川崎病诊治时间还得再提前

科罗拉多州VAIL——一项大规模川崎病儿童患者研究显示，多数冠状动脉异常发生于住院时和接受治疗前。科罗拉多儿童医院Samuel R. Dominguez博士在该院主办的儿科感染性疾病会议指出，这意味着与传统观点相反，并不存在川崎病诊断和治疗的“安全窗口期”。


Samuel R. Dominguez博士

“安全窗口期”的概念可追溯至26年前的一项经典研究，该研究的结论为，在发病第10天之前治疗川崎病患者可大幅降低冠状动脉瘤的发生率，冠状动脉瘤是川崎病最严重的并发症(N. Engl. J. Med. 1986;315:341-7)。由于在临床上观察到的现象与上述结论矛盾， Dominguez医生及其同事决定对该院病例进行一次回顾性分析。

“我们认为，一些患儿发生冠状动脉异常的时间要远远早于根据文献报告得出的结论。并且我们越来越意识到，在出院后冠状动脉病变的发生率也低于我们的预期。”

事实证实确实如此。在4年期间因川崎病被收入院的210例患儿中（所有患儿均接受了正确的静脉免疫球蛋白和阿司匹林治疗），27%在急性期或门诊随访中被发现发生冠状动脉异常。81%的受累儿童是根据入院时首次超声心动图z评分≥2.5确定冠状动脉异常的。21%的受累儿童在发病后5天内被发现有冠脉病变，60%在7天内发现，80%在10天内发现。

Dominguez博士介绍，其他一些相对近期研究的结果也支持其看法。一项对纳入2001~2006年间美国27家儿童医院的近5,200例次川崎病入院信息的儿科健康信息系统数据库的分析显示，3.3%的患者发生冠状动脉瘤，其中81%是在首次住院期间发现的(Pediatrics 2009;124:1-8)。此外，一项儿科心脏网络研究的结论为，入院时超声心动图正常的川崎病患儿仅有6%在之后发生冠脉病变，也就是说多数冠脉异常在入院时已经显现。

有趣的是，在科罗拉多研究中入院时已发生冠脉病变的川崎病患儿中，有46%为不完全川崎病。“这个比例远远高于我们的预期，”Dominguez博士说。“这一现象可能提示，目前有很多川崎病患儿被漏诊和未能及时接受治疗。”

不完全川崎病是新版美国心脏协会指南中提出的一个诊断分类，目的是更早确定川崎病患者的亚型从而更早开始治疗(Circulation 2004;110:2747-71)。对此定义作出更新的基础为：人们认识到婴儿经常无法满足经典的川崎病诊断标准，但这一人群中冠状动脉瘤的发生率很高。新版指南指出，年龄不超过6个月的婴儿如已发热7天而无其他原因可以解释，应接受实验室检查，即使患儿无全身性皮疹、双肺渗出性结膜炎或任何其他经典川崎病的临床标准。如实验室检查发现全身性炎症的证据，则需要进行超声心动检查(Pediatrics 2004;114:1708-33)。

Dominguez博士指出，科罗拉多研究结果表明，为了降低川崎病患儿的冠状动脉异常发生率，需要更早做出诊断和进行必要的治疗。应提高警惕性并在初始诊疗计划中注意使用不完全川崎病的诊断标准以及提早采取超声心动检查，可能有助于对患儿更早进行治疗。“尽管不能保证提早诊治即可预防冠脉病变，但至少可以给患儿带来希望。”

这项科罗拉多研究已于近期发表在《儿科感染性疾病杂志》上(Pediatr. Infect. Dis. J. 2012 July 3 [doi:10.1097/INF.0b013e318266bcf9])。

Dominguez博士披露无相关利益冲突。

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By: BRUCE JANCIN, Cardiology News Digital Network

VAIL, COLO. – The majority of coronary artery abnormalities occurring in a large series of children with Kawasaki disease were detected at the time of hospital admission, prior to treatment.

What this means is that, contrary to the conventional wisdom, there is no such thing as a safe window for diagnosis and treatment of Kawasaki disease, Dr. Samuel R. Dominguez stressed at a conference on pediatric infectious diseases sponsored by the Children’s Hospital Colorado.

The "safe window" concept dates back to a classic 26-year-old study that concluded that treating patients with Kawasaki disease by day 10 of their illness greatly reduced the incidence of coronary artery aneurysms, the most serious disease complication (N. Engl. J. Med. 1986;315:341-7).

Anecdotal experience to the contrary convinced Dr. Dominguez and coworkers at Children’s Hospital Colorado in Aurora that it was time to take a formal look at their institutional experience.

"It was our gestalt that some kids had coronary artery abnormalities much earlier in the course of their illness than what we’d thought from the literature. We had this growing sense that the development of coronary artery lesions was less common after discharge than we’d initially thought," the pediatric infectious disease specialist explained.

Among all 210 patients who were admitted for Kawasaki disease over a 4-year period (all of whom were appropriately treated with intravenous immunoglobulin and aspirin), 27% had coronary artery abnormalities detected during their acute illness or subsequent outpatient follow-up. In 81% of affected kids, the coronary artery abnormalities were identified on the basis of a z score of 2.5 or above on the initial echocardiogram that was obtained at the time of admission. The coronary lesions were identified in 21% of affected children on or before day 5 of their illness, in 60% on or before day 7, and in 80% on or before day 10 of their illness.

The Colorado findings are supported by other fairly recent studies, according to Dr. Dominguez. An analysis of the Pediatric Health Information System database that included nearly 5,200 admissions for Kawasaki disease at 27 U.S. pediatric hospitals during 2001-2006 found that 3.3% of patients developed coronary artery aneurysms, 81% of which were detected during their initial hospitalization (Pediatrics 2009;124:1-8). And a Pediatric Heart Network study concluded that Kawasaki disease patients with a normal echocardiogram on admission had only a 6% incidence of developing coronary lesions at a later time, meaning that most coronary abnormalities were present at admission (Circulation 2007;116:174-9).

Intriguingly, fully 46% of Kawasaki disease patients in the Colorado study who had coronary lesions on admission had incomplete Kawasaki disease.

"That’s a much higher rate than we think of," Dr. Dominguez said. "It raises the concern that many cases of Kawasaki disease may currently be undiagnosed and not treated."

Incomplete Kawasaki disease is a diagnostic category that was created in the revised American Heart Association guidelines in an effort to identify subsets of Kawasaki disease patients earlier so treatment can be started expeditiously (Circulation 2004;110:2747-71). The revision was made in response to recognition that infants often fail to meet the classic diagnostic criteria for Kawasaki disease, yet they have a high incidence of coronary artery aneurysms.

The revised guidelines basically state that infants aged 6 months or younger on day 7 of fever without other explanation should undergo laboratory testing, even if they don’t have a generalized rash, bilateral nonexudative conjunctivitis, or any of the other clinical criteria for classic Kawasaki disease. If lab results yield evidence of systemic inflammation, then echocardiography is warranted (Pediatrics 2004;114:1708-33).

Dr. Dominguez said the clear implication of the Colorado study is that earlier diagnosis and treatment are needed in order to reduce the incidence of coronary artery abnormalities in children with Kawasaki disease. Increased clinical suspicion, greater use of the published algorithm for incomplete Kawasaki disease, and earlier resort to echocardiography in the initial work-up may result in more rapid therapy.

Although there is no guarantee that earlier diagnosis and treatment will prevent coronary lesions, that is the hope, he added.

The Children’s Hospital Colorado study was recently published (Pediatr. Infect. Dis. J. 2012 July 3 [doi:10.1097/INF.0b013e318266bcf9]).

Dr. Dominguez reported having no financial conflicts.