Kawasaki Disease: Laboratory Findings and an Immunopathogenesis on the Premise of a ""Protein Homeostasis System

Lee, Kyung-Yil; Rhim, Jung-Woo; Kang, Jin-Han

For understanding the pathogenesis of KD, a brief review of resembling diseases may be helpful. Among bacterial infections, scarlet fever/acute rheumatic fever (ARF) may be a representative disease resembling KD. Clinical manifestations of scarlet fever, etiologic agents of which are mainly the group A beta-hemolytic streptococci (GAS), are fever, with fibrinogen levels. 70 In addition, IVIG has a systemic protein modulation effect in vivo; all proteins including albumin, transferrin, apolipoprotein A1, and pro-inflammatory cytokine (TNF-α and IL-6) levels were transiently decreased, but the levels of immunoglobulins (IgA and IgM), electrolytes (sodium, potassium, chloride, calcium and phosphorus) and serum osmolarity were not changed by IVIG infusion. [70] [71] [72] Therefore, the beneficial effect of IVIG on KD may, in part, be associated with the control of the proteins which are involved in inflammation in various tissues of the host, although IVIG has multiple modes of action for immune modulation. 11, 73 On the other hand, IVIG non-responders generally have persistently elevated inflammatory parameters, such as neutrophil counts and CRP and lower levels of albumin after IVIG infusion. 59, 74 We recently observed that IVIG non-responders have sustained abnormal laboratory parameters following IVIG (within 24 hrs) as well as prior to IVIG compared to IVIG responders; the cut-off values of >13000/μL for total WBC count, >51% for neutrophil differential and <7.2 g/dL for total protein had reasonable sensitivity (91%, 91% and 64%, respectively) and specificity (89%, 76% and 78%, respectively) as independent characteristics of non-response to IVIG. 75 In addition, the kinetics of some inflammatory parameters following IVIG differed markedly between responders and non-responders. Among them, WBC count and CRP in non-responders increased or remained unchanged following initial IVIG infusion (2 g/kg), in contrast to the marked decline in these parameters in responders. Thus, clinicians can use these parameters easily and rapidly for the evaluation of the severity of inflammation in KD. The definition of IVIG non-responsiveness and the treatment modality for initial IVIG non-responders are not clearly determined among the study groups. Many study groups have observed the patients for 36-48 h after termination of IVIG infusion to see whether or not the patients showed defervescence and improvement of clinical signs. The non-responders also consisted of patients with a different severity of inflammation. It was reported that 20-50% of initial IVIG non-responders also did not respond to a second dose of IVIG. 76, 77 For these severely affected patients, rapid treatment may lead to a better outcome, because of the possibility of rapid progression of CALs in the early stage of the disease. In our hospital, we defined IVIG nonresponders as patients with persistent fever (≥38.0°C) over 24 hrs after termination of IVIG infusion. Our treatment modality for IVIG non-responders is the 2-dose IVIG infusion sis of KD is closer to that of ARF than scarlet fever. In addition, the causes of death in both acute KD and ARF are extensive carditis or complications from distorted cardiac vessels or cardiac valves. There are also rare incidences of a sepsis-like syndrome with multiple organ failure and the fulminating clinical course, which are shown in severely affected patients of GAS infections or any acute infectious diseases, including viral infections. The