Angiogenesis, tumor necrosis factor-α and procoagulant factors in coronary artery giant aneurysm of a fatal infantile Kawasaki disease

BACKGROUND: Kawasaki disease (KD) is an infantile febrile illness of unknown origin characterized by clinical, laboratory and histopathologic features of systemic vasculitis. METHODS AND RESULTS: We report a 3-month-old female infant with incomplete KD who suddenly died despite intravenous immunoglobulin, aspirin, steroid and heparin treatment. Postmortem examination confirmed the echocardiographically detected giant coronary aneurysms and showed occlusive thrombosis in the giant aneurysm of the left anterior descending coronary artery, associated with neoangiogenesis, macrophage infiltration and immunostaining for tissue factor (a strong initiator of the coagulation cascade), thrombopoietin receptor and tumour necrosis factor-alpha. CONCLUSIONS: These findings show the association of angiogenesis, tumor necrosis factor-alpha and procoagulant factors, with macrophage infiltration in coronary artery aneurysms of a fatal infantile KD.     

70例不完全川崎病临床分析

目的总结不完全川崎病（incomplete KD）的临床特征,以便早期诊治,减轻冠状动脉的病变程度,改善预后。方法回顾性分析2006年1月—2008年12月期间70例住院不完全KD患儿的临床资料：（1）总结不完全性KD的临床特征;（2）分析不完全KD出现冠状动脉病变（coronary artery lesion,CAL）的高危因素（3）总结静脉注射免疫球蛋白对不完全KD的疗效;（4）随访观察其中的患儿,比较IVIG400mg/kg、1g/kg和2g/kg治疗的远期疗效。结果 （1）70例不完全KD中结膜充血出现最早,其他临床症状发生出现较晚;（2）不完全KD发生冠状动脉病变,以冠状动脉扩张的发生率最高;（3）不完全KD发生冠状动脉病变与年龄、性别、血小板、CRP、ESR和接受IVIG的时间有密切关系（P〈0.05）。（4）IVIG400mg/kg较1g/kg和2g/kg治疗组的CAL发生率明显增高,具有统计学意义（P〉0.05）;1g/kg和2g/kg治疗组的CAL发生率差异不大,无统计学意义。结论 （1）不完全KD的临床表现不典型,指趾端脱皮可以作为不完全性KD的诊断依据之一,而超声心动图对不完全KD的早期诊断更为重要;（2）年龄、性别、血小板、CRP、ESR和接受IVIG的时间是不完全KD发生冠状动脉病变的高危因素,不完全KD发生冠状动脉病变以冠状动脉扩张最为常见;（3）IVIG1g/kg和2g/kg治疗不完全KD的疗效相似,较400mg/kg治疗KD的疗效佳。     

Pediatric patients with Kawasaki disease and a case report of Kitamura operation

Kawasaki disease (KD), also called mucocutaneous lymph node syndrome, is an acute, self-limiting, small-vessel vasculitis with an unknown cause that affects children between the ages of 6 months and 5 years. It is the most common cause of acquired coronary artery disease in childhood. Acute myocardial infarction and coronary artery aneurysm are major complications. We present a cohort of patients with KD who were followed up and treated in the Heart Center, North Rhine-Westphalia. Included is a review of important relevant items common to cases of KD, such as clinical data and management, including medical management of the acute condition and the diagnosis and management of coronary vasculitis and aneurysms as well as the application of coronary artery bypass grafting (CABG) in those conditions. Between January 2002 and January 2006, we evaluated the findings and characteristics of 18 pediatric patients with a history of KD and their long-term outcome. The acute illness occurred between the ages of 4 months and 14 years of age. Anomalies of the coronary arteries were found in 6 patients ranging in age from 5 months to 10 years. One patient had acute myocardial infarction; another underwent CABG after 5 years from disease onset at the age of 15 years. Kitamura operation was performed successfully. The other patients are still under observation.Coronary artery aneurysms and stenosis requiring surgery are rare in KD; nevertheless, CABG is the standard therapy when myocardial ischemia is detected. Kitamura operation provides good growth potential and long-term graft patency.     

川崎病并发巨大冠状动脉瘤急性期临床特征与危险因素分析

目的 以川崎病（KD）并发巨大冠状动脉瘤（GCAA）的病例对照研究,分析KD急性期的临床特征,并探讨并发GCAA的危险因素。方法选取2001年5月至2009年5月在广州市妇女儿童医疗中心儿童医院住院的KD并发GCAA患儿为GCAA组;选取同期KD并发中小冠状动脉瘤（CAA）患儿为对照组。对两组患儿的临床特征进行比较,对可能影响GCAA发生的因素进行单因素分析,并进行多因素Logistic逐步回归分析。结果GCAA组纳入22例,其中男19例,女3例,发病年龄3个月至10岁,平均（2．9±2．8）岁。中小CAA组纳入65例,其中男51例,女14例。Pearson χ2检验结果提示,年龄≤6个月或≥5岁、发热时间〉14d、延误诊断、确诊前单独使用糖皮质激素、Hb降低、ESR升高和ALB降低与GCAA发生相关（P均〈0．05）。多因素Logistic逐步回归分析提示,延误诊断（OR=2．998,95％CI：1．004～8．950,P=0．047）,确诊前单独使用糖皮质激素（OR=6．556,95％CI：1．561～28．542,P=0．010）,ESR≥100mm·h^-1（OR=3．591,95％CI：1．164～11．079,P=0．026）为发生GCAA的独立危险因素。结论延误诊断、确诊前单独使用糖皮质激素和ESR≥100mm·h^-1为KD并发GCAA的独立危险因素。     

儿童再发川崎病77例临床特征回顾性分析

目的探讨再发川崎病（KD）的临床特点及其预后。方法收集1994年1月至2012年10月重庆医科大学附属儿童医院收治的KD再发病例,比较初发时和复发时的临床特征、实验室指标和随访资料。并选取5～10年未再发KD病例作为对照组,探讨KD再发可能的危险因素。结果19年间收治KD4875例,其中再发KD77例,再发1次74例,再发2次3例,男：女为1．4：1。再发平均间隔时间1．6年,1年以内再发45．4％（35／77）。发热病程再发时较初发时缩短（7．6±3．1）vs（8．9±3．8）d,P〈0．05;WBC和CRP水平再发时较初发时显著降低,（14．3±5．7）vs（16．2±5．4）×10^9·L^-1和（61±58）vs（95±76）mg·L^-1,P均〈0．05。急性期（病程≤30d）冠状动脉病变（CAL）发生率初发时为17．8％（13／73）,再发时为13．3％（10／75）;应用IVIG后亚急性期（病程〉30d）CAL发生率初发时为11．O％（8／73）,再发时为9．3％（7／75）,组间比较差异均无统计学意义。7例初发时与再发时均有CAL,其中l例初发时与再发时均合并冠状动脉瘤（CAA）。52例KD再发患儿有出院后随访资料,随访时间平均2．1年,其中1例再发时合并左侧冠状动脉主干小型CAA的患儿随访中出现新发部位左前降支瘤样扩张,冠状动脉内径回缩至正常后4年7个月再次出现左侧冠状动脉扩张。多因素Logistic分析显示,年龄〈3岁、性别、热程〉10d、并发CAL及WBC〉20×10^9·L^-1均与KD再发无统计学关联。结论KD再发多发生在1年内。再发KD的CAL总发生率并未升高,初发时合并CAL患儿,再发时更易发生CAL。     

单中心9年不完全川崎病回顾性分析

目的探讨不完全川崎病（KD）的临床特征,以提高临床诊治水平。方法回顾性分析2002年1月至2010年12月KD住院患儿的临床资料,比较不完全KD与典型KD在发病年龄、性别、临床表现、实验室检查、治疗及冠状动脉损害等方面的差异。结果 1484例KD患儿进入分析,其中不完全KD262例（17.6%）,典型KD1222例;〈1岁患儿中不完全KD占24.9%。不完全KD和典型KD患儿的平均发热时间分别为（7.8±5.0）和（6.7±3.6）d,差异有统计学意义。不完全KD四肢改变、多形皮疹、眼结膜充血、口唇改变、颈部淋巴结肿大和肛周改变的发生率显著高于典型KD;卡疤改变、扁桃体肿大、阴囊或外阴改变、呕吐和腹泻的发生率与典型KD差异无统计学意义。两组CRP、ESR、Hb、WBC、PLT、ALT、AST、CK-MB和LDH等实验室指标差异无统计学意义。不完全KD与典型KD患儿对IVIG无反应的发生率差异无统计学意义（14.1%vs17.5%）;不完全KD患儿冠状动脉扩张、冠状动脉瘤和巨大冠状动脉瘤的发生率分别为57.5%、14.1%和1.9%,典型KD患儿分别为31.5%、5.9%和0.6%,两组差异有统计学意义。结论不完全KD较典型KD发热时间长,且冠状动脉损害发生率高,但实验室指标差别不大。     

Sudden infant death caused by a ruptured coronary aneurysm during acute phase of atypical Kawasaki disease

This article describe's a case of atypical Kawasaki disease (AKD) with lack of typical clinical signs and rapid fatal course in a 2-month-old infant, who 1 week before hospitalization demonstrated rhinitis, coughing without fever, and later conjunctival hyperemia and allergic exanthema on chest and arms. On admittance, labwork highlighted the following: leukocytosis, thrombocytosis, elevated sedimentation rate, and positive C-reactive protein. General conditions remained mediocre for 7 days until sudden death occurred. The autopsy confirmed death caused by cardiac tamponade caused by a ruptured inflammated aneurysm of the left anterior descending coronary artery. We believe that the currently accepted clinical diagnostics criteria for KD in infants 2 years of age or younger can cause missed in vita diagnosis of AKD. For such, any typical clinical sign of KD whenever associated with thrombocytosis and elevated indices of phlogosis, should led to suspicion of KD and permit cardiovascular examination, and thus early treatment.     

An evaluation of children with Kawasaki disease in Istanbul: a retrospective follow-up study

BACKGROUND:

Kawasaki disease (KD) is an acute, self‐limiting vasculitis of unknown etiology. The incidence of KD is increasing world wide. However, the epidemiological data for KD in Turkey has not been well described.

OBJECTIVE:

To describe the demographic, clinical, and laboratory features of children with KD who were diagnosed and managed in the American Hospital, Istanbul, Turkey.

METHOD:

Patients with KD were retrospectively identified from the hospital discharge records between 2002 and 2010. Atypical cases of KD were excluded. A standardized form was used to collect demographic data, clinical information, echocardiography and laboratory results.

RESULTS:

Thirty‐five patients with KD, with a mean age of 2.5±1.9 years, were identified. Eighty‐five point seven per cent of patients were under 5 years of age. A seasonal pattern favouring the winter months was noticed. In addition to fever and bilateral conjunctival injection, changes in the oral cavity and lips were the most commonly detected clinical signs in our cases. Coronary artery abnormalities were detected in nine patients. The majority of our patients had started treatment with intravenous immunoglobulin in the first 10 days of the onset of fever, and only one patient required systemic steroids for intravenous immunoglobulin‐resistant KD. The coronary artery abnormalities resolved in all nine patients within 8 months.

CONCLUSION:

This study is the most comprehensive series of children from Turkey with KD included in Medline. As adult‐onset ischemic heart disease may be due to KD in childhood, further prospective clinical investigations are needed to understand the epidemiology, management and long‐term follow‐up of the disease.     

Coronary artery aneurysm: management and association with abdominal aortic aneurysm.

BACKGROUND: Coronary artery aneurysm (CAA) is a dilatation that exceeds 1.5 times the diameter of a normal adjacent coronary artery. Several studies suggest that pathogenetic mechanisms involved in this disease and in abdominal aortic aneurysm (AAA) are similar. Surgery for CAA is mandatory when the aneurysm is three to four times larger than the original vessel diameter. We reviewed our experience in the surgical treatment of this unusual disease and analyzed its association with AAA. MATERIALS AND METHODS: Between October 1993 and March 2005, 11 patients (9 men; mean age=66 years) underwent surgery for CAA. In all cases, coronary aneurysms were diagnosed as incidental findings in coronary angiographies. The coronary aneurysms were isolated and longitudinally incised: the proximal and distal openings were identified and sutured. The sacs were obliterated with running sutures. Myocardial protection was achieved by retrograde cardioplegia only. Coronary artery bypass grafting was performed distally to the excluded aneurysms in all patients. RESULTS: One patient died of respiratory failure early after the operations; all other patients are alive, asymptomatic for angina, and free from repeated acute myocardial infarction after a median follow-up of 76 months (range=4-141 months). A total of six patients underwent surgical repair or endoprosthesis implantation because of AAAs. CONCLUSIONS: Our operative techniques ensured durable results. We recommend screening for abdominal aneurysms in all affected patients because of the frequent association between CAA and AAA as a result of their similar pathogenetic mechanism.     

Diagnosis and classification of Kawasaki disease

Kawasaki disease is an acute systemic vasculitis of unknown etiology. Diagnosis is based on clinical criteria that include fever, exanthema, conjunctivitis, changes in the extremities, erythema of oral mucosa and lips and cervical lymphadenopathy. However, these criteria have low sensitivity and specificity and therefore, other clinical and laboratory features may be helpful in establishing the diagnosis, especially for cases of atypical or incomplete Kawasaki disease. Prognosis depends on the extent of cardiac involvement; coronary aneurysms develop in 20–25% of untreated patients and these may lead to myocardial infarction and sudden death. Treatment with high-dose intravenous immunoglobulin is effective in reducing the risk of coronary aneurysms in most cases and is the treatment of choice for initial Kawasaki disease.     

儿童川崎病临床特征分析

目的:分析并比较典型川崎病(KD)与不典型川崎病(IKD)的临床特征。方法:回顾性分析2017-01-01—2017-12-31武汉大学人民医院儿科收治的69例患儿的临床资料,将其分为IKD组(n=25)和KD组(n=44),比较两组患儿的临床特征。结果:两组患儿发热发生率均为100%,IKD组持续发热时间、确诊时间及临床治愈时间均明显高于KD组(P<0.05或P<0.01);两组患儿皮疹、颈淋巴结肿大、口唇皲裂及杨梅舌发生率差异无统计学意义(P>0.05);IKD组手足硬性水肿发生率低于KD组(P<0.05);IKD组肛周脱皮、卡疤红肿、冠状动脉损伤发生率均高于KD组(P<0.05)。结论:IKD具有发热时间久,早期不易确诊,冠状动脉损伤发生率高的特点,影响患儿预后,需早期识别诊断。     

Age-related differences in clinical characteristics of Kawasaki disease

This study aimed to examine and summarize clinical characteristics of Kawasaki disease (KD) at different ages to further strengthen clinicians understanding of children with KD, improving the level of diagnosis, and reducing coronary artery complications of KD. A total of 398 patients with KD who were diagnosed between January 2016 and December 2017 were reviewed retrospectively. These participants were allocated into three groups according to age: group A (<1 year, n=62), group B (≥1 and <5 years, n=286), and group C (≥5 years, n=50). Clinical manifestations, laboratory results, and echocardiographic findings were compared among the groups. Most (71.86%) patients with KD were aged 1-5 years. The prevalence of cervical lymphadenopathy was lowest in group A. The duration of fever before admission was longest in group A. The rate of cervical lymphadenopathy and laboratory data were different among the groups. Group A had higher frequencies of gastrointestinal involvement, neurological symptoms, and redness at the Bacillus Calmette-Guerin inoculation site than the other groups. Infants aged <1 year with KD often have a longer duration of fever before admission, a lower prevalence of cervical lymphadenopathy, and a higher prevalence of gastrointestinal and neurological symptoms.     

Sudden death in a 21-year-old man caused by thrombosed coronary aneurysm: Late sequelae or a very late onset of Kawasaki disease?

Kawasaki disease (KD; mucocutaneous lymph node syndrome) is an infantile febrile illness of unknown origin that occurs in worldwide epidemics. The main clinical features of the disease, such as fever, mucositis, cervical lymphoadenopathy and skin rash, associated with coronary aneurysms or arteritis are diagnostic. Late sequelae of coronary arteritis are very rare in the second decade of life; we describe the case of a 21-year-old male who died suddenly. The autopsy revealed a large thrombotic coronary aneurysm, coronary arteritis and myocarditis, supporting the diagnosis of a late fatal sequela of KD. The hypothesis of a very late onset of the disease is also considered and discussed.     

不同时间应用静脉丙种球蛋白治疗川崎病疗效分析

目的探讨不同时间应用大剂量静脉丙种球蛋白（IVGG）治疗川崎病（KD）疗效,分析其热程及冠状动脉损害（CAL）情况。方法将79例在初次发病10d内接受大剂量IVGG治疗的住院KD患儿按IVGG应用时间不同分成两组,≤6d为A组（32例）,7～10d为B组（47例）;将两组CAL情况及其他临床资料进行对比分析。结果两组病例性别、年龄、ESR、CRP、WBC、HGB、PLT、ALB均衡可比。两组热程比较A组（7.00±0.87）d短于B组（9.00±1.00）d,差异有显著性（P〈0.001）;A组无CAA发生,B组2例发生CAA;发病21d内CAL发生率A组37.5%（12例）低于B组46.8%（22例）,差异无统计学意义（P=0.412）。结论KD发病早期应用IVGG治疗,可缩短热程,减少CAA发生。建议KD确诊病例尽早应用大剂量IVGG治疗。     

超声心动图和64层螺旋CT冠状动脉成像在川崎病冠状动脉瘤随访中的应用价值

目的探讨超声心动图和64层螺旋CT冠状动脉成像（64SCTCA）在川崎病（KD）冠状动脉瘤临床诊断和随访中的应用价值。方法选择2006年12月至2007年5月在首都医科大学附属北京儿童医院门诊随访的KD并发冠状动脉瘤患儿作为研究对象。患儿观察终点随访时依据病变程度除行超声心动图检查外,同时行64SCTCA检查,对各项检查结果进行详细描述,并分析其应用价值。结果研究期间纳入15例患儿,急性期KD超声心动图检查显示急性期累及冠状动脉48／60支（80％）。患儿观察终点随访9个月至8．6年,平均（2．8±2．0）年,超声心动图示14／48支（29．2％）冠状动脉瘤或扩张消退,其余进一步扩张或无明显变化,累及冠状动脉34／60支（56．7％）,同时检测出2处血栓,未发现狭窄及钙化。64SCTCA示累及冠状动脉30／60支（50％）,主要累及右冠状动脉和左前降支,分布部位与超声心动图检查基本一致,64SCTCA与超声心动图检查对冠状动脉瘤最大内径的测量值具有较好的相关性（r=0．837,P〈0．001）,64SCTCA发现4处血栓、5处钙化及3处狭窄。结论64SCTCA和超声心动图在KD并发冠状动脉瘤患儿的随访中具有各自的应用价值,两种方法的联合应用可增加冠状动脉病变的检出率。     

Kawasaki disease: characteristics,diagnosis, and unusual presentations

ABSTRACT

Introduction: Kawasaki disease (KD) is one of the commonest pediatric vasculitides and is associated with a significant risk of development of coronary artery abnormalities if left untreated.

Areas covered: In this review, we have highlighted the incomplete and unusual presentations of KD and also emphasize the controversies pertaining to 2D echocardiography in KD. A PubMed search was performed regarding diagnosis and unusual presentations of KD.

Expert opinion: Diagnosis of KD is essentially clinical and based on recognition of typical clinical features that may appear sequentially and all signs and symptoms may not be present at one point of time. There is no confirmatory laboratory test for diagnosis of this condition. Further complicating the picture is the fact that incomplete and atypical forms KD may be seen in up to 50% patients. Although 2D echocardiography continues to be the preferred imaging modality for cardiac assessment in patients with KD, it has its limitations.     

Intravascular ultrasound findings of coronary wall morphology in a child with Kawasaki disease

Intravascular ultrasound (IVUS) imaging was performed to assess the coronary wall morphology in detail at 22 months after the onset of Kawasaki disease in a girl who had developed coronary aneurysms at 4 yr of age. The sites of persistent aneurysms demonstrated a dilated lumen with a marked symmetrical or asymmetrical thickening of the intima-media complex. This pathologic finding was also present in angiographically normal vessels near an aneurysm but with a mild thickening. Coronary artery calcification was observed at one site in the aneurysms. The sites of normal coronary artery far from an aneurysm showed normal intravascular ultrasound findings with no measurable intima-media complex. Our case indicates that the healing process may continue via cell proliferation, with extension to the proximity of the coronary aneurysms. IVUS is useful to evaluate the coronary wall morphology and may be valuable in the long-term follow-up of coronary lesions due to Kawasaki disease.     

Pathogenesis of Kawasaki disease

Kawasaki disease (KD) most frequently affects infants and young children under 5 years of age. This disease is considered a kind of systemic vasculitis syndrome, and primarily invades the medium-sized muscular arteries, including coronary arteries. Diagnosis of KD is based on characteristic clinical signs and symptoms, which are classified as principal clinical findings and other clinical and laboratory findings. Even though the aetiology of KD is unknown, epidemiological data suggest that some kinds of infectious agents are involved in the onset of KD. In addition, the data indicate that host genetics underlie the disease's pathogenesis. Histologically, coronary arteritis begins 6-8 days after the onset of KD, and leads immediately to inflammation of all layers of the artery. The inflammation spreads completely around the artery; as a result, structural components of the artery undergo intense damage; the artery then begins to dilate. Inflammatory cell infiltration continues until about the 25th day of the disease, after which the inflammatory cells gradually decrease in number. KD arteritis is characterized by granulomatous inflammation that consists of severe accumulation of monocytes/macrophages. Aberrant activation of monocytes/macrophages is thought to be involved in the formation of vascular lesions. The lesions in all the arteries are relatively synchronous as they evolve from acute to chronic injury. There is no fibrinoid necrosis nor any mixture of acute inflammatory lesions and scarring lesions, which are characteristics in polyarteritis nodosa in KD.     

Kawasaki disease: clinical spectrum of 88 patients in a high-prevalence African-American population

Kawasaki disease (KD) is a systemic vasculitis that predominantly affects infants and young children. Asian race has been described as an important factor for the development of this disease. We reported our experience in a cohort of patients with KD. Clinical and laboratory data from initial presentation and follow-up visits were reviewed in 88 patients with KD treated at Children's Hospital of New Orleans between March 1993 and November 2004. Forty-nine (56%) patients were African American, 35 (40%) Caucasian, two (3%) Asian and two (3%) Hispanic. Coronary artery aneurysms (CAAs) were detected in 15 (17%) patients. CAAs were less frequent in African-American patients compared to Caucasians [relative risk (RR)=0.2, 95% CI: 0.04400-0.8405, p=0.0164]. Eighty-three patients responded to one dose of intravenous human immunoglobulin (IVIG), five patients responded to a second infusion of IVIG, and two who were IVIG resistant responded only following methylprednisolone pulse. Hemoglobin (Hb) levels of <10 g/dl and presence of polymorphic rash were significantly correlated with development of CAAs. No deaths were observed.     

Kawasaki Syndrome

Kawasaki syndrome (KS) is an acute, sometimes fatal vasculitis of young children. KS has replaced acute rheumatic fever as the most common cause of acquired heart disease in children in the United States. The illness is manifested by prolonged fever, conjunctival injection, enanthem, exanthem, erythema and swelling of the hands and feet, and cervical adenopathy. These acute features of illness are self-limiting, but coronary artery abnormalities occur in 20% of untreated patients. The etiology of the illness is unknown, but its clinical and epidemiologic features are most consistent with an infectious cause. Common cardiovascular manifestations of the illness include myocarditis, pericardial effusion, and coronary artery aneurysm formation. Treatment with intravenous gamma globulin (IVGG) and aspirin within the first 10 days of illness reduces the prevalence of coronary artery abnormalities from 20% in those treated with aspirin alone to 4%. Patients who develop coronary artery aneurysms, particularly those who develop giant coronary artery aneurysms, may suffer myocardial infarction secondary to thrombosis or stenosis in the abnormal vessel. Additional research to determine the cause of KS is urgently needed to allow for improved diagnosis, more specific therapy, and prevention of the disorder.