KD, also called mucocutaneous lymph node syndrome, is one of the most common vasculitides in children. Typically, this self-limited condition manifests as fever and acute inflammation that last for an average of 12 days without therapy. High doses IVIG have shown efficacy in suppressing inflammation and reducing prevalence of coronary artery abnormalities when administered during early stages of KD development. In the present study, about 1.6% of children with KD still exhibited fever even after two IVIG treatments, which was lower than the 3–4% reported in previous studies . These children are at a high risk of developing coronary artery disease and long-term sequelae [13–15]. Previous studies have shown that the main risk factors for KD coronary artery disease are C-reactive protein, duration of fever and time course of gamma globulin use. The present group patients had a high incidence of coronary artery disease ( 69.05%) with about 90.48% of the children diagnosed with complete KD. Notably, the patients exhibited no response to IVIG treatment, while their fever lasted as long as 14.8 ± 4.0 days. Laboratory test data revealed that they had elevated levels of white blood cells, C-reactive protein, and erythrocyte sedimentation rate, suggesting that children with refractory KD not only have severe inflammatory reactions, but also exhibited thrombocytosis, hypoalbuminemia, and anemia. In this group of patients, disease onset mainly occurres within 12 months, which is consistent with previous reports that found 12 months to be the peak age of KD development.
At present, no unified standard for treatment of refractory KD has been developed. In fact, the choice of medicine is based on efficacious drugs against other vasculitis, including glucocorticoids, TNF inhibitors, other immunosuppressants, and plasma exchange. The use of glucocorticoids for treatment of Kawasaki disease remains controversial, although they are generally used as a remedy for IVIG resistance. Functionally glucocorticoids suppress KD-induced inflammations by inhibiting production of inflammatory mediators, inhibiting migration of white blood cells and reducing capillary permeability. To date, several glucocorticoid treatment options for children with refractory KD have been suggested, including high-dose methylprednisolone sodium succinate (30 mg/kg.d) intravenous pulse therapy for up to 3 days. In Japan, intravenous or oral administration of prednisolone (1–2 mg/kg.d) for at least 15 days has been reported. Numerous studies have reported the use of infliximab for treatment of refractory KD. Songet al. reported continuous and recurrent fever in 16 cases of children diagnosed with refractory KD, within 36 hours following after 2 sessions of adequate IVIG treatment. Notably, 15 of the cases developed coronary Arterial disease. However the authors observed that temperature of 13 children returned to normal after treatment with infliximab. Follow-up echocardiographic observation revealed no damage to the dilated coronary arteries. In the present study, 34 children were treated with medium-dose methylprednisolone sodium succinate, and found to have excellent therapeutic effect. Previous case reports have demonstrated that cyclosporine, cyclophosphamide and methotrexate are efficacious in treating KD, although high-dose sample data is lacking. These drugs were not used in this study.
During our short-term follow-up of the children, we found that their body temperature returned to normal after treatment with salvage drugs. Notably, only about 30.95 and 26.19% of the inflammatory indicators, such as white blood cells and rapid C-reactive protein, returned to normal levels in the acute phase, suggesting that these inflammatory indicators have potential in predicting disease severity as well as efficacy of IVIG[21,22]. White blood cells and rapid C-reactive protein are expected to significantly reduce after acute treatment in children with KD. However, in this group of studies, not many children recover to normal in a short period of time. Considering that their children have severe inflammation, their recovery time is longer. In present study, 10 cases (23.81%) of the coronary artery diameter returned to normal during the 6-month follow-up period, while coronary aneurysms took longer to recover compared to coronary artery dilation.
In summary, there is no unified diagnostic criteria and treatment plan for children with refractory KD. For patients that still experience fever after two IVIG treatments, clinicians needs to consider the possibility of this type of KD. Development of an effective treatment plan is imperative to shortening fever time and prevention of progressive aggravation of coronary artery disease. Longer follow-up observation is also needed for this group of patients with coronary artery outcomes.