Pathogenesis of Kawasaki disease

Abstract

Kawasaki disease (KD) was first described in 1967 by Dr Tomisaku Kawasaki as mucocutaneous lymph node syndrome [1]. The aetiology of this disease remains unknown, and the disease most commonly affects infants and young children. KD is considered a kind of systemic vasculitis syndrome, and it primarily invades the medium-sized muscular arteries. This disease has attracted special interest, because death from this disease is most frequently attributable to ischaemic heart disease in children caused by thrombosed coronary artery aneurysms, secondary to coronary arteritis. The principal symptoms of KD include fever persisting for 5 days or more, bilateral conjunctival congestion, redness of the lips and oral mucosa, polymorphous exanthema, reddening of the palms and soles followed by membranous desquamation, and acute non-purulent cervical lymphadenopathy [2].

In Japan, nationwide surveys have been conducted since 1970. The age distribution at onset of KD shows a peak at 9–11 months, and 70% of all KD occurs in patients younger than 3 years. According to the latest survey, the total number of registered patients is greater than 240 000. The number of KD patients has been increasing and furthermore the incidence of KD in children is increasing due to Japan's low birth rate [3]. In addition, the following were clarified by the surveys: (i) nationwide epidemics have existed three times in the past; (ii) although there has been no nationwide epidemic recently, there is a small epidemic in a limited region and it is moving to the adjoining region; (iii) the number of patients increases in winter and decreases in summer; and (iv) the risk of generation in siblings is significantly higher than that in non-siblings. These findings show that some kinds of infectious agents are involved in the pathogenesis of KD. Rowley et al. observed that immunoglobulin A (IgA) plasma cells infiltrated vasculitis lesions with many monocytes/macrophages and CD8 T lymphocytes in autopsy cases of KD [4]. They hypothesized that a pathogen, probably a virus, which invades via the respiratory or digestive organs is processed by the lymph apparatus in the organ. Local B lymphocytes differentiate into precursors of IgA plasma cells, and then IgA-producing plasma cells reach not only the coronary artery and heart muscle but also various organs throughout the body. They found cytoplasmic inclusion bodies in bronchial epithelium, which react with synthetic antibodies produced by cloning α and κ variable-region genes prevalent in the KD arterial walls [5]. The inclusion bodies in bronchial epithelium could be identified by haematoxylin and eosin staining and observed as an electron-dense non-structured spheroid substance under an electron microscope. Analysis of the structure of this cytoplasmic inclusion body is under way.

Although KD has been reported all over the world, it is most prevalent in Japan and East Asian countries. The incidence in children aged < 5 years is 220/100 000 in Japan and 100 in Korea. The incidence is 10–20 times higher than that of western countries. According to a report from Hawaii, USA the mean rate in Hawaii is 40, but clearly differs by race; 360 for Japanese, 95 for Chinese, 77 for Hawaiians, 56 for Filipino and seven for Caucasians [6]. These data suggest that susceptibility to KD depends more upon racial factors than geographic reasons. In addition, the relative risk for siblings is about 10 times higher and a recent study has revealed that second-generation KD patients exist more often than expected. Identification of genetic factors related to individual susceptibility or different incidence among ethnicities might provide a key to solving the mystery of KD.

Regarding the histopathology of KD, coronary arteritis begins as oedematous dissociation of the tunica media 6–8 days after the onset of KD. On about the 10th day of the disease, lymphocyte and macrophage infiltration into the arterial wall from the luminal and adventitial sides begins, leading immediately to inflammation of all layers of the artery. The inflammation spreads completely around the artery, and the internal elastic lamina, smooth muscle cells of the media and other structural components of the artery undergo intense damage; the artery then begins to dilate. Aneurysms develop on about the 12th day after onset, when the damage is severe. The blood eddies in the aneurysm, making it easy for thrombi to form, and thrombotic occlusion is found in the coronary artery aneurysm of many autopsies of acute-stage KD patients. Arteritis in KD is characterized by proliferative granulomatous inflammation that consists of marked accumulation of monocytes/macrophages, and aberrant activation of those macrophages is thought to be involved in the formation of vascular lesions [7]. However, the lesions in the initial stage of inflammation contain not only macrophages and lymphocytes but also many neutrophils [8]. Inflammatory cell infiltration continues until about the 25th day of the disease, after which the inflammatory cells decrease gradually in number and are almost completely gone by about the 40th day of the disease. Scars from inflammation remain for a long time thereafter.

In acute-phase KD, abnormal activation of immunocompetent cells such as monocytes/macrophages and lymphocytes occurs. These cells synthesize and secrete various inflammatory cytokines and chemokines such as tumor necrosis factor (TNF)-α, interferon (IFN)-γ, interleukin (IL-6) and monocyte chemoattractant protein (MCP)-1, which activate immune cell interactions and also activate the endothelial cells. As a result, adhesion molecules such as ICAM-1 and selectin are expressed in the endothelial cells, and leucocytes adhere firmly to endothelial cells and eventually migrate through the vascular walls. The leucocytes then damage the endothelial cells and smooth muscle cells and cause vasculitis. In addition, it is known that during the acute stage of KD there are increases in various vasoactive substances, including growth factors such as vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF), as well as endothelin and nitric oxide, etc. Those substances induce migration and proliferation of intimal smooth muscle cells and are also involved in increasing vascular permeability and causing coronary artery dilation.

The efficacy of high-dose intravenous immunoglobulin (IVIG) treatment for acute-stage KD patients has become widely recognized [9], and today immunoglobulin is administered to 85% of children with acute-stage KD. IVIG has drastically reduced not only the incidence of coronary artery disorders but also the mortality rate due to KD. The action mechanism of IVIG is variegated, but the fever, plasma C-reactive protein (CRP) and inflammatory cytokines level in acute-stage KD patients reduce early after IVIG treatment. It is also known that the activation of the immunocompetent cells is inhibited by IVIG therapy. Conversely, alternative treatments, including steroids, neutrophil elastase inhibitors, plasma-exchange therapy and anti-cytokine antibody therapy, have been tried for KD patients who are non-responsive to IVIG. The pathogenesis of KD might be clarified by analysing the mechanism of actions of these therapies in detail.