Abstract
Patients infected with SARS-CoV-2 may experience acute and long-term immune disorders. Immunological factors are thought to play an important role in Kawasaki disease. To analyze the impact of COVID-19 infection on Kawasaki disease, this study retrospectively analyzed 161 children with Kawasaki disease onset during the COVID-19 pandemic. The proportion of IVIG-Resistant individuals and the rate of corticosteroid use in the 1–7 weeks from COVID-19 infection to Kawasaki disease onset were higher than that of the noninfected group, even after excluding suspected cases of multiple system inflammatory syndrome. Compared to the noninfected group, the level of CD4 was lower, and the levels of CD3−CD16+CD56+, complement C4, TNF-α, and IFN-γ were higher in the 1–7 weeks after COVID-19 infection. In conclusion, the risk of IVIG resistance was significantly increased in children with Kawasaki disease onset 1–7 weeks after COVID-19 infection, which may be related to the long-term impact of COVID-19 on immunity.
Supplementary Information
The online version contains supplementary material available at 10.1038/s41598-025-91042-8.
Keywords: Kawasaki disease, COVID-19, Immunity, IVIG resistance, Child
Subject terms: Immunology, Cytokines, Infection, Inflammation, Immunological disorders, Vasculitis syndromes
Introduction
Kawasaki disease (KD) is a common vasculitis in children that was first reported by Dr. Tomisaku Kawasaki in 1967. Coronary artery lesions (CAL) due to KD have become common acquired heart diseases in some countries and regions. The cause of KD is still unclear, but it is generally believed that genetics, infectious triggers, and immune factors/dysregulation play an important role in its pathogenesis1.
In adults, the typical features of COVID-19 are pneumonia and respiratory symptoms, as well as excessive activation of inflammatory cascades2. Patients infected with SARS-CoV-2 may experience acute and long-term immune disorders3. Some evidence suggests that COVID-19 in children might manifest as postinfection immune dysregulation, typically occurring several weeks after COVID-19 infection4. It remains unclear whether the immune dysregulation that occurs after COVID-19 infection in children has an impact on the KD that occurs weeks later, leading to changes in treatment efficacy and prognosis. The COVID-19 pandemic in China from late 2022 to early 2023 resulted in a large-scale infection of the population in a short period of time. This study provides a good model for studying the characteristics of KD onset following COVID-19 infection in children. This article investigated the clinical features of KD onset following the COVID-19 pandemic in China from late 2022 to early 2023, hoping to provide a reference for the diagnosis and treatment of KD onset following COVID-19 infection.
Results
Study population
Of a total of 161 children with KD hospitalized in our hospital from November 1, 2022, to March 30, 2023, 91 (56.5%) were boys, with an average age of 37.91 ± 27.57 months. All of them were Han Chinese. The detailed characteristics of the participants who were diagnosed with complete and incomplete KD are shown in the supplemental data (Supplement Table S1). Eighty-four patients were not infected with COVID-19 before the onset of KD, and 77 patients were infected with COVID-19. A comparison was made between the noninfected and infected COVID-19 groups. There was no significant difference in CAL between the two groups (n = 8/84 (9.5%) in the noninfected COVID-19 group vs. n = 5/77 (6.5%) in the infected COVID-19 group, P = 0.481). The IVIG-Resistant rate of the noninfected COVID-19 group was 13/84 (15.5%), and that of the infected COVID-19 group was 26/77 (33.8%). The IVIG-Resistant rate of the infected COVID-19 group was significantly higher than that of the noninfected COVID-19 group (P = 0.007). Furthermore, the proportion of IVIG resistance in 1–7 weeks from COVID-19 infection to the onset of KD was higher than that of the noninfected group and 8–16 weeks from COVID-19 infection to the onset of KD (Fig. 1). Therefore, the study further subdivided the COVID-19-infected group into three distinct subgroups based on the interval between COVID-19 infection and the onset of KD: less than one week group (1 case), one to seven weeks group (56 cases), and more than seven weeks group (20 cases) (Fig. 2).
Fig. 1.
Changes in the percentage of IVIG resistance with the time of Kawasaki disease onset after COVID-19 infection. 0: noninfected with COVID-19. IVIG: intravenous immunoglobulin.
Fig. 2.
Flow of participants through the study. KD: Kawasaki disease, MIS-C: multiple system inflammatory syndrome.
Patient characteristics and laboratory findings
We further analyzed the differences between the noninfected COVID-19 group (n = 84), the more than 7 weeks after COVID-19 infection group (n = 20), and the 1–7 weeks after COVID-19 infection group (n = 56) (Table 1). A comparative analysis revealed no statistically significant disparities in age and gender distribution across the three groups. The IVIG-Resistant rate in the 1–7 weeks after COVID-19 infection group was significantly higher than those in the noninfected with COVID-19 group (n = 23/56 (41.1%) vs. n = 13/84 (15.5%), P = 0.001) and the more than 7 weeks after COVID-19 infection group (n = 23/56 (41.1%) vs. n = 3/20 (15.0%), P = 0.035). There were no significant differences in the proportion of CAL among the three groups.The rate of corticosteroid use was significantly higher in the group 1–7 weeks after COVID-19 infection than those in the noninfected COVID-19 group (n = 22/56 (39.3%) vs. n = 11/84 (13.1%), P < 0.001) and the more than 7 weeks after COVID-19 infection group (n = 22/56 (39.3%) vs. n = 3/20 (15.0%), P = 0.047). The days of hospitalization was significantly longer in the group 1–7 weeks after COVID-19 infection than those in the noninfected with COVID-19 group (7.5 [5.0, 10.0] vs. 5.0 [4.0, 7.0], P = 0.001). It was also higher than that in the more than 7 weeks after COVID-19 infection group (7.5 [5.0, 10.0] vs. 5.0 [5.0, 7.0]), but the difference was not statistically significant (P = 0.141).By incorporating age in months, day of illness at initial treatment, serum sodium, serum aspartate aminotransferase, C-reactive protein, platelet count, percentage of white blood cells representing neutrophils and infection with COVID-19 into a multivariable logistic regression equation (Table 2), it was found that KD onset following 1–7 weeks after COVID-19 infection increased the risk of IVIG resistance, with statistical significance (OR = 3.208, 95% CI 1.263–8.149, P = 0.014). The younger the age, the higher the risk of IVIG resistance, with statistical significance (OR = 0.978, 95% CI 0.957–0.999, P = 0.044). The percentage accuracy in classification of this model was 79.7%. The analysis included 80 children who were not infected with COVID-19 and 53 who were 1–7 weeks post-infection. The age distribution of the groups was as follows: 19 children (14.3%) were under 1 year old, 30 children (22.6%) were aged 1–2 years, 64 children (48.1%) were aged 2–6 years, and 20 children (15.0%) were over 6 years old.
Table 1.
Comparison of the clinical characteristics between the noninfected with COVID-19 group, the group 1–7 weeks after COVID-19 infection and the group more than 7 weeks after COVID-19 infection.
| Noninfected with COVID-19 (n = 84) | 1–7 weeks after COVID-19 infection (n = 56) | More than 7 weeks after COVID-19 infection (n = 20) | P | |
|---|---|---|---|---|
| Number of boys (%) | 44 (52.4%) | 34 (60.7%) | 13 (65.0%) | 0.457 |
| Age (month) | 30.5 [16.0, 51.8] | 27.5 [17.0, 55.0] | 31.0 [17.0, 45.0] | 0.965 |
| Number of IVIG resistance (%)* | 13 (15.5%)a | 23 (41.1%) | 3 (15.0%)a | 0.001 |
| Number of CAL (%) | 8 (9.5%) | 3 (5.4%) | 2 (10.0%) | 0.641 |
| Number of using corticosteroids (%)* | 11 (13.1%)a | 22 (39.3%) | 3 (15.0%)a | 0.001 |
| Hospitalization (day)* | 5.0 [4.0, 7.0]a | 7.5 [5.0, 10.0] | 5.0 [5.0, 7.0] | 0.004 |
*P < 0.05, IVIG: intravenous immunoglobulin, CAL: coronary artery lesions, a: Compared with the group 1–7 weeks after COVID-19 infection, P < 0.05.
Table 2.
Logistic regression models showing variables independently associated with IVIG resistance.
| Effect | B | SE | Wald | Df | Sig. | Exp(B) | 95% C.I. for EXP(B) | |
|---|---|---|---|---|---|---|---|---|
| LL | UL | |||||||
| Age in months | − 0.023 | 0.011 | 4.055 | 1 | 0.044 | 0.978 | 0.957 | 0.999 |
| Day of illness at initial treatment | 0.022 | 0.113 | 0.036 | 1 | 0.849 | 1.022 | 0.818 | 1.276 |
| Serum sodium | − 0.067 | 0.090 | 0.552 | 1 | 0.457 | 0.936 | 0.785 | 1.115 |
| Serum aspartate Aminotransferase | 0.004 | 0.003 | 2.127 | 1 | 0.145 | 1.004 | 0.998 | 1.010 |
| C-reactive protein | 0.010 | 0.005 | 3.197 | 1 | 0.074 | 1.010 | 0.999 | 1.021 |
| Platelet count | − 0.003 | 0.002 | 1.734 | 1 | 0.188 | 0.997 | 0.993 | 1.001 |
| Percentage of WBC representing neutrophils a | 2.338 | 2.074 | 1.271 | 1 | 0.260 | 10.358 | 0.178 | 602.995 |
| Infected with COVID-19 b | 1.166 | 0.476 | 6.010 | 1 | 0.014 | 3.208 | 1.263 | 8.149 |
| Intercept | 6.204 | 12.304 | 0.254 | 1 | 0.614 | 494.803 | ||
Note. Omnibus tests of model coefficients (model) χ2 = 32.065, P < 0.001; Hosmer and Lemeshow test χ2 = 7.216, P = 0.513; CI = confidence interval, LL = lower limit, UL = upper limit. a: WBC = white blood cells; b: 0 = noninfected with COVID-19; 1 = 1–7 weeks after COVID-19 infection.
Comparison of the noninfected with COVID-19 group, the 1–7 weeks after COVID-19 infection excluded from suspected MIS-C group and the more than 7 weeks after COVID-19 infection group
In order to further exclude the influence of suspected multiple system inflammatory syndrome (MIS-C) cases on the study’s results, 27 pediatric patients were identified as suspected cases of MIS-C based on the diagnostic criteria established by the Centers for Disease Control and Prevention5 (Supplement Table S2).
Subsequent analysis was conducted to investigate the disparities between the noninfected COVID-19 group (n = 84), the 1–7 weeks after COVID-19 infection group after excluding the suspected MIS-C cases (n = 29) and the more than 7 weeks after COVID-19 infection group (n = 20). The IVIG-resistant rate in the 1–7 weeks after COVID-19 infection group was significantly higher than that in the noninfected with COVID-19 group (n = 10/29 (34.5%) vs. n = 13/84 (15.5%), P = 0.028). The incidence of bilateral bulbar conjunctival injection 1–7 weeks after COVID-19 infection was lower than that in the noninfected with COVID-19 group (n = 19/29 (65.5%) vs. n = 79/84 (94.0%), P < 0.001). The incidence of gastrointestinal symptoms in the 1–7 weeks after COVID-19 infection group was significantly lower than those in the noninfected with COVID-19 group (n = 0/29 (0%) vs. n = 18/84 (21.4%), P = 0.007) and the more than 7 weeks after COVID-19 infection group (n = 0/29 (0%) vs. n = 5/20 (25.0%), P = 0.004). The rate of corticosteroid use was significantly higher in the group 1–7 weeks after COVID-19 infection (n = 9/29 (31.0%) vs. n = 11/84 (13.1%), P = 0.029) (Table 3).
Table 3.
Comparison of the noninfected with COVID-19 group, the 1–7 weeks after COVID-19 infection group after excluding the suspected MIS-C cases and the more than 7 weeks after COVID-19 infection group.
| Noninfected with COVID-19 (n = 84) | 1–7 weeks after COVID-19 infection excluded from suspected MIS-C (n = 29) | More than 7 weeks after COVID-19 infection (n = 20) | P | |
|---|---|---|---|---|
| Number of boys (%) | 44 (52.4%) | 20 (69.0%) | 13 (65.0%) | 0.232 |
| Age (month) | 30.5 [16.0, 51.8] | 29.0 [17.0, 72.0] | 31.0 [17.0, 45.0] | 0.887 |
| Number of bulbar conjunctival injection (%) * | 79 (94.0%)b | 19 (65.5%) | 18 (90.0%) | < 0.001 |
| Number of rash (% patients) | 63 (75.0%) | 19 (65.5%) | 16 (80.0%) | 0.476 |
| Number of cervical lymphadenopathy (%)* | 76 (90.5%) | 24 (82.8%) | 13 (65.0%) | 0.015 |
| Number of changes in the lips and oral cavity (%) | 73 (86.9%) | 26 (89.7%) | 18 (90.0%) | 0.884 |
| Number of changes in the peripheral extremities (%) | 42 (50.0%) | 14 (48.3%) | 10 (50.0%) | 0.987 |
| Number of shock (%) | 0 | 0 | 0 | - |
| Number of gastrointestinal symptoms (%)* | 18 (21.4%)b | 0 | 5 (25.0%)b | 0.019 |
| Number of IVIG resistance (%)a | 13 (15.5%)b | 10 (34.5%) | 3 (15.0%) | 0.072 |
| Number of CAL (%) | 8 (9.5%) | 1 (3.4%) | 2 (10.0%) | 0.565 |
| Hospitalization (day) | 5 [4, 7] | 6 [5, 9] | 5 [5, 7] | 0.258 |
| Number of using corticosteroids (%)a | 11 (13.1%)b | 9 (31.0%) | 3 (15.0%) | 0.085 |
*P < 0.05, MIS-C: multiple system inflammatory syndrome, IVIG: intravenous immunoglobulin, CAL: coronary artery lesions, a: marginally significant, b: Compared with the 1–7 weeks after COVID-19 infection group after excluding the suspected MIS-C cases, P < 0.05.
In the 1–7 weeks after COVID-19 infection group after excluding the suspected MIS-C cases, the level of platelet count was lower than that in the more than 7 weeks after COVID-19 infection group (320.0 [231.5, 389.5] vs. 388.5 [328.8, 439.5], P = 0.019). The level of creatine kinase MB (CK-MB) was higher than that in the noninfected with COVID-19 group (1.80 [1.43, 2.28] vs. 1.10 [1.00, 2.30], P = 0.005) and the more than 7 weeks after COVID-19 infection group (1.80 [1.43, 2.28] vs. 1.20 [0.10, 1.78], P = 0.003). There were no statistically significant differences between the three groups in terms of white blood cell count, neutrophil count, lymphocyte count, C-reactive protein, procalcitonin, serum sodium, and serum aspartate aminotransferase. (Table 4).
Table 4.
Comparison of laboratory indicators between the noninfected with COVID-19 group, the 1–7 weeks after COVID-19 infection group after excluding the suspected MIS-C cases and the more than 7 weeks after COVID-19 infection group.
| Noninfected with COVID-19 (n = 84) | 1–7 weeks after COVID-19 infection excluded from suspected MIS-C (n = 29) | More than 7 weeks after COVID-19 infection (n = 20) | P | |
|---|---|---|---|---|
| White blood cell | 12.90 ± 4.62 | 13.86 ± 5.43 | 13.36 ± 4.34 | 0.640 |
| Neutrophil | 8.75 ± 4.23 | 9.37 ± 4.26 | 9.29 ± 4.03 | 0.740 |
| Lymphocyte | 2.55 [1.66, 4.05] | 2.88 [1.93, 4.26] | 2.53 [2.03, 4.14] | 0.543 |
| Monocyte | 0.77 [0.51, 1.02] | 0.80 [0.47, 1.23] | 0.74 [0.47, 0.95] | 0.761 |
| Erythrocyte | 4.04 ± 0.38 | 3.97 ± 0.39 | 4.07 ± 0.30 | 0.566 |
| Hemoglobin | 109.83 ± 9.88 | 107.62 ± 11.65 | 108.50 ± 8.71 | 0.573 |
| Platelet* | 325.0 [256.0, 393.0] | 320.0 [231.5, 389.5] | 388.5 [328.8, 439.5]a | 0.037 |
| CRP | 49.71 [29.16, 73.68] | 57.05 [35.17, 99.91] | 72.06 [24.14, 98.75] | 0.466 |
| ESR | 63.28 ± 24.84 | 63.16 ± 23.39 | 69.64 ± 26.03 | 0.598 |
| Procalcitonin | 0.37 [0.11, 0.89] | 0.71 [0.14, 1.33] | 0.45 [0.12, 0.67] | 0.857 |
| Serum sodium | 135.0 [133.0, 137.0] | 135.0 [134.0, 136.3] | 134.5 [132.3, 137.5] | 0.822 |
| Albumin | 35.46 ± 3.33 | 36.63 ± 2.94 | 35.23 ± 3.90 | 0.220 |
| Total bilirubin | 5.60 [4.10, 7.88] | 6.20 [5.35, 7.68] | 5.00 [4.23, 6.80] | 0.232 |
| ALT | 23.0 [13.0, 69.5] | 18.0 [11.0, 40.0] | 13.5 [11.3, 26.8] | 0.261 |
| AST | 36.5 [29.0, 54.0] | 44.0 [34.5, 60.0] | 31.5 [24.3, 55.8] | 0.310 |
| LDH | 325.5 [236.8, 447.8] | 434.5 [268.0, 634.0] | 340.5 [221.8, 539.5] | 0.106 |
| Triglyceride | 1.14 [0.91, 1.54] | 1.04 [0.78, 1.38] | 1.16 [0.86, 1.39] | 0.514 |
| Ferritin | 149.8 [110.4, 193.8] | 121.1 [89.6, 209.4] | 108.0 [92.7, 126.8] | 0.089 |
| Troponin I | 0.050 [0.050, 0.070] | 0.050 [0.050, 0.060] | 0.060 [0.010, 0.070] | 0.942 |
| CK-MB* | 1.10 [1.00, 2.30]a | 1.80 [1.43, 2.28] | 1.20 [0.10, 1.78]a | 0.005 |
| BNP | 110.3 [106.2, 754.1] | 109.6 [98.9, 881.0] | 628.9 [105.7, 993.4] | 0.334 |
*P < 0.05, MIS-C: multiple system inflammatory syndrome, CRP: C-reactive protein, ESR: erythrocyte sedimentation rate, ALT: alanine aminotransferase, AST: aspartate aminotransferase, LDH: lactate dehydrogenase, CK-MB: creatine kinase MB, BNP: B-natriuretic peptide, a: Compared with the 1–7 weeks after COVID-19 infection group after excluding the suspected MIS-C cases, P < 0.05.
Immunity changes after COVID-19 infection
CD4 (35.63 ± 9.79 vs. 42.35 ± 9.15, P = 0.005) was significantly lower in the 1–7 weeks after COVID-19 infection group which excluded from suspected MIS-C than in the noninfected with COVID-19 group (Fig. 3) and recovered after 7 weeks (35.63 ± 9.79 vs. 39.62 ± 5.86, P = 0.151). CD3 was also lower in the 1–7 weeks after COVID-19 infection group which excluded from suspected MIS-C than that in the noninfected with COVID-19 group (61.28 ± 10.11 vs. 66.26 ± 10.59, P = 0.062). CD3−CD16+CD56+ were higher in the 1–7 weeks after COVID-19 infection group which excluded from suspected MIS-C than that in the noninfected with COVID-19 group (6.65 [5.60, 7.65] vs. 4.55 [3.25, 6.70], P = 0.024). There were no significant differences in CD8, or CD19 (Fig. 3). The complement C4 (0.47 ± 0.13 vs. 0.40 ± 0.13, P = 0.035) in the 1–7 weeks after COVID-19 infection group was higher (Fig. 3), and there were no significant differences in complement C3 and immunoglobulin levels between the three groups.
Fig. 3.
The immunity changes after COVID-19 infection. C3: complement C3, C4: complement C4, IL: interleukin, TNF: tumor necrosis factor, IFN: interferon, 0: noninfected with COVID-19, 1–7: onset of Kawasaki disease 1–7 weeks after COVID-19 infection excluded from suspected multiple system inflammatory syndrome, 8–16: onset of Kawasaki disease 8–16 weeks after COVID-19 infection. *P < 0.05, **P < 0.01.
Th1/Th2 cytokine profiling (Fig. 3) revealed that compared to the noninfected with COVID-19 group, tumor necrosis factor (TNF)-α (2.70 [1.85, 3.43] vs. 1.90 [1.30, 2.50], P = 0.012), and interferon (IFN)-γ (6.15 [2.70, 14.70] vs. 3.70 [2.10, 7.60], P = 0.023) were significantly elevated in the 1–7 weeks after COVID-19 infection group which excluded from suspected MIS-C and decreased after 7 weeks. IL-6 was also elevated in the 1–7 weeks after COVID-19 infection group than that in the noninfected with COVID-19 group (116.30 [56.00, 246.68] vs. 71.10 [34.30, 165.90], P = 0.122). There were no significant differences in IL-2, IL-4, and IL-10.
Discussion
KD is a systemic inflammatory disease that mainly affects children under 5 years of age. The pathogenesis remains unclear, and it is currently thought to be related to genetics, vaccine exposure theory, infectious theory/seasonality and immune factors/dysregulation1. Immune factors are believed to play a significant role in the pathogenesis of KD6,7, while COVID-19 has been shown to have acute and long-term effects on the immune system3,8,9. We compared the clinical features of KD between children without COVID-19 infection and those with COVID-19 infection and found that the proportion of IVIG resistance in children with onset of KD following 1–7 weeks after COVID-19 infection was significantly higher than that in children without COVID-19 infection, and most of these children needed treatment with corticosteroids. For the immune status of these children, the levels of CD4 significantly decreased within 1–7 weeks after COVID-19 infection and recovered after 7 weeks, while the levels of CD3−CD16+CD56+, complement C4, TNF-α, and IFN-γ increased significantly within 1–7 weeks after COVID-19 infection. Our study revealed that the risk of IVIG resistance in KD that occurred 1–7 weeks after COVID-19 infection increased, which may be related to changes in immune levels after COVID-19 infection.
COVID-19 infection can lead to a lasting functional impact on the immune system during the acute phase and long after recovery. SARS-CoV-2 enters type II lung cells through angiotensin-converting enzyme 2 in the respiratory system, leading to rapid viral replication and a pro-inflammatory state, including elevated levels of IL-1, IL-6, IL-10, chemokine ligand 8, complement C4, TNF-α, and IFN-γ10–13. In children, there have been reports of elevated levels of IL-6 in COVID-19 patients with Acute Respiratory Distress Syndrome and MIS-C patients14,15. Compared to control groups, significantly higher levels of IL-6 and TNF-α were detected in newborns whose mothers tested positive for COVID-19 4–6 weeks before delivery16. Patients infected with SARS-CoV-2 exhibited defects in some dendritic cell subsets and changes in dendritic cell homing and activation markers, and these changes had not recovered more than 7 months after infection17. Patients with long COVID-19 have highly activated innate immune cells, a lack of initial T and B cells, and high levels of type I interferon and type III interferon, which remain at a high level for 8 months after infection9. Chromatin remodeling has been observed in the innate and adaptive immune cells of COVID-19 survivors. Compared with healthy donors, recovered individuals contain abundant TBET− enriched CD16+ and IRFl− enriched CD14+ monocytes with a continuously trained and activated epigenomic state. The B-cell lineage of recovered individuals exhibits an accelerated developmental program from immature B cells to antibody-producing plasma cells. The SARS-CoV-2-specific CD8+ T-cell epigenomic profile can promote the differentiation of effector or memory cells18. In our study, we found that the levels of CD4 in KD children within 1–7 weeks after COVID-19 infection significantly decreased, while the levels of CD3−CD16+CD56+, complement C4, TNF-α, and IFN-γ were significantly increased compared to noninfected with COVID-19, which may be because COVID-19 had trained cells after infection, so the immune response of children with KD could quickly start after onset, leading to the depletion of immune cells and the production of high-level cytokines, which in turn led to a higher inflammatory response and higher levels of LDH, and CK-MB.
Previous study had found that a large number of CD4 cells infiltrate the early-damaged coronary artery wall in the KD mouse model, while CD4 cells were not seen in the coronary arteries of normal mice19. In mice induced by Candida albicans cell wall extracts, the CD3 and CD4 T lymphocyte subsets in cardiac tissue were reduced20. Endomyocardial biopsies from patients with Kawasaki disease shock syndrome (KDSS) during the acute phase show infiltration of CD3 and CD4 lymphocytes in the myocardium21. This suggests that CD3 and CD4 T cells were involved in the inflammatory response of the blood vessel wall during the acute phase of KD, leading to excessive consumption of CD3 and CD4 T cells in peripheral blood. In a clinical study22, it was found that the levels of CD3, CD4, and C3 in the IVIG non-responsive group were significantly lower than those in the IVIG-sensitive group. IL-6, IFN-γ, and TNF-α are also the most important cytokines in KD. As we all know, IL-6 plays a crucial role in the pathophysiology of KD by promoting megakaryocyte maturation, leading to thrombocytosis. It may also cause vasculitis by triggering a cascade reaction and stimulate the production of polyclonal B cell autoantibodies, leading to acute inflammation and antibody-mediated endothelial injury23. In our previous study, we found that the levels of IL-6, TNF-α, and IFN-γ were significantly increased in KD patients pre-IVIG. Simultaneously, we found that significantly elevated levels of IL-6 were observed in patients who did not respond to IVIG24. Zhang et al. observed that the levels of IFN-γ and TNF-α were higher in the IVIG-resistant group compared to the IVIG-sensitive group25. The same phenomenon was also observed in KDSS. The levels of serum IL-6, TNF-α and IFN-γ in KDSS patients were significant higher than KD patients. KDSS were characteristic as more cytokine production and prone to developing IVIG non-responsiveness26. In summary, it is hypothesized that the immune response of patients who developed KD 1–7 weeks after COVID-19 infection could rapidly initiate, resulting in excessive consumption of CD4 and CD3, as well as excessive production of IL-6, TNF-α, and IFN-γ. The naturally occurring anti-cytokine antibodies in IVIG may not be sufficient to completely block the excessive cytokines, leading to an increased proportion of IVIG non-responders.
Most children are asymptomatic or exhibit mild symptoms from COVID-19 infection. However, in rare cases, MIS-C in children may occur 1–2 months after infection. The clinical manifestations of MIS-C overlap with KD, including fever, rash, conjunctivitis, and skin mucosa manifestations8, but the incidence rate of conjunctivitis is lower27. MIS-C is more common in older children and is associated with left ventricular dysfunction and shock, gastrointestinal abnormalities, and neurological manifestations compared to KD15,28. In laboratory tests, compared to KD patients, MIS-C patients had lower levels of lymphocyte counts, platelet counts, erythrocyte sedimentation rate (ESR), alanine aminotransferase and albumin and higher levels of aspartate aminotransferase, BNP, C-reactive protein (CRP), D-dimer, fibrinogen, ferritin, and creatinine27. Patients with MIS-C have a higher utilization rate of glucocorticoids and a lower utilization rate of IVIG, with a similar incidence of CAL27. Low levels of CD4+ and CD8+ cells in acute-phase peripheral blood were observed29 and the results of this study were consistent with the previous report. Previous research has demonstrated that the effects of IVIG on T cells were limited30. Moreover, higher levels of these cells are associated with a higher likelihood of IVIG resistance31. Based on the results of the previous studies, MIS-C cases might have been included in this study. To exclude the potential impact of MIS-C on the results of this study, we excluded a total of 27 suspected MIS-C cases based on the diagnostic criteria from the Centers for Disease Control and Prevention5. We found that the main outcomes (the proportion of IVIG-resistance and corticosteroid use) remained unchanged. It is noteworthy that these 27 suspected MIS-C cases generally had mild symptoms, with only 2 cases requiring ICU treatment due to shock.
A few studies have reported changes in KD after COVID-19. It was found that compared with the same period before the COVID-19 pandemic, the hospitalization rate of KD during the COVID-19 pandemic was similar to that in previous years, but the age of onset was lower. The incidence of rashes in COVID-19-positive patients was significantly higher, and coronary artery involvement was more common in COVID-19-negative patients32. In a Korean children’s hospital during the SARS-CoV-2 pandemic, patients with KD after COVID-19 infections showed a stronger inflammatory response than those without COVID-19 infections, and there was no difference in cardiac complications33. Our findings align with those previously presented. The incidence of IVIG resistance in KD was elevated following COVID-19, yet the likelihood of CAL had not been demonstrated to increase.
For high-risk IVIG-Resistant children, such as infants and those with high inflammatory markers, early use of corticosteroids is advocated. Jessica Green et al.34 analyzed pooled data from eight studies on corticosteroid therapy for KD and found that compared with not using corticosteroids in the acute phase of KD in children, using corticosteroids can reduce the incidence of coronary aneurysm, shorten the time for CRP and ESR normalization, shorten hospital stay, and shorten the duration of clinical symptoms such as fever and rash. At the same time, there is no evidence to show that corticosteroids can cause adverse reactions or increase mortality. Compared with unused corticosteroids, first-line corticosteroid therapy is more effective in reducing coronary artery abnormalities, but this effect is not significant in the second-line treatment subgroup34. The MIS-C treatment guidelines recommend that if a strong inflammatory response is expected, steroids should be started as early as possible35. Although it has been reported that the purple eyelid sign is a useful finding for differentiating between MIS-C and KD36, early differentiation between MIS-C and KD remains challenging in pediatric patients presenting with typical KD manifestations following COVID-19 infection. Da Eun Roh33 found that in patients with KD after COVID-19, the number of patients requiring additional treatment within 24 h after IVIG administration was high, suggesting that corticosteroid therapy should be started earlier in such patients; that is, if fever does not subside or shock signs appear during hospitalization within 24 h after IVIG treatment, high-dose methylprednisolone therapy should be initiated. We found that the risk of IVIG resistance was significantly increased in children with KD who developed within 1–7 weeks after COVID-19 infection, and the corticosteroid use rate was significantly increased, suggesting that early corticosteroid application may be needed for these children.
This study has some limitations. This is a retrospective study and is limited by its single-center design and relatively small sample size, which may introduce regional and ethnic biases, so the results may not be generalizable to other populations. The children in this study were basically infected with COVID-19 for the first time, and whether the children who were infected with COVID-19 again had similar symptoms needs further observation. There is a possibility of information bias because the method for confirming COVID-19 infection includes interviews with family members.
In summary, it seems likely that the ongoing presence of COVID-19 in the human population will persist for an extended period. In the case of KD, it is of paramount importance to ascertain whether the children in question have been infected with the virus recently. The risk of IVIG resistance in children with KD onset 1–7 weeks after COVID-19 infection increased significantly, which may be related to the long-term impact of COVID-19 on immunity. Early use of corticosteroids may benefit these children, but further clinical trials are still needed for confirmation.
Methods
Inclusion criteria
The children diagnosed with KD who were hospitalized in Children’s Hospital, Zhejiang University School of Medicine from November 1, 2022, to March 30, 2023, were enrolled retrospectively, and the children were subjected to control analysis in combination with medical records, laboratory results and echocardiography tests.
Diagnostic criteria for KD: complete KD37: at least 5 of the following 6 main clinical characteristics: (1) fever; (2) bilateral bulbar conjunctival injection; (2) changes in the lips and oral cavity: reddening of lips, strawberry tongue, diffuse injection of oral and pharyngeal mucosae; (3) rash (including redness at the site of BCG inoculation); (4) changes in the peripheral extremities: (Initial stage) reddening of palms and soles, edema; (Convalescent stage) periungual desquamation; (5) nonsuppurative cervical lymphadenopathy. Incomplete KD: Children with fever for ≥ 5 days and 2–3 clinical criteria, or infants with fever for ≥ 7 days without other explanation were evaluated for incomplete KD according to the process outlined in the 2017 American Heart Association Scientific Statement38: Laboratory tests will be assessed for these children. If the CRP level is below 30 mg/L and the ESR level is below 40 mm/hr, KD will not be considered temporarily. If fever persist, serial clinical and laboratory indexes will be re-evaluated. If typical peeling occurs, an echocardiogram will be performed. If CRP ≥ 30 mg/L and/or ESR ≥ 40 mm/hr, and one of the following criteria is met, incomplete KD will be diagnosed and treatment will be given: 3 or more laboratory finding are met: anemia for age, platelet count of ≥ 450,000 after 7 days of fever, albumin ≤ 30 g/L, elevated ALT level, WBC count ≥ 15,000/mm3, urine ≥ 10 WBC/HPF; or echocardiography is positive. For the purposes of this algorithm, echocardiography is considered positive if any of the following three conditions are met: a Z score of left anterior descending coronary artery or right coronary artery ≥ 2.5, the observation of a coronary artery aneurysm, or the presence of ≥ 3 other suggestive features, including decreased left ventricular function, mitral regurgitation, pericardial effusion, or Z scores in left anterior descending coronary artery or right coronary artery of 2 to 2.5.
Once the KD diagnostic criteria were met, IVIG (2 g/kg) and moderate-dose aspirin (30–50 mg/kg/d) were administered to the child. When aspirin was not appropriate, clopidogrel (0.2-1 mg/kg/d) was selected as a substitute for aspirin. Intravenous immunoglobulin (IVIG) resistance38 was defined as a body temperature of greater than 38 °C at least 36 h after the first IVIG infusion or a fever again within 2 weeks (mostly 2–7 days) after drug use, and there was at least one main clinical manifestation of KD after other possible causes of fever were excluded. CAL were based on echocardiographic measurements of intravascular diameter adjusted for body surface area, and a Z score greater than 2.5 was considered abnormal37,38. As of the writing of this article, all children have been followed up for more than six months.
According to the Centers for Disease Control and Prevention diagnostic criteria, hospitalized children who were positive for current or recent SARS-CoV-2 infection, with fever, laboratory evidence of inflammation, multisystem (≥ 2) organ involvement and no alternative plausible diagnoses were defined as MIS-C5.
Exclusion criteria
Children with comorbid other infections or without regular treatment outside the hospital (for example, methylprednisolone was used before IVIG) were excluded.
Methodology
The clinical characteristics (sex, age, clinical manifestations, inflammatory indices, immunologic function, myocardial injury markers, treatment, complications and echocardiographic data) were collected through medical records. Evidence of COVID-19 infection was obtained through medical records or telephone interviews with parents. The following conditions were considered COVID-19 infection: (1) positive nucleic acid test of SARS-CoV-2; (2) fever with a positive antigen test, and at least one household member was diagnosed with COVID-19 infection simultaneously. The time from COVID-19 infection to KD was the interval from the first day of COVID-19 infection to the onset of KD. Based on the time from COVID-19 infection to KD, cases were divided into three groups: noninfected with COVID-19 group, 1–7 weeks after COVID-19 infection group, and more than 7 weeks after COVID-19 infection group. The primary outcome was the proportion of IVIG resistance, and the secondary outcomes were the incidence of CAL and the length of hospital stay. Additionally, immune changes in KD patients before and after COVID-19 infection were analyzed by comparing immunoglobulin, CD molecules, complement, and Th1/Th2 cytokine profiles.
Statistical methods
The quantitative data were evaluated using the one-sample Kolmogorov–Smirnov test to determine whether they followed a normal distribution. The measurement data conforming to a normal distribution are presented as the mean ± standard deviation (SD), and independent sample t tests were used for hypothesis testing. The measurement data that did not follow a normal distribution are represented as the median [interquartile range], and nonparametric tests (Mann–Whitney U test) were used for hypothesis testing. Counting data were represented as the number of children and percentage (%), and chi-square tests were used for hypothesis testing. To analyze binary and categorical outcomes, logistic and ordinal logistic regression models were used. Statistical analysis was performed using SPSS 23.0 software. A two-sided P value < 0.05 was considered statistically significant.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Author contributions
L.G., Z.X., Y.W. and F.G. conceived and designed the project; J.H., Q.Z., S.F., W.W., C.X. and Y.Z. collected the data; L.G. and Z.X. drafted the paper. L.G., Z.X., J.H., Q.Z., S.F., W.W., C.X., Y.Z., Y.W. and F.G. revised the paper, supervised the analyses, and suggested revisions of the paper. All the authors have read and approved the final manuscript.
Funding
This work was supported, in part, by grants from The National Natural Science Foundation of China (No. 81970434) and Key R&D Program of Zhejiang (2024C03179).
Data availability
Anonymized research data are available from the corresponding author upon reasonable request.
Declarations
Competing interests
The authors declare no competing interests.
Ethics declarations
This retrospective study involving human participants was in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The medical ethics committee of the Children’s Hospital of Zhejiang University School of Medicine approved this study (NO.: 2023-IRB-0256-P-01). Since the information was anonymized and the submission did not include images that may identify the person, The medical ethics committee of the Children’s Hospital of Zhejiang University School of Medicine waived the need of obtaining individual informed consent forms.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Lichao Gao and Zhufei Xu contributed equally to this work and share first authorship.
Contributor Information
Yujia Wang, Email: wangyujia@zju.edu.cn.
Fangqi Gong, Email: gongfangqi@zju.edu.cn.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
Anonymized research data are available from the corresponding author upon reasonable request.