Relationship Between Vitamin D Status and Viral Pneumonia in Children

Abstract

This study investigated the impact of vitamin D status on the susceptibility and severity of viral pneumonia (VP) in children. A total of 236 children with VP, aged from 1 month to 14 years, and 271 gender and age matched healthy children to compare the serum 25(OH)D levels and vitamin D status. Vitamin D indices were compared between subgroups in VP cases. The median [interquartile range (IQR)] serum 25(OH)D level in these 507 children was 23.7 (IQR 17.5–30.6) ng/mL; 134 (26.4%) children were vitamin D sufficient [25(OH)D ≥30 ng/mL], whereas 373 (73.6%) were insufficient, which included insufficient [25(OH)D 20–30 ng/mL], deficient [25(OH)D 10–20 ng/mL], and severely deficient [25(OH)D ≤10 ng/mL]. The median (IQR) serum 25(OH)D level in the VP group was significantly lower than that in the control group [19.6 (12.3–26.4) ng/mL versus 26.6 (21.4–32.9) ng/mL] (P < 0.001). The proportions of vitamin D deficiency (32.2% versus 19.5%) and severe deficiency (19.1% versus 0.4%) in the VP group were significantly higher than those in the control group (P < 0.001). As vitamin D status decreased, the odds ratio (95% confidence interval) for VP showed an increasing trend [sufficiency (0.3; 0.2–0.5), insufficiency (0.9; 0.6–1.3), deficiency (2.0; 1.3–2.9), and severe deficiency (51.7; 7.2–372.2)]. The median (IQR) serum 25(OH)D level in the VP subgroup who accepted mechanical ventilation was significantly lower than that in the nonmechanical ventilation subgroup [12.9(6.5–22.5) ng/mL versus 20.8 (14.2–28.0) ng/mL] (P < 0.001). Poor vitamin D status might be related to the susceptibility and severity of VP in children.

Introduction

Lower respiratory tract infections are among the most important causes of morbidity and mortality in the childhood, approximately two million children aged below five years die each year because of pneumonia.¹ Viral lower respiratory tract infection is the most common acute infectious disease and shows a high morbidity and mortality worldwide.² The causal agents are picornaviruses (including rhinovirus A–C and enteroviruses A–D), orthomyxoviruses (influenza A, influenza B, and influenza C), paramyxoviruses (including parainfluenza viruses, respiratory syncytial virus, and human metapneumovirus), coronaviruses, adenoviruses, and human bocavirus in community-acquired pneumonia (CAP).^2–7 Moreover, usually the patients were in severe situations when viruses are detected in the sputum of patients with CAP admitted into intensive care units (ICUs).^7,8

There is growing evidence that vitamin D plays an important role in immune regulation in the human body by modulating both innate and adaptive immunity as well as regulating the inflammatory cascade.^9,10 Recently, numerous studies have suggested that vitamin D plays a role in various infectious processes at different ages.^11,12 A common example of the relationship between vitamin D insufficiency and the susceptibility to infectious disease was found to be tuberculosis.¹³ Previous studies have shown that CAP and sepsis are linked to vitamin D insufficiency.^14,15

As adequate vitamin D is required for interferon-mediated antimicrobial activity of human macrophages,¹⁶ this effect may play an important role in antiviral infection in children. The relationship between vitamin D status and the risk of viral pneumonia (VP) for children in Beijing, has not been examined. We hypothesized that vitamin D deficiency was one of the risk factors for VP in children. In this study, the vitamin D status of hospitalized children with VP and healthy controls were compared to clarify whether reducing the serum 25(OH) D level increases the risk of VP in Beijing.

Materials and Methods

A matched cohort study was performed from January 2009 to December 2013 in the Affiliated Children's Hospital of Capital Institute of Pediatrics, Beijing, China. This cohort is regarded as a one-center observational study at a 400-bed tertiary teaching hospital, which has more than 3,000 pneumonia-related admissions annually. This study was conducted in accordance with the Declaration of Helsinki and with approval from the Ethics Committee of Affiliated Children's Hospital of Capital Institute of Pediatrics (Approval ID SHERLL: 2013045).

Cohort definition

Patients

A total of 236 children with VP, from January 1, 2009, to December 31, 2013, were selected as the VP group. Pneumonia was defined as clinical pneumonia with cough, increased respiratory rate for age, chest indrawing, or any danger sign (not drinking or breastfeeding, convulsion, vomiting, lethargic or unconscious, stridor, etc.) confirmed by chest radiography. The viral pathogens were identified in the collected clinical sputum by immunofluorescence assay and were typed by nested polymerase chain reaction based on the sequence of the gene encoding hexon. Exclusion criteria included children with chronic lung disease, kidney disease, heart disease, digestive tract disease, congenital malformation, immunodeficiency disease, hematological malignancies, or connective tissue disease complicated by VP. Clinical data were collected from the electronic medical records of the center. A total of 271 healthy controls were selected as the control group from among children who received physical examinations as outpatients during the same time period and were matched with the VP children by age, sex, race, and season of 25(OH)D measurement. For children to be enrolled in the study, their guardians had signed informed consent. The residual blood samples of the routine test were utilized to measure the serum 25(OH) D level on the day of admission for VP cases, whereas for the control group, were acquired on the day of physical examinations. These time points were chosen arbitrarily to assess the differences in serum 25(OH)D levels between the 2 groups. Clinical data of the VP children were also collected, and patients with PaO₂/FiO₂ lower than 200 mmHg or with dyspnea, cyanosis, shock and/or other severe complications who accepted invasive mechanical ventilation (MV) and noninvasive MV therapy were set in the MV subgroup, whereas those who did not accept MV were set in the n-MV subgroup.

25(OH)D measurements

Serum 25(OH)D levels were detected and estimated by chemiluminescence using a Fluoroskan (DiaSorin LIAISON, Stillwater, MN) with micro-whole blood, which recently received a Federal Drug Administration clearance letter (510K). The assay had an intra-assay coefficient of variation as 9% and an inter-assay coefficient of variation as 11%. For categorical analysis of the vitamin D nutritional status according to the serum 25(OH)D level, we set cutoffs of ≥30 ng/mL for sufficiency, 20–30 ng/mL for insufficiency, 10–20 ng/mL for deficiency, and ≤10 ng/mL for severe deficiency, as described previously.¹⁷

Statistical analysis

Statistical analysis was performed using Prism 5 (GraphPad, Inc., La Jolla, CA). Descriptive analysis was performed by determining frequency distributions or rates. Medians [interquartile range (IQR)] were used to summarize the demographic data and patients' baseline characteristics with non-normal distribution. The Mann–Whitney test was used to evaluate quantitative data showing a non-normal distribution. Chi-square test or Fisher's exact test was used for categorical variables. A two-tailed P < 0.05 was considered statistically significant.

Results

General conditions

A total of 507 children were enrolled in this study, including 258 girls and 249 boys, ranging in age from 1 month to 14 years, with a median of 25 (IQR 11.0–38.3) months. Baseline demographics of the VP group and the control group are described in Table 1. Pathogen distributions among VP group were 37.7% influenza virus, 28.8% respiratory syncytial virus, 11.0% adenovirus, 10.2% human metapneumovirus, and 12.3% other virus. Among the VP group, 60 cases received MV (MV subgroup) and 176 cases did not accept MV (n-MV subgroup), Table 2.

Table 1.

Baseline Demographics of the Viral Pneumonia Group and the Control Group

Subjects	VP group n (%)	Control group
Number of subjects	236	271
Age (year)
<1	95 (40.3)	85 (31.4)
1–3	73 (30.9)	96 (35.4)
3–7	64 (27.1)	86 (31.7)
>7	4 (1.7)	4 (1.5)
Sex
Male	119 (50.4)	130 (48.0)
Female	117 (49.6)	141 (52.0)
Vitamin D
Sufficiency	36 (15.3)	98 (36.2)
Insufficiency	79 (33.4)	119 (43.9)
Deficiency	76 (32.2)	53 (19.6)
Severe deficiency	45 (19.1)	1 (0.4)
Season
Spring	41 (17.4)	49 (18.1)
Summer	5 (2.1)	8 (3.0)
Autumn	17 (7.2)	21 (7.7)
Winter	173 (73.3)	193 (71.2)

Data are presented as the number (%) for binary variables; percentage calculated for children with complete data.

VP, viral pneumonia.

Table 2.

Demographics of the Viral Pneumonia Group

Subjects	n (%)
Distribution of the viral pathogen
Influenza virus	89 (37.7)
Respiratory syncytial virus	68 (28.8)
Adenovirus	26 (11.0)
Human metapneumovirus	24 (10.2)
Other virus	29 (12.3)
Mechanical ventilation
MV subgroup	60 (25.4)
n-MV subgroup	176 (74.6)

Data are presented as the number (%) for binary variables. Percentage calculated for children with complete data.

MV, mechanical ventilation.

Overall 25(OH)D levels

The serum 25(OH)D levels of the 507 children were not normally distributed, with a median of 23.7 (IQR 17.5–30.6) ng/mL, typically in the insufficient state. The overall vitamin D status was as follows: 134 cases (26.4%) were in a state of sufficiency, whereas 373 (73.6%) were inadequate. Among the inadequate children, insufficiency was found in 198 cases (53.1%), deficiency in 129 cases (34.6%), and severe deficiency in 46 cases (12.3%). The age and gender between the two groups were matched (P > 0.05), and the distributions of age, gender, season, and vitamin D status in the 2 groups are shown in Table 1.

Comparison of serum 25(OH)D levels between different genders

Comparison of serum 25(OH)D between different genders in the VP group and control group revealed no significant differences (P > 0.05). No significant differences were found of the serum 25(OH)D level both in males and females in 2 groups, the medians of the serum 25(OH)D level of males in the VP group and control group were 20.0(14.0–27.6) ng/mL and 26.7(21.6–35.0) ng/mL, respectively, and the medians of the serum 25(OH)D level of females in the VP group and control group were 19.4(12.7–24.9) ng/mL and 26.2(21.3–32.0) ng/mL, respectively. We can see that VP group showed a low trend on the value for different genders.

Comparison of serum 25(OH)D levels between the VP and control groups

The median of serum 25(OH)D levels in the VP and control groups were 19.6 (IQR 12.3–26.4) ng/mL and 26.6 (IQR 21.4–32.9) ng/mL, respectively. The median serum 25(OH)D level in the VP group was significantly lower than that in the control group (P < 0.001) (Fig. 1).

FIG. 1.

Comparison of serum 25(OH)D levels between VP group and control group. ***Comparison of serum 25(OH) D levels between VP group and control group, P < 0.001. The median of serum 25(OH) D levels of VP group and control group were 19.6 (IQR 12.28–26.35) ng/mL and 26.6 (IQR 21.4–32.9) ng/mL, respectively; the median levels of serum 25(OH) D of VP group were significantly lower than the control group (U18450, P < 0.001). Comparison of serum 25(OH)D levels between MV subgroup and n-MV subgroup. ***Comparison of serum 25(OH) D levels between MV subgroup and n-MV subgroup, P < 0.001. The median of serum 25(OH) D levels in MV subgroup and n-MV subgroup were 12.9 (IQR 6.53–22.5) ng/mL and 20.8 (IQR 14.23–27.98) ng/mL, respectively; the serum 25(OH) D level of MV subgroup was significantly lower than n-MV subgroup (U 3236, P < 0.0001) (A). Data are presented as medians (IQR, interquartile ranges); VP, viral pneumonia; 25(OH)D, 25-hydroxyvitamin D. MV, mechanical ventilation; n-MV, nonmechanical ventilation. ***P < 0.001.

Comparison of the serum 25(OH)D levels for different ages between the 2 groups showed that except for the group that included children older than 7 years, the serum 25(OH)D levels in the other age ranges of the VP group were significantly lower than those in the control group (P < 0.05) (Table 3).

Table 3.

Comparisons of the Serum Concentrations of 25(OH)D in Different Ages Between the 2 Groups [Medians (Interquartile Ranges) ng/mL]

Age (year)	Control group	VP group	P
<1	27.7 (21.9–33.2)	18.8 (6.8–24.9)	0.00^a
1–3	29.2 (23.8–36.2)	22.4 (17.9–28.7)	0.00^a
3–7	23.0 (17.7–27.3)	18.4 (13.0–26.1)	0.01^b
>7	22.4 (13.2–29.8)	7.0 (4.0–11.0)	0.06^c

Data are presented as medians (interquartile ranges).

P < 0.001.

P = 0.05–0.01.

P > 0.05.

25(OH)D, 25 hydroxyvitamin D; VP, viral pneumonia.

Vitamin D status and susceptibility to VP

The proportions of vitamin D deficiency (32.2% versus 19.5%) and severe deficiency (19.1% versus 0.4%) in the VP group were significantly higher than those in the control group (P < 0.001), whereas the proportion of vitamin D insufficient status (15.3% versus 36.2%) in the VP group was significantly lower than that in the control group (P < 0.001). As vitamin D status decreased, the odds for VP showed an increasing tread [sufficiency (odds ratio [OR] 0.3; 95% CI 0.2–0.5), insufficiency (OR 0.9; 95% CI 0.6–1.3), deficiency (OR 2.0; 95% CI 1.3–2.9), and severe deficiency (OR 51.7; 95% CI 7.2–372.2)], as is shown in Table 4.

Table 4.

Comparison of the Nutritional Status of Vitamin D Between the 2 Groups

25(OH)D (ng/mL)	VP group n (%)	Control group n (%)	RR (95% CI)	OR (95% CI)	X²	P
Sufficiency (≥30)	36 (15.3)	98 (36.2)	0.4 (0.3–0.6)	0.3 (0.2–0.5)	28.4	0.00^a
Insufficiency (20–29.9)	79 (33.5)	119 (43.9)	0.9 (0.7–1.2)	0.9 (0.6–1.3)	0.4	0.52^b
Deficiency (10–19.9)	76 (32.2)	53 (19.5)	1.7 (1.5–2.2)	2.0 (1.3–2.9)	10.6	0.00^a
Severe deficiency (<10)	45 (19.1)	1 (0.4)		51.7 (7.2–372.2)		0.00^a

Data are presented as the number (%) for binary variables. Percentage calculated for children with complete data.

P < 0.001.

P > 0.05.

RR, relative risk, refers to the risk of illness compared between VP group and control; OR, odds ratio, is accurate estimates value of relative risk; 95% CL, represent the lower and upper 95% confidence intervals. 25 hydroxyvitamin D; VP, viral pneumonia.

Comparison of serum 25(OH)D levels in MV subgroup and n-MV subgroup

The median serum 25(OH)D levels in the MV and n-MV subgroups were 12.9 (IQR 6.5–22.5) ng/mL and 20.8 (IQR 14.2–28.0) ng/mL, respectively; the serum 25(OH)D level in the MV subgroup being significantly lower than that in the n-MV subgroup (P < 0.001) (Fig. 1).

Discussion

In this study, we investigated whether vitamin D status was associated with VP among children in Beijing. We demonstrated that insufficiency vitamin D status is associated with an increase in the odds of VP in the children. Vitamin D is an essential substance in the human body. Serum 25(OH)D can be activated into 1,25-(OH)₂D by 1-hydroxylase (cytochrome P450 family member 27B1, CYP27B1), which then binds to vitamin D receptors on target cells to exert its physiological functions. Its classic role is to participate in calcium and phosphorus metabolism; bone health improves when the serum level of 25(OH)D is above 20 ng/mL (30 mmol/mL).¹⁸ Recent studies have shown that the surfaces of many tissues and cells contain CYP27B1 and vitamin D receptors, indicating pleiotropic effects of vitamin D, such as participating in the onset of cancer, diabetes, cardiovascular disease, and many other diseases, among which its immunoregulatory roles have received attention in multiple fields. When serum 25(OH)D is over 30 ng/mL (75 mmol/mL), the body shows nonclassical effects, including immunoregulatory roles, which benefits other organs in addition to the bones.^9,10,18 Children do not have a fully developed immune system, and thus in abnormal vitamin D status, their immunoregulatory functions cannot function properly, limiting their ability to fight against various infections, including viruses. The results of this study demonstrate that children with poor vitamin D status are susceptible to pneumonia caused by influenza virus, respiratory syncytial virus, adenovirus, human metapneumovirus, or other viral infections especially in winter time, supporting our hypothesis. The viral infections, including influenza, usually are associated with inadequate amounts of vitamin D with a seasonal variation. High prevalence of VP relative to vitamin D deficiency during winter, might be associated with insufficient sunlight, atmospheric pollution, and restricted outside activities.¹⁹

In our study, the median of serum 25(OH)D level in the 507 children examined was 23.7 (IQR 17.5–30.6) ng/mL, the insufficiency of vitamin D was as high as 73.6%. The results indicated that inadequacy of vitamin D is prevalent in Beijing as in other areas of China and other countries.^20,21 We found significantly higher rates of insufficiency and deficiency of vitamin D in the VP group than control group. The serum 25(OH)D levels of VP cases were even lower than controls 19.6 (IQR 12.3–26.4) ng/mL versus 26.6 (IQR 21.4–32.9) ng/mL. Similar findings have been shown in previous observational studies on CAP in children and adults.^17,22 Sabetta et al. reported that maintenance of a 25-hydroxyvitamin D serum concentration of 38 ng/mL or higher should significantly reduce the incidence of acute viral respiratory tract infections during the fall and winter.²³ Among the enrolled 236 VP cases, the proportion of inadequate vitamin D was higher than control, which indicates that children with lower serum 25(OH)D levels are susceptible to viral infections of the lower respiratory tract.

This study included children with viral community-acquired VP as the research objects, and the viral distributions were influenza virus, respiratory syncytial virus, adenovirus, and metapneumovirus, suggesting that such viruses more easily violate the respiratory tract in children, thus causing pneumonia, when vitamin D status is inadequate. However, the seasonal variation in vitamin D is unlikely to be the main factor affecting the seasonality of influenza and other viral infections.²⁴ The functions of adequate vitamin D on regulating the immune function are mediated by vitamin D receptors located on the immune cell surface. After locally activated 1,25(OH)₂D combines with vitamin D receptors on immune cells, antigen-presenting abilities of the antigen-presenting cells are inhibited, preventing the transformation of CD4 cells toward Th1 and Th17, promoting the generation of Th2, inhibiting the production of tumor necrosis factor-α and interleukin-12, inhibiting the activities of Th1, inducing the expression of antimicrobial peptide LL-37, and activating the Toll-like receptors, thus regulating the immunological balance between Th1/Th2, anti-infection, and inhibiting excessive inflammation.^9,10,25,26 Inadequate vitamin D is evident in people with dysfunctional macrophage activity and decreases Toll-like receptor activation and interferon-γ-dependent T cell responses to infection.¹⁸

Table 3 shows that the serum 25(OH)D level in the VP group was lower than that in the control group in children under 7 years of age (P < 0.05), but children above 7 years showed the same trend; however, the statistical difference was not remarkable in this group. Numerous studies have suggested that the 25(OH)D level is negatively correlated with the incidence of respiratory tract infection.^15,27 Our results also showed that as vitamin D status decreased from sufficiency to severe deficiency, the OR values of the risk of VP showed an increasing trend (from 0.3, 0.9, 2.0 to 51.7). With a decrease in T lymphocytes and the percentage of T-helper cells, differentiation and maturation disorders of B cells occur, followed by low immunoglobulin hyperlipidemia and the reduction of IgA and IgG levels, making children vulnerable to invasion by pathogenic microorganisms.²⁷

In this study, we found that the median 25(OH)D level of the severe VP cases with MV requirement due to severe conditions, such as respiratory failure, severe sepsis, shock, and other complications, was significantly lower than that in those who were not MV patients [12.9 (IQR 6.5–22.5) ng/mL versus 20.8 (IQR 14.2–28.0) ng/mL]. These results indicated that the serum 25(OH)D levels of the critical patients are even low compared with those with common conditions. Some epidemiological studies were found linking vitamin D deficiency with increased risk of infection and infection-associated complications in adults,¹⁴ and similar results also were found in hospitalized children with severity of acute lower respiratory tract infections.^27,28 McNally reported the serum 25(OH)D levels of ICU rescue requirement for children with acute lower respiratory infection is lower than common conditions (19.6 ± 9.6 ng/mL versus 32.4 ± 16.0 ng/mL).²⁹ Sankar et al. reported that severe vitamin D deficiency in children with septic shock for ICU admission seems to be associated with lower rates of shock reversal at 24 h in ICU.³⁰ This suggests that vitamin D deficiency not only weakens the capability for defense against microbial attack, but also reduces the ability to clear pathogenic microorganisms and relieve the system from inflammatory reaction.³¹ In this case, not only does lung injury occur easily, but also occurrence of severe complications increases and the interventions become more comprehensive, such as requirement of MV therapy, when bodies are invaded by viruses with the severe and persistent system inflammation reaction.

The relationship between vitamin D deficiency and infectious pneumonia, provided the evidence of vitamin D as an adjuvant treatment for acute respiratory infection, remains a controversial issue. Some interventions conducted with different dosages, and different course of vitamin D on acute respiratory infections received contrary conclusions.^32–35 Supplementation of nonactivated vitamin D to protect from pneumonia may be insufficient in patients that have a decreased capacity of 25(OH) D to 1,25-(OH)₂D to function properly.¹⁵ On the other hand, the different genotypes of vitamin D receptor binding to 1,25(OH)₂D may have different effects, and well-designed further observations should be conducted to figure out the puzzles.

Conclusion

In conclusion, vitamin D is involved in regulating innate and adaptive immune functions; we found that low vitamin D status is related to the susceptibility to VP in children, and the degree of deficiency affects the critical conditions of VP cases. To understand whether vitamin D supplementation is beneficial for preventing and treating VP in children, further large-sample, transregional, polycentric studies would clarify its role in children.

Footnotes

Acknowledgments

The authors appreciate all their colleagues who provided help in examining patients. Clinical Trial Registration—Approval ID: SHERLL 2010075.

Authors' Contribution

Q.Z., X.D.C. Cui conceptualized and designed the study, drafted the initial article, and approved the final article as submitted. L.Y.G., W.L., X.F.C., C.R.S., J.G., and H.R.L. carried out the initial analysis, reviewed and revised the article, and approved the final article as submitted. G.W.S. designed the data collection instruments, critically reviewed the article, and approved the final article as submitted.

Author Disclosure Statement

No competing financial interests exist.

References

Rudan

, Boschi-Pinto

, Biloglav

, Mulholland

, Campbell

. Epidemiology and etiology of childhood pneumonia. Bull World Health Organ, 2008; 86:408–416.

Burk

, El-Kersh

, Saad

, Wiemken

, Ramirez

, Cavallazzi

. Viral infection in community-acquired pneumonia: a systematic review and meta-analysis. Eur Respir Rev, 2016; 25:178–188.

Ruuskanen

, Lahti

, Jennings

, Murdoch

. Viral pneumonia. Lancet, 2011; 377:1264–1275.

Zhou

, Lin

, Teng

, et al. Prevalence of herpes and respiratory viruses in induced sputum among hospitalized children with non typical bacterial community-acquired pneumonia. PLoS One, 2013; 8:e79477.

Pavia

. What is the role of respiratory viruses in community-acquired pneumonia?: what is the best therapy for influenza and other viral causes of community-acquired pneumonia?. Infect Dis Clin North Am, 2013; 27:157–175.

Yoon

, Jhun

, Kim

. Clinical characteristics and factors predicting respiratory failure in adenovirus pneumonia. Respirology, 2016; 21:1243–1250.

Zyoud

. Global research trends of Middle East respiratory syndrome coronavirus: a bibliometric analysis. BMC Infect Dis, 2016; 16:255.

Choi

, Hong

, Ko

, et al. Viral infection in patients with severe pneumonia requiring intensive care unit admission. Am J Respir Crit Care Med, 2012; 186:325–332.

Adams

, Hewison

. Unexpected actions of vitamin D: new perspectives on the regulation of innate and adaptive immunity. Nat Clin Pract Endocrinol Metab, 2008; 4:80–90.

10.

Hossein-Nezhad

, Holick

. Vitamin D for health: a global perspective. Mayo Clin Proc, 2013; 88:720–755.

11.

Christensen

, Søndergaard

, Fisker

, Christesen

. Infant respiratory tract infections or wheeze and maternal Vitamin D in pregnancy: a systematic review. Pediatr Infect Dis J, 2017; 36:384–391.

12.

, Li

, Guo

, Cui

, Zhang

, Song

. Vitamin D level in children with bloodstream infection. Zhongguo Dang Dai Er Ke Za Zhi, 2016; 18:215–218.

13.

Khandelwal

, Gupta

, Mukherjee

, et al. Vitamin D levels in Indian children with intrathoracic tuberculosis. Indian J Med Res, 2014; 140:531–537.

14.

Jovanovich

, Ginde

, Holmen

, et al. Vitamin D level and risk of community-acquired pneumonia and sepsis. Nutrients, 2014; 6:2196–2205.

15.

Pletz

, Terkamp

, Schumacher

, et al. Vitamin D deficiency in community-acquired pneumonia: low levels of 1,25(OH)₂D are associated with disease severity. Respir Res, 2014; 15:53.

16.

Fabri

, Stenger

, Shin

, et al. Vitamin D is required for IFN-gamma-mediated antimicrobial activity of human macrophages. Sci Transl Med, 2011; 3:104ra102.

17.

Esposito

, Baggi

, Bianchini

, Marchisio

, Principi

. Role of vitamin D in children with respiratory tract infections. Int J Immunopathol Pharmacol, 2013; 26:1–13.

18.

Zittermann

, Gummert

. Nonclassical vitamin D actions. Nutrients, 2010; 2:408–425.

19.

Abhimanyu, Coussens

. The role of UV radiation and vitamin D in the seasonality and outcomes of infectious disease. Photochem Photobiol Sci, 2017; 16:314–338.

20.

Zhang

, Stoecklin

, Eggersdorfer

. A glimpse of vitamin D status in Mainland China. Nutrition, 2013; 29:953–957.

21.

Akkermans

, van der Horst-Graat

, Eussen

, van Goudoever

, Brus

. Iron and vitamin D deficiency in healthy young children in Western Europe despite current nutritional recommendations. J Pediatr Gastroenterol Nutr, 2016; 62:635–642.

22.

Roth

, Shah

, Black

, Baqui

. Vitamin D status and acute lower respiratory infection in early childhood in Sylhet, Bangladesh. Acta Paediatr, 2010; 99:389–393.

23.

Sabetta

, DePetrillo

, Cipriani

, Smardin

, Burns

, Landry

. Serum 25-Hydroxyvitamin D and the incidence of acute viral respiratory tract infections in healthy adults. PLoS One, 2010; 5:e11088.

24.

Cannell

, Vieth

, Umhau

, et al. Epidemic influenza and vitamin D. Epidemiol Infect, 2006; 134:1129–1140.

25.

Holick

. Vitamin D deficiency. N Engl J Med, 2007; 357:266–281.

26.

Gombart

. The vitamin D-antimicrobial peptide pathway and its role in protection against infection. Future Microbiol, 2009; 4:1151–1165.

27.

Sakka

ASE

, Iman

, Amer

, Moustafa

. Vitamin D deficiency and low hemoglobin level as risk factors for severity of acute lower respiratory tract infections in Egyptian children: a case-control study. Egypt Pediatr Assoc Gaz, 2014; 62:1–7.

28.

Inamo

, Hasegawa

, Saito

, et al. Serum vitamin D concentrations and associated severity of acute lower respiratory tract infections in Japanese hospitalized children. Pediatr Int, 2011; 53:199–201.

29.

McNally

, Leis

, Matheson

, Karuananyake

, Sankaran

, Rosenberg

. Vitamin D deficiency in young children with severe acute lower respiratory infection. Pediatr Pulmonol, 2009; 44:981–988.

30.

Sankar

, Ismail

, Das

, Dev

, Chitkara

, Sankar

. Effect of severe Vitamin D deficiency at admission on shock reversal in children with septic shock. J Intensive Care Med, 2017:885066617699802; [Epub ahead of print]. Doi: 10.1177/0885066617699802.

31.

Wei

, Christakos

. Mechanisms underlying the regulation of innate and adaptive immunity by Vitamin D. Nutrients, 2015; 7:8251–8260.

32.

Urashima

, Segawa

, Okazaki

, Kurihara

, Wada

, Ida

. Randomized trial of vitamin D supplementation to prevent seasonal influenza A in schoolchildren. Am J Clin Nutr, 2010; 91:1255–1260.

33.

Aloia

, Li-Ng

. Re: epidemic influenza and vitamin D. Epidemiol Infect, 2007; 135:1095–1098.

34.

Camargo

Jr ., Ganmaa

, Frazier

, et al. Randomized trial of vitamin D supplementation and risk of acute respiratory infection in Mongolia. Pediatrics, 2012; 130:e561–e567.

35.

Martineau

, Jolliffe

, et al. Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data. BMJ, 2017; 356:i6583.