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一位医生毕生致力于解谜川崎病(双语)

已有 823 次阅读 2024-3-3 09:01 |个人分类:Health & Health-Care System|系统分类:科普集锦

译者:早就听说过川崎病,一种罕见的儿童疾病。没有想到,它的起因在“大气中”。

 

一位医生毕生致力于解谜一种儿科罕见病

40 年来,简·伯恩斯 (Jane Burns) 医生一直致力于寻找川崎病的病因。川崎病是一种会导致动脉瘤和心脏病的疾病。 她的研究聚集了一个非常独特的团队。

 

作者:艾米莉·鲍姆加特纳(NYT)

摄影:Ariana Drehsler

2024 年 2 月 27 日

它看起来就像电视犯罪节目“CSI”中的场景。【电视剧CSI:Crime Scene Investigation 简·伯恩斯医生正在圣地亚哥郡法医办公室的多头显微镜下,仔细观察一系列神秘死亡事件的尸检样本。

这样本来自一名 20 岁柔术斗士的心脏。他去健身房后两天,被发现死在床上。 没有任何谋杀或自残的迹象。

载玻片上的血管组织看起来异常。 伯恩斯医生转向检验官:“我想这可能是我的(研究对象)。”

伯恩斯医生是研究一种罕见的儿童疾病,川崎病,的专家。这种疾病是全世界儿童患心脏病的最常见原因。 这也是儿科医学最大的谜团之一:没有人知道它的病因。

伯恩斯医生是加州大学圣地亚哥分校川崎病研究中心的负责人。她一生致力于解开这个谜团。

这种疾病通常发生在 5 岁以下的儿童中,很容易被忽视:没有诊断测试,其症状——高烧、皮疹、嘴唇发红、干裂和“草莓舌”——在许多医生看来就像猩红热, 麻疹或蜱传疾病,尽管其标志性特征是眼睛布满血丝。【译者:眼睛布满血丝是特征。】

川崎病通常可以在几周内自行痊愈。 但如果没有正确的治疗,大约四分之一的患者会出现冠状动脉瘤,这可能会导致突发心脏病和死亡。这种死亡可能在几年或几十年后发生——就像伯恩斯医生正在分析的那位年轻人身上发生的情况一样。

伯恩斯医生和其他科学家认为,儿童从父母那里遗传了某种程度的对该病的易感性,并且这种疾病是由他们吸入的某种物质引起的,无论是病毒、细菌还是毒素。 气候科学家想知道全球变暖是否也会扩大这种疾病的范围。【译者:我被吸引住了。】

她的研究中心的冰箱里保存着世界上最大的川崎病样本生物库。伯恩斯医生在病人和死者身上寻找线索,希望最终能找到罪魁祸首。 她认为,通过确定原因,研究人员可以开发诊断测试,从而获得更及时的治疗并防止更多死亡。

为了实现这一目标,她建立了一个独特的侦探研究团队——海洋学家、统计学家、心脏病学家、历史学家、法医病理学家、微生物学家、人类学家、和其他人——每个人都有特定的专业知识。经过 40 年的调查,该团队可能已经拥有完成这项研究任务的工具。

“这确实是一个探索——一个谜题——但简(即伯恩斯医生)顽强地坚持不懈,”斯克里普斯海洋学研究所的气候学家丹尼尔·卡扬说。卡扬加入了伯恩斯医生的团队,帮助研究气候变化如何影响这种疾病。 “这里有一位出色的组织者和无所畏惧的领头人;他们竭尽全力,全力追击。”

答案来得正是时候。 在日本,川崎病最为猖獗,该病的发病率正在以惊人的速度增加;而美国的医生现在发现,在发病率保持稳定的几年后,川崎病的发病率急剧上升,很可能是因为一些儿童受到了(疫情)大流行时期的社会疏远措施期间的保护,免受川崎病的侵害。

今年,圣地亚哥拉迪儿童医院收治的川崎病患者数量是美国最多的;该医院的医生接诊的病例数是平时的两倍。 波士顿、科罗拉多州和芝加哥的医院也报告了病例激增的情况。

“在我们国家的某个地方,每天都有一个患有 K.D.(即川崎病) 的孩子。 这些病孩常常被误诊,”伯恩斯医生说。 “在此之前,我们没有工具、团队、样本、和数据来真正攻击这种疾病。 现在我们做到了,所以让我们开始吧。”

她补充道,“我们花了半个世纪才走到这一步,但现在我们已经准备好了。”

从儿童游戏室到大气(环流)

川崎病第一次引起伯恩斯医生的注意是在 1981 年。当时她还是一名年资住院医生,负责照顾一名发烧、伴有神秘皮疹的 3 个月大婴儿。 婴儿死了。 伯恩斯医生观看了尸检;当胸部被打开时,她简直不敢相信自己的眼睛:动脉瘤在婴儿心脏的表面上呈珠状排列。

婴儿的父母挨家挨户收集零散的捐款,最后用一个棕色纸袋子将 1,500 美元交给伯恩斯医生,请她研究这种疾病。 伯恩斯医生说服了很多资深教授来帮助她;在第一次见面时,他们就挤在医院病房的游戏间里,蹲在儿童椅上集思广益,制定了一个计划:神经科主任将派出一名研究员进行脑电图检查; 免疫学家会研究 T 细胞的作用。 伯恩斯医生作为主要合作者的职业生涯就此诞生。

在她研究调查的最初几年,川崎病的流行病学看起来很像人与人之间传播的经典感染。 20 世纪 70 年代末和 80 年代,日本发生了三次大规模的全国性流行病,每次都非常剧烈,表明一种新型病原体正在高危人群中传播。 每个阶段之后都会有一段稳定期,通常持续数年。

但到了 20 世纪 90 年代,事情开始变得奇怪了。 尽管出生率下降,但日本患有这种疾病的学龄儿童数量仍在不断增加,这表明每年有越来越多的儿童接触到这种神秘的治病原。

伯恩斯医生研究了一系列潜在的触发因素,包括地毯清洁【译者:需要用地毯清洁剂】。 她和她的丈夫约翰·戈登(John Gordon)医生治疗了数十名漏诊的川崎病成年患者。约翰·戈登是一名心脏病专家。他们在圣地亚哥的家中接待了最早发现这种疾病的医生川崎富作(Tomisaku Kawasaki)医生。 伯恩斯医生前往日本采访了每一位曾参与识别这种新疾病的在世(日本)人。 但开展此类工作的资金很少。

到 2000 年,伯恩斯医生的一名学生注意到:只要下雨,圣地亚哥的川崎病病例就会增加。 伯恩斯医生与气候学家卡扬博士和日本研究人员合作发现,日本的病例随着季节节奏而上升和下降,而且与人与人之间的疫情相比,病例水平在全国大部分地区总是奇怪地保持一致性。

后来,她和包括欧洲气候科学家 Xavier Rodó 在内的同事分析了日本 247,000 多名患者的记录,发现这种疾病最大规模的爆发有一些奇特的共同点:它们都发生在大规模中亚气流过境的时候。 当这些风吹到夏威夷和加利福尼亚州时,那里的病例也有所增加。

就在那时,伯恩斯医生和她的同事开始建议:导致儿童川崎病的原因不仅仅是在人与人之间传播。 “它”可能被风吹到世界各地。

对于一些人来说,有生命的颗粒似乎不太可能在穿越冰冷的对流层的旅程中幸存下来。但伯恩斯医生无法放弃这个假设。她经常在实验室中冷冻病毒以保存它们。

研究小组在等到预计“致病颗粒”可能出现在空中时,派出一架飞机飞越日本上空收集空气样本。 在哥伦比亚大学微生物学家伊恩·利普金的帮助下,他们对过滤器里的空气样本进行了处理。他们发现了一种名为念珠菌的真菌。 但这仍然只是一种可能性——并不是一个确定的致病原因——资金再次枯竭。

 

大自然实验

近年来,伯恩斯医生为她的博学团队招募了新成员,其中包括加州大学环境科学家詹妮弗·伯尼(Dr. Jennifer Burney)博士。 圣地亚哥和数据分析师劳雷尔·德哈恩(Laurel DeHaan) 。他们帮助分析了日本近 50 万川崎病患者30年来的记录,并按年龄和地区对他们进行了分类。

他们的发现很奇怪:近几十年来,3岁以上儿童的发病率增加了五倍,但婴儿的发病率始终保持相对平稳。 更重要的是,不同年龄段的病例季节周期完全不同。

幼儿的年度高峰发生在 2010 年代中期,当时日本政府大幅扩大了家庭的日托选择。

2020 年,一个大自然的实验机会出现了。 新冠疫情爆发导致学校停课;美国儿童川崎病发病率下降了 28%。 但儿童之间传播的最常见呼吸道病毒几乎完全消失,而川崎病却没有——事实上,12 个月以下患有川崎病的儿童数量根本没有太大变化,这表明家庭内的一些“因子”仍在继续影响婴儿。

新加入的查尔斯·科普兰 (Charles Copeland) 表示,大气可能“复杂而混乱”。他利用历史记录和超级计算机天气模型来估计自 20 世纪 70 年代以来全球每小时的风型(wind patterns)。 (他使用一种名为 HYSPLIT 的程序来反向追踪粒子,该程序基于冷战期间开发的一款软件,用于追踪放射性粒子回到其起源。)他在最近的一次团队会议上表示,目标是弄清楚历史上川崎病的随机爆发与特别异常的风型有关。

他说:“要真正尝试解开这个谜团并深入了解这是否确实是一个和“风”有关系的故事,我们必须提出正确的问题。” “如果你问错了问题——在错误的假设下——我认为你会得到错误的答案。”

一个被遗漏(误诊)的案例 —或是两个

在伯恩斯医生领导的圣地亚哥拉迪儿童医院川崎病诊所,照顾受川崎病影响的儿童始终与寻找病因联系在一起。

最近的一个星期三早上,儿科心脏病专家 Kirsten Dummer 医生正在检查一名 2 岁儿童的心脏扫描结果;该儿童的心脏右侧有一个大动脉瘤的迹象。

“家长们最想知道的问题是:这是怎么发生的? 我的孩子是怎么得到这个病的? 在每个病房里,这就是他们最想知道的,”她说。 “年复一年,他们回来问我们,‘你们知道更多(的东西)了吗?’”

伯恩斯医生继续亲自看诊,她说这些家长的询问激励了她。

伯恩斯医生说,“如果我们都是(仅仅在)实验室里研究川崎病病因学的博士们”,那么研究的步伐就会有所不同。 “但这(项研究)很紧迫,因为我们要来来回回,从实验室到患者,说,‘该死,我需要回答这个问题。’这很重要,因为这对这些患者很重要。”

那天早上(晚些时候),伯恩斯医生宣布了这一消息,当时穿着美人鱼装的 4 岁女孩伊内兹·马尔多纳多·迭加 (Inez Maldonado Diega) 和她的母亲一起滚出了培乐多球(balls of Play-Doh)。 17天前,女孩的儿科医生诊室错过了她的川崎病诊断。 超声心动图检查结果显示,她的心脏到目前为止是健康的,但她仍然发烧,这意味着川崎病可能会持续存在。

“很遗憾,我们没有早点替她诊断,”伯恩斯医生一边说,一边听着伊内兹的心跳。她要求伊内兹和她的母亲为她的生物库提供基因样本,并解释说,孩子们可能从父母那里遗传了对该疾病的易感性。

伊内兹的母亲蒂亚拉·迭加 (Tiara Diega) 向伯恩斯医生保证,她小时候从未患过川崎病,只是得了猩红热。 伯恩斯医生扬起眉毛,让迭加女士用免提电话给她母亲打电话。

她问迭加女士的母亲,迭加女士多年前感染时是否眼睛充血? 是的,母亲说。 伯恩斯医生缓缓地吐出一口气。

“你(小时候)得的不是猩红热,”她说。

在那一瞬间,房间非常地安静——迭加女士在半空中还拿着一块培乐多——因为母女俩都意识到了迭加女士所面临的风险。伯恩斯医生建议迭加女士去做心脏扫描—— 看看这些年来是否有严重的危险正在她的体内酝酿。

 

艾米丽·鲍姆加特纳 (Emily Baumgaertner) 是《The Times》(NYT)的国家卫生记者,关注主要影响弱势群体的公共卫生问题。

 

 

A Doctor’s Lifelong Quest to Solve One of Pediatric Medicine’s Greatest Mysteries

For 40 years, Dr. Jane Burns has been working to find the cause of Kawasaki disease, an illness that can lead to aneurysms and heart attacks. Her work has brought together a most unlikely team.

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By Emily Baumgaertner

Photographs by Ariana Drehsler

Feb. 27, 2024

It looked like a scene from the TV crime show “CSI.” Dr. Jane Burns was peering into a multiheaded microscope at the San Diego County medical examiner’s office, scrutinizing autopsy samples from an array of mysterious deaths.

 

This one was from the heart of a 20-year-old jiu-jitsu fighter who was last seen at the gym and was found dead in his bed two days later. There were no signs of foul play or self-harm.

The blood vessel tissue on the slide looked abnormal. Dr. Burns turned to the examiner: “I think this was likely one of mine.”

Dr. Burns is an expert in a rare childhood illness called Kawasaki disease, which is the most common cause of acquired heart disease in children worldwide. It is also one of pediatric medicine’s greatest mysteries: No one knows what causes it.

And Dr. Burns, who leads the investigations at the University of California San Diego’s Kawasaki Disease Research Center, has devoted her life to solving that mystery.

The condition, which usually occurs in children under 5, is easy to miss: There is no diagnostic test, and its symptoms — a high fever, rash, red cracked lips and a “strawberry tongue” — look to many doctors like scarlet fever, measles or a tick-borne illness, despite its signature distinction of bloodshot eyes.

Kawasaki disease can often resolve itself in a matter of weeks. But without the right treatment, about a quarter of patients develop aneurysms of the coronary arteries, which can lead to sudden heart attacks and death, even years or decades later — as apparently happened to the young man whose tissue Dr. Burns was analyzing.

Dr. Burns and other scientists believe that children inherit some level of susceptibility to it from their parents and that the condition is then brought on by something they breathe in, whether a virus, a bacteria or a toxin. Climate scientists wonder if global warming could also be broadening the disease’s scope.

Her freezers hold the world’s largest biobank of Kawasaki disease samples, and she scours for hints — in both the living and the dead — in hopes of eventually discovering the culprit. She believes that by determining the cause, researchers could then develop diagnostic tests that would lead to more timely treatment and prevent more deaths.

 

To get there, she has built a most unlikely network of detectives — an oceanographer, a statistician, a cardiologist, a historian, a forensic pathologist, a microbiologist, an anthropologist and others — each with specific expertise. And after 40 years of sleuthing, she believes, the team might just have the tools to complete the mission.

“This is a quest indeed — a puzzle — but Jane is doggedly persistent,” said Daniel Cayan, a climatologist at the Scripps Institution of Oceanography who has joined Dr. Burns’s team to help investigate how climate variability could be influencing the disease. “Here you have a marvelous organizer and fearless ringleader, pulling on every string and angle, chasing this.”

Answers could not come at a better time. The rate of Kawasaki disease in Japan, where it is most rampant, is increasing at an alarming rate, and doctors in the United States are now seeing a jump in cases after years when the rate remained steady, most likely because some children were protected from exposure during pandemic-era social distancing measures.

This year, doctors at Rady Children’s Hospital-San Diego, which admits the largest number of Kawasaki disease patients in the United States, have seen double the usual number of cases. Hospitals in Boston, Colorado and Chicago have also reported surges.

“Every day in our country, somewhere, a child with K.D. is being misdiagnosed,” Dr. Burns said. “Before now, we didn’t have the tools and the teams and the samples and the data to really attack this disease. Now we do, so let’s get moving.”

She added, “It’s taken a half century to get here, but now we’re ready to roll.”

 

From a children’s playroom to the atmosphere

Kawasaki disease first captured Dr. Burns’s attention in 1981 when she was a senior medical resident and cared for a feverish 3-month-old baby with mysterious rashes. The baby died. Dr. Burns watched the autopsy and, when the chest was opened, could not believe her eyes: Aneurysms beaded on the surface of the infant’s heart.

The baby’s parents went door to door collecting donations in loose bills and eventually handed $1,500 to Dr. Burns in a brown bag, asking her to research the disease. Dr. Burns persuaded so many senior professors to help her that, for their first meeting, they crammed into the hospital ward’s play space, squatting in children’s chairs to brainstorm a plan: The head of neurology would volunteer a fellow to run electroencephalograms; an immunologist would study the role of T-cells. Dr. Burns’s career as master collaborator was born.

In the early years of her investigation, the epidemiology of Kawasaki disease looked much like a classic infection passed between people. There were three large nationwide epidemics in Japan in the late 1970s and the 1980s, each so drastic that it suggested a novel agent was moving through a highly susceptible population. Each was followed by a plateau period, typically of several years.

But in the 1990s, things began to look strange. The number of school-age children with the disease in Japan kept climbing, despite a falling birthrate, hinting that more and more children were being exposed to its mystery cause each year.

Dr. Burns looked into an array of potential triggers, including carpet cleaning. She and her husband, Dr. John Gordon, a cardiologist treating dozens of adult patients with missed cases of Kawasaki disease, hosted the physician who had first identified the disease, Dr. Tomisaku Kawasaki, at their San Diego home. Dr. Burns went to Japan to interview every living person who had ever been involved in recognizing a new disease there. But there was little funding to pursue such work.

 

By 2000, a student of Dr. Burns’s noticed that Kawasaki disease cases in San Diego climbed whenever it rained. Dr. Burns partnered with Dr. Cayan, the climatologist, and Japanese researchers to discover that cases in Japan rose and fell with seasonal rhythms and that, in contrast to what is seen with person-to-person outbreaks, the case levels were always oddly consistent across broad swaths of the country.

Later, she and colleagues including a European climate scientist, Xavier Rodó, analyzed records of more than 247,000 patients in Japan to discover that the biggest outbreaks of the disease had something peculiar in common: They had all occurred when large-scale wind currents were blowing in from Central Asia. When those winds reached Hawaii and California, cases climbed there, too.

It was then that Dr. Burns and her colleagues began to argue that whatever was causing Kawasaki disease in children was not just passing from person to person; it was possibly being blown across the world on the wind.

It seemed unlikely to some that living particles could survive a journey through the icy troposphere — but Dr. Burns, who routinely froze viruses to preserve them in the lab, couldn’t shake the theory.

The team waited until the agent was expected to be present in the air and then dispatched an airplane to fly over Japan and collect air samples. With the help of Ian Lipkin, a microbiologist at Columbia, they processed the filters and found a type of fungus called Candida. But it was still just an association — not a sure cause — and funding once again ran dry.

 

A natural experiment

In recent years, Dr. Burns has recruited new members to her polymathic team, including Dr. Jennifer Burney, an environmental scientist at U.C. San Diego, and Laurel DeHaan, a data analyst, who came aboard to help them analyze the records of almost half a million Kawasaki disease patients in Japan over three decades, stratifying them by age and region.

What they found was bizarre: The rate of cases among children over 3 years old had increased fivefold in recent decades, but the rate among infants had remained relatively flat the whole time. What’s more, the seasonal cycle of cases for the age groups was completely different.

The annual peak for toddlers shifted in the mid-2010s — around the time the Japanese government dramatically expanded day care options for families.

In 2020 came a natural experiment. The dawn of the Covid pandemic brought school closures, and Kawasaki disease among children in the United States fell by 28 percent. But most common respiratory viruses that are transmitted between children faded away almost entirely, and Kawasaki disease did not — in fact, the number of children under 12 months with Kawasaki disease did not change much at all, hinting that some exposure inside homes continued to affect infants.

The atmosphere can be “complicated and chaotic,” said Charles Copeland, the newest recruit, who uses historical records and supercomputer weather models to estimate the globe’s wind patterns for every hour of the day dating back to the 1970s. (He reverse-tracks particles using a program called HYSPLIT, based on a software developed during the cold war to track radioactive particles back to their origins.) The goal, he said in one of the recent team meetings, is to figure out whether seemingly random bursts of Kawasaki disease in history were related to particularly anomalous wind patterns.

“To really try to untangle this and get to the heart of whether this is a wind story, we really have to ask the right questions,” he said. “If you ask the wrong questions — under the wrong assumptions — I think you will get the wrong answer.”

A missed case — or two

At the Kawasaki Disease Clinic at Rady Children’s Hospital-San Diego, led by Dr. Burns, caring for children affected by Kawasaki disease is always linked to the search for the cause.

On a recent Wednesday morning, Dr. Kirsten Dummer, a pediatric cardiologist, was examining the heart scans of a 2-year-old who showed signs of a large aneurysm on the right side of the heart.

“The biggest question from parents is: How did this happen? How did my child get this? In every patient room, that’s what they fundamentally want to know,” she said. “Year after year after year, they come back and ask us, ‘Do you guys know more yet?’”

Dr. Burns, who has continued to see patients herself, said those inquiries motivated her.

“If we were all Ph.D.s in the laboratory working on the etiology of Kawasaki disease,” there would be a different pace to it, Dr. Burns said. “But there’s an urgency to it, because we’re going back and forth, from the lab to the patients, saying, ‘Damn it, I need to answer this question.’ It matters, because it matters to these people.”

Later that morning, Inez Maldonado Diega, a 4-year-old in a mermaid outfit, rolled out balls of Play-Doh with her mother as Dr. Burns broke the news. Seventeen days ago, the girl’s pediatrician’s office had missed her case of Kawasaki disease. A echocardiogram had come back clear — a sign that her heart was so far healthy — but she still had a fever, which meant the disease could be lingering.

“I wish we had seen her sooner,” Dr. Burns said, listening to Inez’s heartbeat. She requested genetic samples for her biobank from both Inez and her mother, explaining that children are believed to inherit a susceptibility to the disease from their parents.

Inez’s mother, Tiara Diega, assured Dr. Burns that she had never had Kawasaki disease as a child — just scarlet fever. Dr. Burns raised her eyebrows and asked Ms. Diega to phone her mother on speakerphone.

Had Ms. Diega had bloodshot eyes during her infection all those years ago, she asked Ms. Diega’s mother? Yes, the mother said. Dr. Burns exhaled slowly.

“That wasn’t scarlet fever,” she said.

For a moment, the room was quiet — Ms. Diega still holding a patty of Play-Doh in midair — as the risks to both mother and daughter sunk in. Then Dr. Burns referred Ms. Diega for a cardiac scan of her own — to see whether a grave danger had been brewing all these years.

 

Emily Baumgaertner is a national health reporter for The Times, focusing on public health issues that primarily affect vulnerable communities. More about Emily Baumgaertner



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