters.
The study that we conducted showed that thrombocytes tend to be lower for all COVID-19 patients, with the lowest value in children over 2 years old and with vitamin D < 30 (median 240.50, IQR: 220.00–316.50 × 103/μL); 2.6% of COVID-19 patients had thrombocytopenia (<150 × 103/μL). We also noted that in COVID-19 children over 2 years of age, there is a positive trend between platelets and vitamin D. Beyond its classic role in calcium metabolism, vitamin D has other functional roles. The vitamin D deficiency has a critical role in coagulation, inflammation, thrombosis, and endothelial dysfunction and it has been implicated in immunological diseases. In the study of Salamanna et al. [59], the explanation proposed was an increased pro-inflammatory cytokine release and via oxidative stress stimulated megakaryopoiesis and PLT activation. The decrease in platelet count is not common in patients with COVID-19. Studies reported variable percentages, going from 4.8% up to 53.6% [37,60,61,62,63]. These studies proposed several mechanisms for thrombocytopenia found in COVID-19, such as a reduction in thrombopoiesis due to direct infection of bone marrow, SARS-CoV-2 inhibition of bone marrow hematopoiesis, destruction of bone marrow progenitor cells by cytokine storm, excessive destruction of the platelets in the immune processes, and platelet aggregation in the lungs. In their meta-analysis, Lippi et al. [64] showed that a low platelet count was related to a threefold enhanced risk of severe illness and it was a significant factor in mortality of COVID-19 patients. The study [35] reported that in children with COVID-19, the platelet count was lower in many cases compared to adult patients and it was closely related to the severity of the disease.
In the conducted study, a series of biochemical parameters were monitored. We found that the CRP values are higher in the group with COVID-19 compared to the NonCOVID-19 group, regardless of the age of the subjects. The results reported by the different studies are contradictory. A similar conclusion as the one drawn from our study is supported by other studies. These show that CRP values are correlated with the severity of the disease and more elevated in the early stages of inflammatory response [12,28,65,66,67,68,69]. Most studies have identified an inverse association between CRP and vitamin D levels [43,50,69,70,71,72,73]. On the other hand, the studies of Alpcan et al. [14] and Pizzini et al. [74] showed no correlation between vitamin D and CRP. The relationship between CRP and vitamin D in COVID-19 is complex. C-reactive protein is a pentameric protein synthesized by the liver as a response to inflammation of various causes. Its secretion is mainly induced by IL-6. The inflammatory cells involved in inflammation express the nuclear receptor for vitamin D, lowering its serum levels. This leads to the conclusion of an inverse association between CRP and vitamin D concentration. Low levels of vitamin D itself induce cytokines such as TNF-α and IL-1p responsible for low-grade inflammation and high levels of CRP [70]. On the other hand, apparently in COVID-19 patients, high levels of CRP are responsible for decreasing vitamin D levels, making it a “negative acute phase reactant” [71].
The study conducted has revealed that serum levels of calcium, magnesium, and iron are lower in subjects with COVID-19 and vitamin D levels below the threshold value of 30 ng/mL. In both the COVID-19 and NonCOVID-19 groups, positive correlations were encountered between serum 25(OH)D and magnesium. One of the main roles of vitamin D is its involvement in phospho-calcic metabolism by stimulating the intestinal absorption and kidney reabsorption of calcium. Magnesium interacts with vitamin D metabolism by converting the inactive form of vitamin D to the active form. The enzymes involved in the activation require magnesium as a cofactor [75,76]. Recent studies showed magnesium as implicated in immune responses, regulating NK cells and CD8 killer T cells’ cytotoxicity, and decreasing monocyte inflammatory cytokine production. Magnesium deficiency is associated with depressed immune responses, macrophage inflammatory responses, chronic low-grade inflammation, increased inflammatory responses during viral infections, and an increased risk for an inflammatory cytokine storm. The studies [77,78] demonstrated that the prevalence of hypomagnesemia was higher in patients with COVID-19 compared to healthy individuals. In SARS-CoV-2 infection, serum magnesium level conditions the clinical outcome [79,80,81,82], severity of the disease, disease progression, and mortality [77,78]. Results of different studies are controversial. Some studies showed that higher levels of magnesium can exert a protective role in COVID-19 [22,82]. The study of Mardani et al. on patients admitted to Shahid Modarres Hospital in Tehran, Iran, demonstrated that magnesium levels at admission correlated with the risk of in-hospital death for COVID-19 patients [57]. Another retrospective study on hospitalized patients in Wuhan showed that hypomagnesemia was more prevalent in the critical group and non-survivors [20]. In their study, Quilliot et al. performed an analysis in a cohort of COVID-19 adult patients. They demonstrated that in moderate cases, the prevalence of hypomagnesemia was higher and the magnesium levels were significantly lower [22].
In our study, calcemia was lower in subjects with COVID-19 and vitamin D levels below 30 ng/mL. Alteration of the intestinal absorption can explain the changes in the serum calcium concentration, but there could be other mechanisms such as modifications in regulatory mechanisms through PTH and vitamin D, or even a direct action of the virus. In the course of viral infections, calcium ions are essential elements for viral replication, entry, virion maturation, and release [83,84,85]. Studies showed that the levels of total and ionized calcium decreased in COVID-19 patients [83]. Bara El-Kurdi et al. [86] showed that maintaining normal serum calcium levels may prevent severe illness. Calcemia appears associated with the severity and prognosis of COVID-19 infection [87,88]. The disruption of iron homeostasis has been described in COVID-19. The parameters correlated with iron showed deviations from normal values in patients infected with SARS-CoV-2, whether hospitalized or not. The greatest deviations were recorded in critically ill patients [89,90,91,92,93,94].
In the study that we conducted, serum creatinine was higher in infected patients with vitamin D levels above the threshold value. Children’s normal values for creatinine are highly age-dependent and influenced by sex, especially in adolescence when the muscle mass grows rapidly for males [95,96]. In a cohort study on over 1200 participants in Spain, González-Molero et al. demonstrated that 25-hydroxyvitamin D levels were correlated with creatinine in the normal population [97].
Our study has some limitations. It is a single-center, retrospective study, including a small sample size of patients with available 25(OH)D levels, considering unbalanced groups of patients (with different median ages) with COVID-19 but also NonCOVID-19 patients (with other pathologies that could determine variation in serological parameters). Also, the clinical significance of the results should be interpreted with caution due to the fact that the clinical evaluation of the patients and the determination of the biological parameters were carried out at different stages of the disease and were not assessed dynamically; due to the thresholds used for comparison (for levels of 25(OH)D, for age); due to inclusion of a relatively narrow number of (available/reported) symptoms and laboratory markers, and to any other potentially induced bias.

5. Conclusions

The analysis of the data, using continuous or categorical values of 25(OH)D, in the COVID-19/NonCOVID-19 groups and subgroups, provide insights regarding the relationship between vitamin D and clinical and laboratory markers. The results of this study may offer further support for future studies exploring the mechanisms of the relationship between vitamin D and clinical and laboratory markers as well as for studies investigating the implications of vitamin D deficiency/supplementation on overall health/clinical outcomes of patients with/without COVID-19.

Author Contributions

Conceptualization, M.T., I.-O.M.-B. and I.M.; methodology M.T., A.H., I.-O.M.-B. and I.M.; software, I.M.; validation, M.T., I.-O.M.-B., A.H. and I.M.; formal analysis, I.M. and M.T.; investigation, M.T., I.-O.M.-B. and I.M.; data curation, M.T. and I.M.; writing—original draft preparation, M.T., I.-O.M.-B. and I.M.; writing—review and editing, M.T., I.-O.M.-B. and I.M.; supervision, I.-O.M.-B. and M.T. All authors have read and agreed to the published version of the manuscript.

Funding

This study was supported by Lucian Blaga University of Sibiu and Hasso Plattner Foundation through the research grants LBUS-IRG-2023.

Institutional Review Board Statement

The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Ethics Committee of the Pediatric Clinical Hospital Sibiu (no. 2218).

Informed Consent Statement

Informed consent was obtained from all subjects involved in the study.

Data Availability Statement

The data presented in this study are available on reasonable request from the corresponding author.

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Sotodeh-Asl, N.; Tamadon, M.R.; Malek, F.; Zahmatkesh, M. Vitamin D deficiency and psychological disorders. J. Parathyr. Dis. 2014, 2, 21–25. [Google Scholar]
  2. Judd, S.E.; Tangpricha, V. Vitamin D deficiency and risk for cardiovascular disease. Am. J. Med. Sci. 2009, 338, 40–44. [Google Scholar] [CrossRef]
  3. Abdelrazic, M.I.; Rateeb, A.M.; Eid, W.A.; Abdelrazik, E.F.; Abuelela, I.S. Impact of vitamin D deficiency on the severity of COVID 19 infection in pediatrics: A cross-sectional study. Egypt. Pediatr. Assoc. Gaz. 2023, 71, 37. [Google Scholar] [CrossRef]
  4. Martens, P.J.; Gysemans, C.; Verstuyf, A.; Mathieu, C. Vitamin D’s effect on immune function. Nutrients 2020, 12, 1248. [Google Scholar] [CrossRef]
  5. Jolliffe, D.A.; Camargo, C.A.; Sluyter, J.D.; Aglipay, M.; Aloia, J.F.; Ganmaa, D.; Bergman, P.; Bischoff-Ferrari, H.A.; Borzutzky, A.; Damsgaard, C.T.; 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. [Google Scholar]
  6. Charan, J.; Goyal, J.P.; Saxena, D.; Yadav, P. Vitamin D for prevention of respiratory tract infections: A systematic review and meta-analysis. J. Pharmacol. Pharmacother. 2012, 3, 300. [Google Scholar] [CrossRef]
  7. Yılmaz, K.; Şen, V. Is vitamin D deficiency a risk factor for COVID-19 in children? Pediatr. Pulmonol. 2020, 55, 3595–3601. [Google Scholar] [CrossRef]
  8. Kazemi, A.; Mohammadi, V.; Aghababaee, S.K.; Golzarand, M.; Clark, C.C.; 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]
  9. Bucurica, S.; Prodan, I.; Pavalean, M.; Taubner, C.; Bucurica, A.; Socol, C.; Calin, R.; Ionita-Radu, F.; Jinga, M. Association of Vitamin D Deficiency and Insufficiency with Pathology in Hospitalized Patients. Diagnostics 2023, 13, 998. [Google Scholar] [CrossRef]
  10. Jonatan, A.; Setyoningrum, R.A. Serum Vitamin D levels in pediatric patients and its association with COVID-19 clinical manifestation: A meta-analysis and systematic review. GSC Biol. Pharm. Sci. 2021, 17, 76–85. [Google Scholar] [CrossRef]
  11. Tomaszewska, A.; Rustecka, A.; Lipińska-Opałka, A.; Piprek, R.P.; Kloc, M.; Kalicki, B.; Kubiak, J.Z. The role of vitamin D in COVID-19 and the impact of pandemic restrictions on vitamin D blood content. Front. Pharmacol. 2022, 13, 836738. [Google Scholar]
  12. Shahin, W.; Rabie, W.; Alyossof, O.; Alasiri, M.; Alfaki, M.; Mahmoud, E.; Alahmari, H. COVID-19 in children ranging from asymptomatic to a multi-system inflammatory disease: A single-center study. Saudi Med. J. 2021, 42, 299. [Google Scholar] [CrossRef]
  13. Khojah, H.M.; Ahmed, S.A.; Al-Thagfan, S.S.; Alahmadi, Y.M.; Abdou, Y.A. The impact of serum levels of vitamin D3 and its metabolites on the prognosis and disease severity of COVID-19. Nutrients 2022, 14, 5329. [Google Scholar] [CrossRef]
  14. Alpcan, A.; Tursun, S.; Kandur, Y. Vitamin D levels in children with COVID-19: A report from Turkey. Epidemiol. Infect. 2021, 149, e180. [Google Scholar] [CrossRef]
  15. Renieris, G.; Foutadakis, S.; Andriopoulou, T.; Spanou, V.M.; Droggiti, D.E.; Kafousopoulos, D.; Giamarellos-Bourboulis, E.J. Association of Vitamin D with severity and outcome of COVID-19: Clinical and Experimental Evidence. J. Innate Immun. 2023, 16, 1–11. [Google Scholar] [CrossRef]
  16. Bagiu, I.C.; Scurtu, I.L.; Horhat, D.I.; Mot, I.C.; Horhat, R.M.; Bagiu, R.V.; Horhat, F.G. COVID-19 Inflammatory Markers and Vitamin D Relationship in Pediatric Patients. Life 2022, 13, 91. [Google Scholar] [CrossRef]
  17. Szeto, B.; Zucker, J.E.; LaSota, E.D.; Rubin, M.R.; Walker, M.D.; Yin, M.T.; Cohen, A. Vitamin D status and COVID-19 clinical outcomes in hospitalized patients. Endocr. Res. 2021, 46, 66–73. [Google Scholar] [CrossRef]
  18. Yarali, N.; Akcabelen, Y.M.; Unal, Y.; Parlakay, A.N. Hematological parameters and peripheral blood morphologic abnormalities in children with COVID-19. Pediatr. Blood Cancer 2021, 68, e28596. [Google Scholar] [CrossRef]
  19. Yamada, T.; Wakabayashi, M.; Yamaji, T.; Chopra, N.; Mikami, T.; Miyashita, H.; Miyashita, S. Value of leukocytosis and elevated C-reactive protein in predicting severe coronavirus 2019 (COVID-19): A systematic review and meta-analysis. Clin. Chim. Acta 2020, 509, 235–243. [Google Scholar] [CrossRef]
  20. Zhu, L.; Bao, X.; Bi, J.; Lin, Y.; Shan, C.; Fan, X.; Wang, X. Serum magnesium in patients with severe acute respiratory syndrome coronavirus 2 from Wuhan, China. Magnes. Res. 2021, 34, 103. [Google Scholar]
  21. Eskander, M.; Razzaque, M.S. Can maintaining optimal magnesium balance reduce the disease severity of COVID-19 patients? Front. Endocrinol. 2022, 13, 843152. [Google Scholar] [CrossRef]
  22. Quilliot, D.; Bonsack, O.; Jaussaud, R.; Mazur, A. Dysmagnesemia in COVID-19 cohort patients: Prevalence and associated factors. Magnes. Res. 2020, 33, 114. [Google Scholar] [CrossRef]
  23. Heil, W.; Erhardt, V. Reference Ranges for Adults and Children-Pre-Analytical Considerations; Roche Diagnostics GmbH: Mannheim, Germany, 2008; pp. 129–137. [Google Scholar]
  24. Holick, M.F.; Binkley, N.C.; Bischoff-Ferrari, H.A.; Gordon, C.M.; Hanley, D.A.; Heaney, R.P.; Weaver, C.M. Evaluation, treatment, and prevention of vitamin D deficiency: An Endocrine Society clinical practice guideline. J. Clin. Endocrinol. Metab. 2011, 96, 1911–1930. [Google Scholar] [CrossRef]
  25. Carpagnano, G.E.; Di Lecce, V.; Quaranta, V.N.; Zito, A.; Buonamico, E.; Capozza, E.; 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]
  26. 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]
  27. Panfili, F.M.; Roversi, M.; D’argenio, P.; Rossi, P.; Cappa, M.; Fintini, D. Possible role of vitamin D in Covid-19 infection in pediatric population. J. Endocrinol. Investig. 2021, 44, 27–35. [Google Scholar] [CrossRef]
  28. Yasuhara, J.; Kuno, T.; Takagi, H.; Sumitomo, N. Clinical characteristics of COVID-19 in children: A systematic review. Pediatr. Pulmonol. 2020, 55, 2565–2575. [Google Scholar] [CrossRef]
  29. Ekpenyong, E.E.; Akpan, U.O.M.; Oloyede, I.P.; Ekanem, A.M.; Umoette, N.; Peters, E. Spectrum of COVID-19 infection in children in Southern Nigeria. Niger. J. Paediatr. 2022, 49, 17–21. [Google Scholar] [CrossRef]
  30. Kainth, M.K.; Goenka, P.K.; Williamson, K.A.; Fishbein, J.S.; Subramony, A.; Barone, S.; Rubin, L.G. Early experience of COVID-19 in a US children’s hospital. Pediatrics 2020, 146, e2020003186. [Google Scholar] [CrossRef]
  31. De Souza, T.H.; Nadal, J.A.; Nogueira, R.J.; Pereira, R.M.; Brandão, M.B. Clinical manifestations of children with COVID-19: A systematic review. Pediatr. Pulmonol. 2020, 55, 1892–1899. [Google Scholar] [CrossRef]
  32. Viner, R.M.; Ward, J.L.; Hudson, L.D.; Ashe, M.; Patel, S.V.; Hargreaves, D.; Whittaker, E. Systematic review of reviews of symptoms and signs of COVID-19 in children and adolescents. Arch. Dis. Child. 2021, 106, 802–807. [Google Scholar] [CrossRef]
  33. Totan, M.; Gligor, F.G.; Duică, L.; Grigore, N.; Silișteanu, S.; Maniu, I.; Antonescu, E. A Single-Center (Sibiu, Romania), Retrospective Study (March–November 2020) of COVID-19 Clinical and Epidemiological Features in Children. J. Clin. Med. 2021, 10, 3517. [Google Scholar] [CrossRef]
  34. Maniu, I.; Maniu, G.; Totan, M. Clinical and Laboratory Characteristics of Pediatric COVID-19 Population—A Bibliometric Analysis. J. Clin. Med. 2022, 11, 5987. [Google Scholar] [CrossRef]
  35. Heidari, S.; Mohammadi, S.; Fathi, M.; Cigary, S.; Alisamir, M.; Mirkarimi, M.; Aminzadeh, M. Association of vitamin D status with COVID-19 disease severity in pediatric patients: A retrospective observational study. Health Sci. Rep. 2022, 5, e569. [Google Scholar] [CrossRef]
  36. Shah, K.; Varna, V.P.; Pandya, A.; Saxena, D. Low vitamin D levels and prognosis in a COVID-19 pediatric population: A systematic review. QJM Int. J. Med. 2021, 114, 447–453. [Google Scholar]
  37. Liu, L.; She, J.; Bai, Y.; Liu, W. SARS-CoV-2 infection: Differences in hematological parameters between adults and children. Int. J. Gen. Med. 2021, 14, 3035–3047. [Google Scholar] [CrossRef]
  38. Lu, X.; Zhang, L.; Du, H.; Zhang, J.; Li, Y.Y.; Qu, J.; Wong, G.W. SARS-CoV-2 infection in children. N. Engl. J. Med. 2020, 382, 1663–1665. [Google Scholar] [CrossRef]
  39. Parri, N.; Lenge, M.; Buonsenso, D. Coronavirus infection in pediatric emergency departments (CONFIDENCE) research group. Children with Covid-19 in pediatric emergency departments in Italy. N. Engl. J. Med. 2020, 383, 187–190. [Google Scholar] [CrossRef]
  40. Chao, J.Y.; Derespina, K.R.; Herold, B.C.; Goldman, D.L.; Aldrich, M.; Weingarten, J.; Medar, S.S. Clinical characteristics and outcomes of hospitalized and critically ill children and adolescents with coronavirus disease 2019 at a tertiary care medical center in New York City. J. Pediatr. 2020, 223, 14–19. [Google Scholar] [CrossRef]
  41. Kosmeri, C.; Koumpis, E.; Tsabouri, S.; Siomou, E.; Makis, A. Hematological manifestations of SARS-CoV-2 in children. Pediatr. Blood Cancer 2020, 67, e28745. [Google Scholar] [CrossRef]
  42. Ozden, A.; Doneray, H.; Erdeniz, E.H.; Altinkaynak, K.; Igan, H. Clinical and laboratory findings by serum vitamin D levels in children with COVID-19. Eurasian J. Med. 2022, 54, 285. [Google Scholar] [CrossRef] [PubMed]
  43. Bayramoğlu, E.; Akkoç, G.; Ağbaş, A.; Akgün, Ö.; Yurdakul, K.; Selçuk Duru, H.N.; Elevli, M. The association between vitamin D levels and the clinical severity and inflammation markers in pediatric COVID-19 patients: Single-center experience from a pandemic hospital. Eur. J. Pediatr. 2021, 180, 2699–2705. [Google Scholar] [CrossRef] [PubMed]
  44. Alkan, G.; Sert, A.; Emiroglu, M.; Tuter Oz, S.K.; Vatansev, H. Evaluation of hematological parameters and inflammatory markers in children with COVID-19. Ir. J. Med. Sci. 2021, 191, 1725–1733. [Google Scholar] [CrossRef]
  45. Argun, M.; İnan, D.B.; Öz, H.T.H.; Duyar, M.O.; Başargan, G.; Elmalı, F.; Çelik, İ. Lymphocyte subsets in mild COVID-19 pediatric patients. Turk. Arch. Pediatr. 2022, 57, 210. [Google Scholar] [CrossRef] [PubMed]
  46. Henry, B.M.; Lippi, G.; Plebani, M. Laboratory abnormalities in children with novel coronavirus disease 2019. Clin. Chem. Lab. Med. 2022, 58, 1135–1138. [Google Scholar] [CrossRef] [PubMed]
  47. Bucurica, S.; Ionita, R.F.; Bucurica, A.; Socol, C.; Prodan, I.; Tudor, I.; Sirbu, C.A.; Plesa, F.C.; Jinga, M. Risk of New-Onset Liver Injuries Due to COVID-19 in Preexisting Hepatic Conditions—Review of the Literature. Medicina 2023, 59, 62. [Google Scholar] [CrossRef]
  48. Lee, P.I.; Hu, Y.L.; Chen, P.Y.; Huang, Y.C.; Hsueh, P.R. Are children less susceptible to COVID-19? J. Microbiol. Immunol. Infect. 2020, 53, 371. [Google Scholar] [CrossRef] [PubMed]
  49. Wei, M.; Yuan, J.; Liu, Y.; Fu, T.; Yu, X.; Zhang, Z.J. Novel coronavirus infection in hospitalized infants under 1 year of age in China. JAMA 2020, 323, 1313–1314. [Google Scholar]
  50. Guner Ozenen, G.; Sahbudak Bal, Z.; Umit, Z.; Bilen, N.M.; Yildirim Arslan, S.; Yurtseven, A.; Saz, E.U.; Burcu, B.; Sertoz, R.; Kurugol, Z.; et al. Demographic, clinical, and laboratory features of COVID-19 in children: The role of mean platelet volume in predicting hospitalization and severity. J. Med. Virol. 2021, 93, 3227–3237. [Google Scholar] [CrossRef]
  51. Pimentel, G.D.; Vega, M.C.D.; Pichard, C. Low vitamin D levels and increased neutrophil in patients admitted at ICU with COVID-19. Clin. Nutr. ESPEN 2021, 44, 466–468. [Google Scholar] [CrossRef]
  52. Lagunas-Rangel, F.A. Neutrophil-to-lymphocyte ratio and lymphocyte-to-C-reactive protein ratio in patients with severe coronavirus disease 2019 (COVID-19): A meta-analysis. J. Med. Virol. 2020, 92, 1733. [Google Scholar] [CrossRef]
  53. Ciccullo, A.; Borghetti, A.; Dal Verme, L.Z.; Tosoni, A.; Lombardi, F.; Garcovich, M.; Group, G.A.C. Neutrophil-to-lymphocyte ratio and clinical outcome in COVID-19: A report from the Italian front line. Int. J. Antimicrob. Agents 2020, 56, 106017. [Google Scholar] [CrossRef] [PubMed]
  54. Asghar, M.S.; Kazmi, S.J.H.; Khan, N.A.; Akram, M.; Khan, S.A.; Rasheed, U.; Memon, G.M. Correction: Clinical profiles, characteristics, and outcomes of the first 100 admitted COVID-19 patients in Pakistan: A single-center retrospective study in a tertiary care hospital of Karachi. Cureus 2020, 12, c34. [Google Scholar]
  55. Bari, A.; Ch, A.; Bano, I.; Saqlain, N. Is leukopenia and lymphopenia a characteristic feature of COVID-19 in children? Pak. J. Med. Sci. 2021, 37, 869. [Google Scholar] [CrossRef] [PubMed]
  56. Yildiz, E.; Cigri, E.; Dincer, Z.; Narsat, M.A.; Calisir, B. High neutrophil/lymphocyte ratios in symptomatic pediatric COVID-19 patients. Cough 2021, 27, 34–42. [Google Scholar]
  57. Mardani, R.; Alamdary, A.; Nasab, S.M.; Gholami, R.; Ahmadi, N.; Gholami, A. Association of vitamin D with the modulation of the disease severity in COVID-19. Virus Res. 2020, 289, 198148. [Google Scholar]
  58. Gulcan, O.; Berrin Zinnet, E.; Pinar, A.; Duygu, K.S.; Feyza, O.U.; Ilknur, A. Is there a relationship between vitamin D levels, inflammatory parameters, and clinical severity of COVID-19 infection? Bratisl. Med. J./Bratisl. Lek. Listy 2022, 123, 421. [Google Scholar]
  59. Salamanna, F.; Maglio, M.; Sartori, M.; Landini, M.P.; Fini, M. Vitamin D and platelets: A menacing duo in COVID-19 and potential relation to bone remodeling. Int. J. Mol. Sci. 2021, 22, 10010. [Google Scholar] [CrossRef] [PubMed]
  60. Kim, E.S.; Chin, B.S.; Kang, C.K.; Kim, N.J.; Kang, Y.M.; Choi, J.P.; Oh, M.D. Clinical course and outcomes of patients with severe acute respiratory syndrome coronavirus 2 infection: A preliminary report of the first 28 patients from the Korean cohort study on COVID-19. J. Korean Med. Sci. 2020, 35, e142. [Google Scholar] [CrossRef]
  61. Cheung, C.K.M.; Law, M.F.; Lui, G.C.Y.; Wong, S.H.; Wong, R.S.M. Coronavirus disease 2019 (COVID-19): A haematologist’s perspective. Acta Haematol. 2021, 144, 10–23. [Google Scholar] [CrossRef]
  62. Xu, X.W.; Wu, X.X.; Jiang, X.G.; Xu, K.J.; Ying, L.J.; Ma, C.L.; Li, L.J. Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-Cov-2) outside of Wuhan, China: Retrospective case series. BMJ 2020, 368, m606. [Google Scholar] [CrossRef] [PubMed]
  63. Chen, W.; Li, Z.; Yang, B.; Wang, P.; Zhou, Q.; Zhang, Z.; Zhou, H. Delayed-phase thrombocytopenia in patients with coronavirus disease 2019 (COVID-19). Br. J. Haematol. 2020, 190, 179–184. [Google Scholar] [CrossRef] [PubMed]
  64. Lippi, G.; Plebani, M.; Henry, B.M. Thrombocytopenia is associated with severe coronavirus disease 2019 (COVID-19) infections: A meta-analysis. Clin. Chim. Acta 2020, 506, 145–148. [Google Scholar] [CrossRef] [PubMed]
  65. Gebrecherkos, T.; Challa, F.; Tasew, G.; Gessesse, Z.; Kiros, Y.; Gebreegziabxier, A.; Wolday, D. Prognostic value of C-reactive protein in SARS-CoV-2 infection: A simplified biomarker of COVID-19 severity in Northern Ethiopia. Infect. Drug Resist. 2023, 16, 3019–3028. [Google Scholar] [CrossRef] [PubMed]
  66. Mohammedsaeed, W.; Alsehli, F.; Alfarsi, L.; Bakhsh, A.; Alzahrani, M.; Almarwani, M.; Dossary, F. COVID-19 in Pediatric Patients: A Study Based on Biomarker Levels. Cureus 2023, 15, e39408. [Google Scholar] [CrossRef] [PubMed]
  67. Bhumbra, S.; Malin, S.; Kirkpatrick, L.; Khaitan, A.; John, C.C.; Rowan, C.M.; Enane, L.A. Clinical features of critical coronavirus disease 2019 in children. Pediatr. Crit. Care Med. 2020, 21, e948–e953. [Google Scholar] [CrossRef] [PubMed]
  68. Luan, Y.Y.; Yin, C.H.; Yao, Y.M. Update advances on C-reactive protein in COVID-19 and other viral infections. Front. Immunol. 2021, 12, 720363. [Google Scholar] [CrossRef] [PubMed]
  69. Yitbarek, G.Y.; Walle Ayehu, G.; Asnakew, S.; Ayele, F.Y.; Bariso Gare, M.; Mulu, A.T.; Melesie, B.D. The role of C-reactive protein in predicting the severity of COVID-19 disease: A systematic review. SAGE Open Med. 2021, 9, 20503121211050755. [Google Scholar] [CrossRef] [PubMed]
  70. Daneshkhah, A.; Agrawal, V.; Eshein, A.; Subramanian, H.; Roy, H.K.; Backman, V. The possible role of vitamin D in suppressing cytokine storm and associated mortality in COVID-19 patients. medRxiv 2020. [Google Scholar] [CrossRef]
  71. Latifi-Pupovci, H.; Namani, S.; Ahmetaj-Shala, B.; Pajaziti, A.; Bunjaku, G.; Ajazaj Berisha, L.; Kotori, A. Biomarkers of Inflammation among Patients with COVID-19: A Single-Centre Prospective Study from Prishtina, Kosovo. Can. J. Infect. Dis. Med. Microbiol. 2022, 2022, 4461647. [Google Scholar] [CrossRef]
  72. Demir, A.D.; Durmaz, Z.H. A Comparison of vitamin D deficiency with neutrophil lymphocyte ratio and CRP levels in Covid-19 patients. Med. Sci. Discov. 2021, 8, 306–309. [Google Scholar] [CrossRef]
  73. Saponaro, F.; Franzini, M.; Okoye, C.; Antognoli, R.; Campi, B.; Scalese, M.; Saba, A. Is there a crucial link between vitamin D status and inflammatory response in patients with COVID-19? Front. Immunol. 2022, 12, 745713. [Google Scholar] [CrossRef]
  74. Pizzini, A.; Aichner, M.; Sahanic, S.; Böhm, A.; Egger, A.; Hoermann, G.; Löffler-Ragg, J. Impact of vitamin D deficiency on COVID-19—A prospective analysis from the CovILD Registry. Nutrients 2020, 12, 2775. [Google Scholar] [CrossRef]
  75. Razzaque, M.S. Magnesium: Are we consuming enough? Nutrients 2018, 10, 1863. [Google Scholar] [CrossRef] [PubMed]
  76. Uwitonze, A.M.; Razzaque, M.S. Role of magnesium in vitamin D activation and function. J. Osteopath. Med. 2018, 118, 181–189. [Google Scholar] [CrossRef] [PubMed]
  77. Guerrero-Romero, F.; Micke, O.; Simental-Mendía, L.E.; Rodríguez-Morán, M.; Vormann, J.; Iotti, S.; Nechifor, M. Importance of magnesium status in COVID-19. Biology 2023, 12, 735. [Google Scholar] [CrossRef] [PubMed]
  78. Guerrero-Romero, F.; Mercado, M.; Rodriguez-Moran, M.; Ramírez-Renteria, C.; Martínez-Aguilar, G.; Marrero-Rodríguez, D.; Sanchez-García, M.L. Magnesium-to-calcium ratio and mortality from COVID-19. Nutrients 2022, 14, 1686. [Google Scholar] [CrossRef]
  79. Sugimoto, J.; Romani, A.M.; Valentin-Torres, A.M.; Luciano, A.A.; Ramirez Kitchen, C.M.; Funderburg, N.; Bernstein, H.B. Magnesium decreases inflammatory cytokine production: A novel innate immunomodulatory mechanism. J. Immunol. 2012, 188, 6338–6346. [Google Scholar] [CrossRef]
  80. Nielsen, F.H. Magnesium deficiency and increased inflammation: Current perspectives. J. Inflamm. Res. 2018, 11, 25–34. [Google Scholar] [CrossRef]
  81. DiNicolantonio, J.J.; O’Keefe, J.H. Magnesium and vitamin D deficiency as a potential cause of immune dysfunction, cytokine storm and disseminated intravascular coagulation in COVID-19 patients. Mol. Med. 2021, 118, 68. [Google Scholar]
  82. Trapani, V.; Rosanoff, A.; Baniasadi, S.; Barbagallo, M.; Castiglioni, S.; Guerrero-Romero, F.; Maier, J.A. The relevance of magnesium homeostasis in COVID-19. Eur. J. Nutr. 2022, 61, 625–636. [Google Scholar] [CrossRef] [PubMed]
  83. Cappellini, F.; Brivio, R.; Casati, M.; Cavallero, A.; Contro, E.; Brambilla, P. Low levels of total and ionized calcium in blood of COVID-19 patients. Clin. Chem. Lab. Med. 2020, 58, e171–e173. [Google Scholar] [CrossRef] [PubMed]
  84. Zhou, Y.; Frey, T.K.; Yang, J.J. Viral calciomics: Interplays between Ca2+ and virus. Cell Calcium 2009, 46, 1–17. [Google Scholar] [CrossRef] [PubMed]
  85. Qu, Y.; Sun, Y.; Yang, Z.; Ding, C. Calcium ions signaling: Targets for attack and utilization by viruses. Front. Microbiol. 2022, 13, 889374. [Google Scholar] [CrossRef]
  86. El-Kurdi, B.; Khatua, B.; Rood, C.; Snozek, C.; Cartin-Ceba, R.; Singh, V.P.; Pannala, R. Mortality from coronavirus disease 2019 increases with unsaturated fat and may be reduced by early calcium and albumin supplementation. Gastroenterology 2020, 159, 1015–1018. [Google Scholar] [CrossRef] [PubMed]
  87. Sun, J.K.; Zhang, W.H.; Zou, L.; Liu, Y.; Li, J.J.; Kan, X.H.; Qi, J.W. Serum calcium as a biomarker of clinical severity and prognosis in patients with coronavirus disease 2019. Aging 2020, 12, 11287. [Google Scholar] [CrossRef] [PubMed]
  88. Beheshti, M.; Neisi, N.; Parsanahad, M.; Rasti, M.; Nashibi, R.; Cheraghian, B. Correlation of vitamin D levels with serum parameters in Covid-19 patients. Clin. Nutr. ESPEN 2023, 55, 325–331. [Google Scholar] [CrossRef] [PubMed]
  89. Suriawinata, E.; Mehta, K.J. Iron and iron-related proteins in COVID-19. Clin. Exp. Med. 2023, 23, 969–991. [Google Scholar] [CrossRef]
  90. Sonnweber, T.; Boehm, A.; Sahanic, S.; Pizzini, A.; Aichner, M.; Sonnweber, B.; Weiss, G. Persisting alterations of iron homeostasis in COVID-19 are associated with non-resolving lung pathologies and poor patients’ performance: A prospective observational cohort study. Respir. Res. 2020, 21, 276. [Google Scholar] [CrossRef]
  91. Hippchen, T.; Altamura, S.; Muckenthaler, M.U.; Merle, U. Hypoferremia is associated with increased hospitalization and oxygen demand in COVID-19 patients. Hemasphere 2020, 4, e492. [Google Scholar] [CrossRef]
  92. Yağcı, S.; Serin, E.; Acicbe, Ö.; Zeren, M.I.; Odabaşı, M.S. The relationship between serum erythropoietin, hepcidin, and haptoglobin levels with disease severity and other biochemical values in patients with COVID-19. Int. J. Lab. Hematol. 2021, 43, 142–151. [Google Scholar] [CrossRef] [PubMed]
  93. Zhao, K.; Huang, J.; Dai, D.; Feng, Y.; Liu, L.; Nie, S. Serum iron level as a potential predictor of coronavirus disease 2019 severity and mortality: A retrospective study. Open Forum Infect. Dis. 2020, 7, 250. [Google Scholar] [CrossRef] [PubMed]
  94. Shah, A.; Frost, J.N.; Aaron, L.; Donovan, K.; Drakesmith, H.; Collaborators. Systemic hypoferremia and severity of hypoxemic respiratory failure in COVID-19. Crit. Care 2020, 24, 320. [Google Scholar] [CrossRef] [PubMed]
  95. den Bakker, E.; Gemke, R.J.; Bökenkamp, A. Endogenous markers for kidney function in children: A review. Crit. Rev. Clin. Lab. Sci. 2018, 55, 163–183. [Google Scholar] [CrossRef] [PubMed]
  96. Chuang, G.T.; Tsai, I.J.; Tsau, Y.K. Serum Creatinine Reference Limits in Pediatric Population—A Single Center Electronic Health Record-Based Database in Taiwan. Front. Pediatr. 2021, 9, 793446. [Google Scholar] [CrossRef]
  97. González-Molero, I.; Morcillo, S.; Valdés, S.; Pérez-Valero, V.; Botas, P.; Delgado, E.; Soriguer, F. Vitamin D deficiency in Spain: A population-based cohort study. Eur. J. Clin. Nutr. 2011, 65, 321–328. [Google Scholar] [CrossRef]
Table 1. Demographics and clinical characteristics of children.
Table 1. Demographics and clinical characteristics of children.
CharacteristicsCOVID-19
78 (32.5)		NonCOVID-19
162 (67.5)		COVID-19 vs. Non-COVID-19
Total
COVID		Vitamin DTotal NonCOVIDVitamin D
Def.
6 (7.69)		Insuf.
15 (19.23)		Normal
57 (73.08)		pDef.
24 (14.81)		Insuf.
44 (27.16)		Normal
94 (58.02)		pp
Gender
Male41 (52.56)3 (50.00)8 (53.33)30 (52.63)0.99092 (56.79)10 (41.67)27 (61.36)55 (58.51)0.2560.537
Female37 (47.44)3 (50.00)7 (46.67)27 (47.37)70 (43.21)14 (58.33)17 (38.64)39 (41.49)
Age
median
(IQR)		10.00
(6; 27)		118.50
(46; 179)		21.00
(8; 52)		9.00
(6; 20)		0.01090.50
(31; 135)		129.50
(93; 178)		119.00
(91; 157)		43.50
(17; 101)		0.0000.000
<1 year45 (57.69)1 (16.67)6 (40.00)38 (66.67)0.00023 (14.20)1 (4.17)1 (2.27)21 (22.34)0.0000.000
1–2 years10 (12.82)0 (0.00)2 (13.33)8 (14.04)13 (8.02)1 (4.17)0 (0.00)12 (12.77)
2–6 years15 (19.23)1 (16.67)4 (26.67)10 (17.54)32 (19.75)0 (0.00)5 (11.36)27 (28.72)
6–10 years2 (2.56)1 (16.67)0 (0.00)1 (1.75)39 (24.07)6 (25.00)17 (38.64)16 (17.02)
>10 years6 (7.69)3 (50.00)3 (20.00)0 (0.00)55 (33.95)16 (66.67)21 (47.73)18 (19.15)
Symptoms
fever68 (87.18)4 (66.67)14 (93.33)50 (87.72)0.24911 (6.79)2 (8.33)2 (4.55)7 (7.45)0.7770.000
loss of appetite45 (57.69)2 (33.33)8 (53.33)35 (61.40)0.38712 (7.41)2 (8.33)4 (9.09)6 (6.38)0.8370.000
cough37 (47.44)2 (33.33)4 (26.67)31 (54.39)0.1247 (4.32)1 (4.17)1 (2.27)5 (5.32)0.7140.000
diarrhea23 (29.49)0 (0.00)3 (20.00)20 (35.09)0.1345 (3.09)0 (0.00)2 (4.55)3 (3.19)0.5820.000
vomiting26 (33.33)1 (16.67)4 (26.67)21 (36.84)0.5058 (4.94)0 (0.00)5 (11.36)3 (3.19)0.0570.000
headache14 (17.95)3 (50.00)4 (26.67)7 (12.28)0.04517 (10.49)5 (20.83)5 (11.36)7 (7.45)0.1580.107
rhinorrhea24 (30.77)2 (33.33)3 (20.00)19 (33.33)0.6037 (4.32)1 (4.17)2 (4.55)4 (4.26)0.9960.000
nasal congest.39 (50.00)4 (66.67)7 (46.67)28 (49.12)0.68710 (6.17)2 (8.33)1 (2.27)7 (7.45)0.4470.000
rash19 (24.36)0 (0.00)1 (6.67)18 (31.58)0.0483 (1.85)0 (0.00)1 (2.27)2 (2.13)0.7650.000
breathing diff.15 (19.23)0 (0.00)0 (0.00)15 (26.32)0.0330 (0.00)0 (0.00)0 (0.00)0 (0.00)-0.000
IQR—interquartile range (IQR: 25th percentile–75th percentile); 25(OH)D levels: Def.—deficiency: <20 ng/mL, Insuf.—insufficiency: 20–30 ng/mL, Normal: ≥30 ng/mL; nasal congest.—nasal congestion; breathing diff.—breathing difficulties.
Table 2. Correlation between vitamin D and laboratory characteristics of children.
Table 2. Correlation between vitamin D and laboratory characteristics of children.
Laboratory CharacteristicsAll
COVID-19		COVID-19
78 (32.5)		All
NonCOVID-19		NonCOVID-19
162 (67.5)
≤2 Years>2 Years≤2 Years>2 Years
rprprprprprp
calcium0.1700.3450.2720.2090.0360.9200.353 **0.0000.390 *0.0270.1620.077
magnesium0.470 *0.0360.4440.111−0.3710.4680.350 **0.0000.0600.7760.270 **0.005
urea−0.1690.145−0.0150.912−0.2120.357−0.0830.3170.3330.0730.1370.143
creatinine−0.1370.2350.311 *0.021−0.547 **0.008−0.446 **0.0000.0460.812−0.281 **0.002
iron0.0110.9260.1010.496−0.2450.2850.0270.7710.3050.1080.0900.392
AST0.247 *0.0410.0530.7160.0550.8180.466 **0.0000.1850.3270.322 **0.001
ALT0.1450.2080.0710.605−0.1210.5930.1240.129−0.0550.7650.0080.928
CRP0.1390.2260.0970.4820.2390.272−0.1550.075−0.0440.816−0.1250.209
hemoglobin−0.1320.2490.2660.050−0.2440.261−0.395 **0.000−0.0030.988−0.214 *0.018
leukocyte−0.0890.441−0.1460.2860.0750.7350.203 *0.0100.0560.7440.0630.489
neutrophils−0.0630.5870.0890.5220.3410.111−0.435 **0.0000.1950.254−0.205 *0.023
lymphocytes0.0280.811−0.0780.576−0.2540.2420.428 **0.000−0.1540.3710.215 *0.017
monocytes0.1600.164−0.0550.695−0.2040.3500.0000.9990.0210.9040.0070.937
eosinophils−0.0230.8420.0320.817−0.2650.2230.1090.173−0.0430.8040.0540.555
basophils0.1090.3440.1480.279−0.1460.507−0.1130.1560.0290.867−0.1080.233
platelet−0.0800.485−0.1920.161−0.0940.6680.0790.3220.0000.998−0.0740.413
NLR−0.0400.7310.0950.4940.2920.176−0.439 **0.0000.1130.510−0.209 *0.020
PLR−0.0620.594−0.0430.7550.2270.297−0.267 **0.001−0.0140.938−0.197 *0.029
LMR−0.1230.287−0.0280.840−0.2530.2440.332 **0.000−0.0280.8720.1660.066
RBC0.0480.6760.283 *0.036−0.0780.723−0.313 **0.000−0.2130.213−0.1720.055
MCV−0.330 *0.003−0.2370.081−0.3670.085−0.355 **0.0000.1090.526−0.277 **0.002
MCH−0.270 *0.017−0.2100.1230.0140.948−0.183 *0.0200.0550.750−0.0630.484
MCHC0.0930.4190.1020.4600.553 **0.0060.287 **0.000−0.0690.6900.339 **0.000
AST—asparate aminotransferase, ALT—alanine aminotransferase, CRP—C-reactive protein, NLR—neutrophil lymphocyte ratio, PLR—platelet lymphocytes ratio, LMR—lymphocytes monocytes ratio, RBC—erythrocite, MCV—erythrocite mean cell volume, MCH—mean cell hemoglobin, MCHC—mean cell hemoglobin concentration, *, ** correlation is significant at 0.05, 0.01 level.
Table 3. Comparison of median values of laboratory characteristics according to vitamin D levels and age.
Table 3. Comparison of median values of laboratory characteristics according to vitamin D levels and age.
≤2 Years>2 Years
COVID-19,
vit. D < 30		COVID-19,
vit. D ≥ 30		NonCOVID-19, vit. D < 30NonCOVID-19, vit. D ≥ 30pCOVID-19,
vit. D < 30		COVID-19,
vit. D ≥ 30		NonCOVID-19, vit. D < 30NonCOVID-19, vit. D ≥ 30p
calcium2.36
(2.28; 2.48)		2.40
(2.34; 2.48)		2.49
(2.41; 2.57)		2.53
(2.47; 2.60)		0.0012.41
(2.27; 2.43)		2.45
(2.36; 2.47)		2.41
(2.35; 2.49)		2.43
(2.38; 2.51)		0.354
magnesium0.83
(0.76; 0.89)		0.97
(0.92; 1.01)		0.86
(0.81; 0.90)		0.87
(0.85; 0.93)		0.0320.82
(0.80; 0.88)		0.86
(0.86; 0.86)		0.81
(0.79; 0.85)		0.85
(0.80; 0.88)		0.023
urea17.00
(14.00; 20.00)		18.00
(13.00; 22.00)		16.00
(7.00; 47.00)		18.00
(15.00; 22.00)		0.91320.00
(17.50; 27.60)		19.00
(17,00; 27.00)		25.00
(21.00; 30.00)		27.00
(22.00; 31.00)		0.060
creatinine0.39
(0.35; 0.41)		0.43
(0.37; 0.46)		0.36
(0.32; 0.44)		0.41
(0.38; 0.43)		0.1970.60
(0.50; 0.72)		0.48
(0.45; 0.55)		0.57
(0.52; 0.65)		0.52
(0.47; 0.60)		0.011
iron5.53
(3.61; 8.01)		6.68
(3.86; 9.06)		7.02
(6.05; 7.98)		11.56
(8.72; 14.93)		0.0025.27
(2.48; 14.67)		4.25
(2.74; 7.48)		12.51
(9.30; 18.20)		14.40
(7.34; 19.21)		0.000
AST53.00
(47.00; 71.00)		55.00
(41.50; 64.00)		37.50
(26.00; 49.00)		41.00
(36.50; 49.50)		0.02127.00
(21.50; 48.00)		39.00
(30.00; 43.00)		23.00
(18.00; 29.00)		30.00
(24.50; 33.00)		0.001
ALT27.00
(23.00; 41.00)		29.00
(20.00; 40.00)		22.00
(11.00; 49.00)		24.00
(17.00; 31.00)		0.33518.50
(14.50; 26.00)		16.50
(12.00; 21.00)		16.00
(12.00; 22.00)		16.00
(13.00; 24.00)		0.830
CRP3.51
(2.00; 6.97)		4.35
(2.04; 11.86)		2.00
(2.00; 2.00)		2.00
(2.00; 2.00)		0.0007.69
(2.00; 25.41)		9.46
(2.00; 26.50)		2.00
(2.00; 3.00)		2.00
(2.00; 2.00)		0.009
hemoglobin9.60
(9.40; 10.40)		11.10
(10.20; 11.70)		10.30
(7.20; 11.10)		11.40
(10.80; 11.80)		0.00412.80
(11.85; 13.40)		12.60
(11.80; 13.40)		13.40
(12.40; 14.20)		12.58
(11.90; 13.60)		0.039
leukocyte6.98
(4.82; 7.91)		6.31
(4.69; 9.94)		9.76
(8.34; 12.32)		9.67
(7.91; 12.10)		0.0066.99
(5.10; 9.59)		6.95
(5.49; 8.71)		7.28
(6.28; 9.11)		7.35
(6.31; 8.95)		0.741
neutrophils37.10
(31.30; 47.30)		41.10
(24.90; 53.80)		18.60
(11.50; 29.20)		16.70
(13.80; 23.60)		0.00064.60
(47.20; 76.50)		69.20
(52.10; 84.00)		48.80
(37.40; 53.40)		40.90
(29.70; 53.30)		0.000
lymphocytes44.90
(29.70; 57.60)		42.60
(31.30; 56.10)		72.60
(55.60; 79.60)		70.50
(61.50; 74.80)		0.00025.15
(16.15; 41.65)		24.40
(11.30; 33.60)		40.00
(34.50; 50.10)		46.10
(34.75; 54.70)		0.000
monocytes15.60
(12.70; 19.60)		15.20
(9.90; 21.00)		6.50
(6.10; 12.30)		9.20
(7.50; 10.40)		0.0007.50
(5.75; 10.80)		5.50
(4.40; 8.60)		8.70
(7.20; 10.10)		9.00
(7.60; 10.70)		0.020
eosinophils0.20
(0.00; 0.80)		0.35
(0.00; 1.10)		2.40
(2.30; 2.50)		2.80
(2.40; 3.50)		0.0000.15
(0.00; 3.10)		0.30
(0.00; 0.70)		2.40
(1.40; 4.60)		2.70
(1.60; 3.90)		0.000
basophils0.30
(0.20; 0.40)		0.20
(0.20; 0.50)		0.20
(0.10; 0.30)		0.30
(0.20; 0.40)		0.6690.15
(0.10; 0.45)		0.20
(0.10; 0.30)		0.30
(0.20; 0.50)		0.30
(0.20; 0.50)		0.010
platelet348.00
(315.00; 422.00)		283.50
(230.00; 368.00)		356.00
(251.00; 644.00)		360.00
(291.00; 446.00)		0.038240.50
(220.00; 316.50)		263.00
(212.00; 324.00)		315.00
(245.00; 372.00)		281.50
(223.00; 345.00)		0.201
NLR0.90
(0.64; 1.44)		0.99
(0.46; 0.68)		0.26
(0.14; 0.53)		0.24
(0.19; 0.40)		0.0002.57
(1.23; 4.64)		2.84
(1.55; 7.43)		0.24
(0.80; 1.59)		0.88
(0.52; 1.60)		0.000
PLR7.85
(6.31; 12.80)		7.30
(5.32; 11.19)		4.90
(3.15; 11.58)		5.39
(4.17; 6.68)		0.01212.97
(5.54; 15.48)		10.78
(6.42; 30.97)		8.20
(5.88; 10.65)		6.05
(4.89; 9.01)		0.003
LMR1.94
(1.54; 4.95)		2.58
(1.81; 4.52)		11.90
(4.52; 12.25)		7.69
(5.88; 9.72)		0.0004.70
(1.83; 5.80)		3.36
(2.46; 4.44)		4.47
(3.69; 5.72)		5.04
(3.91; 6.24)		0.038
RBC4.02
(3.32; 4.40)		4.27
(3.93; 4.59)		4.99
(4.27; 5.20)		4.24
(4.10; 4.52)		0.0904.44
(4.29; 4.54)		4.40
(4.20; 4.71)		4.73
(4.43; 5.01)		4.65
(4.31; 4.87)		0.039
MCV77.30
(64.50; 84.30)		77.80
(73.80; 80.80)		70.00
(65.60; 70.50)		76.40
(74.30; 79.00)		0.19182.45
(78.90; 83.10)		79.10
(76.90; 81.50)		82.30
(80.10; 85.40)		79.20
(76.90; 83.20)		0.001
MCH27.00
(21.80; 28.90)		27.00
(25.60; 28.00)		22.20
(20.40; 24.10)		26.70
(26.20; 27.80)		0.17028.10
(27.55; 28.90)		28.10
(27.10; 28.90)		28.20
(27.20; 28.90)		27.80
(26.80; 29.00)		0.639
MCHC34.30
(33.80; 35.00)		34.60
(34.10; 35.10)		34.10
(31.50; 34.40)		34.80
(34.30; 35.20)		0.12334.60
(34.40; 35.30)		35.40
(35.10; 36.00)		34.00
(33.20; 34.90)		35.00
(34.20; 35.50)		0.000
AST—asparate aminotransferase, ALT—alanine aminotransferase, CRP—C-reactive protein, NLR—neutrophil lymphocyte ratio, PLR—platelet lymphocytes ratio, LMR—lymphocytes monocytes ratio, RBC—erythrocite, MCV—erythrocite mean cell volume, MCH—mean cell hemoglobin, MCHC—mean cell hemoglobin concentration.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Totan, M.; Matacuta-Bogdan, I.-O.; Hasegan, A.; Maniu, I. Vitamin D Levels in COVID-19 and NonCOVID-19 Pediatric Patients and Its Relationship with Clinical and Laboratory Characteristics. Biomedicines 2024, 12, 905. https://doi.org/10.3390/biomedicines12040905

AMA Style

Totan M, Matacuta-Bogdan I-O, Hasegan A, Maniu I. Vitamin D Levels in COVID-19 and NonCOVID-19 Pediatric Patients and Its Relationship with Clinical and Laboratory Characteristics. Biomedicines. 2024; 12(4):905. https://doi.org/10.3390/biomedicines12040905

Chicago/Turabian Style

Totan, Maria, Ioana-Octavia Matacuta-Bogdan, Adrian Hasegan, and Ionela Maniu. 2024. "Vitamin D Levels in COVID-19 and NonCOVID-19 Pediatric Patients and Its Relationship with Clinical and Laboratory Characteristics" Biomedicines 12, no. 4: 905. https://doi.org/10.3390/biomedicines12040905

APA Style

Totan, M., Matacuta-Bogdan, I. -O., Hasegan, A., & Maniu, I. (2024). Vitamin D Levels in COVID-19 and NonCOVID-19 Pediatric Patients and Its Relationship with Clinical and Laboratory Characteristics. Biomedicines, 12(4), 905. https://doi.org/10.3390/biomedicines12040905

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop