Blood routine risk factors for coronary artery aneurysm in infants younger than 8 months with Kawasaki disease

Kawasaki disease (KD) is an acute systemic vasculitis of unknown cause that preferentially affects the coronary artery [1]. The most frequent age at onset of KD ranges from 9 to 11 months, and an onset age younger than 6 months is relatively infrequent [2]. Infants, especially those younger than 6 months, are also reported to have a higher prevalence of incomplete KD, coronary artery aneurysms (CAAs) and adverse cardiac events [3‐6]. Acute KD patients at high risk for the development of CAA may benefit from primary therapy with IVIG and adjunctive anti-inflammatory medications, as outlined by the 2017 AHA guidelines [1]. Therefore, early identification of infants with KD at high risk of CAA and the provision of timely primary treatment with adjunctive therapies are very important to improve the prognosis of infants with KD. It has been reported that peripheral blood cell parameters are not only helpful to diagnose incomplete KD but also indicators of the risk of CAA among KD patients [1, 5]. However, the dynamic change of these laboratory values in infants with KD during the acute phase has rarely been reported. The aims of this study were to characterize the dynamic change of laboratory values within the first 10 days of illness and the coronary artery outcome in infants younger than 8 months with KD, and to describe the use of laboratory data to identify risk factors for coronary aneurysms in this population.

We retrospectively enrolled 78 consecutive infants younger than 8 months and 86 patients between 8 months and 7 years who were treated for KD and received intravenous immunoglobulin (IVIG) (2 g/kg × 1 day or 1 g/kg × 2 days) therapy within the first 10 days of illness at Children’s Hospital, Capital Institute of Pediatrics. Seventy patients were treated at the Department of Critical Care Medicine between October 1, 2015 and December 31, 2020, while the remaining patients were treated at the Department of Rheumatology between March 1, 2019 and December 31, 2020. Patients with congenital heart disease and patients with incomplete data were excluded from the study. We collected clinical data, including age, illness day at diagnosis (illness day 1 = first day of fever), response to IVIG therapy, complete blood count (white blood cell [WBC] count, percentage neutrophils, percentage lymphocytes, neutrophil to lymphocyte ratio [NLR], hemoglobin, platelet count), plasma concentrations of C-reactive protein (CRP) and coronary artery status. Complete blood count and CRP were collected and analyzed at 2 time points: 1st day (illness days 1–2) and 5th day (illness days 4–6). For patients with multiple laboratory values within a time interval, only the laboratory values on the 1st and 5th days of illness were analyzed. The maximal laboratory value, defined as the highest complete blood count and CRP values at any time point during the first 10 days after fever onset, was also analyzed.

Complete KD was defined as fever ≥5 days and ≥ 4 of the following clinical signs: Bilateral conjunctival injection, polymorphous skin rash, changes in the lips or oral mucosa, changes (edema/redness/peeling) of the extremities, and unilateral cervical lymphadenopathy. Patients with fever ≥5 days plus < 4 criteria with or without echocardiogram abnormalities were classified as having incomplete KD. IVIG resistance was defined as recrudescent or persistent fever at least 36 h after completion of the first IVIG infusion [1]. IVIG-resistant patients were given additional IVIG doses and steroids.

Echocardiography was performed at the time of initial diagnosis and at 1–2 weeks, 3–4 weeks and 6–8 weeks after KD onset. In addition, patients with coronary artery damage underwent echocardiograms every one to 3 months depending on the severity of CAA. Patients were classified as having normal (< 2.5 standard deviations [Z-score] from the mean, normalized for body surface area) or aneurysmal (Z ≥ 2.5) coronary arteries on the basis of the maximal internal diameters of the following segments measured by echocardiography during the first 6 weeks after fever onset: Left main coronary artery, proximal and distal left anterior descending artery (LAD), left circumflex, and right coronary artery (RCA) (proximal, middle, and distal). The Z-max was defined as the largest Z-score for any coronary artery segment on each echocardiogram at any time point during the first 6 weeks after fever onset. Persistent CAA was defined as a Z-score of ≥2.5 for the maximal internal diameters of the proximal LAD and proximal RCA on echocardiograms at 12 months after KD onset. CAA regression was defined as a Z-score < 2.5 on echocardiograms during the follow-up period. Z-scores were calculated using the Dallaire equations (https://​www.​pedz.​de/​en/​welcome.​html) [7]. The study was approved by the regional ethics committee.

The data of this study showed that 37.2% of infants younger than 8 months had incomplete KD, 47.4% of these infants had CAA, and 9.0% had persistent CAA at 1 year after KD onset. Consistent with the results described in this study, Salgado et al. [4] found that infants < 6 months old with acute KD are more likely to present with incomplete KD and develop CAA despite timely treatment with IVIG within the first 10 days. As KD is a form of systemic vasculitis, it may lead to dynamic changes in peripheral blood cells, characterized by an elevated WBC count, percentage neutrophils, platelet count, and anemia over time [8]. As CAA most often occurs within 8 days after the onset of fever [9], we focused on the dynamic nature of peripheral blood cells over 10 days and found that WBC, percentage neutrophils, platelet count and hemoglobin peaked on different days after KD onset, suggesting that peripheral blood cell parameters played significantly different roles in the dynamic process of KD inflammation. Further, we also found that peak percentage neutrophils was significantly associated with the risk of CAA in infants younger than 8 months, which was not suitable for patients ≥8 months old. Last, another finding was that hemoglobin on the 5th day was closely related to persistent CAA.

These data showed that the median peaks of WBC and percentage neutrophils were at 3–5 days of illness onset. Furthermore, the peak percentage neutrophils was an independent predictor of CAA. Previous studies showed that the number of circulating functionally activated neutrophils increased and produced excessive reactive oxygen species and elastase, which may contribute to the formation of coronary artery lesions in patients with KD during the acute phase [10, 11]. Takahashi et al. [12] also reported that numerous neutrophils were identified in the coronary artery lesions of patients who died 10 days after KD onset, and these high numbers of neutrophils were involved in the initial damage to the coronary artery during the acute phase of KD. Ha et al. [13] reported that KD patients with CAA had a higher acute NLR than patients without CAA, and we also found a significant difference in the peak NLR between infants younger than 8 months with and without CAA in this study. Therefore, the domination of leukocytes by neutrophils plays an important role during the early stage of KD and is significantly associated with the risk of CAA.

In this study, the platelet count peaked within 8–10 days of illness and had independent predictive value for CAA. This was consistent with the findings of Ueno et al. [14], who reported that platelet-neutrophil aggregates were significantly associated with pathological developments of CAA in KD. During the acute phase of KD, coronary artery injury leads to increased platelet activation and an increase in platelet-neutrophil aggregates, resulting in amplified vascular inflammation and tissue injury. Prednisolone could inhibit platelet-neutrophil aggregate-induced amplified vascular inflammatory activation [14, 15]. Therefore, platelets had an important effect on coronary vascular inflammation after initial neutrophil infiltration, especially on illness days 8–10, and were predictive of CAA development.

Another significant finding in our study was that the median illness day of the lowest hemoglobin level was 7 and that hemoglobin on the 5th day was closely related to persistent CAA at 1 year after KD onset. Kosaka et al. [16] also found that lower acute age-adjusted hemoglobin levels were correlated with the risk of coronary dilation in patients with incomplete KD. Tremoulet et al. [8] revealed that anemia was normocytically normochromic and resolved spontaneously over a period of 6 weeks. Previous studies demonstrated that anemia of inflammation caused by iron sequestration and impaired erythropoiesis in the setting of acute or chronic inflammation was an independent predictor of increased mortality in critically ill patients [17‐19]. Hence, the lower the hemoglobin level is in the acute phase of KD, the more severe the coronary artery damage will be. Hemoglobin during the acute phase, especially on the 5th day, can be used for risk stratification in infants with KD.

There are some limitations to our study. This was a single-center retrospective study. Therefore, further multicenter studies with adequate sample sizes are warranted to assess the generalizability of these findings. In addition, we analyzed only blood cell counts and CRP as other laboratory values were not available for all 2 selected time points. Nevertheless, the laboratory markers we analyzed in this study are the most readily available and inexpensive parameters. Last, the acute phase treatment was not standardized, and the coronary Z-score was not based on the normal value for Chinese children.

In conclusion, incomplete KD and CAA occurred frequently in infants. Peak percentage neutrophils within 2–5 days of illness and peak platelet count within 8–10 days of illness were significantly associated with the risk of CAA. Hemoglobin within 4–6 days was associated with persistent CAA and may be used as a predictor of persistent CAA due to KD in infants. For infants with high peak percentage neutrophils within 2–5 days of illness, the use of steroids, cyclosporine, or infliximab in combination with initial IVIG should be considered in the early stages of KD.