Coronary Artery Dilatation in Toxic Shock-Like Syndrome: The Kawasaki Disease Shock Syndrome

Kawasaki disease is a common systemic vasculitis of childhood that may result in life-threatening coronary artery abnormalities. Despite an overlap of clinical features with toxic shock syndrome, children with Kawasaki disease generally do not develop shock. We report two cases of older children who presented with a toxic shock-like illness, and were diagnosed with Kawasaki disease when coronary artery abnormalities were found on echocardiography, in keeping with the recently described ‘Kawasaki disease shock syndrome’. Clinicians should consider Kawasaki disease in all children presenting with toxic shock and assess for coronary artery damage.     

Abnormalities in urinary pterin levels in Rett syndrome.

The pterins, neopterin and biopterin, occur naturally in body fluids including urine. Increased neopterin levels are associated with activation of the cellular immune system and reduced biopterins are essential for biosynthesis of the monoamine neurotransmitters. The present study measured urinary neopterin and biopterin by high-performance liquid chromatography in 40 subjects with Rett syndrome, eight of their healthy sisters and 29 female control volunteers (age range 2-54 years). The results confirm earlier preliminary findings that urinary neopterin levels are raised in a proportion of young girls with Rett syndrome but not in the older women. In contrast urinary biopterin levels are not different from controls in the youngest children but remain low while control values increase with age. These findings may indicate immune activation during the regression phase of Rett syndrome but also raise the possibility that an inherited fault in tetrahydrobiopterin metabolism increases the risk of developing the disorder.     

血清新蝶呤、D-二聚体水平与川崎病冠状动脉扩张的关系

目的检测川崎病(KD)患儿血清新蝶呤(NP)、D-二聚体水平,探讨二者与冠状动脉扩张(CAD)的关系及冠状动脉病变的危险因素。方法KD患儿45例。其中21例发生CAD,24例无CAD。分别用酶联免疫吸附法(ELISA)测定其血清NP、D-二聚体水平。冠状动脉病变与PLT、单核细胞(M)、肌酸激酶同工酶(CK-MB)、CRP、ESR、心肌肌钙蛋白I(cTnI)、NP、D-二聚体行多元回归分析。结果与恢复期比较,KD患儿急性期PLT、M、CK-MB、CRP、ESR、cTnI显著升高(Pa<0.01)。血清NP升高26例中CAD 18例;NP正常19例中CAD 3例。D-二聚体升高30例中CAD 17例;D-二聚体正常15例中CAD 4例。静脉用免疫球蛋白(IVIG)治疗25例中CAD 7例;未予IVIG治疗20例中CAD 14例。多因素多元回归分析显示NP、D-二聚体水平与冠状动脉病变密切相关。血清NP水平与M数量呈正相关(r=0.49 P<0.01);D-二聚体水平与血小板数量呈正相关(r=0.51 P<0.01)。结论血清NP、D-二聚体在KD急性期升高,可能是反映冠状动脉异常的预测标志,对评价KD预后有重要意义。     

Children with screening-detected coeliac disease show increased levels of nitric oxide products in urine

Aim: Increased concentration of nitric oxide (NO) metabolites, nitrite and nitrate, in the urine is a strong indication of ongoing small intestinal inflammation, which is a hallmark of the enteropathy of coeliac disease (CD). It has previously been shown that children with symptomatic, untreated CD have increased levels of NO oxidation products in their urine. The aim of this study was to investigate whether screening‐detected, asymptomatic coeliac children display the same urinary nitrite/nitrate pattern. Methods: In a multicenter screening study, serum samples were collected from 7208 12‐year‐old children without previously diagnosed CD. Sera were analysed for anti‐human tissue transglutaminase (tTG) of isotype IgA. Small bowel biopsy was performed in antibody‐positive children, yielding 153 new cases of CD. In the screening‐detected individuals, the sum of nitrite and nitrate concentrations in the urine was analysed and used as an indicator of NO production. For comparison, 73 children with untreated, symptomatic CD were studied. Results: The nitrite/nitrate levels in children with screening‐detected CD and those with untreated symptomatic CD did not differ significantly. Both groups had significantly increased urinary nitrite/nitrate concentrations compared to the children with normal small bowel biopsy (p < 0.001). Conclusion: Children with screening‐detected CD have increased production of NO just as children with untreated symptomatic CD. High NO metabolite levels in the urine may indicate a pathogenetic feature of CD and be a marker of major clinical importance.     

Nitric oxide affects serum ferritin levels in children with iron deficiency

In iron deficiency, serum levels of ferritin decrease. The lack of iron has been thought to be the main factor in this decrease, but another potential factor is nitric oxide, which has been shown to affect ferritin metabolism in vitro. The aim of this study was therefore to evaluate in children with iron deficiency the relation of serum ferritin, nitric oxide degradation products (nitrate and nitrite), and endothelin-1, a protein closely related to nitric oxide function. A total of 80 children were included in the study (39 with iron deficiency, 41 controls). Serum levels of ferritin, nitrate, nitrite, and endothelin-1 were measured in all participants. In children with iron deficiency, nitrate and nitrite levels were significantly higher (p < .009 and .01, respectively). Also, serum ferritin was negatively correlated with serum levels of nitrate and nitrite (p = .034, r = -.254 for nitrate and p = .01, r = -.593 for nitrite). No statistical relationship was found between serum ferritin and endothelin-1.     

川崎病冠状动脉损伤与纤维蛋白原Bβ-148C/T基因多态性的关系

目的：探讨纤维蛋白原Bβ-148C/T基因多态性与川崎病冠状动脉损伤的关系。方法：收集36例川崎病患儿与49例健康对照儿童的空腹静脉血,用辅助血浆纤维蛋白原活性测定系统测定纤维蛋白原水平和纤维蛋白原的分子功能;采用多聚酶链反应,限制性酶切方法对纤维蛋白原Bβ-148C/T位点的基因型进行测定。结果：川崎病儿童冠状动脉扩张组血浆纤维蛋白原水平明显高于非扩张组及健康对照组(P<0.01); 川崎病儿童冠状动脉扩张组T等位基因频率明显高于健康对照组及非扩张组 (P<0.01)。结论：纤维蛋白原β-148基因多态性及血浆纤维蛋白原水平与川崎病患儿冠状动脉扩张有相关性。［中国当代儿科杂志,2010,12（7）：518-520］     

Management of Kawasaki disease in the British Isles.

Kawasaki disease in the British Isles was surveyed by an active reporting scheme, based on all cases reported to the British Paediatric Surveillance Unit that were diagnosed between 1 January and 31 December 1990. The study was prompted by the need to investigate the high case fatality rate of Kawasaki disease of 2% observed in 1988. One hundred and sixty three patients were identified of whom six (3.7%) died. Forty five children (28%) suffered cardiac complications of which 39 (24%) were coronary artery abnormalities; five children were diagnosed at postmortem examination, and coronary artery abnormalities were detected by echocardiography in 34. One hundred and forty nine children (93%) had echocardiography. High thrombocytosis, leucocytosis, duration of fever, and younger age were associated with the presence of coronary artery abnormalities. Erythrocyte sedimentation rate, sex, and the number of diagnostic criteria were not. One hundred and thirty three children (87%) received aspirin. Ninety three children (61%) received intravenous gammaglobulin (IVGG). Children were more likely to receive IVGG if they had thrombocytosis or typical Kawasaki disease. The incidence of coronary artery abnormalities was found to be similar in those treated with IVGG (29%) and those untreated (20%), including those treated within 10 days of onset. This may have reflected selection of the more serious cases to receive IVGG or that Kawasaki disease in the British Isles is a different illness to that experienced elsewhere. It amy be, however, that IVGG is less effective in the treatment of British patients with Kawasaki disease than has been the experience in the United States and Japan. These observations emphasise the need for a therapeutic trial of treatment modalities for Kawasaki disease in the UK and the Republic of Ireland.     

Incomplete Kawasaki disease with coronary artery involvement

We report four patients with Kawasaki disease in whom characteristic coronary artery abnormalities developed after illnesses that did not meet diagnostic criteria. An additional patient lacked a history of acute manifestations of Kawasaki disease, but severe Kawasaki-like arterial changes were noted at autopsy. Fever was present in four of the five patients, in three lasting from 7 to 14 days. Despite manifestation of few classic acute clinical features of Kawasaki disease, three of four patients had desquamation of the fingers and toes 10 to 14 days after onset of illness, and the fifth had desquamation several months prior to death. These patients were seen over a 2-year period during which 22 other children were seen with Kawasaki disease with coronary artery abnormalities. Thus, strict adherence to currently accepted criteria for diagnosis of Kawasaki disease may lead to failure to recognize incomplete forms of this illness, with potential sequelae of myocardial infarction or sudden death. This finding suggests that children with prolonged unexplained febrile illnesses, especially those associated with subsequent peripheral desquamation, should undergo echocardiography 3 to 4 weeks after onset of the illness. This practice would help to identify those patients with illnesses characterized by incomplete diagnostic criteria but in whom significant coronary abnormalities develop.     

The pathophysiology of coronary artery aneurysms in Kawasaki disease: role of matrix metalloproteinases.

Kawasaki disease is an acute inflammatory syndrome that takes the form of systemic vasculitis, and predominantly affects children. Important complications of this disease are coronary artery dilation and aneurysm formation. Recent studies indicate that Kawasaki disease patients have elevated expression, activity, or protein levels of matrix metalloproteinases (MMPs), and suggest that imbalances in MMPs or MMP/tissue inhibitor of MMP (TIMP) play important pathophysiological roles in the development of coronary artery lesions in this disease. However, it remains unclear whether MMP activities at the site of coronary artery lesions are indeed increased. Further studies on the effects of MMP inhibition on coronary outcome are needed to define the roles of MMPs and TIMPs in the formation of coronary artery lesions in Kawasaki disease; findings of such studies may support the use of MMP inhibitors for the prevention of coronary artery complications in patients with this disease.     

The pathophysiology of coronary artery aneurysms in Kawasaki disease: role of matrix metalloproteinases

Kawasaki disease is an acute inflammatory syndrome that takes the form of systemic vasculitis, and predominantly affects children. Important complications of this disease are coronary artery dilation and aneurysm formation. Recent studies indicate that Kawasaki disease patients have elevated expression, activity, or protein levels of matrix metalloproteinases (MMPs), and suggest that imbalances in MMPs or MMP/tissue inhibitor of MMP (TIMP) play important pathophysiological roles in the development of coronary artery lesions in this disease. However, it remains unclear whether MMP activities at the site of coronary artery lesions are indeed increased. Further studies on the effects of MMP inhibition on coronary outcome are needed to define the roles of MMPs and TIMPs in the formation of coronary artery lesions in Kawasaki disease; findings of such studies may support the use of MMP inhibitors for the prevention of coronary artery complications in patients with this disease.     

川崎病患儿血清中hs-CRP与基质金属蛋白酶及抑制剂联合检测的临床意义

目的：检测基质金属蛋白酶(MMP)-2、MMP-9、基质金属蛋白酶抑制剂(TIMP)-1及hs-CRP在川崎病患儿血清中的表达,并探讨其与冠状动脉损伤的关系。方法：选取151例川崎病患儿作为观察组（无冠状动脉损伤40例,有冠状动脉损伤111例）,60例健康儿童作为对照组,采用酶联免疫吸附实验(ELISA)检测血清中MMP-2、MMP-9和TIMP-1含量,应用终点散射比浊法检测血清hs-CRP的含量。结果：MMP-2,MMP-9及hs-CRP含量在冠脉损伤组及无冠脉损伤组与对照组比较差异均有显著性,在冠脉损伤组量最高（P<0.05）;川崎病患儿中MMP-2、MMP-9及TIMP-1之间的检测量呈正相关（P<0.05）。结论：MMP-2、MMP-9、TIMP-1及hs-CRP在川崎病的发生发展中可能起重要作用,MMP-2、MMP-9及hs-CRP的联合检测可能对判断病变程度有重要帮助。［中国当代儿科杂志,2009,11（12）：989-991］     

Increased urinary nitric oxide oxidation products in children with active coeliac disease

BACKGROUND: Nitric oxide (NO) production catalyzed by iNOS (inducible NO synthase) is thought to take place mainly in macrophages after activation by inflammatory mediators. NO is subsequently oxidized to nitrite and nitrate, which are excreted in urine. The concentration of inflammatory mediators in small bowel biopsy specimens from patients with coeliac disease is increased. The latter could induce increased NO production by stimulation of intestinal macrophage iNOS, resulting in high levels of urinary NO oxidation products, nitrite and nitrate (NOx). AIM: In the present study we evaluated the urinary NOx/creatinine ratios in children with active coeliac disease (n = 22), coeliac disease patients on a gluten-free diet (n = 9), healthy (n = 11) and sick control children (n = 18). METHODS: The Griess reagent method was used for measuring urinary NOx. RESULTS: Median NOx/creatinine ratios of active coeliac disease patients, coeliac disease patients on a gluten-free diet, healthy and sick control patients were 1.21, 0.19, 0.10 and 0.13 mmol/mmol, respectively. All active coeliac disease patients showed increased NOx/ creatinine ratios. Urinary NOx/creatinine ratios of the active coeliac disease patients were significantly higher than those of healthy controls (p < 0.0001), sick controls (p < 0.0001) and coeliac disease patients on a gluten-free diet (p < 0.0001). CONCLUSION: The urinary NOx/creatinine ratio is increased in patients with active coeliac disease and reverts to normal on a gluten-free diet.     

Myocardial infarction and atypical Kawasaki disease in a 3-month-old infant

Diagnosing atypical Kawasaki disease (AKD) in children is often difficult and frequently delayed. As a result, children may present with life-threatening cardiovascular complications of the disease. Such complications include myocarditis, coronary artery abnormalities (eg, aneurysms), and myocardial infarction. In this report, we describe the case of a 3-month-old infant who presented to our emergency department in cardiovascular collapse. She was found to have multiple coronary artery aneurysms and a myocardial infarction and was subsequently diagnosed with AKD. This report reviews the diagnostic criteria for Kawasaki disease and AKD, common cardiovascular sequelae, and the presentation of children with these cardiovascular complications.     

Failure to diagnose Kawasaki disease at the extremes of the pediatric age range

To learn about physician practices in diagnosing Kawasaki disease, we surveyed general pediatricians and pediatric infectious disease physicians by questionnaire. A high proportion of general pediatricians (>50%) and infectious disease subspecialists (25%) did not consider the diagnosis of Kawasaki disease in children younger than 6 months and older than 8 years. Failure to consider the diagnosis at the extremes of the pediatric age range puts children at risk because coronary artery abnormalities occur more often in young infants and adolescents with Kawasaki disease.     

Kawasaki disease in India–Lessons learnt over the last 20 years

Over the last 20 years, Kawasaki disease is being increasingly recognized in India and it may soon replace acute rheumatic fever to become the commonest cause of acquired heart disease amongst children. However, the vast majority of children with Kawasaki disease in India are still not being diagnosed. Diagnosis of Kawasaki disease is based on a constellation of clinical findings which have a typical temporal sequence. All pediatricians must we familiar with the nuances involved in arriving at a diagnosis of Kawasaki disease. With early diagnosis and prompt treatment, the risk of coronary artery abnormalities can be significantly reduced.     

CASP3基因一个新的功能性SNP rs72689236与川崎病相关性的Meta分析

目的：综合分析半胱氨酸蛋白酶3基因 (CASP3)一个新的功能性单核苷酸多态位点（SNP） rs72689236与川崎病发生发展的相关性。方法：国内外数据库中检索川崎病与CASP3基因相关性研究的文献,根据纳入与排除标准筛选文献,获取2012年11月以前公开发表的病例-对照研究与家系传递不平衡研究（TDT）的资料,结合作者的相关研究结果,评价质量后采用RevMan 5.1软件进行Meta分析。结果：川崎病患者中rs72689236的A等位基因频率显著增高（P<0.001,OR=1.34,95% CI：1.24~1.46)。rs72689236风险等位基因A的携带者（AG+AA）相较于GG个体,患病风险增加约44% （P<0.001, OR=1.44,95% CI：1.27~1.65）。该SNP的风险等位基因A增加了川崎病并发冠状动脉损伤的风险（P=0.01, OR=1.51,95% CI：1.10~2.07）,携带风险等位基因A的川崎病患者相比于非携带者,并发冠状动脉损伤的风险增加约59%（P=0.05, OR=1.59,95% CI：1.00~2.53）。未发现该SNP与川崎病患者静脉注射免疫球蛋白（IVIG）疗效相关联的证据。结论：CASP3基因功能性SNP rs72689236的A等位基因增加了川崎病的发生风险,该SNP的风险等位基因有可能作为川崎病并发冠状动脉损伤的易感遗传标记。目前还没有足够的证据提示该SNP对川崎病的重要治疗手段IVIG的疗效存在影响,需要更多的相关研究以进一步评价其应用于临床个体化治疗方案选择的可行性。     

川崎病冠状动脉损害易患基因研究进展

川崎病是一种好发于5岁以下儿童的急性全身性中、小血管炎性综合征,该病的病因和发病机制至今尚未明确.流行病学资料显示川崎病的发病存在明显的种族差异,在亚裔人群中的发病率明显高于非亚裔人群.冠状动脉损害是川崎病最为严重的并发症,可导致缺血性心肌病、心肌梗死甚至猝死,未经治疗的患儿约25％会发生冠状动脉损害,而经过治疗的患儿冠状动脉损害发生率仍为5％.近年来该病已取代风湿热成为发达国家儿童获得性心脏病最常见的病因.目前关于冠状动脉损害的研究是川崎病的研究热点,而遗传因素在川崎病及冠状动脉损害的发生过程中起重要作用.研究显示ITPCK、CASP3、TNF-α、CD40、IL-10、PELI1、GRIN3A、CTLA-4、SNX24、LRP1B等多种基因易患性与川崎病冠状动脉损害密切相关,该文就川崎病患儿冠状动脉损害易患基因研究进展作一综述.     

Factor VIII related antigen (von Willebrand's factor) in Kawasaki disease

Kawasaki disease is a systemic vasculitis in which secondary development of coronary artery aneurysms can occur. Because Factor VIII related antigen has been found increased in other vasculiditides, VIII R:Ag was measured serially in patients with Kawasaki disease. Factor VIII related antigen was prospectively evaluated in the acute phase of ten patients with Kawasaki disease, all of whom showed increased values at this stage (p greater than 0001). In six children a second sample was drawn at the convalescent phase, and all were normal. Of the original ten patients, two developed coronary artery aneurysms. Acute Factor VIII related antigen levels were not higher nor did Factor VIII related antigen fail to return to baseline in these two patients. Based on our findings, Factor VIII related antigen is elevated in the acute phase of Kawasaki disease and returns to normal levels in the convalescent phase.     

Prevention of giant coronary artery aneurysms in Kawasaki disease by intravenous gamma globulin therapy

Previous studies have demonstrated the efficacy of intravenous gamma globulin in the prevention of coronary artery abnormalities in Kawasaki disease. We retrospectively reviewed our single-hospital experience with patients in whom Kawasaki disease was diagnosed from January 1979 to July 1987. Only 3 of 68 (4%) patients treated with intravenous gamma globulin in the first 10 days of illness developed coronary artery abnormalities (one of the three had abnormalities before gamma globulin therapy), in comparison with 39 of 119 (33%) patients not treated with gamma globulin (p less than 0.001). Giant coronary artery aneurysms, which are associated with the greatest morbidity and mortality rates in Kawasaki disease, developed in none of the 68 patients treated with gamma globulin but in 7 of 119 patients (6%) not treated with gamma globulin (p = 0.04). Intravenous gamma globulin appears to be effective not only in reducing the overall prevalence of coronary artery abnormalities in Kawasaki disease but, more important, in preventing the formation of giant aneurysms, the most serious form of coronary abnormality after this illness.