The present study supports the possibility that outcomes are favorable in cases where plasma exchange is used to treat Kawasaki disease when coronary artery lesions have developed and the course is unresponsive to IVIG therapy. Moreover, we showed that plasma exchange could be safely performed in children with this disease.
Recent reports have shown the effectiveness of plasma exchange in patients with IVIG-unresponsive Kawasaki disease [6, 8]. According to one report, plasma exchange therapy reduced the incidence of coronary artery lesions in Kawasaki disease to < 1% [8]. Hokosaki et al. described that there were no sequelae when plasma exchange was initiated before the beginning of coronary artery dilatation. However, when dilatation had already begun before the therapy, about 30% (6/20) patients showed persistent sequelae. Further, the size of aneurysms increased in all patients in whom sequelae remained and developed into giant aneurysms in five of the six patients in the late period (≧1 year after onset) [7]. However, despite starting plasma exchange after the beginning of coronary artery expansion, we demonstrated that plasma exchange could improve the size of coronary artery lesions in almost all of the patients. For example, after plasma exchange, coronary artery lesions regressed to within normal limits in six of the ten patients and improved in another two patients. This is consistent with a previous case report that plasma exchange therapy significantly improved coronary artery lesions [10]. Furthermore, the aneurysms did not develop into giant aneurysms even in more than 1 year after onset in all of our patients. The period of until the start of the plasma exchange after onset was 13.7 ± 5.7 days in our study, whereas 8.1 ± 1.9 days reported by Hokosaki et al. [7]. Though plasma exchange was started late, coronary artery lesions regressed in almost all of our patients. In addition, there were no stenosis of the coronary artery. Therefore, plasma exchange may be effective not only in treating coronary artery lesions but also in preventing sequelae in patients with IVIG-unresponsive disease when plasma exchange performed after coronary artery dilatation.
In this study, one patient died due to a ruptured giant coronary aneurysm (patient 9), and another patient showed progression to a giant aneurysm (patient 1). In Japan, approximately 0.3–0.4% of patients are reported to develop giant coronary aneurysms [11, 12], and their formation is one of the most important factors affecting the prognosis of Kawasaki disease. Giant coronary aneurysms pose the greatest risk of thrombosis and stenosis (myocardial infarction). However, there is only a slight risk of rupture, and the incidence of rupture as a cause of death is very low compared with either myocardial infarction or myocarditis. There have been very few reports of ruptures of giant coronary aneurysms due to Kawasaki disease, although whenever reported, these were fatal [13]. Unfortunately, patient 9 died owing to a ruptured giant coronary aneurysm. Although plasma exchange basically should be indicated to IVIG-resistant patients, this patient had received IVIG and plasma exchange on the same day. Unstable circulation and anticoagulant associated with plasma exchange might influence the rupture of the aneurysm. In addition, it has been reported that the use of corticosteroids in the acute phase of Kawasaki disease for patients with evolving coronary artery aneurysms might be associated with worsening involvement and impaired vascular remodeling [14]. Therefore, plasma exchange and the use of corticosteroids may have serious concerns in some situation.
Recently, the age less than 1 year has been reported to be a significant risk factor for giant coronary aneurysms [15, 16], with increased likelihoods also associated with age more than 5 years, especially in males [16]. In the present study, two cases of giant coronary aneurysms occurred in patients younger than 1 year. In addition, patient 3 was male and younger than 1 year, while patient 10 was older than 5 years and male. Therefore, both age and sex appear to be important for the management of Kawasaki disease and should be considered when stratifying the risk of developing coronary aneurysms.
When plasma exchange was started before coronary artery dilatation began, there were no sequelae [7]. Hokosaki et al. also found that the outcome of plasma exchange was better when plasma exchange started before day 9 after onset [7]. In the present study, two cases of giant coronary aneurysms were treated after more than 20 days had passed since the disease onset. These results are compatible with the view that plasma exchange should be started as early as possible, before coronary artery dilatation has started.
The pathogenesis of coronary artery aneurysm formation in Kawasaki disease remains unknown. It has been reported that elevations in proinflammatory cytokines, such as interleukin (IL)-6, tumor necrosis factor (TNF)-α, and IL-1β, are closely related to the pathogenesis of Kawasaki disease [17,18,19]. Fujimura et al. reported that IL-6, TNF-α (including TNF receptors 1 and 2), granulocyte colony-stimulating factor, and IL-17 were significantly decreased after plasma exchange treatment [20]. In particular, TNF-α has been shown to be necessary for the development of coronary artery lesions in Kawasaki disease [21]. Although we did not measure TNF-α in these patients, we did show that serum C-reactive protein levels and fever both improved rapidly after the initiation of plasma exchange treatment. Therefore, we speculate that the effect of plasma exchange might be related to the removal of these cytokines.
Adverse effects associated with plasma exchange, such as hypotension, bleeding, allergy, and infection, have been reported [22]. Although complications occurred in some patients, they were treatable and plasma exchange could be continued. Moreover, there were no deaths attributable to plasma exchange therapy. These findings indicate that plasma exchange is a safe treatment modality in children.
These results should, however, be considered in the context of the study’s limitations. Notably, it had a small sample size and was not performed as a controlled clinical trial. We also did not compare plasma exchange with other therapies like infliximab, and the initial IVIG doses and timings may have differed from those used in other hospitals. A further clinical study that takes these issues into account might be needed.