Arterial immune protein expression demonstrates the complexity of immune responses in Kawasaki disease arteritis.

A more complete understanding of immune-mediated damage to the coronary arteries in children with Kawasaki disease (KD) is required for improvements in patient treatment and outcomes. We recently reported the transcriptional profile of KD coronary arteritis, and in this study sought to determine protein expression of transcriptionally up-regulated immune genes in KD coronary arteries from the first 2 months after disease onset. We examined the coronary arteries of 12 fatal KD cases and 13 childhood controls for expression of a set of proteins whose genes were highly up-regulated in the KD coronary artery transcriptome: allograft inflammatory factor 1 (AIF1), interleukin 18 (IL-18), CD74, CD1c, CD20 (MS4A1), Toll-like receptor 7 (TLR-7) and Z-DNA binding protein 1 (ZBP1). Immunohistochemistry and immunofluorescence studies were performed to evaluate protein expression and co-localization, respectively. AIF1 was expressed transmurally in KD arteritis and localized to macrophages and myeloid dendritic cells. CD74, which interacts with major histocompatibility complex (MHC) class II on antigen-presenting cells, localized to the intima-media. CD1c, a marker of myeloid dendritic cells, was expressed in a transmural pattern, as were IL-18 and CD20. ZBP1 and TLR-7 were up-regulated compared to controls, but less highly compared to the other proteins. These findings provide evidence of antigen presentation and interferon response in KD arteritis. In combination with prior studies demonstrating T lymphocyte activation, these results demonstrate the complexity of the KD arterial immune response.

High-dose aspirin for Kawasaki disease: outdated myth or effective aid?

OBJECTIVES: To compare the efficacy and safety of intravenous immunoglobulin (IVIG) plus high-dose aspirin (HDA) vs. IVIG plus low-dose aspirin (LDA) for the treatment of Kawasaki disease, with an emphasis on coronary artery outcomes. METHODS: This study was a retrospective, medical record review of paediatric patients with Kawasaki disease comparing 6 centres that routinely used HAD for initial treatment and 2 that used LDA in 2004-2013. Treatment response and adverse events were compared. The primary outcome measure was the occurrence of coronary aneurysm at the subacute or convalescent stage. RESULTS: The cohort included 358 patients, of whom 315 were initially treated with adjunctive HDA and 43 with LDA. There were no demographic differences between the groups. Coronary aneurysms occurred in 10% (20/196) of the HDA group and 4% (1/24) of the LDA group (p=0.34). Equivalence tests indicate it is unlikely that the risk of coronary aneurysm in LDA exceeds HDA by more than 3.5%. There were no significant between-group differences in the need for glucocorticoid pulse therapy or disease recurrence. Coronary ectasia rate and hospitalisation time were significantly greater in the HDA group. Adverse events were similar in the two groups. CONCLUSIONS: We found no significant clinical benefit in using IVIG+HDA in Kawasaki disease compared to IVIG+LDA. The use of adjunctive HDA in this setting should be reconsidered.

Immunoglobulin G4-related multiple cardiovascular lesions successfully treated with a combination of open surgery and corticosteroid therapy.

Immunoglobulin G4-related disease, a newly emerging systemic autoimmune disorder, can potentially involve the cardiovascular system. The standard treatment for immunoglobulin G4-related cardiovascular disease has not been established. We encountered a very rare case of an immunoglobulin G4-related inflammatory abdominal aortic aneurysm coexisting with a coronary artery aneurysm and periarteritis. The patient underwent surgical resection for the abdominal aortic aneurysm, followed by successful corticosteroid therapy for the coronary artery lesions. This is the first report of steroid-sensitive immunoglobulin G4-related coronary artery disease. A carefully planned treatment strategy for the multiple cardiovascular lesions was invaluable in the present case.

Rapid progression of a coronary artery aneurysm caused by IgG4-related disease.

BACKGROUND: IgG4-related disease (IgG4-RD) is a recently recognized fibro-inflammatory disorder that can affect almost any organ. IgG4-RD has also been reported in coronary arteries as periarteritis. IgG4-related coronary periarteritis may cause coronary artery aneurysms, and IgG4-related coronary artery aneurysms (IGCAs) are life-threatening. We describe a case of a patient with IGCA that highlights the usefulness and limitations of various IGCA evaluation modalities and provides insight into disease pathophysiology. CASE SUMMARY: A 60-year-old man with IgG4-RD diagnosed 2 years before and with IGCA at the proximal right coronary artery (RCA) on coronary angiography (CAG) 9 months prior to admission to the hospital presented with acute coronary syndrome. Emergent CAG revealed the rapid progression of IGCA at the RCA, an obstruction of the diagonal branch, and stenosis of the left anterior descending artery (LAD) and the high lateral branch (HL). The patient underwent percutaneous coronary intervention for the diagonal branch. The RCA aneurysm was resected and bypassed with a saphenous vein graft (SVG); coronary bypass grafting (left internal mammary artery to LAD and SVG to HL) was performed. Pathological findings showed inflammatory cell infiltration and disruption of the elastic plate. CONCLUSION: IGCAs require careful follow-up with computed tomography scans for early detection of aneurysmal enlargement.

Kawasaki disease: basic and pathological findings.

Kawasaki disease (KD) is considered to be a kind of systemic vasculitis syndrome. It most frequently affects infants and young children and primarily invades medium-sized muscular arteries, including the coronary arteries. The etiology of KD is unknown, but epidemiological data suggest involvement of infectious agents, such as bacteria and viruses, in the onset of KD. In addition, host genetics underlie the disease's pathogenesis. Histologically, coronary arteritis begins 6-8 days after KD onset, and inflammation of all layers of the artery rapidly ensues. The inflammation spreads completely around the artery, resulting in severe damage to structural components. Then, the artery begins to dilate. KD arteritis is characterized by inflammation consisting of marked accumulation of monocytes/macrophages. Aberrant activation of monocytes/macrophages is thought to be involved in the formation of vascular lesions. Inflammatory-cell infiltration persists until about the 25th day of the disease, after which the inflammatory cells gradually decrease in number. Lesions in all arteries are relatively synchronous, as they evolve from acute to chronic injury. If a giant aneurysm remains or vessel recanalization occurs after thrombotic occlusion of an aneurysm, remodeling of the vascular structure, sometimes including even reocclusion, continues even in the remote stage.

Monocyte-Derived Interleukin-1ß As the Driver of S100A12-Induced Sterile Inflammatory Activation of Human Coronary Artery Endothelial Cells: Implications for the Pathogenesis of Kawasaki Disease.

OBJECTIVE: Kawasaki disease (KD) is an acute vasculitis of childhood, predominantly affecting the coronary arteries. S100A12, a granulocyte-derived agonist of both the receptor for advanced glycation end products (RAGE) and Toll-like receptor 4 (TLR-4), is strongly up-regulated in KD. This study was undertaken to investigate the potential contributions of S100A12 to the pathogenesis of KD. METHODS: Serum samples from patients with KD (n = 30) at different stages pre- and post-intravenous immunoglobulin (IVIG) treatment were analyzed for the expression of S100A12, cytokines, chemokines, and soluble markers of endothelial cell activation. Primary human coronary artery endothelial cells (HCAECs) were analyzed for responsiveness to direct stimulation with S100A12 or lipopolysaccharide (LPS), as assessed by real-time quantitative reverse transcription-polymerase chain reaction analysis of cytokine and endothelial cell adhesion molecule messenger RNA expression. Alternatively, HCAECs were cultured in conditioned medium obtained from primary human monocytes that were stimulated with LPS or S100A12 in the absence or presence of IVIG or cytokine antagonists. RESULTS: In the serum of patients with KD, pretreatment S100A12 levels were associated with soluble vascular cell adhesion molecule 1 titers in the course of IVIG therapy (rs = -0.6, P = 0.0003). Yet, HCAECs were not responsive to direct S100A12 stimulation, despite the presence of appropriate receptors (RAGE, TLR-4). HCAECs did, however, respond to supernatants obtained from S100A12-stimulated primary human monocytes, as evidenced by the gene expression of inflammatory cytokines and adhesion molecules. This response was strictly dependent on interleukin-1ß (IL-1ß) signaling (P < 0.001). CONCLUSION: In its role as a highly expressed mediator of sterile inflammation in KD, S100A12 appears to activate HCAECs in an IL-1ß-dependent manner. These data provide new mechanistic insights into the contributions of S100A12 and IL-1ß to disease pathogenesis, and may therefore support current IL-1-targeting studies in the treatment of patients with KD.

Kawasaki disease associated with reactive hemophagocytic lymphohistiocytosis.

We report a case of Kawasaki disease with significant coronary artery aneurysms subsequently associated with reactive hemophagocytic lymphohistiocytosis in a young child with low T-cell perforin expression and NK-cell dysfunction. The patient was treated with a selective T-cell costimulation modulator in an effort to regulate T-cells. This case is unique for several reasons: (1) the severe degree of coronary artery aneurysms; (2) low T-cell perforin and NK-cell values; and (3) treatment with a selective T-cell costimulation modulator, none of which has been described in prior cases.

Histopathological aspects of cardiovascular lesions in Kawasaki disease.

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.

Could neutrophil/lymphocyte ratio be an indicator of coronary artery disease, coronary artery ectasia and coronary slow flow?

Objective To determine whether neutrophil/lymphocyte ratio (NLR) differed between patients with isolated coronary artery disease (CAD), isolated coronary artery ectasia (CAE), coronary slow flow and normal coronary anatomy. Methods Patients who underwent coronary angiography were consecutively enrolled into one of four groups: CAD, coronary slow flow, CAE and normal coronary anatomy. Results The CAD ( n = 40), coronary slow flow ( n = 40), and CAE ( n = 40) groups had similar NLRs (2.51 ± 0.7, 2.40 ± 0.8, 2.6 ± 0.6, respectively) that were significantly higher than patients with normal coronary anatomy ( n = 40; NLR, 1.73 ± 0.7). Receiver operating characteristics demonstrated that with NLR > 2.12, specificity in predicting isolated CAD was 85% and sensitivity was 75%, with NLR > 2.22 specificity in predicting isolated CAE was 86% and sensitivity was 75%. With NLR > 1.92, specificity in predicting coronary slow flow was 89% and sensitivity was 75%. Multivariate logistic regression analyses identified NLR as an independent predictor of isolated CAE (ß = -0.499, 95% CI -0.502, -0.178; P < 0.001), CAD (ß = -0.426, 95% CI -1.321, -0.408; P < 0.001), and coronary slow flow (ß = -0.430, 95% CI -0.811, -0.240; P = 0.001 Table 2 ). Conclusions NLR was higher in patients with CAD, coronary slow flow and CAE versus normal coronary anatomy. NLR may be an indicator of CAD, CAE and coronary slow flow.

CD8 T lymphocytes do not express cytotoxic proteins in coronary artery aneurysms in acute Kawasaki disease.

Coronary arterial inflammation in acute Kawasaki disease (KD) is characterized by transmural infiltration of CD8 T lymphocytes, suggesting that CD8 T lymphocyte cytotoxic activity may be important in the pathogenesis of coronary arterial damage in acute KD. We performed immunohistochemistry for the cytotoxic proteins perforin and granzyme B on paraffin-embedded, formalin-fixed coronary artery aneurysm tissue from 6 children who died in the acute stage of KD. Neither perforin nor granzyme B was detected in the KD coronary aneurysm wall. We speculate that the etiologic agent of KD interferes with expression of these cytotoxic proteins by CD8 T lymphocytes, prolonging inflammation in the arterial wall and leading to coronary artery aneurysm formation.

Review and hypothesis: the eosinophil and peripartum heart disease (myocarditis and coronary artery dissection)--coincidence or pathogenetic significance?

OBJECTIVES: To examine a possible relationship between peripartum heart disease (myocarditis and spontaneous coronary dissection) and the presence of eosinophils. BACKGROUND: Eosinophils have been shown to have potential collagenolytic and cytotoxic activity. Eosinophils may play a role in postpartum uterine involution. The presence of eosinophils in spontaneous coronary dissection and myocarditis in the postpartum period raises the possibility of a role for eosinophils in these diseases. METHODS: We reviewed the files of one of us (S.M.F.) for cases of peripartum myocarditis and spontaneous coronary dissection and assessed the frequency of eosinophilic inflammation. Seventeen postpartum myocarditis and/or cardiomyopathy cases were found and two spontaneous coronary dissections. Fifteen sex- and age-matched controls on non-postpartum myocarditis and borderline myocarditis were evaluated and eosinophil counts per unit area compared. Also, a Medline search of all previously published cases of spontaneous coronary dissection was performed back to 1966. RESULTS: Of the 16 heart biopsies and one autopsy in the peripartum period, 10 were shown to contain easily identified eosinophils (6 myocarditis, 1 borderline, 3 cardiomyopathy). When presence of eosinophils was compared with the control group, a statistically significant difference was obtained (P = 0.036). The two new spontaneous coronary dissection cases had eosinophils along the dissection plane; the literature search produced 13 of 24 autopsied peripartum spontaneous coronary dissections with eosinophils for a total of 15 of 26 with our cases. CONCLUSIONS: An association exists between eosinophils and peripartum cardiac disease (myocarditis and spontaneous coronary dissection). The role of eosinophils in labor, uterine involution and collagenolysis and the possible relation to cardiac disease are discussed.

Imbalance among T-cell subsets in patients with coronary arterial aneurysms in Kawasaki disease.

The populations of T cells were studied in 46 patients with Kawasaki disease, separated into 2 groups: group I--11 patients with coronary aneurysms; and group II--35 patients with normal coronary arteries. Patients from both groups with early acute illness, before day 5, had a significant reduction in the population of OKT3+ (p less than 0.001), OKT4+ (p less than 0.02) and OKT8+ cells (p less than 0.002), but normal OKT4/OKT8 ratios compared with age-matched control subjects. These abnormal values quickly returned to normal levels during week 2 in patients with normal coronary arteries. In contrast, patients in whom coronary aneurysms developed within 3 weeks of the onset had an imbalance between OKT4 and OKT8 during week 2, characterized by a decrease in the number of OKT8+ cells and an increase in the number of OKT4+ cells, resulting in a high OKT4/OKT8 ratio (p less than 0.01). Three patients in whom large coronary aneurysms developed had ratios higher than 4.50. Follow-up analysis of T-cell subsets from individual patients with coronary aneurysms showed that the OKT4/OKT8 ratio during the acute stage was reduced during the convalescent stage (p less than 0.005). In contrast, the ratio in patients with normal coronary arteries was normal during the course of the illness. These observations suggest that an immune regulatory process operating in coronary aneurysm formation is present.

Sudden coronary death due to IgG4-related disease.

A 54-year-old male entered the emergency room in cardiorespiratory arrest after syncope at home. Resuscitation was attempted, but the patient died a few hours later. At necropsy, aneurysms were found at the right and left anterior descending coronary arteries. At microscopic examination, there was no significant coronary atherosclerosis, and a dense inflammatory infiltrate was detected, with a high number of igG4-positive cells (94.0 positive cells/hpf). The case illustrates that IgG4-related disease can cause coronary disease and sudden cardiac death.

IgG4-related disease underlying the pathogenesis of coronary artery disease.

Immunoglobulin G4 (IgG4)-related disease is a newly emerging clinicopathological entity that is characterized by increased serum IgG4 levels and tissue infiltration of IgG4-positive plasma cells. IgG4-related immune inflammation has been reported to be present in inflammatory aortic aneurysm, albeit not in every case. Several recent studies have suggested that IgG4-related disease may underlie certain coronary artery abnormalities, such as coronary aneurysm, pseudotumor, wall calcification, and intimal thickening. Here, what is known about IgG4-related coronary artery lesions, as well as questions that remain to be answered thus far, are discussed.

Late intravenous immunoglobulin treatment in patients with Kawasaki disease.

OBJECTIVE: To evaluate the effectiveness of intravenous immunoglobulin (IVIG) treatment of Kawasaki disease ≥10 days after illness onset. METHODS: We selected patients initially treated with IVIG on days 11 to 20 in the database of the 20th nationwide survey in Japan. We then selected pair-matched control subjects of the same gender and age, who were initially treated with IVIG on days 4 to 8 with the same dose at the same institutions. We compared the proportions of additional treatments and coronary artery lesions (CALs) between the groups. We also compared fractional changes in various laboratory data before and after IVIG. Fractional change was defined as follows: (Y - X)/X, in which X represents the data before treatment and Y the data after treatment. RESULTS: One hundred fifty patients (75 pairs) were studied. The proportion of patients who received additional treatments among those given initial IVIG after days 10 was slightly lower than those treated earlier (12% vs 16%). The fractional changes in the white blood cell count, % neutrophils, and C-reactive protein were similar. Among all patients, the proportions of CALs during the convalescent phase were significantly higher in the late than in the early group (27% vs 1%). Among patients who had not developed CALs before initial treatment, the proportions with CALs during the acute phase were similar (8% vs 8%). CONCLUSIONS: IVIG treatment ≥10 days after illness onset achieves resolution of inflammation but was found to be insufficient for preventing CALs.

Searching for the cause of Kawasaki disease--cytoplasmic inclusion bodies provide new insight.

Kawasaki disease (KD) has emerged as the most common cause of acquired heart disease in children in the developed world. The cause of KD remains unknown, although an as-yet unidentified infectious agent might be responsible. By determining the causative agent, we can improve diagnosis, therapy and prevention of KD. Recently, identification of an antigen-driven IgA response that was directed at cytoplasmic inclusion bodies in KD tissues has provided new insights that could unlock the mysteries of KD.

Matrix metalloproteinases and inflammatory markers in coronary artery ectasia: their relationship to severity of coronary artery ectasia.

OBJECTIVE: Although underlying mechanisms of coronary artery ectasia (CAE) are clearly unknown, destruction of extracellular matrix may be responsible for the ectasia formation. Thus, we investigated the role of matrix metalloproteinases (MMP), tissue inhibitor of matrix metalloproteinases (TIMP-1), and inflammatory markers [high-sensitive C-reactive protein, interleukins (ILs)] in CAE patients. METHODS: This study consisted of 28 consecutive CAE patients, 27 obstructive coronary artery disease (CAD) patients, and 22 controls with normal coronary arteries undergoing cardiac catheterization. Plasma levels of MMP-3, MMP-9, TIMP-1, and inflammatory markers were measured. RESULTS: Plasma level of MMP-3 was significantly higher in CAE patients compared with both CAD patients and controls (17.2+/-6.1, 11.2+/-3.2, and 9.2+/-3.4 ng/ml, respectively, both P=0.001) and so did MMP-9 level (27.4+/-5.9, 24.8+/-4.4, and 20.6+/-4.6 ng/ml, respectively, both P<0.05). IL-6 level was also higher in CAE patients than in controls (60.9+/-22.1 vs. 36.1+/-21.5 pg/ml, P=0.001) but were comparable in CAE and CAD patients. Plasma high-sensitive C-reactive protein, IL-1, and TIMP-1 levels were similar in three groups. MMP-3 levels correlated with diffuse (r=0.46, P=0.01) and multivessel ectasia (r=0.45, P=0.02). CONCLUSION: Our results suggest that the increased level of MMP-3, MMP-9, and IL-6 may be responsible for ectasia formation in patients with CAE.

The IL-10 (-627 A/C) promoter polymorphism may be associated with coronary aneurysms and low serum albumin in Korean children with Kawasaki disease.

Kawasaki disease (KD) is an acute febrile vasculitic syndrome of unknown etiology that preferentially affects the coronary artery. Interleukin-10 (IL-10) is a key proinflammatory cytokine, and a polymorphism near the major transcriptional start site of the IL-10 gene was shown to influence IL-10 production in vitro. This study investigated the association of the IL-10 promoter polymorphism with KD and its clinical parameters in Korean children. A total of 194 children with congenital heart disease (CHD) and 95 children with KD were included in this study. IL-10 (-627 A/C) polymorphism genotypes were determined using the single-base extension method. There was no difference in the allele frequencies of IL-10 (-627 A/C) polymorphism between CHD children and KD children. KD children with one or two copies of the IL-10 (-627C) allele showed significantly lower albumin levels (p = 0.020) and higher frequencies of early coronary artery aneurysm [62.22% versus 37.78%, adjusted odds ratio (aOR) = 3.50, 95% confidence interval (CI): 1.50-8.16] compared with KD children with the common IL-10 (-627A) allele. These findings suggest that the IL-10 (-627 A/C) promoter polymorphism might be a genetic marker for the risk of early coronary artery complication in KD.