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. 2021 Jan 15;100(2):e23827. doi: 10.1097/MD.0000000000023827

Vitamin D status was associated with sepsis in critically ill children

A PRISMA compliant systematic review and meta-analysis

Weijie Yu a, Qinlai Ying a, Wen Zhu a, Lisu Huang b, Qiuying Hou a,∗
Editor: Yan-Ren Lin
PMCID: PMC7808475  PMID: 33466129

Abstract

Background:

Sepsis leads to the high mortality in critically ill infants and children. It is still controversial whether vitamin D deficiency was associated with the incidence of sepsis. Thus we designed the systematic review and meta-analysis.

Methods:

The Ovid Medline, Embase, PubMed, and Cochrane library were systematically searched until April 5, 2020. The 25 hydroxyvitamin D (25-OHD) level was recorded and set 20 ng/mL as cut-off in cohort study to divide the lower and higher 25-OHD group. The odds ratio (OR) and 95% confidence intervals (CIs) were calculated for comparing the impact of vitamin D deficiency on the incidence of sepsis in critically ill children.

Results:

A total of 27 studies were included with 17 case-control studies and 10 cohort studies. In those case-control studies, the maternal 25-OHD level and neonatal 25-OHD level in sepsis group was significant lower than non-sepsis group (P < .001). The percentage of severe vitamin D deficiency was significant higher in sepsis group comparing to non-sepsis group (odds ratio [OR] = 2.66, 95% CI = 1.13–6.25, P < .001). In those cohort studies, the incidence of sepsis in lower 25-OHD group was 30.4% comparing with 18.2% in higher 25-OHD level group. However, no statistical significant difference in terms of mechanical ventilation rate and 30-day mortality.

Conclusion:

We demonstrated that critically ill infants and children with sepsis could have a lower 25-OHD level and severe vitamin D deficiency comparing to those without sepsis. Future studies should focus on the association of vitamin D supplement and the occurrence of sepsis in critically ill children.

Keywords: children, infant, sepsis, vitamin D deficiency

1. Introduction

Vitamin D is an important nutrient for the human body and it was first discovered in 1921. At first, it focused on the role of calcium and phosphorus metabolism and bone growth and development and therefore it was mainly used to resist rickets.[1] Until the 1980s, its extra-osseous role became research hotspots, studies have found that vitamin D can affect cell proliferation and mutation, hormone secretion regulation and immune regulation, and its role in many acute and chronic diseases has been confirmed and recognized, including infectious diseases, autoimmune diseases, cancer, Type 2 diabetes, cardiovascular diseases, and infectious diseases.[2–5] The biologically active form of vitamin D is 1,25 (OH)2 D3, but the concentration of 25 hydroxyvitamin D (25-OHD) is easy to detect and stable in blood, which could represent the vitamin D level in human body.[6] Recent studies showed that 25-OHD deficiency is widespread in children and adults worldwide, and the 25-OHD deficiency rate in critically ill patients is as high as about 30% to 70%.[7–10]

Sepsis was first defined as a systemic inflammatory response caused by infection in 1991. When combined with organ dysfunction, it was defined as severe sepsis.[11] Sepsis develops fiercely and is prone to be complicated by multiple organ damage which has the characteristics of high mortality, long hospital stay, and high cost of treatment.[12] In 2016, the European Society of Critical Care Diseases redefined sepsis, emphasizing that infection is the cause of sepsis.[13] The unsteady-state host reaction caused by infection is extremely lethal, and the uncontrolled inflammation and immune function disorders are the key links. Sepsis has gradually become a high-risk species in the intensive care unit, and the disease is developing rapidly. If it is not effectively controlled, it can easily develop into multiple organ dysfunction syndrome (MODS), and the mortality rate of sepsis in children with pediatric intensive care unit (PICU) could reach as higher as 21.9%.[14]

Recent researches have shown that 25-OHD deficiency is an independent risk factor affecting the prognosis of sepsis adult patients.[15] And the mechanism related to sepsis may relate to the target of vitamin D treatment. Therefore, vitamin D supplementation may become a new method of adjuvant therapy for patients with sepsis. However, it is still controversial whether there is an association between vitamin D deficiency and sepsis in infant and children. Thereafter, we designed the systematic review and meta-analysis in assessing the vitamin D deficiency in associating with the occurrence of sepsis in children.

2. Methods

The ethical approval was waived from the local institution due to the study design and this study was designed in accordance with the preferred reporting items for systematic review and meta-analysis (PRISMA) guidelines.[16]

2.1. Search strategy

This study aimed to discuss the risk of blood vitamin D status in associating with the occurrence of sepsis in children. The Ovid Medline, Embase, PubMed, Cochrane Central Register of Controlled trials and Cochrane Database of Systematic reviews were systematically searched due to April 5, 2020. Moreover, grey literature was searched in related website and Google Scholar to find more related articles. The keywords and Medical Subject Heading (MeSH) were designed by an experienced librarian. Briefly, the MeSH and keywords included “sepsis,” “septic shock,” “vitamin D,” “25-OHD.” All the studies containing titles and abstracts were imported into Endnote for deleting the duplication and literature screening.

2.2. Criteria for inclusion and exclusion

All the studies discussing the risks of vitamin D status in occurrence of sepsis in children were included in the meta-analysis. The inclusion criteria were as follow: the study measured the 25-OHD in either maternal or neonatal level, or the study classified the vitamin D level into severe, deficiency, or insufficiency; the sepsis occurrence was limited in infant or children, whose age <18-year old; the sepsis was diagnosed by blood test; the study type limited in case-control study or cohort study in discussing the relationship between vitamin D level and occurrence of sepsis. The other meta-analysis, reviews, letter, comment, and conference reviews were reading for the further inclusion of the studies.

The exclusion criteria were: case reports or the case sample <10; the study did not report the vitamin D level; the study did not limit in sepsis in infant or child; the study was without full data to extract the odds ratio (OR) or relative risks (RR); the study data overlapped with those of another study; the study was not written in English.

2.3. Literature screening, data extraction and quality assessment

Two investigators (W-jY and Q-lY) independently screened the titles and abstracts according to the inclusion and exclusion criteria. The full text was further assessed if the titles and abstracts could not be determined. The third investigator (Q-yH) was adapted for discussion if disagreement existed.

The data were extracted into a standard form and recorded the information as follow: the study characteristics (author, publish year, country, institution, recruitment period, study design, and etc), vitamin D deficiency definition, patient characteristics (birthweight, age, sex, APGAR score, maternal or neonatal 25-OHD level, and etc), and the outcome assessment (sepsis rate, mechanical ventilation rate, and mortality).

Two investigators (L-sH and WZ) independently assess the quality of the including papers. The cohort studies were assessed based on the Newcastle-Ottawa Quality Assessment Scale (NOS), with a high quality of 6 to 9, whereas low quality was scored as 0 to 5.[17]

2.4. Statistical analysis

The meta-analysis was performed with Stata 15.0 software (Stata Corporation, College station, TX). In terms of case-control study, the risks of vitamin D status in associating with the sepsis were compared using OR and 95% confidence interval (CI). Moreover, 25-OHD level was compared using standard mean difference (SMD) using mean and standard deviations (SD). If the data provided as medians and ranges, we converted medians and ranges into means and SD using the formula provided by Hozo et al.[18] For cohort study, the sepsis occurrence, mechanical ventilation rate, and 30-day mortality were compared using RR and 95% CI. All P value <.05 was considered to be statistical significance for all the analyses.

3. Results

3.1. Selection of included studies

A total of 1130 studies were found based on the search strategy. Four studies were identified through grey literature screening. And 917 studies were screened through abstracts and titles after deleting the duplication studies. Finally, a total of 27 studies were included based on the inclusion and exclusion criteria.[3,7–10,19–40] The flowchart of the literature screening was shown in Fig. 1.

Figure 1.

Figure 1

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The flowchart of literature screening.

3.2. Characteristics and meta-analysis in the case-control studies

Due to the different study group in case-control study and cohort study, we divided the included studies based on the study type. The characteristics of case-control study were shown in Table 1. A total of 17 case-control studies with 1358 sepsis children and 1956 non-sepsis children. The case-control studies covering 6 countries, including India, Turkey, Egypt, Thailand, China, and USA. The median birthweight in sepsis group was 2602 g (range from 1294 to 3454 g) while that was 2678 g (range from 1750 to 3223 g). 56.6% of children were boys in sepsis group comparing to 55.1% of which in non-sepsis group. The median 1 and 5 minutes APGAR score was 7.7 and 8.8 in sepsis group comparing to 8 and 9 in non-sepsis group.

Table 1.

The characteristics of included case-control study.

Author Year Recruitment year Country Vitamin D deficiency definition NOS Group Sample Birthweight Male, % APGAR score 1 min APGAR score 5 min Maternal 25-OHD levels Neonatal 25-OHD levels Deficiency in total Severe vitamin D deficiency Insufficiency vitamin D deficiency
Singh, P. 2020 2015–2016 India Serum 25-OHD level: severe deficiency <11 ng/mL; insufficiency 11–32 ng/mL, and >32–100 ng/mL was adequate 8 Sepsis 70 2640 ± 480 43 (61) 9 (9–10) 9 (9–10) NG 16± 10.5 56 (80) 29 (41) 27 (39)
Non-sepsis 70 2580 ± 370 40 (57) 9 (9–10) 9 (9–10) NG 29.07 ± 8.4 41 (59) 4 (6) 37 (53)
Dogan, P. 2020 2014–2015 Turkey Serum 25-OHD level: severe vitamin D deficiency <5 ng/mL, insufficiency 5–15 ng/mL, sufficient >20 ng/mL 8 Sepsis 42 1294 (1018–1883) 18 (43) 7 (5–8) 8 (7–9) 9.5 (8–13) 8.1 (5–9.5) 40 (95) 19 (45) 21 (50)
Non-sepsis 66 1750 (1198–2290) 41 (62) 7 (5–8) 8 (6–9) 14.1 (10.3–18) 12.2 (8.5–15.4) 49 (74) 14 (21) 35 (53)
Behera, C. K. 2020 2015–2016 India Serum 25-OHD level: severe vitamin D deficiency <12 ng/mL, insufficiency 12–20 ng/mL, sufficiency > 20 ng/mL 8 Sepsis 40 2712 ± 648 28 (70) 8 ± 2 9 ± 1 20.92 ± 3.92 12.71 ± 2.82 39 (98) 31 (78) 8 (20)
Non-sepsis 40 2890 ± 350 24 (60) 8 ± 1 9 ± 0 27.31 ± 6.83 25.46 ± 7.02 0 (0) 0 (0) 0 (0)
Ozdemir, A. A. 2019 2017–2018 Turkey Serum 25-OHD level: severe vitamin D deficiency <12 ng/mL, insufficiency 12–20 ng/mL, sufficiency >20 ng/mL 6 Sepsis 51 NG 40 (78) 8 ± 1 9 ± 1 10.8 ± 5.6 11.0 ± 5.5 NG NG NG
Non-sepsis 56 NG 26 (46) 8 ± 1 9 ± 1 14.9 ± 10 13.8 ± 10.6 NG NG NG
Hagag, A. A. 2019 2017–2019 Egypt NG 5 Sepsis 60 2557 ± 41 NG NG NG 16.95 ± 2.60 NG NG NG
Non-sepsis 30 2577 ± 45 NG NG NG 24.36 ± 3.35 NG NG NG
Agrawal, A. 2019 2016–2017 India Serum 25-OHD level: severe vitamin D deficiency <5 ng/mL, insufficiency 5–15 ng/mL, sufficient >20 ng/mL 7 Sepsis 175 2441 ± 670 81 (46) NG NG NG 12.28 ± 6.11 151 (86) 36 (21) 115 (65)
Non-sepsis 50 2630 ± 510 27 (54) NG NG NG 14.88 ± 7.2 37 (74) 7 (14) 30 (60)
Zheng, G. 2018 2015–2017 China NG 6 Sepsis 75 NG 37 (49) 8.4 ± 0.8 9.5 ± 0.5 NG 14.85 ± 6.14 NG NG NG
Non-sepsis 100 NG 50 (50) 8.2 ± 0.7 9.6 ± 0.4 NG 26.38 ± 6.56 NG NG NG
Tayel, S. I. 2018 2016–2017 Egypt NG 7 Sepsis 49 3000 ± 100 24 (49) 6.3 ± 1.1 8.5 ± 1.7 21.4 ± 4.8 8.7 ± 0.7 NG NG NG
Non-sepsis 40 3000 ± 100 17 (43) 9.3 ± 0.6 10 ± 0 36.9 ± 4.2 19.1 ± 4.7 NG NG NG
Li, W. 2018 2009–2011 China Serum 25-OHD level: severe vitamin D deficiency <10 ng/mL, insufficiency 10–20 ng/mL, sufficient >30 ng/mL 5 Sepsis 433 NG 255 (59) NG NG NG 15.96 ± 9.03 NG NG NG
Non-sepsis 785 NG 426 (54) NG NG NG 31.71 ± 14.82 NG NG NG
Dhandai, R. 2018 2015–2016 India Serum 25-OHD level: vitamin D deficiency <120 ng/mL, insufficiency 20–30 ng/mL, sufficient >30 ng/mL 6 Sepsis 60 2625.12 ± 486.2 35 (58) NG NG 17.87 ± 11.89 15.37 ± 10 NG NG NG
Non-sepsis 60 2495.58 ± 490.1 42 (70) NG NG 23.65 ± 9.55 21.37 ± 9.53 NG NG NG
Gamal, T. S. 2017 2015–2016 Egypt Serum 25-OHD level: severe vitamin D deficiency <12 ng/mL, insufficiency 12–20 ng/mL, sufficiency >20 ng/mL 6 Sepsis 50 NG NG NG NG 42.5 ± 20.7 6.4 ± 1.8 NG NG NG
Non-sepsis 30 NG NG NG NG 50.4 ± 21.4 24.6 ± 2.2 NG NG NG
Korwutthikulrangsri, M 2015 NG Thailand NG 6 Sepsis 32 NG NG NG NG NG 16.6 (13.3–19.5) NG NG NG
Non-sepsis 36 NG NG NG NG NG 24.2 (21.0–27.9) NG NG NG
Cizmeci, M. N. 2015 2011–2012 Turkey Serum 25-OHD level: vitamin D deficiency <12 ng/mL, insufficiency 20–30 ng/mL, sufficient >30 ng/mL 6 Sepsis 40 2877 ± 652 27 (68) NG NG NG NG NG NG 35 (87)
Non-sepsis 43 3120 ± 440 28 (65) NG NG NG NG NG NG 23 (53)
Cetinkaya, M 2015 2012 Turkey. Serum 25-OHD level: severe deficiency <11 ng/mL; insufficiency 11–32 ng/mL, and >32–100 ng/mL was adequate 7 Sepsis 50 3454 ± 460 26 (52) 8 ± 3 8 ± 2 22.2 ± 6.8 8.6 ± 3.1 NG NG NG
Non-sepsis 50 3223 ± 460 29 (58) 7 ± 2 8 ± 2 36.2 ± 1.8 19.0 ± 4.8 NG NG NG
Cekmez, F. 2014 2011–2012 Turkey NG 5 Sepsis 40 2420 ± 368 NG NG NG NG 69 ± 7.5 NG NG NG
Non-sepsis 20 2520 ± 280 NG NG NG NG 35 ± 19 NG NG NG
Aydemir, G. 2014 NG Turkey NG 5 Sepsis 40 NG NG NG NG NG 74 ± 8 NG NG NG
Non-sepsis 20 NG NG NG NG NG 28 ± 12 NG NG NG
Madden, K. 2012 2009–2010 USA Serum 25-OHD level: vitamin D deficiency <12 ng/mL, insufficiency 20–30 ng/mL, sufficient >30 ng/mL 5 Sepsis 51 NG NG NG NG NG 19.2 (12.6–24.8) NG NG NG
Non-sepsis 460 NG NG NG NG NG 22.5 (16.4–31.3) NG NG NG
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NOS = the Newcastle-Ottawa Quality Assessment Scale.

The comparison of 25-OHD level between sepsis group and non-sepsis group was summarized in Fig. 2. The maternal 25-OHD level was 20.7 ng/mL in sepsis group, which is lower than non-sepsis group with 29.05 ng/mL (SMD = –1.58, 95% CI = –2.42 to –0.74, P < .001). Similarly, the neonatal 25-OHD level in sepsis group was significant lower than non-sepsis group (SMD = –1.61, 95% CI = –2.09 to –1.10, P < .001). Based on the neonatal 25-OHD level in different children, several study classified the vitamin D deficiency into severe and insufficient vitamin D deficiency. The comparison of the percentage of severe and insufficient vitamin D deficiency was shown in Fig. 3. The percentage of severe vitamin D deficiency was significant higher in sepsis group comparing to non-sepsis group (OR = 2.66, 95% CI = 1.13–6.25, P < .001). However, no statistically difference was found in terms of insufficient vitamin D deficiency between 2 groups (OR = 1.04 95% CI = 0.76–1.41, P = .364).

Figure 2.

Figure 2

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The comparison of maternal 25-OHD level and neonatal 25-OHD level in critically ill children with sepsis to those children without sepsis.

Figure 3.

Figure 3

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The comparison of severe vitamin D deficiency and insufficient vitamin D deficiency in critically ill children with sepsis to those children without sepsis.

3.3. Characteristics and meta-analysis in the cohort studies

Ten studies designed the cohort study to demonstrate the association between 25-OHD level and the outcome of critically ill children. The characteristics were summarized in Table 2. The publish year ranged from 2012 to 2020, and the recruitment year range from 2005 to 2017. Seven countries (China, Korea, India, Ireland, Spain, Australia, Canada) were covered. All the studies divided the cohort into lower 25-OHD level group and higher 25-OHD level group with cut-off of 20 ng/mL. A total of 925 patients were diagnosed as low 25-OHD level and 694 patients were high 25-OHD level. The percentage of boys was 59.5% in lower 25-OHD level group comparing to 56.9% in higher 25-OHD level group.

Table 2.

The characteristics of included cohort study (the cutoff of 25OHD level was defined as 20 ng/mL).

Author Year Recruitment year Country NOS Group Sample Age, mo Male, % Sepsis, % Mechanical ventilation 30 days mortality, %
Dang, H. 2020 2016–2017 China 8 Lower 25OHD group 116 21.5 (7–52.5) 67 (58) NG 97 (84) 22 (19)
Higher 25OHD group 180 19 (7–58) 99 (55) NG 131 (73) 17 (9)
Kim, I. 2018 2013–2017 Korea 7 Lower 25OHD group 150 NG 84 (56) 26 (17) NG NG
Higher 25OHD group 38 NG 15 (39) 3 (8) NG NG
Shah, S. K. 2016 NA India 8 Lower 25OHD group 128 48 (6.5–108) 81 (63) 84 (66) 87 (68) 54 (42)
Higher 25OHD group 26 9.5 (6–32) 21 (81) 16 (62) 22 (85) 14 (54)
Sankar, J. 2016 2013 India 8 Lower 25OHD group 75 NG 36 (48) 47 (63) 43 (57) 23 (31)
Higher 25OHD group 26 NG 16 (62) 16 (62) 10 (38) 8 (31)
Prasad, S. 2015 2013–2014 India 8 Lower 25OHD group 67 12 (5–72) 46 (69) 9 (13) 30 (45) NG
Higher 25OHD group 13 13 (8–30) 9 (69) 2 (15) 3 (23) NG
Onwuneme, C. 2015 2012–2015 Ireland 7 Lower 25OHD group 71 NG NG 32 (45) 64 (90) NG
Higher 25OHD group 49 NG NG 3 (6) 37 (76) NG
Rey, C. 2014 NA Spain 7 Lower 25OHD group 46 97 (44.5–145) 28 (61) 6 (13) 18 (39) NG
Higher 25OHD group 110 34 (14–98) 65 (59) 18 (16) 45 (41) NG
Dayal, D. 2014 2012 India 6 Lower 25OHD group 23 NG 14 (61) 4 (17) 8 (35) NG
Higher 25OHD group 69 NG 53 (77) 5 (7) 13 (19) NG
Rippel, C. 2012 2010–2011 Australia 7 Lower 25OHD group 24 29.1 (11.5–73.7) 16 (67) 5 (21) 18 (75) 1 (4)
Higher 25OHD group 82 24.1 (16.3–35.5) 53 (65) 16 (20) 67 (82) 5 (6)
McNally, J. D. 2012 2005–2008 Canada 6 Lower 25OHD group 225 3.9 (0.5–13.1) 114 (51) 33 (15) NG NG
Higher 25OHD group 101 2.5 (0.6–11.5) 53 (52) 15 (15) NG NG
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NOS = the Newcastle-Ottawa Quality Assessment Scale.

The comparison of the occurrence rate of sepsis, mechanical ventilation and 30-day mortality in critical children were summarized in Fig. 4. The sepsis rate was 30.4% in lower 25-OHD level group comparing to which was 18.2% in higher 25-OHD level group. Although the higher sepsis rate was found in lower 25-OHD level group, there was no statistically significance between 2 groups (RR = 1.24, 95%CI = 0.98–1.56, I2 = 28.7%, P = .068, Fig. 4A). The mechanical ventilation rate was 66.3% in lower 25-OHD level group and 59.1% in higher 25-OHD level group, and no significant difference between 2 groups (RR = 1.07, 95% CI = 0.94–1.22, I2 = 31.6%, P = .289, Fig. 4B). Besides, the 30-day mortality was 29.1% in lower 25-OHD level group compared with 14.0% in higher 25-OHD level group, but without statistical difference (RR = 1.15, 95%CI = 0.83–1.59, I2 = 0%, P = .398, Fig. 4C).

Figure 4.

Figure 4

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The comparison of the incidence of sepsis (A), mechanical ventilation (B), and 30-day mortality (C) in lower 25-OHD level group and higher 25-OHD level group.

3.4. Quality assessment in included studies

We assessed the quality of included studies based on the NOS approach, 12 studies were regarded as high quality in case-control study,[7,19,21,23,24,27,28,30,34,38–40] and all the cohort studies were regarded as high quality with NOS >6.[3,8,9,25,26,32,33,35–37]

4. Discussion

Our systematic review and meta-analysis demonstrated that both the maternal 25-OHD level and neonatal 25-OHD level were lower in infant with sepsis comparing to those infant without sepsis in PICU. Specially, the percentage of severe vitamin D deficiency was higher in sepsis group comparing to non-sepsis group. Although a higher rate of mechanical ventilation rate and 30-day mortality was found in lower 25-OHD level group in cohort study, there was no statistical significance between lower and higher 25-OHD level critically ill children.

Vitamin D can be ingested from food, but mainly from the body's own synthesis. 7-dehydrocholesterol isomerized in the skin under ultraviolet light (296–310 nm) to produce vitamin D3, which enters the blood circulation and binds to vitamin D specific binding protein (VDBP). It is transported to the liver and kidney successively and then hydroxylated by the action of 25-hydroxylase and 1-αhydroxylase into biologically active 1,25 (OH)D, and then carried by VDBP to various target organs through blood circulation, and vitamin D receptor (VDR) combines to play a biological role. The intestine, kidney, and bone are the main target organs. Most tissues and cells in the body can express VDR, and some contain the active enzyme required for the hydroxylation of vitamin D in the body, which generates 1,25(OH)2D3 by itself. On this basis, vitamin D plays an important role in extra-osseous diseases, such as infectious diseases, autoimmune diseases, diabetes, cancer, cardiovascular diseases, and etc.[1,2] Vitamin D levels are affected by various factors such as sex, age, season, geographic location, disease, drugs, and etc, and healthy children also have vitamin D deficiency and deficiency.[41] Vitamin D is a nutritional vitamin, but surveys have shown that children with critical illness have a high incidence of nutritional risk, and children with sepsis have a high incidence of nutritional risk of 86.4%.[40] In our meta-analysis, we demonstrated that critically ill children with sepsis might have a lower 25-OHD level than those without sepsis.

However, the mechanism of vitamin D deficiency to increase the sepsis rate and mortality in children is not yet clear. In recent years, several studies confirmed the regulatory effect of vitamin D on the immune system. Some studies suggested that the lack of 25-OHD will reduce immune function, affect hormone metabolism, lead to an increase in the incidence of various infections and critical illnesses, thereby increasing mortality. Sepsis involves pathological and physiological changes such as uncontrolled inflammatory response, immune dysfunction, high metabolic state, and multiple organ damage, or may become the target of vitamin D treatment.[42] Moreover, studies have shown that VDR is expressed on the surface of immune cells such as mononuclear macrophages, T cells, and B cells. 25-OHD may affect the occurrence and development of sepsis by regulating immune function.[43] Moreover, vitamin D can enhance the body's resistance to pathogen invasion, suppress adaptive immune response, protect the body from various autoimmune diseases, and limit the rejection of grafts. Biological functions have been widely recognized.[44] Studies have found that VDR is expressed in most immune cells, including T cells, B cells, monocytes, and antigen-presenting cells, such as macrophages and dendritic cells.[45] Because the regulation of vitamin D is mediated by VDR, this further confirms that vitamin D has a wide range of regulatory effects on the immune system. 1,25(OH)2D3 can inhibit the maturation and differentiation of dendritic cells (DCs) through interaction with VDR[38]; it can also regulate the expression and secretion of cytokines and chemokines by DCs derived from monocytes: such as promoting IL-10, the secretion of IL-12 and IL-23 inhibits the secretion of TNF-α and IFN-γ. More importantly, 1,25(OH)2D3 can indirectly inhibit the function of B cells by changing the response of CD4 T lymphocytes and inhibiting monocyte/macrophage secretion of cytokines and therefore had an anti-infection effect for curing inflammation.

There was a slight difference between case-control study and cohort study. In the case-control study, we suggested that infants and children with sepsis may have a lower 25-OHD level and a higher severe vitamin D deficiency rate than those without sepsis, and the results were statistically difference. However, in those included cohort studies, although the results showed a higher occurrence of sepsis and 30-day mortality in lower 25-OHD level group, there were no statistically difference were found. For one reason, all the studies defined the cut-off of 25-OHD level was 20 ng/mL, which was higher than the definition of severe deficiency, and thus increase the sepsis rate in the higher 25-OHD level group. For another, most study in case-control group only included the infants with new born, while the cohort study included more children with an elder age, which may result to the difference between 2 study type. Nevertheless, future evidence still needed to be undertaken for evaluating the risks of 25-OHD level and the occurrence of sepsis in critically ill children.

There are some limitations in our study. Firstly, although we analyzed the relationship between vitamin D deficiency and the occurrence of sepsis in critically illness children in case-control study and cohort study separately, the variables, such as participants age, associated medical conditions and original diseases among studies could be fully balanced which may result in the bias among studies. Secondly, we only include the studies written by English which may increase the publication bias in some certain condition. Thirdly, due to the scarce of the studies discussing the vitamin D supplement in reducing the occurrence of sepsis in critically ill children, we could not analyze the effect of vitamin D supplement in treatment of critical ill children. More large-scale observational study and randomized control trials still needed for the further demonstration the effect of vitamin D in association with sepsis in critically ill children.

5. Conclusion

We demonstrated that critically ill infants and children with sepsis could have a lower 25-OHD level and severe vitamin D deficiency comparing to those without sepsis. Future studies should focus on the association of vitamin D supplement and the occurrence of sepsis in critically ill children.

Author contributions

Conceptualization: Weijie Yu, Wen Zhu, Lisu Huang, Qiuying Hou.

Data curation: Weijie Yu, Wen Zhu, Qinlai Ying, Qiuying Hou.

Design of the meta-analysis: Weijie Yu and Qiuying Hou.

Formal analysis: Qiuying Hou.

Investigation: Weijie Yu, Qinlai Ying.

Literature screening: Weijie Yu and Qinlai Ying.

Methodology: Lisu Huang, Qiuying Hou.

Quality assessment: Wen Zhu and Lisu Huang.

Software: Lisu Huang.

Statistics analysis: Weijie Yu and Lisu Huang.

Supervision: Qiuying Hou.

Writing – original draft: Weijie Yu, Wen Zhu, Qinlai Ying, Lisu Huang, Qiuying Hou.

Writing – review & editing: Weijie Yu, Wen Zhu, Qinlai Ying, Lisu Huang, Qiuying Hou.

Glossary

Abbreviations: 25-OHD = 25 hydroxyvitamin D, CI = confidence interval, DCs = dendritic cells, MeSH = Medical Subject Heading, MODS = multiple organ dysfunction syndrome, NOS = the Newcastle-Ottawa Quality Assessment Scale, OR = odds ratio, PICU = pediatric intensive care unit, PRISMA = systematic review and meta-analysis, RR = relative risks, SD = standard deviations, SMD = standard mean difference, VDBP = vitamin D specific binding protein, VDR = vitamin D receptor.

References

  • [1].Holick MF. Vitamin D deficiency. N Engl J Med 2007;357:266–81. [DOI] [PubMed] [Google Scholar]
  • [2].Wacker M, Holick MF. Vitamin D - effects on skeletal and extraskeletal health and the need for supplementation. Nutrients 2013;5:111–48. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [3].Kim I, Kim S, Park G, et al. Association between vitamin D level at birth and respiratory morbidities in very-low-birth-weight infants. Am J Perinatol 2018;35:S1–26. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [4].Chen S, Swier VJ, Boosani CS, et al. Vitamin D deficiency accelerates coronary artery disease progression in swine. Arterioscler Thromb Vasc Biol 2016;36:1651–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [5].Hoffman RM, Lake JE, Wilhalme HM, et al. Vitamin D levels and markers of inflammation and metabolism in HIV-infected individuals on suppressive antiretroviral therapy. AIDS Res Hum Retroviruses 2016;32:247–54. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [6].Hansen CM, Binderup L, Hamberg KJ, et al. Vitamin D and cancer: effects of 1, 25 (OH) 2D3 and its analogs on growth control and tumorigenesis. Front Biosci 2001;6:D820–48. [DOI] [PubMed] [Google Scholar]
  • [7].Dogan P, Ozkan H, Koksal N, et al. The role of low 25-hydroxyvitamin D levels in preterm infants with late-onset sepsis. Fetal Pediatr Pathol 2020;1–0. [DOI] [PubMed] [Google Scholar]
  • [8].Shah SK, Kabra SK, Gupta N, et al. Vitamin D deficiency and parathyroid response in critically-ill children: association with illness severity and clinical outcomes. Indian Pediatr 2016;53:479–84. [DOI] [PubMed] [Google Scholar]
  • [9].Rippel C, South M, Butt WW, et al. Vitamin D status in critically ill children. Intensive Care Med 2012;38:2055–62. [DOI] [PubMed] [Google Scholar]
  • [10].Madden K, Feldman HA, Smith EM, et al. Vitamin D deficiency in critically ill children. Pediatrics 2012;130:421–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [11].Bone RC, Balk RA, Cerra FB, et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest 1992;101:1644–55. [DOI] [PubMed] [Google Scholar]
  • [12].Campaign SS, Dellinger R, Levy M, et al. International guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med 2013;41:580–637. [DOI] [PubMed] [Google Scholar]
  • [13].Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016;315:801–10. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [14].Khan MR, Maheshwari PK, Masood K, et al. Epidemiology and outcome of sepsis in a tertiary care PICU of Pakistan. Indian J Pediatr 2012;79:1454–8. [DOI] [PubMed] [Google Scholar]
  • [15].Gottschlich MM, Mayes T, Khoury J, et al. Clinical trial of Vitamin D2 vs D3 supplementation in critically ill pediatric burn patients. JPEN J Parenter Enteral Nutr 2017;41:412–21. [DOI] [PubMed] [Google Scholar]
  • [16].Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 2009;6:e1000097. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [17].Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol 2010;25:603–5. [DOI] [PubMed] [Google Scholar]
  • [18].Hozo SP, Djulbegovic B, Hozo I. Estimating the mean and variance from the median, range, and the size of a sample. BMC Med Res Methodol 2005;5:13. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [19].Agrawal A, Gupta A, Shrivastava J. Role of Vitamin-D deficiency in term neonates with late-onset sepsis: a case-control study. J Trop Pediatr 2019;65:609–16. [DOI] [PubMed] [Google Scholar]
  • [20].Aydemir G, Cekmez F, Kalkan G, et al. High serum 25-hydroxyvitamin D levels are associated with pediatric sepsis. Tohoku J Exp Med 2014;234:295–8. [DOI] [PubMed] [Google Scholar]
  • [21].Behera CK, Sahoo JP, Patra SD, et al. Is lower Vitamin D level associated with increased risk of neonatal sepsis? A prospective cohort study. Indian J Pediatr 2020;87:427–32. [DOI] [PubMed] [Google Scholar]
  • [22].Cekmez F, Aydemir G, Yildirim S, et al. Diagnostic value of 25-hydroxyvitamin D level and new cytokines in neonatal sepsis. Eur J Inflamm 2014;12:297–304. [Google Scholar]
  • [23].Cetinkaya M, Cekmez F, Buyukkale G, et al. Lower vitamin D levels are associated with increased risk of early-onset neonatal sepsis in term infants. J Perinatol 2015;35:39–45. [DOI] [PubMed] [Google Scholar]
  • [24].Cizmeci MN, Kanburoglu MK, Akelma AZ, et al. Cord-blood 25-hydroxyvitamin D levels and risk of early-onset neonatal sepsis: a case-control study from a tertiary care center in Turkey. Eur J Pediatr 2015;174:809–15. [DOI] [PubMed] [Google Scholar]
  • [25].Dang H, Li J, Liu C, et al. 25-Hydroxy vitamin d deficiency is associated with cardiovascular sequential organ failure assessment and pediatric risk of mortality III scores in critically ill children. Front Pediatr 2020;8:66. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [26].Dayal D, Kumar S, Sachdeva N, et al. Fall in Vitamin D levels during hospitalization in children. Int J Pediatr 2014;2014:291856. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [27].Dhandai R, Jajoo M, Singh A, et al. Association of vitamin D deficiency with an increased risk of late-onset neonatal sepsis. Paediatr Int Child Health 2018;38:193–7. [DOI] [PubMed] [Google Scholar]
  • [28].Gamal TS, Madiha AS, Hanan MK, et al. Neonatal and maternal 25-OH Vitamin D serum levels in neonates with early-onset sepsis. Children (Basel) 2017;4:09. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [29].Hagag AA, El Frargy MS, Houdeeb HA. Therapeutic value of Vitamin D as an adjuvant therapy in neonates with sepsis. Infect Disord Drug Targets 2020;20:440–7. [DOI] [PubMed] [Google Scholar]
  • [30].Korwutthikulrangsri M, Mahachoklertwattana P, Lertbunrian R, et al. Vitamin D deficiency and adrenal function in critically ill children. J Med Assoc Thai 2015;98:365–72. [PubMed] [Google Scholar]
  • [31].Li W, Cheng X, Guo L, et al. Association between serum 25-hydroxyvitamin D concentration and pulmonary infection in children. Medicine (Baltimore) 2018;97:e9060. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [32].McNally JD, Menon K, Chakraborty P, et al. The association of vitamin D status with pediatric critical illness. Pediatrics 2012;130:429–36. [DOI] [PubMed] [Google Scholar]
  • [33].Onwuneme C, Carroll A, Doherty D, et al. Inadequate vitamin D levels are associated with culture positive sepsis and poor outcomes in paediatric intensive care. Acta Paediatr 2015;104:e433–8. [DOI] [PubMed] [Google Scholar]
  • [34].Ozdemir AA, Cag Y. Neonatal Vitamin D status and the risk of neonatal sepsis. Pak J Med Sci 2019;35:420–5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [35].Prasad S, Raj D, Warsi S, et al. Vitamin D Deficiency and Critical Illness. Ind J Pediatr 2015;82:991–5. [DOI] [PubMed] [Google Scholar]
  • [36].Rey C, Sánchez-Arango D, López-Herce J, et al. Vitamin D deficiency at pediatric intensive care admission. J Pediatr (Rio J) 2014;90:135–42. [DOI] [PubMed] [Google Scholar]
  • [37].Sankar J, Lotha W, Ismail J, et al. Vitamin D deficiency and length of pediatric intensive care unit stay: a prospective observational study. Ann Intensive Care 2016;6:3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [38].Singh P, Chaudhari V. Association of early-onset sepsis and vitamin d deficiency in term neonates. Indian Pediatr 2020;57:232–4. [PubMed] [Google Scholar]
  • [39].Tayel SI, Soliman SE, Elsayed HM. Vitamin D deficiency and vitamin D receptor variants in mothers and their neonates are risk factors for neonatal sepsis. Steroids 2018;134:37–42. [DOI] [PubMed] [Google Scholar]
  • [40].Zheng G, Pan M, Li Z, et al. Effects of vitamin D on apoptosis of T-lymphocyte subsets in neonatal sepsis. Exp Ther Med 2018;16:629–34. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [41].Amrein K, Zajic P, Schnedl C, et al. Vitamin D status and its association with season, hospital and sepsis mortality in critical illness. Crit Care 2014;18:R47. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [42].Lee P, Nair P, Eisman JA, et al. Vitamin D deficiency in the intensive care unit: an invisible accomplice to morbidity and mortality? Intensive Care Med 2009;35:2028–32. [DOI] [PubMed] [Google Scholar]
  • [43].Berry DJ, Hesketh K, Power C, et al. Vitamin D status has a linear association with seasonal infections and lung function in British adults. Br J Nutr 2011;106:1433–40. [DOI] [PubMed] [Google Scholar]
  • [44].Bikle DD. Vitamin D and immune function: understanding common pathways. Curr Osteoporos Rep 2009;7:58–63. [DOI] [PubMed] [Google Scholar]
  • [45].Sadeghi K, Wessner B, Laggner U, et al. Vitamin D3 down-regulates monocyte TLR expression and triggers hyporesponsiveness to pathogen-associated molecular patterns. Eur J Immunol 2006;36:361–70. [DOI] [PubMed] [Google Scholar]

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