As a febrile disease that primarily occurs in children < 5 years old, the pathological mechanism of KD is an immune-mediated systemic vascular inflammatory change. Although self-limited, it has a high incidence of coronary artery damage, generally caused by coronary artery dilatation, stenosis, and even atretic rupture (15). Currently, KD diagnosis is mainly made by doctors according to clinical manifestations, laboratory results, and echocardiography. No specific laboratory tests are available for distinguishing KD from febrile illness. Current diagnostic methods are subjective, but timely diagnosis and treatment for KD is vital for preventing long-term sequela of CAL. Although changes in laboratory indicators are not specific, some indicators are still of great value in differentiating KD. In this study, we used univariate, multivariate logistic regression, ROC curve, and nomogram to establish a novel prediction score system with WBC, CRP, albumin, ALT, and eosinophil, among which eosinophil has the highest weight point for differentiating KD from febrile illness.
In many reports, for KD children during the acute stage, the peripheral blood WBC count significantly increases, as do the plasma levels of CRP, but these changes cannot effectively distinguish KD from other illness with fever of more than 3 days. Some studies have reported that total WBC counts were significantly higher in KD children than that of non-KD febrile illness (maybe most from viral infection) (16). The total WBC of KD is higher than in viral fever children but lower than in bacterial fever children (17). The WBC counts were higher in KD with delayed diagnosis and associated with left ventricular systolic function (16).
Many studies have reported that CRP is significantly increased in KD patients with coronary artery complications (CALs) compared with KD patients without CALs (18). Although the specificity of these two conventional inflammatory indicators (WBC, CRP) is not high enough, they are widely used in clinical practice and have more practical guiding significance for clinical diagnosis in the AHA guidelines for KD (19).
In our report, E% is the highest weighted score for risk factor of KD, making it an important predictor in the novel nomogram prediction model. Elevated eosinophil in KD, which was also found in our previous studies, showed that eosinophilia was associated with IVIG-responsiveness and could prevent CAL formation (6, 20). Some data showed that the eosinophils percentage and absolute eosinophil count were elevated in acute KD and that the percentage of eosinophils continued to rise, peaking in the convalescent phase (21). Some studies have pointed out that the incidence of eosinophilia in the peripheral blood of patients with incomplete KD is significantly higher than that of the KD group. For diagnosing incomplete KD, unexplained eosinophilia may be helpful in suggesting the diagnosis (22). The mechanism of increased eosinophils in KD remains unclear, but eosinophils accumulation in micro vessels and the increase of eosinophils in peripheral blood may be involved in the pathogenesis of KD (23). Altogether, eosinophil may play a protective role or have an anti-inflammatory effect through the T-helper 2 cytokine (IL-4) in KD (6, 24).
In our study, albumin reduction is one of the predictors of the KD diagnostic model, but the mechanism of albumin reduction in KD children is still unclear. Dominguez et al. reported that the plasma levels of albumin were significantly lower in KD children than in febrile controls (25). Decreased albumin levels may be related to increased vascular permeability caused by the acute vascular inflammatory response of KD. Increased vascular permeability can cause the extravasation of endovascular substances, which may possibly be mediated by hormones, nerve innervation, or cytokines (especially il-2, interferon-alpha, and il-6) (26). The degree of decrease in albumin levels can reflect the severity of vascular inflammatory response. A study by Kuo et al. indicated that the lower the albumin level in KD children, the greater the risk of CALs (27).
In this study, increased ALT is also one of the independent predictors differentiating between KD and non-KD febrile illness. Most patients with elevated transaminase had only a mild elevation, less than twice the normal upper limit. ALT elevation is not an important cause of morbidity or mortality in KD patients, but it is a common finding during acute KD. Liver involvement ranges from the mild asymptomatic elevation of liver enzymes to severe cholestatic hepatitis and/or cholecystoid effusion (28). A US study identified ALT > 60 IU/L as a risk factor for IVIG non-responsive KD (29). Studies have indicated that KD patients with abnormally elevated liver enzymes tend to have an increased proportion of CALs (30).
From the literature review, this model is the first prediction model that uses a nomogram to distinguish KD from non-KD febrile illness. Compared with other clinical prediction tools or scoring systems, the nomogram has higher precision and optimal identification characteristics. The nomogram uses continuous scales to calculate the continuous probability of a particular outcome (10). Therefore, the nomogram provides superior personalized risk estimates that can contribute to modern medical decision-making.
This study has certain limitations. First, this is a single retrospective study but not of an entire country or multiple centers and thus may have selection bias. Second, the sample size is relatively small, but the variables of the qualified patients enrolled are complete and correct.