Background

Kawasaki Disease (KD) is a systemic vasculitis characterized by inflammation of small to medium-sized arteries, with coronary artery involvement representing a critical complication [1]. The spectrum of coronary lesions associated with KD includes coronary stenosis, ectasia, aneurysms, and myocardial infarction. Timely diagnosis and treatment with IVIG are pivotal in preventing coronary artery lesions (CAL) in KD, as delayed intervention escalates the risk of these serious complications [1]. However, up to 20% of patients do not respond to intravenous immunoglobulin (IVIG) and require adjunctive therapies such as monoclonal antibodies [2]. The intricate pathogenesis involves systemic inflammatory processes and immune activation during the acute phase of KD. This phase is characterized by heightened proliferation and activation of immune cells, including T cells, neutrophils, and macrophages. These immune cells exhibit activation of nuclear transcription factor-B (NF-κB) and an increased release of proinflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), interleukin (IL)-1β, IL-6, and monocyte chemoattractant protein-1 [3,4,5,6]. Additionally, endothelial cells demonstrate increased expression of adhesion molecules like intercellular adhesion molecule-1 and E-selectin, coupled with the activation of NF-κB, leading to heightened leucocyte infiltration and cytokine release [3, 7].

In recent years, several studies demonstrated that 1,25dihydroxyvitamin D3 (1,25-(OH)2D3), the active form of vitamin D, not only fulfills its conventional role in calcium and phosphorus homeostasis but also exhibits significant anti-inflammatory and immunomodulatory effects [6, 8]. It plays a pivotal role in suppressing immune responses by inhibiting dendritic cells and macrophages’ activation and restraining T and B cell proliferation through adjusting various signaling pathways like ERK1/2 [9, 10]. 1,25-(OH)2D3 can also upregulate regulatory T cells and induce immune tolerance [9]. Furthermore, 1,25-(OH)2D3 hinders the synthesis of immunoglobulins and downregulates the transcription of various cytokines, including IL-1, IL-2, IL-6, IL-12, TNF-α, and INF-γ [11,12,13]. NF-κB activation in macrophages and TNF-α-induced expression of adhesion molecules in endothelial cells are also modulated by 1,25-(OH)2D3 [8, 14]. Given the substantial role of 1,25-(OH)2D3 in the inflammatory process of KD, prior studies propose that 1,25-(OH)2D3, as a potential immunomodulatory agent, could be advantageous in Kawasaki patients, particularly in those resistant to IVIG and in need of adjunctive therapy.

In this systematic review, we aim to comprehensively evaluate the association between serum vitamin D levels and the risk of coronary artery involvement in Kawasaki Disease, shedding light on the potential therapeutic role of vitamin D in managing this vasculitis.

Methods

This systematic review was performed adhering to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations [15]. The study protocol also was logged in PROSPERO under the registration code CRD42024493204.

Eligibility criteria

This study included all peer-reviewed observational and interventional human studies investigating the correlation between serum 25(OH)-vitamin D levels and developing coronary artery lesions in patients with KD. We excluded studies that investigated animal studies, review studies, and conference abstracts.

Search strategy

A systematic search was conducted using all pertinent keywords related to Kawasaki disease, coronary artery lesion, and coronary aneurysm across the PubMed, Embase, Scopus, and Web of Science databases until December 10th, 2023. There were no restrictions regarding language and publication dates. Detailed search strategies can be found in Supplementary Table 1.

Selection process

Two independent reviewers (Z.A. and E.K.) initially screened the records by title and abstract utilizing the Rayyan web app. The publications were labeled as either “Excluded” or “Maybe” during the screening based on the pre-specified eligibility criteria. Records marked as “Maybe” went through a full-text evaluation for probable addition in the systematic review. In a disagreement between the two authors, a third author (M.G.) expertly intervened to resolve discrepancies and made the final decision. Figure 1 shows an overview of the entire selection process.

Fig. 1
figure 1

PRISMA flowchart

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Data extraction

Two reviewers (Z.A. and E.K.) independently extracted data from all studies meeting the eligibility criteria and resolved disagreements through consensus. The extracted data encompassed the first author, publication year, country, study subjects, study design, sample size, sample characteristics, serum vitamin D levels, vitamin D insufficiency definitions, and incidence rates of CALs and IVIG resistance. Both significant and non-significant findings were comprehensively extracted, with a p-value of < 0.05 considered as the significance level.

Risk of bias and study quality assessment

The quality of the animal studies was assessed using the Newcastle-Ottawa Scale (NOS) checklist [16]. Two independent reviewers (Z.A. and E.K.) comprehensively evaluated the quality of each included study. A third reviewer (M.G.) resolved disagreements.

Results

Literature search and baseline characteristic of the included studies

The initial search yielded 259 results, comprising 32 from PubMed, 70 from Embase, 93 from the Web of Science, and 64 from Scopus. Subsequent removal of duplicates (N = 81) led to 173 unique studies, which underwent screening based on titles and abstracts. Following this initial screening, 24 studies remained for comprehensive full-text evaluation. After applying exclusion criteria for various reasons, five peer-reviewed studies were ultimately included in this review [17,18,19,20,21]. The selection process and rationale for exclusions are elucidated in Fig. 1.

The included studies, conducted between 2014 and 2022 in China [17, 19], Italy [20], Korea [18], and Japan [19], each contributed one study. In total, the investigation involved 442 patients with Kawasaki Disease (KD), comprising 85 with coronary artery lesions (CAL) and 357 without CAL, alongside 594 healthy control cases. All the included studies were observational, with no experimental studies on the administration of vitamin D in KD found.

Regarding serum sampling for 25(OH)-vitamin D level assessment, three studies collected serum samples before IVIG treatment, one collected samples both before and after IVIG treatment, and one study did not provide information in this area. Three of the included studies enrolled both complete and incomplete KD patients, one enrolled only complete KD patients, and one study did not specify whether the patients were complete or incomplete. Notably, none of the included studies performed an analysis to compare vitamin D status between complete and incomplete patients. Regarding the risk assessment of the studies, the Newcastle-Ottawa Scale (NOS) scores ranged from 4 to 7, with an average score of 5.8. Table 1 provides a summary of the included studies.

Table 1 Summary of articles included in review
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Serum vitamin D levels in KD patients compared to healthy controls

Four studies compared serum vitamin D levels in KD patients with those in healthy subjects [17, 19,20,21]. In the study by Stagi et al., it was observed that before receiving treatment for KD, 98.7% of KD patients exhibited insufficient or deficient levels of serum 25(OH)-vitamin D (< 30 ng/mL). This prevalence was significantly higher than the 78.6% found in healthy control groups. Additionally, the serum 25(OH)-vitamin D levels in the KD group were significantly lower than those in the healthy controls, measuring 9.17 ± 4.94 ng/mL and 23.3 ± 10.6 ng/mL, respectively [20].

Similarly, Zhang et al. observed that the CAL and NCAL subgroups of KD patients had significantly lower serum 25(OH)-vitamin D levels compared to healthy controls (40 ± 10 ng/mL for healthy controls vs. 22 ± 5 ng/mL for NCAL patients and 15 ± 4 ng/mL for CAL patients) [21].

In a recent study, Okazaki et al. consistently corroborated that 25(OH)-vitamin D serum levels in KD patients were notably lower than controls (median: 17 ng/mL vs. 25 ng/mL). The number of patients with sub-normal 25(OH)-vitamin D serum levels (< 20 ng/ mL) (64% vs. 27% for controls) and deficient status (< 12 ng/ mL) (37% vs. 7% for controls) was also significantly higher in KD patients [19].

Conversely, Chen et al. reported that serum 25-(OH)-vitamin D levels in both CAL and NCAL groups were higher than healthy controls. However, the difference between NCAL and healthy controls did not reach statistical significance, with measurements of 83.9 ± 26.3 ng/ml, 49.2 ± 23.8 ng/ml and 44.1 ± 30.2 ng/ml for CAL, NCAL, and healthy controls, respectively [17].

Chen et al. did not mention the overall 25-(OH)-vitamin D serum level for KD patients. However, with respect to measured indices for CAL and NCAL subgroups of KD patients, the approximate serum 25-(OH)-vitamin D level for all KD patients could be calculated as 58 ± 24 ng/ml using a formula for pooling the mean and standard deviation. This estimated value is numerically higher than the serum 25-(OH)-vitamin D levels for healthy controls (58 ± 24 ng/mL vs. 44.1 ± 30.2 ng/ml), which is quite unexpected with regard to the previously mentioned studies [17].

Association between serum 25-(OH)-vitamin D levels and coronary artery involvement in KD patients

The reports on the association between 25-(OH)-vitamin D serum levels and developing CAL in KD patients were highly heterogeneous, both in terms of outcome measures and results.

Stagi et al. observed that the development of coronary artery aneurysm (CAA) was associated with significantly lower serum levels of 25-(OH)-vitamin D (4.92 ± 1.36 ng/mL) compared to patients without CAA (9.41 ± 4.95 ng/mL) [20]. Similarly Zhang et al., demonstrated that KD patients with CAL had lower serum levels of 25-(OH)-vitamin D both before or after IVIG treatment compared to those without CAL [21].

In contrast, Okazaki et al. found no association between 25(OH)-vitamin D levels at the time of KD diagnosis and CAL [19]. Similarly, Jun et al. reported no significant difference in developing CAL in KD patients with vitamin D deficiency (< 20 ng/mL) compared to those without deficiency (> 20 ng/mL) (17.9% vs. 7.7%) [18].

Interestingly, Chen et al. observed that serum 25-(OH)-vitamin D levels were markedly elevated in children with CALs compared to ones without (83.9 ± 26.3 ng/ml vs. 49.2 ± 23.8 ng/ml). They introduced a cutoff point of 65 ng/ml to predict subsequent CALs, possessing a 0.73 specificity, 0.78 sensitivity, and 0.74 diagnostic accuracy [17].

Association between serum vitamin D levels and IVIG resistance in KD patients

Three studies reported the association between serum 25-(OH)-vitamin D levels and IVIG resistance in KD patients. Jun et al. revealed an increase in IVIG resistance incidence in KD patients with vitamin D deficiency (< 20 ng/mL) compared to those without deficiency (> 20 ng/ml) (30.8% vs. 11.5%) [18]. Zhang et al. similarly reported lower serum levels for IVIG resistance KD patients compared to responders (14 ± 4 ng/ml vs. 21 ± 6 ng/ml) [21]. However, the other study by Okazaki et al. did not find any association between 25-(OH)-vitamin D serum levels at the time of diagnosis of KD and IVIG resistance [19].

Discussion

This systematic review identified evidence from observational studies of an association between serum vitamin D status and susceptibility to coronary artery lesions in KD patients. Additionally, comparisons were made between serum vitamin D levels in KD patients and healthy controls, as well as associations between serum vitamin D and IVIG resistance. No evidence from intervention studies was found.

The primary finding indicates that KD patients generally have lower serum vitamin D compared to healthy controls. Three out of four included studies support this finding, although one study revealed conflicting results with higher serum vitamin D in KD patients versus controls [17, 19,20,21]. Regarding the association between serum vitamin D and developing CAL in KD, this review failed to reach a consensus due to heterogeneous study results. Two studies reported lower vitamin D levels in KD patients with CAL compared to those without [20, 21]. However, two other studies found no significant association between vitamin D status and CAL, and notably one study demonstrated an inverse correlation, with higher serum vitamin D levels associated with increased risk of CAL [17,18,19]. For IVIG resistance, trends leaned towards lower serum vitamin D being associated with higher resistance [18, 21].

Several factors may explain the inconsistent study results, including differences in sample size, variations in vitamin D status classification and CAL determination, population heterogeneity, and timing of outcome assessments.

In vitro studies support the immunomodulatory functions of vitamin D in KD vasculitis [22, 23]. Kudo et al. found vitamin D significantly inhibited TNF-α-induced vascular cellular adhesion molecule-1 expression and interleukin-8 production [8]. Furthermore, Suzuki et al. showed the anti-inflammatory effects of 1α,25-dihydroxyvitamin D3 in human coronary arterial endothelial cells, suggesting vitamin D could modulate KD inflammation via NF-kappaB activation [14]. Beyond KD, previous studies demonstrated vitamin D deficiency accelerates coronary artery disease progression by increasing chronic inflammation, while supplementation benefits disease progression by dampening vascular inflammation and atherosclerosis [6, 24, 25].

Given the anti-inflammatory functions of vitamin D, it remains biologically plausible that insufficient 25(OH)-vitamin D levels can negatively impact coronary artery complications in KD patients. However, due to the limited number of studies whether vitamin D deficiency increases CAL risk cannot be definitively concluded.

Strengths and limitations

This systematic review has several strengths. It is the most comprehensive review assessing serum vitamin D and the development of CAL in Kawasaki disease. The systematic approach to identifying studies makes it unlikely that relevant studies were missed. No language or time limitations were imposed, and the review assessed the risk of bias of evidence. However, an inability to quantitatively analyze data due to study heterogeneity and insufficient information represented limitations. The small number of included studies from only four countries reduced generalizability and challenged result interpretation. Finally, as studies only evaluated associations between vitamin D and CAL incidence, the therapeutic value of vitamin D in KD remains unknown.

Conclusions

Although the current evidence is inconclusive overall, the results show more support for a potential benefit of sufficient vitamin D levels in Kawasaki disease rather than evidence that refutes any association with clinical outcomes.