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Is Vitamin D Deficiency a Risk Factor for Covid 19 in Children? Running Title: Vitamin D Deficiency in Covid 19

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Objective Coronavirus disease 2019 (COVID‐19) is a global health problem that can result in serious complications. The aim of this study was to investigate the prevalence and clinical importance of vitamin D deficiency in children with COVID‐19. Material and Methods This study includes 40 patients who were diagnosed to have COVID‐19 and hospitalized with the real‐time reverse transcription polymerase chain reaction method, 45 healthy matched control subjects with vitamin D levels. The age of admission, clinical and laboratory data, and 25‐hydroxycholecalciferol (25‐OHD) levels were recorded. Those with vitamin D levels which are below 20 ng/ml were determined as Group 1 and those with ≥20 ng/ml as Group 2. Results Patients with COVID‐19 had significantly lower vitamin D levels 13.14 μg/L (4.19–69.28) than did the controls 34.81 (3.8–77.42) μg/L (p < .001). Patients with COVID‐19 also had significantly lower serum phosphorus (4.09 ± 0.73 vs. 5.06 ± 0.93 vs. (U/L) (p < .001)) values compared with the controls. The symptom of fever was significantly higher in COVID‐ 19 patients who had deficient and insufficient vitamin D levels than in patients who had sufficient vitamin D levels (p = .038). There was a negative correlation found between fever symptom and vitamin D level (r = −0.358, p = .023). Conclusion This is the first to evaluate vitamin D levels and its relationship with clinical findings in pediatric patients with COVID‐19. Our results suggest that vitamin D values may be associated with the occurrence and management of the COVID‐19 disease by modulating the immunological mechanism to the virus in the pediatric population.
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Kamil YILMAZ ORCID iD: 0000-0001-5137-0501
Is Vitamin D Deficiency a Risk Factor for Covid 19 in Children?
Running Title: Vitamin D Deficiency in Covid 19
Kamil Yılmaz, Assist. Prof. of Dicle University School of Medicine, Department of
Pediatric, Diyarbakir, Turkey, E-mail:drkamilyilmaz@gmail.com tel
number:+905333905847
Velat Şen, Associate. Prof. of Dicle University School of Medicine, Department of
Pediatric Pulmonology, Diyarbakir, Turkey, E-mail: drvelatsen@hotmail.com, tel
number:+905052425804
Correspondence:
Associate. Prof. Velat Şen; Dicle University Medical Faculty, Department of
Pediatric Pulmonology, 21010, Diyarbakır, Turkey. Tel: +90 505 242 58 04. Fax: +90
412.248-8523. Email: drvelatsen@hotmail.com
Conflict of Interest
None
Funding
This research received no specific grant from any funding agency in the public,
commercial, or not for profit sectors.
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Introduction
A new coronovirus (CoV) infection was reported to begin in late 2019 in Wuhan,
Hubei, China, which the World Health Organization (WHO) called COVID-19 on
February 11, 2020 (1). On March 11, 2020, COVID-19 infection was declared a
pandemic by WHO due to the global logarithmic increase of cases (2). Studies have
reported that crude mortality rates worldwide due to the COVID-19 outbreak vary
between 5.6% and 15.2%. The risk of death was found to be higher for elderly
individuals and those with comorbid conditions such as hypertension and diabetes
mellitus. In an article reviewing 46,248 cases, hypertension, diabetes mellitus,
cardiovascular disease and respiratory morbidity were specified to be the most
common comorbidities (3).
Otherwise COVID-19 is also occurenced in healthy children commonly, Chinese data
reported that only 2 % of the 44 672 cases with COVID‐19 were children (4). In an
italian paper reported that only 1.2% of 22 512 confirmed cases of COVID‐19 were
children (5). Although studies from Asia and America report that new corona virus
disease in children may be less serious than adults (6,7).
Vitamin D deficiency is a major public health problem in all age groups. More than
one billion people all over the world are estimated to have vitamin D deficiency.
Vitamin D is a pluripotent hormone modulating the adaptive and innate immune
response (8). The risk of infection by several mechanisms can be reduced by vitamin
D. Vitamin D induces cathelicidins and defensins that can reduce the viral replication
rate. In addition, it increases the concentrations of anti-inflammatory cytokines and
decreases the concentration of pro-inflammatory cytokines that cause pneumonia and
lung damage (1). In previous studies, vitamin D deficiency has been shown to increase
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respiratory infections risk including respiratory syncytial virus (RSV), tuberculosis
and flu, and is a risk factor for acute respiratory distress syndrome (ARDS) (8).
The SARS-CoV-2 virus among the COVID-19 patients, enters host cells by
binding to receptors of angiotensin-converting enzyme 2 (ACE2) in the respiratory
tract of infected patients (9). The primary targets of coronaviruses are type-II
pneumocytes and there is high expression of ACE2 receptors in these cells. The level
of surfactant can be reduced due to dysfunction of Type-II pneumocytes, and this can
lead to increased surface tension in COVID-19 (10). It has been shown that surfactant
synthesis in alveolar type-II cells is stimulated by 1,25-dihydroxyvitamin D
metabolites (11).
The vitamin D agonist calcitriol is thought to have protective effects against
acute lung injury by modulating the expression of members of the renin-angiotensin
system such as ACE 2 in lung tissue (12). This information suggests that vitamin D
deficiency may have a potential role as a pathogenic factor in COVID-19. CD26 is a
putative adhesion molecule for COVID-19 host cell invasion. Adjustment of vitamin
D deficiency is thought to suppress CD26. Vitamin D may also reduce, interleukin-6
(IL-6) and interferon gamma (IFNγ) inflammatory reactions, both potent predictors of
worse clinical outcome in severe COVID-19 (13).
Vitamin D is a secosteroid with a wide range of immunomodulatory, anti-
inflammatory, antifibrotic and antioxidant effects. It is thought that inflammatory
cytokine expression is inhibited by vitamin D and its deficiency is associated with
overexpression of Th1 cytokines (14).
Epidemiological studies have reported an association between vitamin D deficiency
and acute lung injury and viral respiratory infections (15). A randomized trial from
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China reported the beneficial effects of vitamin D is appropriate for the prevention of
seasonal influenza as proved by rapid relief from symptoms, fast reduce, in viral loads
and disease recovery (16). Another randomized trial of daily high dose versus
standard dose of vitamin D in Canadian children showed that the incidence of
influenza infections in the high-dose group was reduced by 50% (17). The immune
response against respiratory virus infections might be improved by a sufficient level
of 25 (OH) D in serum (18).
In the face of the COVID-19 pandemic, and in the lack of a vaccine or any effective
anti-viral treatment, supplementation of vitamin D hospital inpatients might be
beneficial. In this study, we aimed to determine the prevalence and clinical
importance of vitamin D deficiency in children and adolescent patients who were
hospitalized with the diagnosis of COVID-19.
Material and Methods
This study included 85 children between the ages of 1 month to 18 years in Dicle
University Faculty of Medicine between March 2020 and May 2020.
40 patients who were diagnosed to have COVID-19 and hospitalized with the real-
time reverse transcription polymerase chain reaction (RT-PCR) method were
included. The control group was composed of 45 healthy children who were
previously examined in Pediatric Endocrinology or Pediatric outpatient clinics and
whose vitamin D level was checked. Cases with chronic diseases and co-morbidities,
and those younger than 1 month and older than 18 were excluded from the patients
group and control group.
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The data of the cases included in the study were obtained from retrospective file
records. The age of admission, clinical and laboratory data, and 25-
hydroxycholecalciferol (25-OHD) and parathormone (PTH) levels were recorded. 25-
hydroxycholecalciferaol level was examined in Shimatzu device by high performance
liquid chromatography method. PTH level was examined by electro
chemiluminescence method in Siemens Advia Centaur device. Those with 25-OHD
level <12ng/ml were considered as vitamin D deficient, those between 12-20 ng/ml
were considered vitamin D insufficient and those with >20 ng/ml were considered to
have a normal vitamin D (19). Patients diagnosed with COVID-19 were divided into 2
groups. Those with vitamin D levels which are below 20 ng/ml were determined as
Group 1 and those with ≥20 ng/ml as Group 2, and clinical and laboratory variables
between the 2 groups were compared.
The severity of the disease was classified as asymptomatic, mild, moderate, severe,
and critical according to the clinical characteristic, laboratory results, and chest
radiography findings (20).
Asymptomatic: Cases with a positive RT-PCR test without any clinical and
radiological findings
Mild: Cases with upper respiratory tract infection symptoms such as fever, fatigue,
myalgia, cough, sore throat, nasal flow with normal espiratory system examination
Moderate: Cases with pneumonia with complaints of fever and cough but without the
symptoms of dyspnea and hypoxemia or cases with findings of COVID-19 on chest
CT scan without any symptoms
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Severe: Cases with fever and cough in the early period who develop dyspnea and
central cyanosis within a week (arterial oxygen saturation of <92%)
Critical: Cases who develop acute respiratory distress or respiratory failure rapidly,
and who tend to develop shock, encephalopathy, myocardial affection, coagulation
dysfunction, and acute kidney injury.
The study was conducted based on the rules of Declaration of Helsinki and approved
by the Institutional Ethics Committee of Dicle University, Faculty of Medicine.
Statistical Analysis
Data analyses were examined by using Statistical Package for Social Sciences (SPSS),
Version 20.0 for Windows (SPSS Inc., Chicago, IL, USA). The variables were
investigated using visual (histograms, probability plots) and analytical methods
(Kolmogorov-Simirnov test) whether or not they were normally distributed. Normally
distributed variables were presented using means and standard deviations, and non-
normaly distributed variables using median and range (maximum and minimum).
Comparisions of the groups were performed using the Student t (normally distributed
variables) and Mann-Whitney U (non normally distributed variables). The chi-square
test was used to analyze of categorical variables. P values <0.05 were considered
statistically significant.
Results
The mean age and age ranges of the groups were as follows: COVID-19 patients,
101.76 ± 27.91 months (range, 3 months-18 years) and the healthy control subjects,
75.68 ± 27.34 months (range, 1 month-18 years).
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47.5% (n=19) of the patients and 60% (n=27) of the control group were male. No
difference was found between the groups in terms of age and gender distribution (p =
0.061, p=0.248, respectively). The median levels of vitamin D level were 13.14 μg/L
(4.19-69.28) in the group of patients with COVID-19 and 34.81 μg/L (3.8-77.42) in
the control group. The COVID-19 patient group and the healthy control group were
compared, there were statistically significantly lower serum phosphorus level
(p<0.001) and vitamin D level (p<0.001) in the COVID-19 diagnosed patient group.
Table 1 summarizes the comparison of demographic and laboratory characteristics
between COVID-19 patient group and healty control subject group.
Patients diagnosed with COVID-19 were divided into 2 groups. Those who had
deficient and insufficient vitamin D levels were determined as Group 1 (n: 29, 72.5%)
and normal patients were determined as Group 2 (n: 11, 27.5%). 18 children in the
COVID-19 patient group had vitamin D deficient and 11 children had vitamin D
insufficient values. Eight children in the healthy group had vitamin D deficient and 3
children had vitamin D insufficient values.
The clinical and laboratory parameters of Group 1 and Group 2 are compared, at
admission, the symptom of fever (34.5%) was significantly higher in Group 1 than in
Group 2 (0%) (p = 0.038). There were significantly lower levels of vitamin D
(p<0.001) and serum phosphorus (p=0.013) in group 1 than those in group 2. No
significant difference was found between other clinical and laboratory parameters
between the groups. Comparison of demographic, clinical and laboratory
characteristics between COVID-19 diagnosed children who had deficient and
insufficient level of vitamin D (group 1) and COVID-19 diagnosed children who had
normal level of vitamin (group 2) is shown in Table 2.
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The distribution of disease severity according to vitamin D levels was not found
significantly different (Table 3).
There was a negative correlation found between fever symptom and vitamin D level
(p = 0.023, Table 4). However, no significant correlations were found between other
clinical parameters and vitamin D level (data were not shown).
Discussion
Our study evaluated the vitamin D deficiency prevalence and the association
between vitamin D deficiency and clinical and inflammatory markers in our patients
hospitalized for COVID-19 infection. To the best of our knowledge, we have not
found any study on vitamin D levels in pediatric patients diagnosed with COVID-19
in our literature review of resources in English. We aim to investigate whether
children diagnosed with COVID-19 had vitamin D deficiency as well as the
relationship between vitamin D deficiency and clinical outcomes.
Although there are no adequate studies on vitamin D levels and its effects in
children with COVID-19, there are several studies evaluated the relationship between
other respiratory pathogens and vitamin D. In some clinical studies, vitamin D has
been shown to protect children from lung infection. Children with vitamin D
deficiency or insufficiency are more susceptible to respiratory infection (21). A meta-
analysis and systematic review of 25 randomized controlled trials by Martineau et al.
showed that vitamin D generally protects against acute respiratory infection (22). In
an important study covering 1582 people by Li et al. with aim of determining the
relationship between 25(OH)D in children and pulmonary infection, the community-
acquired pneumonia group displayed a lower value than the control group, and there
were also significant differences between the pneumonia group and pneumonia-
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derived sepsis group ( p <0.001), and there was association between lower serum
25(OH)D level and more serious symptoms (23).
Daneshkhah et al. observed that high CRP was inversely correlated with
25(OH)D, and they thought vitamin D to have a possible role in reduction of
complications caused by abnormal inflammation and cytokine storm given the CRP as
a marker for cytokine storm and considering its association with vitamin D deficiency
(24). Some previous studies found negative correlation between 25(OH) D vitamin
level and pneumonia severity, CRP level, increased risk of sepsis, ARDS risk and
increased production of proinflammatory cytokines such as IL-6 (25-29).
In a study conducted by Alipio M. et al. observed that vitamin D level was low
or insufficient in 74.1% of patients diagnosed with COVID-19 and also found a
statistically significant difference between serum 25(OH)D level and clinical
outcomes (p <0.001) (30). In another study of Lau et al. regarding the relationship
between vitamin D deficiency and the severity of COVID-19 disease in adult age
group, low levels of vitamin D were found in 75% of the cases and 84.6% of the
patients in intensive care unit (31). In a study conducted on adults, Raharusa et al.
found deficient or insufficient levels of vitamin D in 47.3% of 780 patients diagnosed
with COVID-19. Vitamin D was insufficient in 27.3% of them and deficient in 20%
of them. They observed mortality in 49.1% of vitamin D insufficient cases, 46.7% of
deficient ones and 4.1% of normal ones, and found statistically significant results
between vitamin D level and mortality (p <0.001). However, the comorbid factors
concomitant with the majority of those with deficient and insufficient vitamin D levels
in their studies make it difficult to evaluate the relationship between mortality and
vitamin D alone (32).
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In our study, 72.5% of our cases were vitamin D deficient or insufficient, and 2
patients in need of treatment in the intensive care unit had the vitamin D level of
below 10 ng/ml, and had comorbid diseases, but there were no reported cases of
mortality. In our study, the distribution of disease severity according to vitamin D
levels was not found significantly different (p = 0.097). Yet, although the virulence
mechanisms related to COVID-19 are not fully characterized, the fact that clinical
severity and mortality rate of the disease generally progress better in children
compared to adults suggests that the SARS-CoV-2 S protein binds to the angiotensin-
converting enzyme (ACE) 2 and that children may be protected against SARS-CoV-2
because this enzyme is less mature at a younger age (33). COVID-19 diagnosed
children who had deficient and insufficient level of vitamin D (group 1) and COVID-
19 diagnosed children who had normal level of vitamin (group 2) were compared at
admission, Group 1 had significantly higher fever symptom (34.5%, 10) than Group 2
(0%) (p = 0.038). A negative correlation was found between vitamin D level and fever
symptom (p = 0.023), but there was no significant finding in terms of CRP level and
clinical severity. We suggest that the relationship between fever and vitamin D may
be related to the inflammatory process and cytokine release caused by the virus in the
body. Patients with COVID 19 were reported to have increased plasma concentrations
of proinflammatory cytokines, including interleukin (IL)-6, IL-10, granulocyte-colony
stimulating factor (G-CSF), macrophage inflammatory protein, and tumor necrosis
factor (TNF)-α (34). Vitamin D may also reduce, interleukin-6 (IL-6) and interferon
gamma (IFNγ) inflammatory reactions, both potent predictors of worse clinical
outcome in severe COVID-19 (13). Cytokines are proteins manufactured throughout
the body, primarily, by macrophages and T cells to coordinate the immune reactions,
within the body, control inflammatory and may induce fever.
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The pathology of COVID-19 involves a complex interaction between the virüs and the
body immune system. COVID-19 is provoke, the release of pro-inflammatory
cytokines. Vitamin D has been found to modulate macrophages’ response, preventing
them from releasing too many inflammatory cytokines and chemokines. Recently
children have been presenting with a systemic inflammatory response, sharing
features with other paediatric inflammatory conditions such as, Kawasaki disease,
toxic shock syndrome, and macrophage activation syndrome. In a study reported an
important serious vitamin D deficiency in children with Kawasaki disease as
compared to healthy controls, and low levels of vitamin D appears to correlate to the
risk in developing cardiovascular lesions (35).
A study conducted by Ilie et al., found that average vitamin D levels in each country
and the COVID-19 cases were negatively correlated with the number of deaths caused
by COVID-19 (36). Since there were no patients in our study who died, there was no
evaluation of the relationship between vitamin D levels and mortality. In addition,
there were no significant differences in length of stay in COVID 19 diagnosed
childrens who had deficient and insufficient level of vitamin D (group 1) and COVID
19 diagnosed childrens who had normal level of vitamin (group 2).
To our knowledge, there is no published data regarding using vitamin D in treatment
of COVID-19 and the difference it made to outcomes. In our view, randomised
controlled trials of vitamin D supplementation for the prevention and treatment of
COVID-19 are needed to test for causality.
This study has several limitations. First, it is possible the data may be incomplete or
incorrect due to the retrospective study design. Second, during this time some of the
clinical parameters may not be able to be assessed in all of the age group eg anosmia
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and loss of taste. In addition, the number of patients in our study group may be small,
but despite all these limitations, it may provide insight into future studies on whether
there is a real relationship between vitamin D deficiency and COVID-19.
In conclusion, our study is the first to evaluate vitamin D levels and its relationship
with clinical findings in pediatric patients diagnosed with COVID-19. There are
significantly lower levels of vitamin D in children with COVID-19 than those in the
control group. In spite of we don't assume that vitamin D plays a role in the
physiopathology of COVID-19 whether there is really an association between vitamin
D deficiency and COVID-19 needs to be further addressed. Deficient/insufficient
Vitamin D levels are associated with fever. Since there were no reported cases of
death in our study, the relationship with vitamin D deficiency and mortality could not
be evaluated. More studies are needed in children for evaluation of the association
between vitamin D with clinical and laboratory findings of the disease and its effect
on mortality.
Conflict of Interest
None
Funding
This research received no specific grant from any funding agency in the public,
commercial, or not for profit sectors.
Authors’ Contributions and Acknowledgements
KY and VS wrote the manuscript. All authors read and approved the final manuscript.
References
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1. Grant WB, Lahore H, McDonnell SL, et al. Evidence that Vitamin D
Supplementation Could Reduce Risk of Influenza and COVID-19 Infections and
Deaths. Nutrients. 2020;12(4).
2. Caccialanza R, Laviano A, Lobascio F, et al. Early nutritional supplementation in
non-critically ill patients hospitalized for the 2019 novel coronavirus disease
(COVID-19): Rationale and feasibility of a shared pragmatic protocol. Nutrition
(Burbank, Los Angeles County, Calif). 2020; 74:110835.
3. Misra DP, Agarwal V, Gasparyan AY, Zimba O. Rheumatologists' perspective on
coronavirus disease 19 (COVID-19) and potential therapeutic targets. Clinical
Rheumatology. 2020:1-8.
4. Zhang Y. TheEpidemiological Characteristics of an Outbreak of 2019 Novel
Coronavirus Diseases (COVID-19) — China, 2020. Chinese Journal of Epidemiology
(by The Novel Coronavirus Pneumonia Emergency Response Epidemiology Team).
2020.
5. Livingston E, Bucher K. Coronavirus disease 2019 (COVID-19) in Italy. JAMA.
2020.
6. Yuanyuan Dong, Xi Mo, Yabin Hu, Xin Qi, Fan Jiang, Zhongyi Jiang,
Epidemiology of COVID-19 Among Children in China. Pediatrics, 2020:145, 6.
7. Stephanie Bialek, Ryan Gierke, Michelle Hughes, Lucy A. McNamara.
Coronavirus Disease 2019 in Children United States, February 12April 2, 2020.
MMWR Morb Mortal Wkly Rep. 2020 Apr 10; 69(14): 422–426.
This article is protected by copyright. All rights reserved.
Accepted Article
8. Marik PE, Kory P, Varon J. Does vitamin D status impact mortality from SARS-
CoV-2 infection? Medicine in drug discovery. 2020:100041.
9. Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 cell entry depends
on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell.
2020.
10. Bombardini T, Picano E. Angiotensin-converting enzyme 2 as the molecular
bridge between epidemiologic and clinical features of COVID-19. Canadian Journal
of Cardiology. 2020; 36(5):784. e1-. e2.
11. Rehan VK, Torday JS, Peleg S, et al. 1α, 25-Dihydroxy-3-epi-vitamin D3, a
natural metabolite of 1α, 25-dihydroxy vitamin D3: production and biological activity
studies in pulmonary alveolar type II cells. Molecular genetics and metabolism.
2002;76(1):46-56.
12. Xu J, Yang J, Chen J, et al. Vitamin D alleviates lipopolysaccharide‑induced acute
lung injury via regulation of the renin‑angiotensin system. Molecular medicine
reports. 2017;16(5):7432-8.
13. D.M. McCartney, D.G. Byrne. Optimisation of Vitamin D Status for Enhanced
Immuno-protection Against Covid-19. Ir Med J; Vol 113; No. 4; P58
14. Hughes D, Norton R. Vitamin D and respiratory health. Clinical & Experimental
Immunology. 2009;158(1):20-5.
15. Hansdottir S, Monick MM. Vitamin D effects on lung immunity and respiratory
diseases. Vitamins & hormones. 86: Elsevier; 2011. p. 217-37.
This article is protected by copyright. All rights reserved.
Accepted Article
16. Zhou, J.; Du, J.; Huang, L.; Wang, Y.; Shi, Y.; Lin, H. Preventive Effects of
Vitamin D on Seasonal Influenza A in Infants: A Multicenter, Randomized, Open,
Controlled Clinical Trial. Pediatr. Infect. Dis. J. 2018, 37,749–754.
17. Aglipay M, et al. Effect of High-dose vs standard-dose wintertime vitamin d
supplementation on viral upper respiratory tract infections in young healthy children.
Jama. 2017;318(3):245–254.
18. Greiller CL, Martineau AR. Modulation of the immune response to respiratory
viruses by vitamin D. Nutrients. 2015;7(6):4240-70.
19. Yeşiltepe-Mutlu G, Aksu ED, Bereket A, et al. Vitamin D Status Across Age
Groups in Turkey: Results of 108742 Samples from a Private Laboratory. Journal of
clinical research in pediatric endocrinology. 2020.
20. Shen K, Yang Y, Wang T, et al. Diagnosis, treatment, and prevention of 2019
novel coronavirus infection in children: experts' consensus statement World J Pediatr.
2020;1‐9.
21. Baqui AH, Black RE, Arifeen S, et al. Causes of childhood deaths in Bangladesh:
results of a nationwide verbal autopsy study. Bulletin of the World Health
Organization. 1998;76(2):161.
22. Martineau AR, Jolliffe DA, Hooper RL, et al. Vitamin D supplementation to
prevent acute respiratory tract infections: systematic review and meta-analysis of
individual participant data. bmj. 2017;356:i6583.
23. Li W, Cheng X, Guo L, et al. Association between serum 25-hydroxyvitamin D
concentration and pulmonary infection in children. Medicine. 2018;97(1).
This article is protected by copyright. All rights reserved.
Accepted Article
24. Daneshkhah A, Eshein A, Subramanian H, et al. The Role of Vitamin D in
Suppressing Cytokine Storm in COVID-19 Patients and Associated Mortality.
medRxiv. 2020.
25. Lu D, Zhang J, Ma C, et al. Link between community-acquired pneumonia and
vitamin D levels in older patients. Zeitschrift für Gerontologie und Geriatrie.
2018;51(4):435-9.
26. Zhou Y-F, Luo B-A, Qin L-L. The association between vitamin D deficiency and
community-acquired pneumonia: A meta-analysis of observational studies. Medicine.
2019;98(38).
27. Manion M, Hullsiek KH, Wilson EM, et al. Vitamin D deficiency is associated
with IL-6 levels and monocyte activation in HIV-infected persons. PLoS One.
2017;12(5):e0175517.
28. Dalvi SM, Ramraje NN, Patil VW, et al. Study of IL-6 and vitamin D3 in patients
of pulmonary tuberculosis. Indian Journal of Tuberculosis. 2019;66(3):337-45.
29. Poudel-Tandukar K, Poudel KC, Jimba M, et al. Serum 25-hydroxyvitamin d
levels and C-reactive protein in persons with human immunodeficiency virus
infection. AIDS research and human retroviruses. 2013;29(3):528-34.
30. Alipio M. Vitamin D Supplementation Could Possibly Improve Clinical Outcomes
of Patients Infected with Coronavirus-2019 (COVID-19). Available at SSRN
3571484. 2020.
31. Lau F. Vitamin D Insufficiency is Prevalent in Severe COVID-19. medRxiv. 2020
Apr 24
This article is protected by copyright. All rights reserved.
Accepted Article
32. Raharusun P, Priambada S, Budiarti C, et al. Patterns of COVID-19 Mortality and
Vitamin D: An Indonesian Study. 2020.
33. Wrapp D, Wang N, Corbett KS, et al. Cryo-EM structure of the 2019-nCoV spike
in the prefusion conformation. Science. 2020;367:1260-1263.
34. Zhou Y., Fu B., Zheng X., Wnag D., Zhao C., Qi Y., Sun R., Tian Z., Xu X., Wei
H. Pathogenic T cells and inflammatory monocytes incite inflammatory storm in
severe COVID-19 patients. Journal. 2020
35. Stagi S, Rigante D, Lepri G, Matucci Cerinic M, Falcini F (2016) Severe vitamin
D deficiency in patients with Kawasaki disease: a potential role in the risk to develop
heart vascular abnormalities? Clin Rheumatol 35(7):1865–1872
36. Ilie PC, Stefanescu S, Smith L. The role of vitamin D in the prevention of
coronavirus disease 2019 infection and mortality. Aging Clinical and Experimental
Research. 2020:1. Clinical and Experimental Research. 2020:1.
Table 1. Comparison of demographic and laboratory characteristics between
COVID 19 patient group and healty control subject group
Parameters COVID 19
patients
(n=40)
Healthy Controls
(n=45)
P
Age (month)
101.76±27.91 75.68±27.34 0.061
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Gender (M/F)
19/21 27/18 0.248
Serum calcium (mg/dL), ref:(8.8-10.6) 9.55±0.61 9.83±0.53 0.028
Serum phosphorus (U/L), ref:(2.5-4.5) 4.09±0.73 5.06±0.93 <0.001
Alkaline phosphotase (mg/dL), ref:(74-
390)
205.80±67.38 197.69±64.71 0.625
Vitamin D levels (µg/L) 13.14 (4.19-
69.28)
34.81 (3.8-77.42) <0.001
Parathyroid hormone levels (pg/mL),
ref:(14-72)
51.04±14.01 44.90±13.83 0.242
ref: references
Table 2: Comparison of demographic, clinical and laboratory characteristics between
COVID 19 diagnosed childrens who had deficient and insufficient level of vitamin D
(group 1) and covid 19 diagnosed childrens who had normal level of vitamin (group
2).
Parameters Group 1 (n=29) Group 2 (n=11) P
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Age (month)
94.96±38.30 104.56±31.97 0.677
Gender (M/F)
11/18 8/3 0.049
Fever >38 °C (n,%) 10 (34.5%) 0 (0%) 0.038
Dry cough (n,%)
9 (31%) 1 (9.1%) 0.233
Loss of taste (n,%)
0 (0%) 1 (9.1%) 0.275
Headache (n,%)
6 (20.7%) 3 (27.3%) 0.686
Diarrhea (n,%)
1 (3.4%) 1 (9.1%) 0.479
Sore throat (n,%)
3 (10.3%) 0 (0%) 0.548
Anosmia (n,%)
2 (6.9%) 1 (9.1%) 0.814
Lassitude and fatigue (n,%)
7 (24.1%) 3 (27.3%) 0.838
Vitamin D ( µg/L) 10.83(4.19-1 7.69) 24.01 (21.50-
69.28) <0.001
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PTH (pg/mL) 46.80 (16.46-
120.70)
42.10(24.80-
78.50) 0.380
Serum calcium(mg/dL) 9.46±0.62 9.80±0.50 0.084
Serum phosphorus(mg/dL) 3.92±0.68 4.55±0.67 0.013
Alkaline phosphotase(U/L)
193.24±54.60 238.91±40.60 0.096
CRP (mg/dL), ref:(0.0-0.05) 0.1 (0.02-16.00) 0.07 (0.02-1.08) 0.202
Procalcitonin(ng/mL),ref:(0.0-0.12) 0.001 (0.00-4.80) 0.001 (0.00-0.21) 0.884
D-dimer(mg/dL), ref:(0.08-0.583) 0.31 (0.08-55.10) 0.25 (0.15-1.47) 0.449
Fibrinogen(mg/dL), ref:(170-420) 232.19±67.69 218.52±50.68 0.604
Ferritine 40.20 (3.10-795) 29.20 (4.50-78) 0.112
WBC (10^3/uL) 7.54±2.61 7.60±2.82 0.944
Neutrophil count (10^3/uL) 3.49±1.48 3.29±1.01 0.727
Lymphocyte count (10^3/uL) 3.14±1.26 3.45±1.13 0.700
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Body temperatures, °C 36.97±0.66 36.70±0.39 0.203
Respiratory rate 25.72±7.27 21.34±3.41 0.969
Length of hospital stay (in days) 5(1-14) 5(1-7) 0.260
Chest CT findings (n,%) 7 (33.3%) 3 (37.5%) 0.833
PA chest X-ray findings(n,%) 16, (57.1%) 5, 45.5% 0.510
Ref: references, WBC: White blood cell, PTH: Parathyroid hormone, CRP: C-
reactive protein, PA: posteroanterior, CT: computerized tomography
Table 3: The distribution of disease severity according to vitamin D level.
Asymptomati
c Mild Moderate Severe p
Normal level of
vitamin D (n,
%)
5 (45.5%) 4 (36.4%) 2 (18.2%) 0 (0%)
0.097
Low level of
vitamin D (n,
%)
3 (10.3%) 17 (58.6%) 7 (24.1%) 2 (6.9%)
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Table 4. Correlation analysis between Vitamin D levels and laboratory
parameters
r p
Serum
Calcium(mg/dL)
0.365 0.021
Phosphorus(mg/dL)
0.364 0.020
Fever -0.358 0.023
... With regard to the pediatric population, only few studies are currently available concerning the effects of vitamin D deficiency on COVID-19 disease. A retrospective cohort study performed on hospitalized patients aged 0-18 years showed a significant relationship between low serum vitamin D concentrations, severe disease and elevated inflammatory markers: in particular, vitamin D levels were positively correlated with white cell blood count and negatively with C-reactive protein and fibrinogen levels (63,64). However, the actual impact of vitamin D deficiency on COVID-19 infection is still under debate and further investigations are yet needed to clarify this matter. ...
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Severe acute respiratory coronavirus 2 (SARS-CoV-2) interacts with the host cells through its spike protein by binding to the membrane enzyme angiotensin-converting enzyme 2 (ACE2) and it can have a direct effect on endocrine function as ACE2 is expressed in many glands and organs with endocrine function. Furthermore, several endocrine conditions have features that might increase the risk of SARS-CoV-2 infection and the severity and course of the infection, as obesity for the underlying chronic increased inflammatory status and metabolic derangement, and for the possible changes in thyroid function. Vitamin D has immunomodulatory effects, and its deficiency has negative effects. Adrenal insufficiency and excess glucocorticoids affect immune conditions also besides metabolism. This review aims to analyze the rationale for the fear of direct effects of SARS-Cov-2 on endocrinological disorders, to study the influence of pre-existing endocrine disorders on the course of the infection, and the actual data in childhood. Currently, data concerning endocrine function during the pandemic are scarce in childhood and for many aspects definite conclusions cannot be drawn, however, data on properly managed patients with adrenal insufficiency at present are re-assuring. Too little attention has been paid to thyroid function and further studies may be helpful. The available data support a need for adequate vitamin D supplementation, caution in obese patients, monitoring of thyroid function in hospitalized patients, and confirm the need for an awareness campaign for the increased frequency of precocious puberty, rapidly progressive puberty and precocious menarche. The changes in lifestyle, the increased incidence of overweight and the change in the timing of puberty lead also to hypothesize that there might be an increase in ovarian dysfunction, as for example polycystic ovarian disease, and metabolic derangements in the next years, and in the future we might be facing fertility problems. This prompts to be cautious and maintain further surveillance.
... D Vit level was found to be significantly lower in children infected with Cov19. In addition, a negative correlation was observed between fever and D Vit level in children infected with Cov19 (9). There are also reviews reporting that optimal vitamin supplementation should be taken to survive the Cov19 pandemic with minimal damage (10)(11)(12)(13)(14). ...
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... No COI were identified in 16 studies in the sample. Of these, 12 acknowledge funding via grants from governments, universities or academic research centers (25, 27, 31, 33-35, 37, 41, 43, 45, 47, 52) and three studies explicitly stated that there had been no sources of funding and no sponsorships (30,40,50). One study did not mention whether or not funding was available (32). ...
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The use of scientific evidence to support the process of formulating and implementing public policies might be biased by studies funded by the pharmaceutical and food industry, which more often than not meet corporate interests. This review aimed to analyze the occurrence of conflict of interest (COI) in academic production regarding vitamin D and COVID-19, considering the facility offered during the pandemic for academic publications of heterogeneous quality. A scoping review of observational studies published in Medline, Lilacs, and Google Scholar databases was carried out. The selected studies were published between December 2019 and August 2021, focused on the relationship between vitamin D and prevention or treatment of COVID-19 in non-institutionalized individuals, with no language restrictions. Twenty-nine studies met eligibility criteria. COI was disclosed in five papers and further identified by review authors in eight other papers, meaning COI was present in thirteen papers (44.8%). Studies were funded by companies in the diagnostics, pharmaceutical and food sectors. Conclusions favorable to vitamin D supplementation were more prevalent in papers where COI was identified (9/13, 69.2%) than among papers where COI was not found (4/16, 25.0%). Omissions of disclosure of COI, funding source, and sponsor functions were observed. The identification of possible corporate political activities in scientific papers about vitamin D published during the COVID-19 pandemic signals a need for greater transparency and guideline development on the prevention of COI in scientific production.
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Few works studied the levels of vitamins and minerals in Saudi Arabia among COVID-19 patients, especially in the region of Taif (high altitude). So, this work aims to study the serum vitamin D, vitamin B12, calcium, Phosphorous, Magnesium and hemoglobin levels in recovered patients with COVID-19 and compare them to mortalities. The levels of a sample of 100 recovered patients and 93 mortalities were chosen from the Covid 19 patient records between March 2020 and February 2021 in King Faisal Hospital, Taif, Saudi Arabia. Vitamins and Minerals data were distilled for statistical analysis. The results reported that vitamin D was the highest in recovered patients compared with coronavirus mortalities, whilst vitamin B12 was the highest in mortalities compared with recovered patients with coronavirus. Calcium, as well as hemoglobin, were relatively elevated in recovered patients with coronavirus compared to mortalities with coronavirus. The results indicated that there is a significant difference between recovered patients and mortalities in age, Vitamin B12, Calcium, Phosphorous, Magnesium and hemoglobin. There is a significant positive correlation between Age and Vitamin B12 and Phosphorous. There is a significant negative correlation between Age and Magnesium and Hemoglobin. On the other hand, there is a significant positive correlation between Vitamin D and Vitamin B12. Finally, there is a significant positive correlation between Calcium and Phosphorous and between Calcium Hemoglobin. As a result, deficiency of vitamin D, calcium, phosphorus and hemoglobin levels may cause a failure in the immune system against COVID-19 and cause a quick transfer to severe disease.
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Objective Vitamin D has many immune benefits and because its deficiency impacts most age groups, it became a nutrient of interest in the coronavirus disease 2019 (COVID-19) era. The objective of this study was to highlight the contribution of vitamin D status to the disease severity of hospitalized pediatric patients suffering from COVID-19 infection. Methods This was a cross-sectional study that was conducted on 42 children with documented positive polymerase chain reaction for COVID-19 infection. Detailed history taking and thorough clinical examination were done for each recruited patient. Besides the laboratory and radiological assessment done for COVID-19 patients, 25 hydroxy vitamin D levels [25(OH) D] in the serum were estimated using enzyme linked immunosorbent assay. Results Using the cutoff level of 10 ng/mL, only 40% of the patients were below this level and 60% had their vitamin D level more than or equal to 10 ng/mL. Significantly more patients of the first group needed oxygen support (denoting more severe COVID-19 infection and lung involvement). The older the patients, the more evident was vitamin D deficiency among them, and 25(OH) D values were not correlated to weight for length nor weight categories in the studied series of patients suffering from COVID-19. Conclusion Vitamin D deficiency affects the severity of pediatric COVID-19 infection in hospitalized patients. It is prudent to advise vitamin D level assessment in such cases and promptly manage the patients accordingly. We recommend further studies to assess the effect of vitamin D supplementation on the clinical outcome of COVID-19 in the pediatric population and other vulnerable groups.
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Objective Multiple factors being overweight, asthmatic, or being of Asian or black ethnic origins have been reported vis-à-vis the “multisystem inflammatory syndrome in children” (MIS-C). There is an association between these conditions and vitamin D deficiency, which explains why MIS-C is more common in these patients. In the present study, we attempted to retrospective evaluate the 25-hydroxy vitamin D levels of patients with MIS-C, its association with acute phase reactants, its treatment, and clinical status. Methods Patients aged between 1.5 months to 18 years with MIS-C were included in the study. All of the laboratory parameters, treatment, and response to the treatment were evaluated retrospectively. Two groups were formed. Patients had 25‐hydroxycholecalciferol D vitamin < 20 ng/mL in group 1 and ≥ 20 ng/mL in group 2. Results A total of 52 patients were included in the study. There was no statistical difference between groups in terms of acceptance of the intensive care unit treatment (p = 0.29) and response to the first-line treatment (p = 0.56). A lower median lymphocyte count (p = 0.01) and a higher median C-reactive protein (p = 0.04) and procalcitonin (p = 0.01) with N-terminal pro-B-type natriuretic peptide (p = 0.025) values were found in group 1. Conclusion Vitamin D deficiency was associated with an increased inflammatory response in children with MIS-C. More studies are required to determine the potential impact of vitamin D deficiency on the clinical outcome of MIS-C.
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The ongoing pandemic coronavirus disease 19 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a matter of global concern. Environmental factors such as air pollution and smoking and comorbid conditions (hypertension, diabetes mellitus and underlying cardio-respiratory illness) likely increase the severity of COVID-19. Rheumatic manifestations such as arthralgias and arthritis may be prevalent in about a seventh of individuals. COVID-19 can result in acute interstitial pneumonia, myocarditis, leucopenia (with lymphopenia) and thrombocytopenia, also seen in rheumatic diseases like lupus and Sjogren’s syndrome. Severe disease in a subset of patients may be driven by cytokine storm, possibly due to secondary hemophagocytic lymphohistiocytosis (HLH), akin to that in systemic onset juvenile idiopathic arthritis or adult-onset Still’s disease. In the absence of high-quality evidence in this emerging disease, understanding of pathogenesis may help postulate potential therapies. Angiotensin converting enzyme 2 (ACE2) appears important for viral entry into pneumocytes; dysbalance in ACE2 as caused by ACE inhibitors or ibuprofen may predispose to severe disease. Preliminary evidence suggests potential benefit with chloroquine or hydroxychloroquine. Antiviral drugs like lopinavir/ritonavir, favipiravir and remdesivir are also being explored. Cytokine storm and secondary HLH might require heightened immunosuppressive regimens. Current international society recommendations suggest that patients with rheumatic diseases on immunosuppressive therapy should not stop glucocorticoids during COVID-19 infection, although minimum possible doses may be used. Disease-modifying drugs should be continued; cessation may be considered during infection episodes as per standard practices. Development of a vaccine may be the only effective long-term protection against this disease.Key Points• Patients with coronavirus disease 19 (COVID-19) may have features mimicking rheumatic diseases, such as arthralgias, acute interstitial pneumonia, myocarditis, leucopenia, lymphopenia, thrombocytopenia and cytokine storm with features akin to secondary hemophagocytic lymphohistiocytosis.• Although preliminary results may be encouraging, high-quality clinical trials are needed to better understand the role of drugs commonly used in rheumatology like hydroxychloroquine and tocilizumab in COVID-19.• Until further evidence emerges, it may be cautiously recommended to continue glucocorticoids and other disease-modifying antirheumatic drugs (DMARDs) in patients receiving these therapies, with discontinuation of DMARDs during infections as per standard practice.
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Background Vitamin D deficiency (serum 25(OH)D<50nmol/l) is common in Ireland, particularly amongst older adults, hospital inpatients and nursing home residents. Vitamin D deficiency is associated with increased risk of acute viral respiratory infection and community acquired pneumonia, with several molecular mechanisms proposed to explain this association. Vitamin D supplementation has also been shown to reduce the risk of respiratory infection. Vitamin D and Covid-19 Correction of vitamin D deficiency is thought to suppress CD26, a putative adhesion molecule for Covid-19 host cell invasion. Vitamin D may also attenuate interferon gamma (IFNγ) and interleukin-6 (IL-6) inflammatory responses, both potent predictors of poorer outcome in critically-ill ventilated patients including those with Covid-19. Vitamin D Requirements Irish adults require 25-30µg/d of vitamin D3, an intake not achievable by diet alone, to reliably maintain serum 25(OH)D levels >50nmol/l. Supplementation with doses up to 100µg/d has been shown to be safe for adults, and many agencies and expert groups now advocate supplementation in older adults, albeit at lower levels than this. Conclusions and Recommendations Vitamin D deficiency is common and may contribute to increased risk of respiratory infection including Covid-19. We recommend that all older adults, hospital inpatients, nursing home residents and other vulnerable groups (e.g. those with diabetes mellitus or compromised immune function, those with darker skin, vegetarians and vegans, those who are overweight or obese, smokers and healthcare workers) be urgently supplemented with 20-50µg/d of vitamin D to enhance their resistance to Covid-19, and that this advice be quickly extended to the general adult population.
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As of April 2, 2020, the coronavirus disease 2019 (COVID-19) pandemic has resulted in >890,000 cases and >45,000 deaths worldwide, including 239,279 cases and 5,443 deaths in the United States (1,2). In the United States, 22% of the population is made up of infants, children, and adolescents aged <18 years (children) (3). Data from China suggest that pediatric COVID-19 cases might be less severe than cases in adults and that children might experience different symptoms than do adults (4,5); however, disease characteristics among pediatric patients in the United States have not been described. Data from 149,760 laboratory-confirmed COVID-19 cases in the United States occurring during February 12-April 2, 2020 were analyzed. Among 149,082 (99.6%) reported cases for which age was known, 2,572 (1.7%) were among children aged <18 years. Data were available for a small proportion of patients on many important variables, including symptoms (9.4%), underlying conditions (13%), and hospitalization status (33%). Among those with available information, 73% of pediatric patients had symptoms of fever, cough, or shortness of breath compared with 93% of adults aged 18-64 years during the same period; 5.7% of all pediatric patients, or 20% of those for whom hospitalization status was known, were hospitalized, lower than the percentages hospitalized among all adults aged 18-64 years (10%) or those with known hospitalization status (33%). Three deaths were reported among the pediatric cases included in this analysis. These data support previous findings that children with COVID-19 might not have reported fever or cough as often as do adults (4). Whereas most COVID-19 cases in children are not severe, serious COVID-19 illness resulting in hospitalization still occurs in this age group. Social distancing and everyday preventive behaviors remain important for all age groups as patients with less serious illness and those without symptoms likely play an important role in disease transmission (6,7).
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2019 novel coronavirus(2019-nCoV) outbreak is one of the public health emergency of international concern.Since the 2019-nCoV outbreak, China has been adopting strict prevention and control measures, and has achieved remarkable results in the initial stage of prevention and control.However, some imported cases and sporadic regional cases have been found, and even short-term regional epidemics have occurred, indicating that the preventing and control against the epidemic remains grim.With the change of the incidence proportion and the number of cases in children under 18 years old, some new special symptoms and complications have appeared in children patients.In addition, with the occurrence of virus mutation, it has not only attracted attention from all parties, but also proposed a new topic for the prevention and treatment of 2019-nCoV infection in children of China.Based on the second edition, the present consensus further summarizes the clinical characteristics and experience of children's cases, and puts forward recommendations on the diagnostic criteria, laboratory examination, treatment, prevention and control of children's cases for providing reference for further guidance of treatment of 2019-nCoV infection in children.
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WHO declared SARS-CoV-2 a global pandemic. The present aim was to propose an hypothesis that there is a potential association between mean levels of vitamin D in various countries with cases and mortality caused by COVID-19. The mean levels of vitamin D for 20 European countries and morbidity and mortality caused by COVID-19 were acquired. Negative correlations between mean levels of vitamin D (average 56 mmol/L, STDEV 10.61) in each country and the number of COVID-19 cases/1 M (mean 295.95, STDEV 298.7, and mortality/1 M (mean 5.96, STDEV 15.13) were observed. Vitamin D levels are severely low in the aging population especially in Spain, Italy and Switzerland. This is also the most vulnerable group of the population in relation to COVID-19. It should be advisable to perform dedicated studies about vitamin D levels in COVID-19 patients with different degrees of disease severity.