Abstract
Background
Recurrent respiratory tract infections (RRTIs) and vitamin deficiencies are significant public health concerns in pediatrics. While the immunomodulatory effects of vitamins A and E are widely recognized, their specific roles and associations with RRTIs in children require further clarification. This study aims to evaluate differences in serum levels of vitamins vitamin A and E levels between children with RRTIs and healthy controls in Xiangtan, China. It also aims to analyse the association between deficiencies in vitamins A and E during respiratory tract infections (RTIs) in children with RRTIs.
Methods
A total of 4,782 children attending the Pediatric Department of Xiangtan Central Hospital between June 2017 and December 2020 were enrolled in the study. Of these children, 3,236 had RRTIs and 1,546 were healthy controls. Serum vitamin A and E levels were measured using high-performance liquid chromatography (HPLC). To minimize selection bias, propensity score matching (PSM) was performed at a 1:1 ratio based on age, gender, and season. The levels and deficiency rates of vitamins A and E were then compared between the matched groups, and their association with RRTIs was analyzed.
Results
After PSM with gender, age, and season as the matching factors, the final sample size for each group was 1,213. Subsequent analysis revealed that the vitamin A levels in the RRTIs and control groups were 0.225 mg/L ± 0.087 and 0.328 mg/L ± 0.078, respectively, and the vitamin E levels were 7.93 mg/L ± 2.58 and 9.18 mg/L ± 2.55, respectively. The detection rates of serum vitamin A marginal deficiency and deficiency in the control group of healthy children were 34.30% and 4.45% respectively, and the rates of vitamin E marginal deficiency and deficiency were 14.67% and 1.15% respectively. These rates were significantly lower than those observed in the RRTIs group for both vitamin A (40.73%, 42.04%) and vitamin E (31.90%, 8.90%) (p < 0.001).
Conclusion
Children with RRTIs exhibit significantly lower serum Vitamin A and E levels and higher deficiency rates compared to healthy group. The presence of RRTIs or RTIs is closely associated with vitamin A and E deficiencies in children, suggesting that RRTIs may exacerbate vitamin A and E depletion.
Keywords: Recurrent respiratory tract infections, Vitamin A, Vitamin E, Children
Background
Pre-school children are at high risk of respiratory tract infections (RTIs). RTIs are the most common diseases in pediatrics, with recurrent respiratory tract infections (RRTIs) accounting for a large percentage [1]. RRTIs can prolong the duration of an illness and lead to various complications. The consequences of these issues are evident and have a considerable impact on the quality of life of the children themselves, affecting their physiological and social functions. Additionally, these issues significantly affect the physical, mental, and economic well-being of the children’s family members [2].
Fat-soluble vitamins A and E are micronutrients essential for children’s growth and development. Current research confirms that vitamin A deficiency is associated with impaired airway epithelial regeneration [3]. Vitamin A is vital for preserving the integrity of respiratory epithelial cells and mucociliary clearance, which act as the body’s primary defence against pathogens. A deficiency in vitamin A compromises these barrier functions, thereby increasing the risk of pathogens invading the respiratory tract. As an effective fat-soluble antioxidant, vitamin E protects cell membranes from oxidative stress induced by inflammatory responses during infection. Research suggests that adequate vitamin E levels are essential for normal T-cell function and immune signalling. Vitamin E enhances the immune response and protects against various infectious diseases [4]. Therefore, vitamins A and E play a vital role in the immune response to RTIs. The relationship between vitamins A and E and RRTIs in children remains controversial. A recent meta-analysis indicates that the available data do not support an association between vitamin A levels in preschool children and RRTIs [5]. However, some case-control and clinical trial studies have identified such a correlation between vitamin A levels and RRTIs in children [6–9]. At the same time, these researchers believe that the evidence linking vitamin E levels to RRTIs is relatively insufficient [8, 9].
Overall, the limitations of these studies include small sample sizes and the failure to account for key factors that may influence vitamin A and E levels, such as age, gender, and season. Studies have clearly demonstrated that vitamin A and E levels are correlated with factors such as children’s age, season, and region [10, 11]. Thus, we used propensity score matching (PSM) to adjust for age, gender, and seasonal biases, focusing exclusively on the Xiangtan area to reduce regional variability. This study measured serum vitamin A and E levels in children with RRTIs in the Xiangtan region during acute respiratory tract infection (ARTI) episodes and compared them with a healthy control group. By comparing the prevalence of vitamin A and E deficiency, this study examined the association between RRTIs in children and vitamin A and E deficiency. The findings are expected to inform clinical interventions.
Methods
The investigation region and clinical data collection
Xiangtan City (111°58′ to 113°05′ E, 27°20′50″ to 28°05′40″ N) is located in the central region of Hunan Province, China. As of 2020, it has a population of more than 2.7 million and covers a total area of over 5,000 square kilometers, comprising five counties or districts. The clinical data of children admitted to the outpatient and inpatient departments of Xiangtan Central Hospital from January 2017 to December 2020 were retrospectively analyzed. The data were retrieved from the clinical case database, the objective of which is the collection of basic information about children, including sex, age, admission date, diagnosis, annual frequency of healthcare visits attributable to RTIs, and test results for vitamin A and E. Two physicians independently verified the data and addressed any discrepancies by re-exporting and conducting a subsequent review, adhering to a rigorous procedure to ensure the accuracy of the data. A total of 4,782 cases were finally included in this analysis. This retrospective study adhered to ethical standards and was approved by the Ethics Committee of Xiangtan Central Hospital (NO. 2023-KC-58-09-019).
Determination of serum vitamin A and vitamin E
A volume of 2 mL of fasting venous blood was obtained from the children in the morning and subsequently subjected to centrifugation at 3,000 rpm for a duration of 10 min with the objective of isolating the serum. The serum levels of vitamin A and vitamin E were detected by high-performance liquid chromatography (HPLC) (Agilent company, USA). Quality control was ensured using commercial control sera (Beijing Hehe Medical Technology Co., Ltd., Beijing, China). Calibration was performed daily using standard reference materials. To ensure the reliability of the data, the intra-assay and inter-assay coefficients of variation (CV) were 5% and 8%, respectively. Blood samples were collected and tested with the informed consent of the guardians.
The reference standard [12] sets out the grading of serum levels of vitamins A and E. It was stipulated that a serum vitamin A level of ≥ 0.30 mg/L is normal, 0.21–0.29 mg/L indicates marginal deficiency and ≤ 0.20 mg/L indicates deficiency. Serum vitamin E levels of > 7.00 mg/L are normal, 5.00–7.00 mg/L indicate marginal deficiency and < 5.00 mg/L indicate deficiency. The definitions of vitamin A and vitamin E deficiencies align with World Health Organization [13] and National Institutes of Health [14] standards, respectively.
Study design
Inclusion criteria
(1) Children with RRTIs meet the diagnostic criteria. Children with RRTIs were diagnosed according to the definition or standard of RRTIs at different age groups (0–2 years, > 2–5 years, and > 5–14 years) [1]. (2) Age 1 month ~ 14 years. (3) The guardian consents to or requests vitamin A and vitamin E testing. (4) Inclusion criteria for healthy pediatric participants encompassed full-term birth, absence of chronic conditions including malnutrition and anemia, and overall good health status.
Exclusion criteria
Combined with infections in systems other than the respiratory system, liver and kidney dysfunction, immune deficiency, or other chronic diseases.
RRTIs are upper or lower RTIs that occur more frequently than is normal for their age group within a year. For specific diagnostic criteria, refer to reference [1]. According to the occurrence of RTIs, the patients were divided into healthy group and RRTIs group. Using age, season, and gender as matching variables, PSM was applied to match the data between the two groups (healthy group and RRTIs group). Subsequently, the differences in vitamin A and vitamin E levels between the two groups were re-evaluated and analyzed.
Statistical analysis
A 1:1 matched pair analysis was performed using the nearest neighbour matching method with a caliper value of 0.1, with age, sex and season as covariates and the healthy group as the reference group. Matching effectiveness was assessed by p-values.
The SPSS 26.0 statistical software package was used, and the count data were expressed as percentages. The count data for the detection of serum vitamin A and vitamin E marginal deficiency and deficiency in the two groups of children were expressed as a rate. The measure data for serum vitamin A and vitamin E levels in the two groups were expressed as (
±s). A t-test was used to compare the two groups, and a one-way ANOVA was performed. Use stratified chi-squared tests to analyze the prevalence of vitamin A and E marginal deficiency or deficiency across different groups. Report the relative risk (RR) values from stratified chi-square tests, along with the results of homogeneity tests based on RR values. P < 0.05 was regarded as statistically significant.
Results
Vitamin A and E levels in the study population
This study included clinical data from 4,782 children, of whom 1,546 (32.33%) were in the healthy group and 3,236 (67.67%) were in the RRTIs group. There was no statistically significant difference in the gender distribution between the two groups, but differences were observed in the age and seasonal distribution of the participants (Table 1).
Table 1.
Overview frequency of Vitamin A and E deficiency in the 2,426 case matched using PSM from 4,782 case
| Characteristics Subgroup |
Total (n = 4782, 100%) |
Healthy control group (n = 1546,32.33%) |
RRTIs group (n = 3236, 67.67%) |
χ2/t | p-value | Healthy control group (n = 1213, 50.0%) |
RRTIs group (n = 1213, 50.0%) |
χ2/t | p-value |
|---|---|---|---|---|---|---|---|---|---|
| Gender | |||||||||
|
Male Female |
2892 (60.48%) 1890 (39.52%) |
943 (61.00%) 603 (39.00%) |
1949(60.23%) 1287(39.77%) |
0.255 | 0.612 |
726 (59.85%) 487 (40.15%) |
684(55.15%) 529(44.85%) |
2.98 | 0.084 |
| Age (y, M) | |||||||||
|
0−2years > 2−5years > 5−14years |
2421 (50.63%) 1391 (29.09%) 970 (20.28%) |
5.249 ± 3.757 505(32.66%) 385(24.90%) 656(42.43%) |
2.529 ± 2.288 1916(59.21%) 1006(31.09%) 314(9.70%) |
30.90 711.82 |
< 0.001 < 0.001 |
3.75 ± 2.95 505(41.63%) 385(31.74%) 323(26.63%) |
3.82 ± 2.76 490(40.39%) 434(35.78%) 289(23.83%) |
1.35 5.171 |
0.246 0.075 |
| Season | |||||||||
|
Spring (Mar-May) Summer (Jun-Aug) Autumn (Sep-Nov) Winter (Jan-Feb, Dec) |
907 (18.97%) 1560 (32.62%) 1225 (25.62%) 1090 (22.79%) |
271(17.52%) 691(44.70%) 285(18.43%) 299(19.34%) |
636(19.65%) 869(26.85%) 940(29.05%) 791(24.44%) |
162.54 | < 0.001 |
200(16.49%) 496(40.89%) 252(20.77%) 265(21.85%) |
209(17.23 %) 475(39.16%) 281(23.17%) 248(20.45%) |
2.79 | 0.425 |
| Vitamin A levels | |||||||||
|
marginal deficiency (0.2-0.3 mg/L) deficiency (< 0.2 mg/L) |
1781 (37.24%) 1303 (27.25%) |
438 (28.33%) 63 (4.08%) |
1343 (41.50%) 1240 (38.32%) |
77.65 618.86 |
< 0.001 < 0.001 |
416 (34.30%) 54 (4.45%) |
494 (40.73%) 510 (42.04%) |
10.70 480.35 |
< 0.001 < 0.001 |
| Vitamin E levels | |||||||||
|
marginal deficiency (5-7 mg/L) deficiency (< 5 mg/L) |
1202 (25.14%) 230 (4.81%) | 264 (17.08%) 21 (1.36%) | 938 (28.99%) 209 (6.46%) | 78.86 59.44 | < 0.001 < 0.001 | 178 (14.67%) 14 (1.15%) | 387 (31.90%) 108 (8.90%) | 100.78 76.26 | < 0.001 < 0.001 |
According to the two age groups, the average age of the healthy group was (5.249 ± 3.757) years, while that of the RRTIs group was (2.529 ± 2.288) years. Following a t-test, the t-value = 30.90, p < 0.001, indicating a significant difference between the two groups. Furthermore, after grouping participants by age and season, and conducting chi-squared tests on the composition ratios within each group, the results consistently showed differences in the composition ratios between the healthy group and the RRTIs group (p < 0.05) (Table 1). Therefore, when comparing differences in vitamin A and E levels between two groups, it is necessary to adjust for variations in age and season. Otherwise, the results will be inaccurate.
Results of PSM
To ensure comparability, PSM was performed. This study reports the propensity score-matched adjusted rates as the primary outcome measure to account for confounding factors.
After matching, all imbalanced covariates between groups were balanced (p > 0.05), resulting in 1,213 successfully matched pairs (Table 1). Following PSM, the respective mean levels of vitamins A and E were 0.225 ± 0.087 mg/L and 7.93 ± 2.58 mg/L, and 0.328 ± 0.078 mg/L and 9.18 ± 2.55 mg/L in the RRTIs and healthy groups, respectively (Table 2).
Table 2.
Vitamin A and E levels in 2,426 children’s serum samples following PSM
| Characteristics Subgroup |
Healthy control group (n) |
Vitamin A levels | Vitamin E levels | RRTIs group (n) |
Vitamin A levels | Vitamin E levels | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
( ±S, mg/L) |
t/F | P | ( ±S, mg/L) |
t/F | P | ( ±S, mg/L) |
t/F | P | ( ±S, mg/L) |
t/F | P | |||
| Total | 1213 | 0.328 ± 0.078 | 9.18 ± 2.55 | 1213 | 0.225 ± 0.087 | 30.84 | < 0.001 | 7.93 ± 2.58 | 11.99 | < 0.001 | ||||
| Gender | ||||||||||||||
|
Male Female |
726 487 |
0.327 ± 0.078 0.330 ± 0.078 |
0.87 | 0.451 |
8.87 ± 2.38 9.62 ± 2.73 |
4.86 | < 0.001 |
669 544 |
0.222 ± 0.088 0.227 ± 0.085 |
1.02 | 0.567 |
7.78 ± 2.59 8.11 ± 2.54 |
2.22 | 0.60 |
| Age | ||||||||||||||
|
0−2years > 2−5years > 5−14years |
505 385 323 |
0.336 ± 0.085a 0.326 ± 0.072a 0.318 ± 0.072b |
5.29 | 0.005 |
10.23 ± 2.89a 8.55 ± 2.15b 8.28 ± 1.73b |
78.33 | < 0.001 |
490 434 289 |
0.234 ± 0.086a 0.220 ± 0.085b 0.216 ± 0.087b |
5.08 | 0.006 |
9.22 ± 2.94a 7.15 ± 1.96b 6.90 ± 1.65b |
126.61 | < 0.001 |
| Season | ||||||||||||||
|
Spring (Mar-May) Summer (Jun-Aug) Autumn (Sep-Nov) Winter (Jan-Feb, Dec) |
200 496 252 265 |
0.330 ± 0.075a 0.331 ± 0.071a 0.329 ± 0.075ab 0.312 ± 0.092b |
4.74 | 0.003 |
9.09 ± 2.40ab 9.47 ± 2.58a 9.22 ± 2.44ab 8.64 ± 2.63b |
6.42 | < 0.001 |
349 305 371 188 |
0.219 ± 0.088a 0.220 ± 0.092a 0.238 ± 0.085b 0.216 ± 0.076a |
4.54 | 0.004 |
7.95 ± 2.54a 8.18 ± 2.64a 8.10 ± 2.70a 7.14 ± 2.14b |
7.56 | < 0.001 |
1. P > 0.05 indicates no statistical difference between groups and P < 0.001 indicates differences between groups; 2.Comparison between subgroups labeled with the same letter indicates no statistical difference, while a different letter indicates a statistical difference between the two groups
Effects of age, gender, and season on vitamin A and E levels
In the healthy control group, there was no statistically significant difference in vitamin A levels between genders among the children (p > 0.05). However, there was a significant difference in vitamin E levels between the sexes (p = 0.004): vitamin E levels were lower in male children (8.65 ± 2.30 mg/L) than in female children (9.42 ± 2.62 mg/L). Levels of vitamins A and E varied significantly with age and season (p < 0.05), decreasing gradually with increasing age. The average levels of vitamins A and E were lowest in winter, at 0.312 ± 0.090 mg/L and 8.51 ± 2.54 mg/L, respectively, while the highest average levels were observed in summer, at 0.339 ± 0.074 mg/L and 9.20 ± 2.47 mg/L, respectively (Supplementary Tables 1 and Table 2).
In the RRTIs group, no gender differences in vitamin A levels were observed in infected children (p > 0.05); however, significant differences were observed between age and season (p < 0.001). Significant differences in vitamin E levels were observed across gender, age, and season (p < 0.001). Overall, the trends in vitamin A and E levels were consistent with those observed in the healthy group. However, the mean values were significantly lower (Supplementary Tables 1 and Table 2).
Comparison of marginal deficiency and deficiency rates of vitamins A and E in two groups of children
The detection rates of serum vitamin A marginal deficiency and deficiency in the control group of healthy children were 34.30% and 4.45%, respectively, and those of vitamin E marginal deficiency and deficiency were 14.67% and 1.15%. Both of these were significantly lower than the detection rates of marginal deficiency and deficiency in the group of children with RRTIs for both vitamin A (40.73%, 42.04%) and vitamin E (31.90%, 8.90%) (P < 0.001) (Table 1). The prevalence of vitamin A and E deficiency in children with RRTIs is significantly higher than in the healthy group (Fig. 1C、D).
Fig. 1.
Comparison of the rates of marginal deficiency and deficiency of vitamins A and E by gender, age and season in two groups of children. The red horizontal line indicates p < 0.05, signifying that OR values differ significantly between layers. OR values should be reported by group. Note: *(p < 0.05) indicates a difference between the two groups, **(p < 0.001) indicates a significant difference between the two groups
We conducted a stratified analysis using the Cochran–Mantel–Haenszel test to adjust for potential confounding factors, such as gender, age and season. The homogeneity test (Breslow-Day test) results for the odds ratio (OR) showed that p < 0.05 for four subgroups (Fig. 1), indicates heterogeneity in the OR values across these subgroups, and the results must be presented separately for each subgroup (Table 3). After adjusting for confounding factors such as age, gender and season, we found that the prevalence of vitamin A and E deficiency was significantly associated with RRTIs in children during episodes of infection (see Fig. 1; Table 3 for p-values, OR and 95% confidence intervals).
Table 3.
Health group vs. RRTIs group: OR values and 95% confidence intervals (CI) for vitamin A and E marginal deficiency and deficiency in stratified chi-square tests
| Characteristics Subgroup |
Vitamin A marginal deficiency | Vitamin E marginal deficiency | Vitamin A Deficiency | Vitamin E Deficiency | ||||
|---|---|---|---|---|---|---|---|---|
| OR | 95% Cl | OR | 95% Cl | OR | 95% Cl | OR | 95% Cl | |
| Gender | ||||||||
|
Male Female |
1.145 | 1.057–1.240 |
1.443 1.685 |
1.298–1.604 1.515–1.873 |
2.395 | 2.246–2.554 | 1.846 | 1.709–1.993 |
| Age | ||||||||
|
0−2years > 2−5years > 5−14years |
1.344 1.127 0.891 |
1.188–1.521 0.990–1.283 0.747–1.062 |
1.543 | 1.431–1.664 |
2.197 2.385 2.780 |
1.984–2.433 2.150–2.646 2.415-3.20 |
1.846 | 1.709–1.993 |
| Season | ||||||||
|
Spring (Mar-May) Summer (Jun-Aug) Autumn (Sep-Nov) Winter (Jan-Feb, Dec) |
1.145 | 1.057–1.240 | 1.543 | 1.431–1.664 |
1.993 3.469 1.918 2.383 |
1.702–2.217 3.022–3.982 1.740–2.116 1.965–2.891 |
1.846 | 1.709–1.993 |
Discussion
Vitamins A and E are essential micronutrients for human growth and development processes, and they have significant biological functions. Current meta-analyses suggest that vitamin A supplementation for children under five can reduce their morbidity and mortality rates [15]. RRTIs are common pediatric diseases, particularly prevalent among children under six years of age. Our findings show that the deficiency rates for vitamins A and E among children with RRTIs in the Xiangtan area were 38.32% and 6.46%, respectively, during their RTIs. Following PSM, these rates increased to 42.04% and 8.90%, respectively. These rates were significantly higher than those observed in healthy children (4.08% and 1.36%, respectively) (Table 1). Secondly, vitamin A and E levels were significantly lower in the RRTIs group than in the healthy children group (Table 2). This suggests that decreased levels of vitamin A and E are closely associated with RRTIs or the presence of RTIs. RTIs, particularly RRTIs, result in the continuous regeneration and repair of airway epithelial cells, which may contribute to vitamin A deficiency [3]. At the same time, the increased metabolic demand and oxidative stress related to RTI will reduce the body’s vitamin E reserves [4]. Consequently, RRTIs exacerbate vitamin A and E deficiencies in children, creating a vicious cycle whereby these deficiencies increase susceptibility to subsequent ARTI, which in turn further reduce serum vitamin A and E levels. However, an increasing number of meta-analyses suggest that conclusive evidence supporting the effectiveness of vitamin A and E supplements during the acute phase of RTIs is still lacking, and that routine use or supplementation does not appear to offer any significant benefit in preventing RTIs [16–18]. Furthermore, there is insufficient data to demonstrate the effectiveness of oral vitamin A supplementation in preventing RTIs in children under the age of seven [19]. Therefore, we should prioritize addressing vitamin A and E deficiencies among children suffering from RRTIs.
Currently, rates of vitamin A deficiency among children under five remain alarmingly high [20]. Children are particularly susceptible to vitamin A deficiency, especially in low- and middle-income countries [21]. The prevalence of vitamin A marginal deficiency in the Xiangtan region is 28.33% (Table 1). This finding is consistent with survey results from several other Chinese cities [11, 22] and is relatively high compared to other regions. This study analyzed vitamin A levels in healthy children and children with RRTIs and found that vitamin A levels decline with age, reaching their lowest levels in winter. It also found that vitamin A levels in the RRTIs group were significantly lower than those in the healthy children group (Table 2). The prevalence of vitamin A deficiency was 42.04% in the RRTIs group. Several factors may explain this discrepancy. Firstly, winter is a peak season for ARTI, with a particularly high incidence among children [23]. This, combined with differences in winter diets (fruit and vegetables) [10], may explain why children’s vitamin A levels are lower in winter than in other seasons. Secondly, our study population consisted of hospitalized or outpatient children with RRTIs. Children with RRTIs may have higher metabolic demands and may experience reduced dietary intake during periods of illness. Finally, as previous studies have shown, children in the acute inflammatory phase have lower vitamin A levels than healthy children. This can lead to an overestimation of deficiency prevalence when standard WHO cutoffs are used during active infection [24]. Therefore, future research is needed to measure vitamin A levels during the rehabilitation period of children with RRTIs in order to determine their baseline nutritional status. In addition, we adopted the threshold criteria established by the WHO for healthy populations. Without testing for inflammatory markers such as C-reactive protein (CRP), we cannot fully distinguish between chronic deficiency and depletion caused by infection. However, a comparing with the healthy control group (4.45% vs. 42.04%) suggests that children with RRTIs may be at increased risk of vitamin A deficiency, regardless of whether it is due to prior deficiency or infection-related depletion. Upon analyzing the data following PSM, we found that the odds ratio (OR) for vitamin A deficiency increased gradually with age in both groups. This suggests that the association between RRTIs and vitamin A and E deficiency becomes stronger as children grow older (Figures 1C, Table 3). However, only children aged 0–2 years had an OR > 1 for marginal vitamin A deficiency. This may be due to the expert consensus recommending routine vitamin A supplementation for this age group [25]. Conversely, the 0–2 age group coincides with a peak period for RTIs in children [23], suggesting that RTIs may contribute to vitamin A deficiency in this age group. Research has shown that insufficient dietary intake of vitamin A may be associated with RRTIs [7]. Another study suggests that vitamin A levels may be beneficial or alleviate pathological changes in cystic fibrosis complicated by pulmonary infections [26], indicating that vitamin A levels may be beneficial for lower RTIs. Further research is needed to determine whether vitamin A supplementation would benefit children with RRTIs.
China has recently updated its expert consensus on the prophylactic supplementation of vitamin A for children under six years of age. This now includes guidance on administering vitamin A to children with RRTIs [24], but there are no such guidelines for vitamin E supplementation in children, particularly for children with RRTIs. Compared to studies on vitamin A, research into vitamin E deficiency rates among children is scarce. Large-scale survey data on vitamin E deficiency in children is limited, and some believe that deficiency may be relatively common among children [27]. Our data show that the prevalence of marginal and deficient vitamin E levels among healthy children in the Xiangtan region is 17.08% and 1.36%, respectively (Table 1). Additionally, boys generally had lower vitamin E levels than girls (Table 2). This finding is consistent with the results of a recent study [28]. This may be related to differences in dietary patterns, oestrogen levels and metabolic rates between boys and girls. Further research is needed to fully understand these gender-specific mechanisms. As with vitamin A, we observed that children with RRTIs had significantly lower vitamin E levels than healthy children (Table 2), and vitamin E deficiency was significantly more prevalent (Fig. 1D and Table 3). Recent studies have found a certain degree of interaction between vitamins E and A in children. When vitamin E levels exceed a certain threshold, the relationship with vitamin A levels tends to stabilise [28]. This suggests a linear relationship between the two vitamins within the body, which may indirectly confirm the reliability of this study’s findings. Therefore, we also believe that there is an association between RRTIs in children and vitamin E deficiency. However, this conclusion is inconsistent with the findings of these researchers [8, 9]. Vitamin E, primarily as α-tocopherol, acts as a critical lipid-soluble antioxidant that neutralizes reactive oxygen species generated by activated immune cells [4]. We found that RRTIs are associated with reduced serum vitamin E levels, which likely reflects increased oxidative consumption during the inflammatory response, accelerated metabolic turnover and inflammation-driven redistribution. Together with fever-induced hypermetabolism, these processes contribute to the decline in vitamin E levels observed during ARTI episodes. Although an early study has demonstrated that administering nutrients such as vitamin E, during the initial phase of RTIs in elderly individuals does not appear to substantially reduce the incidence of ARTI or significantly alleviate their severity [29]. However, other studies suggest that taking daily vitamin E supplements may boost immunity [4, 17]. Consequently, when administering prophylactic vitamin A supplementation to children with RRTIs in clinical practice, consideration should be given to whether vitamin E should also be administered.
Overall, this study used PSM to minimise bias by controlling for factors such as gender, age, and season. The analysis focused on serum levels of vitamin A and E, and deficiency rates, in healthy children and children with RRTIs. However, this study does have some limitations. Firstly, it is important to note that vitamin levels were measured during ARTI. Although previous studies have demonstrated that children with RRTIs exhibit lower vitamin A and E levels during infection than those without [8, 9, 30], this study did not include a control group of children without RRTIs to measure their vitamin A and E levels during infection. Therefore, future longitudinal studies are needed to investigate the effect of the frequency or severity of RTIs on vitamin A and E levels in children. Secondly, even though PSM was employed, unmeasured confounding factors such as nutritional status, dietary habits, socioeconomic differences and the use of vitamin A and E supplements may still be present due to the specific characteristics of the study population. When conducting prospective studies, it is necessary to consider controlling for the effects of these confounding factors. Further research is needed to determine whether supplementation with vitamins A and E can address deficiency in these vitamins in children with RRTIs or reduce the incidence of RTIs, in order to provide practical guidance for clinical practice. Studies could also be conducted to compare the efficacy of different doses and administration routes of vitamins A and E in children with RRTIs. In addition, other feasible interventions must be implemented to prevent RTIs in children with RRTIs.
Conclusions
Children with RRTIs in the Xiangtan region exhibit significantly lower serum levels of vitamins A and E levels and a higher prevalence of deficiency compared to healthy controls during ARTI. These findings suggest a strong association between low vitamin A and E status and RRTIs in this pediatric population. However, given the potential influence of the acute phase response on serum vitamin levels, a causal relationship cannot be confirmed. We recommend routine nutritional assessment and monitoring of vitamin A and E status in children with RRTIs. The potential benefits of targeted supplementation in this specific population warrant further investigation through prospective randomised controlled trials.
Acknowledgements
The authors thank our colleagues at the Children’s Diagnostic and Treatment Center, Xiangtan Central Hospital.
Abbreviations
- RRTIs
Recurrent respiratory tract infections
- ARTI
Acute respiratory tract infection
- RTIs
Respiratory tract infections
- PSM
Propensity score matching
- OR
Odds ratio
- WHO
World Health Organization
Authors’ contributions
FY: Investigation, Methodology, Data curation, Writing - original manuscript, Writing - review&editing. PJ, CXL: Data collection, proofreading and editing. LH and LS: Specimen Collection. ZYF: Supervision, Visualization, Funding acquisition. LHP: Writing - review&editing, Visualization, Funding acquisition. All authors have read and approved the published version of the review.
Funding
This study was supported by the Shenzhen Science and Technology Programme (No. RCJC20231211085923029), the Sanming Project of Medicine in Shenzhen (No. SZSM202311027) and the Hunan Provincial Health Commission Fund (No. D20230619358).
Data availability
The datasets for this study can be found in the Xiangtan Central Hospital Research Platform Data Centre. The datasets analysed during the current study are available from the corresponding author on reasonable request.
Declarations
Ethics approval and consent to participate
This study adheres to the relevant requirements of the Declaration of Helsinki. This study has been approved by the Ethics Committee of Xiangtan Central Hospital (NO. 2023-KC-58-09-019). The study has obtained informed consent from the legal guardians of all participants. Clinical trial number: not applicable.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Contributor Information
Yinfei Zhou, Email: zyf02582023@163.com.
Hongping Li, Email: hongping_li@126.com.
References
- 1.Sun JQ, Nong GM, Cao L, Chen X, Chen ZM, Deng JK, et al. Clinical Diagnosis and Treatment Pathway for Recurrent Respiratory Infections in Children (2022 Edition) [J]. Chin J Practical Pediatr. 2022;37(03):161–8. 10.19538/j.ek2022030601. [Google Scholar]
- 2.Toivonen L, Karppinen S, Schuez-Havupalo L, Teros-Jaakkola T, Vuononvirta J, Mertsola J, et al. Burden of Recurrent Respiratory Tract Infections in Children: A Prospective Cohort Study. Pediatr Infect Dis J. 2016;35(12):e362–9. 10.1097/INF.0000000000001304. [DOI] [PubMed] [Google Scholar]
- 3.Lin B, Shah VS, Chernoff C, Sun J, Shipkovenska GG, Vinarsky V, et al. Airway hillocks are injury-resistant reservoirs of unique plastic stem cells. Nature. 2024;629(8013):869–77. 10.1038/s41586-024-07377-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Lee GY, Han SN. The Role of Vitamin E in Immunity. Nutrients. 2018;10(11):1614. 10.3390/nu10111614. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Lu X, Xu J, Gu X, Shao P. Risk Factors for Recurrent Respiratory Tract Infections in Preschool Children: A Meta-Analysis. J Paediatr Child Health. 2026 Feb;24. 10.1111/jpc.70329. [DOI] [PubMed]
- 6.Wang X, Li X, Jin C, Bai X, Qi X, Wang J, et al. Association Between Serum Vitamin A Levels and Recurrent Respiratory Tract Infections in Children. Front Pediatr. 2021;9:756217. 10.3389/fped.2021.756217. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Zhang X, Dai X, Li X, Xie X, Chen Y, Chen Y, et al. Recurrent respiratory tract infections in children might be associated with vitamin A status: a case-control study. Front Pediatr. 2024;11:1165037. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Sun R, Yan Z, Yi W, Tian W, Sun M, Zhang J. Clinical Monitoring of Serum Levels of Vitamins A, D and E in Children with Recurrent Respiratory Tract Infections of Different Ages: A Clinical Controlled Trial. Int J Gen Med. 2022;15:6627–32. 10.2147/IJGM.S347728. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Tian W, Yi W, Zhang J, Sun M, Sun R, Yan Z. The association between the vitamin A, D, and E levels and recurrent respiratory tract infections in children of different ages. Am J Transl Res. 2021;13(5):5665–71. [PMC free article] [PubMed] [Google Scholar]
- 10.Huang P, Lin XM, Wang QS, Ke G, Wei ZR, Guo DP, et al. association analysis between vitamin A, D and E levels with the altitude, seasonal variation and other factors in children with 0–6 years old in Tibetan Plateau of Ganzi Prefecture. [J]. Chin J Appl Clin Pediatr. 2021;36(22):1736–41. 10.3760/cma.j.cn101070-20200409-00603. [Google Scholar]
- 11.Wu QH, Chen Q, Yang T, Chen J, Chen L, Xiang XL, et al. Survey of Serum Vitamin A and Vitamin D Levels in Children Aged 2–7 Years Across 20 Chinese Cities. Chin J Pediatr. 2024;62(03):231–8. 10.3760/cma.j.cn112140-20230923-00216. [DOI] [PubMed] [Google Scholar]
- 12.Jiang ZF, Shen KL, Shen Y, Zhu FT. Practical Pediatrics [M]. 8th ed. Beijing: People’s Medical Publishing House; 2014. pp. 553–5. [Google Scholar]
- 13.World Health Organization. Global prevalence of vitamin A deficiency in populations at risk 1995–2005: WHO global database on vitamin A deficiency. Geneva: World Health Organization; 2009. [Google Scholar]
- 14.National Institutes of Health. Office of dietary supplements. vitamin E. https://ods.od.nih.gov/factsheets/VitaminE-HealthProfessional. Accessed 20 Jan 2026.
- 15.Imdad A, Mayo-Wilson E, Haykal MR, Regan A, Sidhu J, Smith A, et al. Vitamin A supplementation for preventing morbidity and mortality in children from six months to five years of age. Cochrane Database Syst Rev. 2022;3(3):CD008524. 10.1002/14651858.CD008524. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Vlieg-Boerstra B, de Jong N, Meyer R, Agostoni C, De Cosmi V, Grimshaw K, et al. Nutrient supplementation for prevention of viral respiratory tract infections in healthy subjects: A systematic review and meta-analysis. Allergy. 2022;77(5):1373–88. 10.1111/all.15136. [DOI] [PubMed] [Google Scholar]
- 17.Crawford C, Brown LL, Costello RB, Deuster PA. Select Dietary Supplement Ingredients for Preserving and Protecting the Immune System in Healthy Individuals: A Systematic Review. Nutrients. 2022;14(21):4604. 10.3390/nu14214604. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Milani GP, Alberti I, Abodi M, Lakoumentas J, Konstantinou GN, Papadopoulos NG, et al. A systematic review and meta-analysis on nutritional and dietary interventions for the treatment of acute respiratory infection in pediatric patients: An EAACI taskforce. Allergy. 2024;79(7):1687–707. 10.1111/all.15997. [DOI] [PubMed] [Google Scholar]
- 19.Cheng X, Li D, Yang C, Chen B, Xu P, Zhang L. Oral vitamin A supplements to prevent acute upper respiratory tract infections in children up to seven years of age. Cochrane Database Syst Rev. 2024;5(5):CD015306. 10.1002/14651858.CD015306.pub2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Zhao T, Liu S, Zhang R, Zhao Z, Yu H, Pu L, et al. Global burden of vitamin A deficiency in 204 countries and territories from 1990–2019. Nutrients. 2022;14:950. 10.3390/nu14050950. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Song P, Adeloye D, Li S, Zhao D, Ye X, Pan Q, Global Health Epidemiology Research Group (GHERG), et al. The prevalence of vitamin A deficiency and its public health significance in children in low- and middle-income countries: A systematic review and modelling analysis. J Glob Health. 2023;13:04084. 10.7189/jogh.13.04084. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Song P, Wang J, Wei W, Chang X, Wang M, An L. The prevalence of vitamin A deficiency in Chinese children: a systematic review and Bayesian meta-analysis. Nutrients. 2017;9:1285. 10.3390/nu9121285. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.GBD 2021 Upper Respiratory Infections Otitis Media Collaborators. Global, regional, and national burden of upper respiratory infections and otitis media, 1990–2021: a systematic analysis from the Global Burden of Disease Study 2021. Lancet Infect Dis. 2025;25(1):36–51. 10.1016/S1473-3099(24)00430-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Golden CD, Zamborain-Mason J, Levis A, Rice BL, Allen LH, Hampel D, et al. Prevalence of micronutrient deficiencies across diverse environments in rural Madagascar. Front Nutr. 2024;11:1389080. 10.3389/fnut.2024.1389080. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Subspecialty Group of Child Healthcare, the Society of Pediatrics, Chinese Medical Association. Subspecialty Group of Developmental and Behavioral, the Society of Pediatrics, Chinese Medical Association; Editorial Board, Chinese Journal of Pediatrics. Expert consensus on prophylactic vitamin A supplementation for children under 6 years of age (2025) [J]. Chin J Pediatr. 2025;63(5):462–7. 10.3760/cma.j.cn112140-20241123-00857. [DOI] [PubMed] [Google Scholar]
- 26.Sealy RE, Surman SL, Vogel P, Hurwitz JL. Might Routine Vitamin A Monitoring in Cystic Fibrosis Patients Reduce Virus-Mediated Lung Pathology? Front Immunol. 2021;12:704391. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Lobo LMC, Hadler MCCM. Vitamin E deficiency in childhood: a narrative review. Nutr Res Rev. 2023;36(2):392–405. 10.1017/S0954422422000142. [DOI] [PubMed] [Google Scholar]
- 28.Liu W, Bi Y, Wang Q, Li Z, Zheng J, Chen C. Two-phase linear relationship and threshold effects between Vitamin E and Vitamin A levels in children aged 0-10.8 years: a cross-sectional study. Sci Rep. 2025;15(1):38851. 10.1038/s41598-025-22785-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Graat JM, Schouten EG, Kok FJ. Effect of daily vitamin E and multivitamin-mineral supplementation on acute respiratory tract infections in elderly persons: a randomized controlled trial. JAMA. 2002;288(6):715–21. [DOI] [PubMed] [Google Scholar]
- 30.Gao XY, Chang YJ, Tai Y, Sun XJ. Vitamin A and Vitamin E Levels in Children with Recurrent Respiratory Infections [J]. Chin Community Physician. 2021;37(35):18–9. [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The datasets for this study can be found in the Xiangtan Central Hospital Research Platform Data Centre. The datasets analysed during the current study are available from the corresponding author on reasonable request.