Kawasaki disease (KD) is a vasculitis that particularly affects the coronary arteries. Systemic inflammation plays an important role in KD pathogenesis, but specific disease markers are lacking. Instead, the diagnosis depends on characteristic clinical findings. However, if these findings are not found, laboratory data can be used to support a diagnosis of KD. Because uncontrolled and persistent inflammation promotes poor outcomes such as the development of coronary artery abnormalities (CAAs) as well as intravenous immunoglobulin (IVIG) resistance, biomarkers of inflammation may be useful for diagnosis and prognosis. Leukocytes are the main mediators of inflammation, and changes in their populations reflect the response of the immune system to systemic inflammation. In general, neutrophils are considered a marker of ongoing nonspecific inflammation, while lymphocytes are a marker of the immune regulatory response. The neutrophil-to-lymphocyte ratio (NLR) thus represents the balance between inflammation and immune regulation. The NLR has been reported to be a powerful biomarker of surgical stress, systemic inflammation, and sepsis, as the severity and clinical courses of such conditions correlate with neutrophilia and lymphocytopenia. Moreover, the NLR is believed to be predictive of the severity of coronary artery disease. In patients with KD, the acute febrile phase is associated with normal to elevated leukocyte counts with predominant neutrophils. However, the value of the NLR for predicting outcomes in patients with KD has never been evaluated. The present retrospective cohort study was performed to determine whether the NLR can predict clinical outcomes, namely, CAAs and IVIG resistance, in patients with KD.

Methods

This retrospective cohort study was approved by the institutional review board of Korea University Medical Center. The medical records of all consecutive patients with KD who were treated at the center from January 2008 to December 2013 were reviewed. KD was diagnosed when a patient exhibited ≥5 principal clinical manifestations, including fever >38°C. When the clinical manifestations did not fulfill the diagnostic criteria but other diagnoses could be excluded, incomplete KD was diagnosed if the patient had symptoms that associate frequently with KD and elevated inflammatory indexes. Of the patients with incomplete KD, only those who exhibited typical subacute findings later, such as skin peeling or thrombocytosis, were included in this analysis. Of the patients with complete and incomplete KD who were identified, only those whose total and differential leukocyte counts were measured during the acute febrile phase before IVIG, 2 days after IVIG (regardless of whether defervescence had occurred), and 3 to 4 weeks after defervescence were included in the study ( Figure 1 ). The total and differential leukocyte counts in each blood sample were measured using an automated blood cell counter. The NLR was calculated by dividing the neutrophil count by the lymphocyte count.

Identification of the study cohort. CBC = complete blood count.

All patients were initially treated with IVIG (2 g/kg), and IVIG resistance was defined as persistent or recrudescent fever for >48 hours after IVIG completion. Echocardiography was performed during the acute febrile phase and repeated 3 to 4 and 8 to 10 weeks later. CAAs were diagnosed on the basis of the criteria proposed by the Japanese Kawasaki Disease Research Committee in 1984. Patients who had CAAs at any time, regardless of whether they resolved later, were considered to have CAAs. This CAA group was further subdivided into those who exhibited dilatation and those who exhibited aneurysm.

Statistical analysis was performed using SPSS version 20 (SPSS, Inc., Chicago, Illinois). Data are expressed as mean ± SE or as percentages, as appropriate. The groups were compared in terms of nominal data using chi-square tests and in terms of continuous data using unpaired Student’s t tests. To examine the significance of changes in leukocyte profiles over time within each group, paired Student’s t tests were performed. To assess the ability of the NLR to predict IVIG resistance and CAA development, receiver-operating characteristic curves were constructed, and the most discriminating cut-off values were identified. Variables that showed significant differences between the groups on univariate analysis were tested again by multivariate logistic regression analysis. A p value <0.05 was considered to indicate statistical significance.