A CAA is the most important complication of KD. CAAs develop in 15%–25% of untreated patients; this rate decreases to 5% with treatment within the first 10 days.[3]
Early diagnosis and treatment is very important because it directly affects mortality. To provide early intervention for CALs caused by KD, we analyzed the clinical characteristics of typical and incomplete KD patients. In this study there was no significant difference between the frequency of clinical findings in patients diagnosed with typical and atypical KD. The most common findings in both groups were mucosal involvement in the mouth, polymorphic exanthema, and non-exudative conjunctive injection. The most common clinical finding (80%) in some studies was non-exudative conjunctive injection followed by polymorphic exanthema and mucosal involvement in the mouth.[7] Asian patients with changes in the oral mucosa, cervical lymphadenopathy, swelling of the extremities, and polymorphous rashes were more likely to be IVIG-resistant, but in non-Asian patients there was no significant difference among these symptoms and IVIG resistance.[17] In the population in our study, we did not note any significant difference between IVIG resistance and the risk of developing coronary lesions and clinical findings.
The prevalence of coronary artery abnormalities in a clinical trial of initial treatment was 23% 4 weeks after enrollment, which reduced to 8% with 4 infusions of low-dose IVIG. In a subsequent trial of single high-dose IVIG, this was further reduced to approximately 4%.[8,9] In our study, CAAs were detected in 11.6% of patients. There is no conclusive data regarding the incidence of the disease and complications due to the lack of large-scale research in South Korea with a sufficient number of cases. Several different risk scores are used to predict IVIG resistance and CALs. Shin et al.[10] reported that among the risk scoring systems, the Kobayashi risk score demonstrated significant differences between IVIG resistance and responder groups in Korean patients with KD.
Many researchers have scrutinized the clinical data and laboratory parameters at onset predicting the risk of CAA.[11,12] Risk factors for CAA are duration of fever > 2 weeks, platelet count, increased acute phase reactants, and age < 5 years.
Demonstration of CALs by echocardiography is important for prognostication. Damage to coronary arteries is a substantial risk for a significant percentage of children with KD, most often for those with resistance to IVIG.
Maximal efforts should be made to visualize all major coronary artery segments. In order of highest-to-lowest frequency of occurrence, typical sites of CAAs include the proximal LAD and proximal RCA, followed by the LMCA, LCx, distal RCA, and the junction between the RCA and posterior descending coronary artery. Enlargement of the LMCA caused by KD does not involve the orifice and rarely occurs without associated dilation of the LAD, the LCx, or both arteries.[2] In our study CALs existed in 45 patients; the RCA alone (20%), the LCA alone (44.5%), and the RCA and LCA were involved together (35.5%). The LMCA affected 20 patients, the LAD affected nine patients, the LCx affected two patients, and LAD and LCx together affected two patients. IVIG resistance was more common in infants and the hospitalization times were longer in this group. The coronary involvement rate in our patients was 17.3%. This rate was 12.8% in the IVIG-responsive group and 50% in the IVIG-resistant group.
KD has no specific diagnostic laboratory markers. Recent studies have investigated factors for predicting resistance to IVIG and CALs. These data include the duration of fever, polymorphonuclear neutrophil (PMN) cell count, hemoglobin level, platelet count, and CRP, transaminase, total bilirubin, and NT-proBNP, albumin, and sodium levels.[13] In our study, when the laboratory findings of the group in which coronary artery aneurysms were detected in KD, the leukocyte and platelet counts, and CRP, troponin T, and NT-proBNP levels were significantly increased and the albumin level was decreased.
Several previous studies demonstrated that a higher PMN percentage, and NT-proBNP, total bilirubin, CRP, aspartate aminotransferase, and alanine aminotransferase levels were considered predictive factors for patients with KD resistance to IVIG treatment.[13-16]
In our study a statistically significant decrease in the sodium level was observed in IVIG-resistant patients. The cause of hyponatremia is still unknown in patients with KD. Lim et al.[17] found that there was a strong negative correlation between the level of serum sodium and inflammatory factors, including CRP and interleukin-6 (IL-6) in children with KD. The most probable pathophysiologic mechanism underlying hyponatremia is non-osmotic secretion of antidiuretic hormone (ADH). Several studies have confirmed that the release of ADH is promoted by IL-6 and tumor necrosis factor-α (TNF-α) during inflammation.[18] IL-6, TNF-α, and other cytokines participate in inflammation among KD patients in the acute phase,[19] suggesting that hyponatremia may be associated with inappropriate release of ADH. The marked increase in plasma IL-6 and TNF-α in IVIG-resistant infants compared with IVIG-responsive patients[20,21] may explain the significant hyponatremia in IVIG non-responders. In our study it was observed that hyponatremia and hypoalbuminemia were correlated with an increase in acute phase reactants in IVIG-resistant patients. In addition to KD, studies involving patients with inflammatory diseases, such as pneumonia, urinary tract infections, and lupus erythematosus, also demonstrated that hyponatremia is an important marker for severity and prognosis.[22,23] The mechanisms underlying hypoalbuminemia consist of the following: increased vascular permeability leading to leakage of albumin,[24,25] liver dysfunction resulting in decreased albumin synthesis; and a lack of essential amino acids due to low nutrient intake or malnutrition, resulting in reduced albumin synthesis.[26]
In our study thyrombocytosis was detected in patients with CAL and IVIG resistance. This increase was statistically significant in CAL patients. Although some studies recognized both thrombocytopenia and significant thrombocytosis as predictors of CAA or IVIG resistance; however, the majority of studies showed no association.[27,28] The mechanism underlying thrombocytosis is unclear. It has been suggested that the elevated thrombopoietin level caused by acute inflammatory responses can lead to thrombocytopoiesis.[29]
In our study IVIG resistance was detected in 12.4% of the patients. When the group developing coronary artery aneurysms was examined, we found that aneurysms developed more frequently in < 1 year and the risk of developing IVIG resistance and length of hospital stay were significantly increased. Several studies have reported that the frequency of developing CAA increases in < 1 year and > 5 years.[5,6] Based on a meta-analysis, when patients who were IVIG-resistant and -responsive were compared, the hemoglobin level, leukocyte and platelet counts, and ESR were statistically significant.[30] In our study the increased risk of IVIG resistance was shown to be statistically significant, especially in the group < 5 years of age. When the laboratory findings of our IVIG-resistant patients were examined, a significant increase existed in the leukocyte count (marked neutrophil increase), platelet count, and CRP, ALT, troponin T and NT-proBNP levels, while the hematocrit and sodium levels were significantly decreased.
Although IVIG is the established treatment for acute KD,[2,3] in some studies < 10% of patients with KD were resistant to this treatment. Patients resistant to IVIG were at a higher risk of developing CALs than patients responding to IVIG.[15,16]
Considering the frequency of IVIG resistance by age group, a significant increase in risk occurred in infants (p <0.001). In our study the risk of developing IVIG resistance increased as age decreased. Indeed, there are several studies with similar results.[30-33]