This retrospective study included 633 pediatric patients with KD who underwent standard IVIG treatment in the hospital from January 2016 to March 2019. The inclusion criterion was pediatric patients with KD having a definitive diagnosis and complete data, referring to the diagnostic criteria proposed by American Heart Association 2017 . Patients complicated with other autoimmune diseases, infectious diseases, and tumors were excluded. Further, 200 pediatric patients with an upper respiratory infection and hospitalized in the hospital during the same period were considered as the control group. Two groups of pediatric patients were not given hormones, immunosuppressants, or IVIG within 2 weeks. The experimental group received standard IVIG treatment combined with aspirin and was subdivided into IVIG-responsive group and IVIG-nonresponsive group based on the response to IVIG treatment (IVIG nonresponsive was defined as persistent fever of >38℃ for 36 h after the first-dose IVIG treatment, abatement of fever for 2–7 days after drug administration, fever recurring after 2 weeks, with at least one of KD symptoms). The IVIG-nonresponsive group received the second treatment and then was distributed into Protocol 1 group (20 participants), Protocol 2 group (36 participants), and Protocol 3 group (30 participants). Following the second treatment, the IVIG-nonresponsive group was further classified into responsive group (Group A) and nonresponsive group (Group B), depending on whether the fever was abated. The family members of all pediatric patients included in this study signed the informed consent, and the approval was obtained from the Medical Ethics Committee of the hospital under the grant number:  Lun Shen Zi (22).
General data: The clinical and experimental data of all the pediatric patients with KD during hospitalization and follow-up visit were recorded. The blood drawn from the experimental and control groups when admitted to the hospital was retained for testing the serum levels of Meprin A, interleukin-1β (IL-1β), and interferon-induced protein-10 (IP-10). White blood cell (WBC) count, erythrocyte sedimentation rate (ESR), and levels of C-reactive protein (CRP), interleukin-6 (IL-6), and interleukin-17A (IL-17A) were tested during hospitalization. The time of fever abatement (the time from the day of second treatment to the resumption of normal body temperature without a recurrent fever) and the experimental data before and after the second treatment (pretreatment: prior to the second IVIG treatment, i.e., within 3–5 days after the first IVIG treatment; post-treatment: within 3–5 days after the second IVIG treatment), including WBC count, ESR, and levels of CRP,Meprin A, IL-1β, IL-6, IL-17A, and IP-10, were recorded for pediatric patients with KD in the IVIG-nonresponsive group. All the pediatric patients with KD in these groups were subjected to an ultrasonic cardiogram test from the onset to the 1-year follow-up visit (1, 2, 4, 8, and 12 weeks, and 6 and 12 months after the onset). The findings suggested coronary artery dilation or coronary aneurysm, defined as CAL. The diagnostic criterion for coronary artery dilation was as follows: coronary artery diameter >3 mm if participants aged <5 years; and coronary artery diameter >4 mm if participants aged >5 years. The diagnostic criterion for coronary artery aneurysm was as follows: coronary artery localized or diffused dilation, and its diameter 1.5 times higher compared with the adjacent normal coronary artery. Small coronary aneurysm was identified if the inner diameter was 4.1–4.9 mm; medium coronary aneurysm was identified if the inner diameter was 5.0–7.9 mm; and huge coronary aneurysm was identified if the inner diameter was ≥8 mm. Post-treatment CALs included CALs appearing during the follow-up visit after the second treatment, excluding those found before the second treatment.
For serum meprin A, IL-1β, and IP-10 test, 4 mL of fasting venous blood was drawn from all pediatric patients with KD during the acute phase (course of disease: 3–7 days), 4 mL from the IVIG-nonresponsive group within 3–5 days after the first IVIG treatment, and 4 mL from the IVIG-nonresponsive group within 3–5 days after the second IVIG treatment. The blood was then centrifuged at 3000 rpm for 10 min. The serum was separated from the residue and stored in a refrigerator at -80℃ for testing. Then, 4 mL of fasting venous blood was drawn from all pediatric patients in the control group and processed in the same manner as for the KD group. The serum was collected, and the levels of Meprin A, IL-1β, and IP-10 s were detected using Meprin A ELISA kit, IL-1β ELISA kit, and IP-10 kit, respectively (all supplied by BD Biosciences）.
Standard protocol: All pediatric patients with KD were given IVIG 2 g/kg once, combined with 30–50 mg/(kg × day) aspirin. The dosage of aspirin was reduced to 3–5 mg/kg 3 days after the abatement of fever.
Second treatment protocol: IVIG-nonresponsive group: Protocol 1 group was given IVIG 1 g/kg once again; Protocol 2 group was given IVIG 2 g/kg once again; Protocol 3 group was given IVIG 1 g/kg + Solu-Medrol injection 2 mg/kg (intravenous ×3 days, changed to oral administration of prednisone tablets, and dosage gradually reduced until withdrawn, with a cycle of 1–2 weeks).
Third treatment protocol: If Protocol 1 group and Protocol 2 group were nonresponsive after the second treatment: Solu-Medrol injection 2 mg/kg was given (intravenous ×3 days, changed to oral administration of prednisone tablets, and dosage gradually reduced until withdrawn, with a cycle of 1–2 weeks; if Protocol 3 was nonresponsive, IVIG 1g/kg was administered.
The body temperatures of all the pediatric patients with KD were under control after the third treatment.
All patients were given immunoglobulins produced by the same company (Chengdu Rongsheng Pharmaceuticals Co., Ltd., under State Food and Drug Administration (SFDA) Approval No.: S19993042, 50 mL: 2.5 g/vial), aspirin enteric-coated tablets (Cisen Pharmaceutical Co., Ltd., under SFDA Approval No.: H37023270, 25 mg/tablet), Solu-Medrol injection (Pfizer Manufacturing Belgium NV, under imported drug reg. standard: JX20160069, 40 mg/vial), and prednisone acetate tablets (Zhejiang Xianju Pharmaceutical Co., Ltd., under SFDA Approval No.: H33021207, 5 mg/tablet).
SPSS19.0 was used for statistical analysis. The normal distribution data were expressed as mean ± standard deviation and checked using the independent-samples t test. The data with non-normal distribution were expressed as median (interquartile range) and compared using the Wilcoxon rank-sum test. The counting data were expressed as a percentage (%) and processed using the chi-square test. P value less than 0.05 was considered to be statistically significant.