Serum amyloid A as a biomarker for immunoglobulin resistance in Kawasaki disease

Abstract

Background

Intravenous immunoglobulin (IVIG) resistance is of prime importance in Kawasaki disease (KD). In this study, we examined the value and mechanism of serum amyloid A (SAA) level in predicting IVIG resistance in patients with KD.

Methods

SAA levels were measured in 497 consecutive patients with KD before IVIG therapy in the training set. The patients were divided into two groups (IVIG-responsive and IVIG-resistant) according to the American Heart Association (AHA) definition of IVIG resistance. Demographic, echocardiographic, and laboratory data were also retrospectively analyzed and tabulated to predict IVIG resistance. The predictive value of SAA was validated on test sets of prospective data. Cytokine microarrays were analyzed from 4 patients with resistant to IVIG, 4 patients with responsive to IVIG and 4 healthy volunteers.

Results

During the training set, 409 patients with KD were enrolled, of whom 43 (10.5%) were resistant to initial IVIG treatment and 47 (11.49%) had coronary artery lesions (CALs). Serum levels of SAA were higher in the IVIG resistant group compared to the IVIG responsive group, (380.00 [204.40–547.25] vs 230.85 [105.40–490.00] mg/L; p = .008). The values of total bilirubin, C-reactive protein, neutrophils, alanine aminotransferase, aspartate aminotransferase, interleukin-6(IL-6), and procalcitonin were significantly higher in the IVIG-resistant group than in the IVIG-responsive group (p < .05); however, the lymphocytes, platelets, serum sodium levels, and duration of fever before IVIG therapy were significantly lower (p < .05). There was no significant difference in SAA levels between patients with KD with and without CALs. Binary logistic regression analysis showed that SAA (p = .008), neutrophils (p < .001), total bilirubin (p = .001), platelet count (p = .004), and serum sodium level (p = .019) were independent factors influencing IVIG resistance. The optimal cutoff value of SAA for IVIG resistance prediction was 252.45 mg/L, with a corresponding clinical sensitivity of 69.8% and specificity of 54.4%. Based on receiver operating characteristic (ROC) curve analyses, the area under the curve (AUC) of combined detection with these five indicators was 0.800, clinical sensitivity was 69.8%, and specificity was 76.2%. In the prospective data, the sensitivity, specificity, and accuracy of SAA for identifying IVIG resistance KD were 77.8%,69.0%, and 70.0%, respectively. Compared with IVIG- responsive group and healthy children, the levels of IL-6 was upregulated significantly in IVIG-resistant group through cytokine microarrays.

Conclusions

SAA may be a potential biomarker for predicting IVIG responsiveness to KD, Combined detection of SAA levels, total bilirubin, neutrophil count, platelet count, and serum sodium levels is superior to that of any other single indicator for predicting IVIG resistance in KD. And elevated SAA may accompany with IL-6 in KD patients, its use in clinical practice may be helpful for treatment management.

Keywords:

• Binary logistic regression
• intravenous immunoglobulin
• Kawasaki disease
• resistance
• serum amyloid A
• cytokines

Acknowledgements

We would like to acknowledge the hard and dedicated work of all the staff who implemented the intervention and evaluation components of the study.

Authors contributions

Huang XB participated in the design of the study, collected data, did the statistical analysis, and wrote the initial draft report. Zhao S, Liu ZY and Xu YY contributed to the data analysis and revised the report. Deng F contributed the design of the study and reviewed the manuscript, and approved the final manuscript as submitted. All authors have read and approved the submitted version.

Ethical statement

Approval for this study was obtained from the Medical Committee of Anhui Provincial Children’s Hospital (Approval Number EYLL-2022-020), and informed consent was obtained from the parents of each subject. This study was conducted in accordance with the Declaration of Helsinki.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

Data used to support the findings of this study are available from the corresponding author upon request.

Additional information

Funding

This work was supported by the MOE Key Laboratory of Population Health Across Life Cycle (No. JK20213).