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We conducted an autopsy on a 3‐month‐old boy in whom Kawasaki disease (KD) was strongly suspected based on the autopsy findings. The infant had a fever and was brought to a nearby clinic, where he was prescribed antipyretics and kept under observation. However, 15 days after onset of the fever, he suddenly died in bed. He exhibited no obvious redness of the lips, tongue, or conjunctiva. Membranous desquamation was present on his distal fingers. Vasculitis was observed in the coronary arteries, renal artery, splenic artery, and pulmonary vein. In addition, coronary artery aneurysms were present in the right coronary artery and left anterior descending artery. Thrombotic occlusion was observed in one aneurysm in the right coronary artery, resulting in acute myocardial infarction. The coronary artery wall showed infiltration of numerous macrophages and neutrophils. This case was classified as incomplete KD because the coronary artery aneurysm could not be demonstrated before death and was only recognized at autopsy. Pathologists and forensic scientists need to be aware that there are cases in which KD goes undiagnosed and untreated, leading to coronary artery aneurysm formation and sudden death. [ABSTRACT FROM AUTHOR]

Abstract Background Intravenous immunoglobulin (IVIg) treatment results in an effective response from patients with acute-phase Kawasaki disease (KD), but 16.5% of them remain nonresponsive to IVIg. To address this therapeutic challenge, we tried a new therapeutic drug, mizoribine (MZR), in a mouse model of KD, which we have established using injections of Candida albicans water-soluble fractions (CAWS). Methods CAWS (4 mg/mouse) were injected intraperitoneally into C57BL/6N mice for 5 consecutive days. MZR or IgG was administered for 5 days. After 4 weeks, the mice were sacrificed and autopsied, the hearts were fixed in 10% neutral formalin, and plasma was taken to measure cytokines and chemokines using the Bio-Plex system. The incidence of panvasculitis in the coronary arteries and aortic root was 100% in the control group. The incidence of panvasculitis in the MZR group decreased to 50%. Moreover, the scope and severity of the inflammation of those sites were significantly reduced in the MZR group as well as the IgG group. On the other hand, increased cytokines and chemokines, such as IL-1α, TNF-α, KC, MIP-1α, GM-CSF, and IL-13, in the nontreatment group were significantly suppressed by treatment with MZR, but the MCP-1 level increased. In addition, IL-1α, TNF-α, IL-10, IL-13, and MIP-1α were suppressed by treatment in the IgG group. Results The incidence of panvasculitis in the coronary arteries and aortic root was 100% in the control group. The incidence of panvasculitis in the MZR group decreased to 50%. Moreover, the scope and severity of the inflammation of those sites were significantly reduced in the MZR group as well as the IgG group. On the other hand, increased cytokines and chemokines, such as IL-1α TNF-α, KC, MIP-1α, GM-CSF, and IL-13, in the nontreatment group were significantly suppressed by treatment with MZR, but the MCP-1 level increased. In addition, IL-1α, TNF-α, IL-10, IL-13, and MIP-1α were suppressed by treatment in the IgG group. Conclusion MZR treatment suppressed not only the incidence, range, and degree of vasculitis, but also inflammatory cytokines and chemokines in the plasma of the KD vasculitis model mice, suggesting that MZR may be useful for treatment of KD.

Abstract Background/Objective To examine tenascin C (TN-C) expression in coronary artery lesions (CALs) and myocardial lesions (MLs) in Kawasaki disease (KD). Methods and Results Twenty-five KD autopsy cases (post-KD-onset range of 6 days to 17 years) were examined in this study. Time-course analysis based on the disease day was performed of the histological findings for the CALs and MLs, as well as the localization and intensity of expression of TN-C. TN-C expression was observed to coincide with the areas where inflammatory cell infiltration was present in both coronary arteries and myocardium during the acute stage of KD, and the intensity of its expression correlated with the degree of inflammation. Obvious TN-C expression persisted in the thickened intima and media of CALs even after Disease Day 27. However, in spite of the presence of inflammatory cell infiltration, TN-C expression became weaker in the adventitia and surrounding connective tissue. After 8 months or more, TN-C was not expressed in the vasculitis scars of most cases, but expression was observed around newly formed vessels in the thickened intima and around recanalized vessels after thrombotic occlusion. Conclusions The findings suggest a correlation between the degree of inflammation and TN-C expression in the cardiovascular lesions of acute–stage Kawasaki disease. Highlights • Serum TN-C is a useful predictor of cardiovascular lesion in acute Kawasaki disease. • TN-C expression in cardiovascular lesions was examined immunohistochemically. • TN-C expression coincided with the area of acute inflammation in cardiovascular system. • Elevation of serum TN-C originates in acute vascular injury in Kawasaki disease. [ABSTRACT FROM AUTHOR]

Abstract: Kawasaki disease (KD) is the commonest vasculitic syndrome. It affects medium‐sized arteries, principally the coronary arteries. Histologically, coronary arteritis begins at 6 to 8 days after the onset of KD and the inflammation rapidly involves all layers of the artery. This results in severe damage to the structural components of the artery leading to arterial dilation. The inflammatory infiltrate in KD arteritis is characterized predominantly by infiltration of monocytes and macrophages. Activated neutrophils, monocytes and macrophages are believed to be involved in the initial stage of coronary arteritis. Inflammatory cell infiltration may continue for up to 25 days of disease following which the inflammatory cells gradually decline in number. Inflammatory lesions in the arteries are relatively synchronous as they evolve from an acute to the chronic stage. If a giant aneurysm remains or vessel recanalization occurs after thrombotic occlusion of an aneurysm, the remodeling of vascular structures may continue for a much longer time. [ABSTRACT FROM AUTHOR]

• Calcification of coronary aneurysms in Kawasaki disease starts within a few months. • Calcification shows two localization: thrombotic organizing and deep intima. • Calcification in the early remote stage is often due to the organizing of thrombi. Calcification of coronary artery aneurysms (CAAs) is common in the remote phase of Kawasaki disease (KD), but the detailed features of its development remain unclear. This study aimed to elucidate the histological characteristics of calcification in KD CAAs. The study materials consisted of 24 coronary artery branches with aneurysms that were obtained from 14 Japanese patients who died during the period from 40 days to 3 years after the onset of KD. We first examined the CAAs for the presence of thrombi and calcification. When calcifications were observed, we determined their location and shape, and investigated the time-course of the changes based on the time-interval from KD onset until death. Then we measured the area of each calcification and examined for correlations between the calcified area, and (1) the disease duration, and (2) the aneurysm diameter. Calcification was observed in 14 of 24 CAAs (in 7 of 13 LCA and 7 of 11 RCA). Thrombi were also seen in 13 of 14 CAAs with calcification. Calcification showed two localizations: in the organized portion of the thrombus (seen in 12 CAAs) and deep in the thickened tunica of the intima (3 CAAs). The earliest observation of calcification was in an infant who died on the 49th disease day: it was a small, band-shaped calcified lesion in granulation tissue that had formed at the boundary between the thrombus and the blood vessel wall. As the duration of KD increased, the calcified lesion increased in size, and nodular shapes were formed. Moreover, the calcified area tended to increase as the diameter of the aneurysm increased. Histologically, CAA calcification starts early in the remote phase of KD, and it is closely related to organization of thrombi. [ABSTRACT FROM AUTHOR]

Objectives Various inflammatory cytokines, including tumor necrosis factor-α (TNF-α), have been reported to play roles in Kawasaki disease (KD). Recently, anti-TNF-α therapy was reported to show efficacy in patients who do not respond to high-dose intravenous immunoglobulin therapy. However, there are many gaps in our understanding of the role that TNF-α plays in the development of KD arteritis as well as whether anti-TNF-α therapy causes any histological changes in the arteritis. Accordingly, the present histopathological study was carried out to elucidate the inhibitory effect of anti-TNF-α therapy on vasculitis as well as the role of TNF-α in the development of vasculitis in a murine model of KD vasculitis. Methods We used two anti-TNF-α drugs (etanercept and infliximab) to treat a Candida albicans-induced murine model of KD vasculitis. We investigated the histopathological changes in terms of the incidence of vasculitis, the scope of lesions and the degree of inflammation. Results Administration of etanercept to the mice reduced not only the incidence of vasculitis but also the scope of lesions and the degree of inflammation. Conclusion Based on the histological findings, TNF-α is deeply involved in the development of vasculitis. [ABSTRACT FROM AUTHOR]

Aims: To review the histopathological features of cervical LNs, and to clarify the changes in extracervical LNs, in acute Kawasaki disease (KD). Methods and results: The samples were obtained from 33 patients with acute-phase KD. We divided the LNs into those in the neck ( n = 23) and those located elsewhere ( n = 26), and investigated them histologically. Changes occur not only in the cervical region, but also in LNs throughout the body. Most lymphadenopathy is non-specific, caused by sinus expansion and paracortical zone enlargement, but there are also necrotic lesions of various sizes that can be surmised to result from ischaemic changes in some LNs. Necrotic foci start to develop immediately below the capsule, and are accompanied by fibrin thrombi in the small vessels and perivascular nuclear debris. Especially in the case of cervical LNs with necrosis, a high degree of non-purulent inflammation develops in the LN capsule and surrounding connective tissue. Conclusions: In addition to lymphadenopathy with necrosis, KD should be suspected if there is non-purulent inflammation of the LN capsule and/or surrounding connective tissue featuring mainly monocytes/macrophages. [ABSTRACT FROM AUTHOR]

Harada M, Yokouchi Y, Oharaseki T, Matsui K, Tobayama H, Tanaka N, Akimoto K, Takahashi K, Kishiro M, Shimizu T & Takahashi K (2012) Histopathology Histopathological characteristics of myocarditis in acute-phase Kawasaki disease Aims: To elucidate the histopathological characteristics of myocarditis in acute-phase Kawasaki disease (KD). Methods and results: The examined materials were from 29 autopsied KD patients who died within 40 disease days following onset. Each heart was divided into three levels: base, middle and apex. At each of these levels, the myocardium was divided further into the epicardial, middle and endocardial layers, and the time-courses of the changes in the myocarditis and the distribution of inflammation were analysed. Inflammatory cell infiltration, consisting mainly of lobulated leucocytes and large mononuclear cells, was seen in the myocardial interstitium in all cases. Inflammatory cell infiltration was already seen by disease day 6 in a patient with no coronary arteritis; it became prominent after day 10 and gradually disappeared after day 20. Myocarditis was initially distributed diffusely throughout the heart, but after day 10 it was localized in the base and epicardial layer. Conclusions: In KD, myocarditis develops even earlier than epicardial coronary arteritis; it peaks by disease day 10 and then disappears gradually after day 20. The myocarditis is distributed unevenly, ranging from the entire heart to the epicardial layer of the base of the heart. [ABSTRACT FROM AUTHOR]

The patient was a 40-year-old Japanese woman. At 37 years of age she underwent stent implantation in LAD#7 for an acute myocardial infarction. Subsequently, coronary intervention was performed four times because of occlusion of the stent. Sudden death occurred at 40 years of age due to ventricular tachycardia. Clinically, the patient had had no history of collagen disease, anti-phospholipid antibody syndrome or coagulation disorder. The autopsy revealed only very mild atherosclerotic changes in the aorta and various other organs, but concentric thickening of the intima was observed in all three branches of the coronary arteries. Also, aneurysms accompanied by calcification were observed at each of LAD #6, LCx #11 and RCA #4PD. The stent was occluded with a thrombus, and the vascular walls showed infiltration by lymphocytes, plasma cells and numerous eosinophils. The eosinophil infiltration was confined to the site of the stent. It was surmised that the patient had experienced late stent thrombosis due to a hypersensitivity reaction to the DES on the basis of a development of a state of high susceptibility to thrombus formation because of a coronary aneurysm. The aneurysm was suspected of being a post-inflammatory change of Kawasaki disease. [ABSTRACT FROM AUTHOR]

Background: There has been no morphological evidence that polymorphonuclear leukocytes (PMNL) infiltrate the coronary arterial lesions of acute Kawasaki disease (KD) patients, although clinical data indicate the activation of PMNL.Methods: The experimental materials consisted of eight autopsy patients who died during the acute phase of KD. Duration of the illness ranged from 6 to 32 days. The tissues were fixed and embedded in paraffin. Hematoxylin and eosin, elastica van Gieson and azan–Mallory stainings were performed for routine histological examination. In addition, antibodies to CD3, CD20, CD68 and neutrophil elastase were used for immunohistochemistry to identify infiltrating cells in arterial lesions.Results: The inflammatory cells that appeared in the coronary arterial lesions were mainly composed of macrophages in all patients. In addition, numerous neutrophils were also identified in the coronary arterial lesions of the patients who died 10 days after the onset of KD. Neutrophilic infiltration reached a peak earlier than the peaks of CD68+ macrophages, CD3+ T lymphocytes and CD20+ B lymphocytes.Conclusions: These results suggest that neutrophils are involved in the damage occurring to coronary arteries in the early stage of KD. Vasodilation might occur as a result of injury to vascular walls caused by neutrophils, as well as macrophages. [ABSTRACT FROM AUTHOR]

• Syk is involved in the development of the CAWS vasculitis. • Syk inhibitors suppress the development of CAWS vasculitis. • Low dose-CAWS evokes vasculitis that is smaller and less frequent than of high dose. The activation of innate immunity may be involved in the development of Candida albicans -induced murine vasculitis, which resembles Kawasaki disease (KD) vasculitis. This study aimed to histologically clarify the time course of the development of vasculitis in this model in detail and to estimate the potential role of spleen tyrosine kinase (Syk) inhibitors in KD vasculitis. DBA/2 male mice were intraperitoneally injected with a vasculitis-inducing substance and treated with a Syk inhibitor (R788 or GS-9973). Systemic vasculitis, especially in the aortic annulus area, was histologically evaluated. Regarding lesions in the aortic annulus area, some mice in the untreated control group already showed initiation of vasculitis 1 day after the final injection of a vasculitis-inducing substance. The vasculitis expanded over time. Inflammation occurred more frequently at the aortic root than at the coronary artery. The distribution of inflammatory cells was limited to the intima, intima plus adventitia, or all layers. In the Syk inhibitor-treated groups, only one mouse had vasculitis at all observation periods. The severity and area of the vasculitis were reduced by both Syk inhibitors. Candida albicans -induced murine vasculitis may occur within 1 day after the injection of a vasculitis-inducing substance. Additionally, Syk inhibitors suppress murine vasculitis. [ABSTRACT FROM AUTHOR]

• Inflammation also involves the aortas in Kawasaki disease. • Formation of aortic aneurysms are rare in Kawasaki disease. • The degree of inflammation is different between the sites of the aortas. • The inflammatory cells infiltrate into the media from the adventitial and the intimal sides. Kawasaki disease (KD) is a systemic vasculitis syndrome that occurs most frequently in children. Most clinical and pathological studies have focused on its coronary artery lesions. To date, no detailed studies of the aorta have been conducted. We studied KD autopsy cases with the aims of clarifying the time-course of changes in aortic lesions, the differences in the inflammatory cells and degree of inflammation at various aortic sites, and the progression of the inflammation. The study materials were aortic specimens taken from 37 KD autopsy cases (acute phase: 19; remote phase: 18). Twenty-seven of the cases also had coronary aneurysms. We chose 3 aortic sites, i.e., the thoracic aorta, aortic root and aortic bifurcation, and we histologically observed and compared those sites in regard to the changes with time, the kinds of infiltrating cells and the number of inflammatory cells. We also observed the relationship between the vasa vasorum and inflammatory cell localization in the tunica media, and examined the progression of inflammation in the tunica media. Destruction of the vascular architecture was not seen in any of the 37 cases, but inflammatory cell infiltration was observed in 90% of the acute-phase cases. The inflammatory cell infiltration involved the tunica intima and tunica adventitia of the aorta on the 6th disease-day, and all layers of the aorta on the 13th disease-day; the infiltration peaked on the 18th disease-day. The infiltration gradually disappeared thereafter, and no significant infiltration was seen in the remote phase. The infiltrating inflammatory cells consisted mainly of CD163-positive macrophages. Comparison of the 3 sites of the aorta showed that the inflammatory cell infiltration was more severe in the aortic root and aortic bifurcation than in the thoracic aorta. The progression of inflammation to the aortic tunica media from the adventitia showed 2 patterns: 1 in which macrophages were aggregated around the vasa vasorum; and a second in which there was no such aggregation around the vasa vasorum, but there was diffuse inflammatory cell infiltration of the tunica media. In addition to this, there were findings of direct infiltration of cells from the tunica intima into the tunica media. Inflammation in KD occurs in the aorta. The changes with time and the kinds of infiltrating cells were the same as reported to date for coronary arteries in KD. There were differences in the degree of inflammation among the 3 aortic sites. It can be thought that the inflammation from the adventitia to the media progresses via the vas vasorum, and also, there is a possibility of spreading directly. From the intima to the media, inflammation spreads directly. However, formation of aneurysms and destruction of the vascular architecture of the aorta were absent in this study, unlike in coronary arteries. [ABSTRACT FROM AUTHOR]