Introduction
Kawasaki disease (KD), also referred to as mucocutaneous lymph node syndrome, is an autoimmune disease that was initially identified by Kawasaki [
1] in 1967. This pediatric disorder is characterized by moderate systemic vasculitis and predominantly affects children under the age of 5 worldwide, with Asia exhibiting the highest incidence rates. Despite continued efforts to address the condition, the incidence rate of KD is on the rise [
2,
3].
Although the exact mechanism behind the onset of KD remains unclear, most researchers believe that it arises from an excessive immune system response of genetically vulnerable children following infection [
4]. While the symptoms of KD typically resolve spontaneously within 4—8 weeks [
5], a significant number of children – ranging from 20%—40%—may suffer from heart damage [
6]. This damage is predominantly due to the development of coronary artery lesions (CAL) – the primary complication associated with KD. In cases where timely treatment measures (e.g., intravenous immunoglobulin (IVIG) and aspirin treatment) are not administered, the outcome can potentially lead to death in 2% ~ 3% of patients [
7]. Therefore, the development of coronary artery abnormalities is considered the leading cause of acquired heart disease in children.
Vitamin D is a group of fat-soluble secosteroids that play a crucial role in activating the innate immune system and dampening the adaptive immune system through its antibacterial, antiviral, and anti-inflammatory effects [
8,
9]. The circulating 25-hydroxyvitamin D (referred to hereafter as 25(OH)D) [
10], consisting of 25-hydroxyvitamin D2 (25(OH)D2, mainly via diet) and 25-hydroxyvitamin D3 (25(OH)D3, synthesized in the skin, or absorbed from an animal source), are widely used to assess an individual’s vitamin D status. In the body, 25(OH)D is converted and hydroxylated to the biologically active 1,25-hydroxyvitamin D (1,25(OH)D) in the liver and kidneys [
11]. However, the form of 1,25(OH)D is quantitatively minor, unstable with a very short half-life, and is induced by the drop in ionized calcium. So, generally, the 25(OH)D test in serum is an accepted indicator of vitamin D status [
12], and is widely used in studies. 25(OH)D is critical in regulating immunologic processes and plays a significant role in the pathological status of cardiovascular disease. Accordingly, the hypothesis emerged that the level of 25(OH)D could impact the development of KD in CAL.
However, the association between 25(OH)D and KD is still unestablished and even contradictory. Serological studies comparing 25(OH)D levels in patients with KD against healthy controls have reported divergent results. Twelve case–control studies [
13‐
24] reported a significant reduction in serum 25(OH)D levels in KD patients, other studies [
25‐
28] have shown converse outcomes or failed to obtain a significant difference [
29]. The uncertainty in these results has been attributed to various factors, including small sample size, varied detection methods, and unspecific complications of individual differences (e.g., age, sex, seasonality, and the presence or absence of CAL). These findings underscore the criticality of serum vitamin D status in serum in the pathogenesis of KD in children and the need for understanding the underlying relationship between the two.
In order to arrive at a definitive conclusion, this study performed a meta-analysis to estimate the disparity in serum 25(OH)D levels between children with KD and a healthy control group. We sought to evaluate the potential impact of vitamin D levels on children with KD and examine the relationship between vitamin D status and the development of vascular abnormalities related to KD.
Discussion
In this meta-analysis, we confirmed the crucial impact of vitamin D on the occurrence of Kawasaki disease. Our study delved into the correlation between vitamin D status and KD while examining the impact of several pertinent factors on their relationship. Our analyses revealed a significant link between vitamin D status and KD, with children affected by KD displaying considerably lower serum 25(OH)D levels compared to healthy controls. Nevertheless, our subsequent hierarchical analysis indicated that the correlation between serum vitamin D status and KD may not be associated with the progression of CAL complications in KD patients.
A growing body of evidence from various studies demonstrates the crucial role of vitamin D in the systemic inflammatory response and the release of anti-inflammatory cytokines [
39,
40]. Researchers posit that vitamin D can regulate the immune system and hence, influence the occurrence and development of KD [
16]—an autoimmune disease—and its therapeutic treatment through immune system regulation [
22]. This hypothesis is backed by animal, cell, and human studies which indicate that activated vitamin D (25(OH)D) plays an integral role in regulating immunologic processes [
41]. It follows that individual with higher serum 25(OH)D levels may have a lower chance of developing KD [
25]. This meta-analysis of seventeen published studies with approximately 1,394 KD patients and 1,527 healthy controls confirms that serum vitamin D status is significantly correlated with KD. Specifically, the serum 25(OH)D level of KD patients is significantly lower compared with that of healthy controls.
Acute systemic vasculitis, known as KD, is characterized by a range of clinical symptoms including fever, chapped lips, strawberry tongue, red eyes, and other acute systemic inflammation characteristics. However, the pathological differences that result in such broad clinical manifestations are yet to be established. Epidemiological studies have also highlighted the gender [
2], age [
42], and race/ethnicity-specific [
43,
44] features of children with KD. The status of vitamin D can vary depending on factors such as age, sex, race, and seasonal alterations. This variability might contribute to the inconsistent findings regarding the association between serum vitamin D levels and KD observed across different case–control studies [
45‐
48]. Moreover, the clinical manifestation heterogeneity of immune diseases linked to vitamin D metabolism further complicates the understanding of the current relationship between VD and KD. Reverse causality mentioned by Chakhtoura et al. [
49] is another factor should be taken into account [
50]. These factors serve as potential sources of heterogeneity that could influence the results of our analysis. Despite the extreme heterogeneity observed in all eligible studies, the meta-regression test revealed that the influence of these potential covariates was not significant enough to affect the relationship between vitamin D status and KD.
CAL is the most serious complication of KD, with about 9—20% of patients experiencing it even after routine treatment [
51]. As the pathological agents for KD have not yet been determined, the development process of CAL in KD patients remains unknown [
52]. Consequently, researchers have sought to understand the development process of the coronary artery and its influencing factors to intercept or reduce the risk of CAL in KD patients. Some studies have revealed a notable association between low levels of serum 25(OH)D in KD patients with CAL when compared to those without CAL and control groups [
22,
27,
53]. Additionally, vitamin D supplementation and adjuvant treatment have been found to effectively mitigate the risk of CAL and improve IVIG treatment response [
14]. However, seven eligible studies revealed discrepancies in their findings, with four studies indicating that the serum 25(OH)D level of KD patients with CAL was lower than that of patients without CAL [
20‐
22,
54], and the remaining three studies revealing the opposite phenomenon [
15,
26,
27] (Table
1). These inconsistent results might explain why subgroup analyses of CAL complications have not yielded consistent outcomes, signifying that the pathology of CAL in KD patients is likely multifaceted and unpredictable based solely on vitamin D levels.
The present study boasts strengths. Firstly, in addition to commonly used meta-analysis tests (such as heterogeneity, sensitivity, and publication bias analyses), the inclusion of outlier studies was detected and addressed, effectively reducing the influence of any such outlier(s); secondly, the potential impacts of other model-related covariates were also analyzed using meta-regression analysis; and lastly all estimates obtained from the meta-analysis were adjusted by permutations test. Notably, the present study employed both the random-effects model and the meta-regression method to quantitatively analyze the influence of potential variables on the relationship between vitamin D status and KD. As such, the study provides a more precise, defensible conclusion compared to previous research reports.
It is important to acknowledge the limitations of this review. Firstly, the majority of participants in the eligible studies were of Chinese ethnicity, with insufficient representation of other ethnic groups. As a result, the findings of this study may only be applicable to the relationship between vitamin D status and KD in the Chinese population, despite similar estimates found within subgroup analyses based on nationality; secondly, a surfeit immune response can theoretically give rise to a reduction in VD levels in the blood. Given that having a fever for at least 5 days is one of the criteria for diagnosing KD, the temporal gap between the occurrence of KD and the measurement of vitamin D levels, as well as the possible existence of a reverse causality [
50], might disrupt our precise assessment of the relationship between the two; thirdly, it is worth noting that the activity and status of vitamin D exhibit seasonal variations [
55], and the incidence of KD also demonstrates a clear seasonal pattern [
56]. However, due to the limited available data, this meta-analysis cannot confirm whether seasonality is also a contributing factor to the relationship of our currently discussing. Therefore, in-depth and rigorous trials and experiments are necessary to better comprehend the potential mechanisms of vitamin D in KD incidence and development. Additionally, the impact of differences in study design, diagnostic methods, and techniques for vitamin D measurement cannot be ignored.
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