Outbreak of life-threatening thiamine deficiency in infants in Israel caused by a defective soy-based formula
Outbreak of life-threatening thiamine deficiency in infants in Israel caused by a defective soy-based formula
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DOI：
10.1542/peds.2004-1255
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发表时间：
2005-02-01
期刊：
影响因子：
8
通讯作者：
Eshel, G
中科院分区：
文献类型：
--
作者：
Fattal-Valevski, A;Kesler, A;Eshel, G
客观的。 2003年10月至11月期间，几名患有脑病的婴儿在以色列的儿科重症监护室住院。其中两人死于心肌病。对累积数据的分析表明，所有人都喂食同一品牌的大豆配方奶粉（Remedia Super Soya 1），该品牌专为以色列市场生产。消息来源于 2003 年 11 月 6 日被确认，当时一名 5.5 个月大的婴儿因眼球震颤、眼肌麻痹和呕吐被送入 Sourasky 医疗中心。怀疑韦尼克脑病，并开始补充硫胺素治疗。他的病情在数小时内得到改善。详细的病史显示，这名婴儿正在喂食相同的配方奶粉，这引发了婴儿缺乏硫胺素的怀疑。该配方经以色列公共卫生当局检测，硫胺素含量检测不到（<0.5μg/g）。该产品已下架，并向公众发出警报。在发达国家，婴儿硫胺素缺乏症非常罕见。本研究的目的是报告此次疫情的流行病学，并描述我们护理中 9 名受影响婴儿的诊断、临床病程和结果。方法。在出现指示病例后，我们的中心通过病史、体检和实验室检测确认了另外 8 名婴儿。该组由 6 名男婴和 3 名女婴组成，年龄为 2 至 12 个月。所有这些均通过红细胞转酮醇酶活性测定进行评估，其中硫胺素缺乏的程度以与基线相比的刺激百分比（硫胺素焦磷酸效应[TPPE]）表示。正常值范围为 0% 至 15%； 15%至25%表明硫胺素缺乏，>25%表明严重缺乏。 6 名婴儿测量了血乳酸水平（正常：0.5 - 2 mmol/L），2 名婴儿测量了脑脊液乳酸水平（正常：0.5 - 2 mmol/L），4 名婴儿测量了血丙酮酸水平（正常：0.03 - 0.08 mmol/L）。硫胺素缺乏症的诊断标准是转酮酶活性异常和/或无法解释的乳酸性酸中毒。治疗包括肌肉注射硫胺素 50 毫克/天，持续 14 天，并改用另一种婴儿配方奶粉。结果。早期症状非特异性，主要包括呕吐 (n = 8)、嗜睡 (n = 7)、烦躁 (n = 5)、腹胀 (n = 4)、腹泻 (n = 4)、呼吸道症状 (n = 4)、发育迟缓 (n = 3) 和生长迟缓 (n = 2)。所有病例均发现感染。六名婴儿因发烧入院。 1例患者患有临床痢疾和C组沙门菌败血症；其余为轻度感染：急性胃肠炎（n = 2）；上呼吸道感染（n = 2）；支气管肺炎、急性支气管炎和病毒感染（各 n = 1）。两名婴儿接受了抗生素治疗。 3 名婴儿出现眼肌麻痹的神经系统症状，伴有双侧外展缺陷，伴或不伴乐观性眼球震颤。 3 名患者均出现血乳酸性酸中毒，其中 2 名患者脑脊液乳酸水平较高。患者 1，我们的索引病例，因乐观眼球震颤和眼肌麻痹入院，此外，自 4 个月大以来每天都有呕吐发作，体重减轻 0.5 公斤。脑部计算机断层扫描结果正常。血乳酸水平高，TPPE为37.8%。脑部磁共振成像（MRI）未显示异常。患者 2 在 5 个月时出现嗜睡、呕吐、咕噜声和腹部压痛，经腹部超声检查发现肠套叠，并接受了 2 次空气灌肠复位尝试，每次尝试间隔数小时。然而，嗜睡未能缓解，第二天出现眼肌麻痹，导致人们怀疑韦尼克脑病。实验室检查显示硫胺素严重缺乏（TPPE 31.2%）。在患者 1 和 2 中，治疗使症状完全消失。第三名婴儿是一名 5 个月大的女孩，于 2003 年 10 月 10 日入院，远早于发现疫情，当时她出现呕吐、发烧和眼肌麻痹。她的病情恶化为癫痫发作、呼吸暂停和昏迷。脑部 MRI 显示基底节、乳头体和导水管周围灰质出现双侧对称高信号。由于怀疑患有代谢性疾病，静脉注射液中添加了维生素，其中包括硫胺素 250 毫克，每天两次。 1天后观察到临床改善。开始硫胺素治疗后进行的 TPPE 测定仍然异常（17.6%）。在宣布硫胺素缺乏症后 4 周后，她的配方奶粉被更换。尽管5周后MRI检查结果有所改善，但婴儿出现了眼肌麻痹和运动异常的后遗症，目前正在接受物理治疗。所有 3 名出现神经系统症状的患者均仅食用大豆配方奶粉 2 至 3.5 个月，而其他患者则接受固体食物补充剂。长期服用配方奶粉（即慢性硫胺素缺乏）与发育迟缓有关。例如，一名 12 个月大的女孩接受了有缺陷的配方奶粉 8 个月，出现拒绝进食、呕吐、发育迟缓（第 75 个百分位至 < 5 个百分位）、肌张力低下、虚弱和运动迟缓等症状。广泛的检查显示吸收不良和免疫缺陷呈阴性。入院时，患者患有沙门氏菌胃肠炎和败血症，并接受了抗生素治疗。诊断出硫胺素缺乏症后，她接受了为期两周的大剂量硫胺素（50 毫克/天）治疗。与其他 5 名没有神经系统受累的婴儿一样，她的临床体征和症状在治疗 2 至 3 周内完全消失，TPPE 水平在 1 至 7 天内恢复正常。没有副作用。作为调查的一部分，以色列卫生部对 156 名喂食大豆配方奶粉的婴儿进行了硫胺素缺乏筛查，但到那时，大多数婴儿已经开始喂食替代配方奶粉，并开始口服硫胺素治疗。 8 名正在接受固体食物补充剂的婴儿（其中 3 名男性和 5 名女性）的 TPPE 结果异常（> 15%），这些婴儿均年龄 > 1 岁。尽管他们的父母没有注意到任何症状，但检查医生记录了他们的烦躁、嗜睡、呕吐、厌食、发育迟缓和发育迟缓。没有人有神经系统受累的迹象。治疗包括口服硫胺素补充剂 2 周。结论。临床医生认识到即使营养良好的婴儿也可能缺乏硫胺素，这对于早期识别和预防不可逆的脑损伤非常重要。应在最早怀疑维生素缺乏时开始大剂量硫胺素治疗，甚至在获得实验室证据之前以及出现神经或心脏病症状之前。
Objective. Between October and November 2003, several infants with encephalopathy were hospitalized in pediatric intensive care units in Israel. Two died of cardiomyopathy. Analysis of the accumulated data showed that all had been fed the same brand of soy-based formula (Remedia Super Soya 1), specifically manufactured for the Israeli market. The source was identified on November 6, 2003, when a 5.5-month-old infant was admitted to Sourasky Medical Center with upbeat nystagmus, ophthalmoplegia, and vomiting. Wernicke's encephalopathy was suspected, and treatment with supplementary thiamine was started. His condition improved within hours. Detailed history revealed that the infant was being fed the same formula, raising suspicions that it was deficient in thiamine. The formula was tested by the Israeli public health authorities, and the thiamine level was found to be undetectable (< 0.5 mu g/g). The product was pulled from the shelves, and the public was alerted. Thiamine deficiency in infants is very rare in developed countries. The aim of this study was to report the epidemiology of the outbreak and to describe the diagnosis, clinical course, and outcome of 9 affected infants in our care.Methods. After the index case, an additional 8 infants were identified in our centers by medical history, physical examination, and laboratory testing. The group consisted of 6 male and 3 female infants aged 2 to 12 months. All were assessed with the erythrocyte transketolase activity assay, wherein the extent of thiamine deficiency is expressed in percentage stimulation compared with baseline ( thiamine pyrophosphate effect [TPPE]). Normal values range from 0% to 15%; a value of 15% to 25% indicates thiamine deficiency, and > 25% indicates severe deficiency. Blood lactate levels ( normal: 0.5 - 2 mmol/L) were measured in 6 infants, cerebrospinal fluid lactate in 2 ( normal: 0.5 - 2 mmol/L), and blood pyruvate in 4 ( normal: 0.03 - 0.08 mmol/L). The diagnostic criteria for thiamine deficiency were abnormal transketolase activity and/or unexplained lactic acidosis. Treatment consisted of intramuscular thiamine 50 mg/day for 14 days combined with a switch to another infant formula.Results. Early symptoms were nonspecific and included mainly vomiting ( n = 8), lethargy ( n = 7), irritability ( n = 5), abdominal distension ( n = 4), diarrhea ( n = 4), respiratory symptoms ( n = 4), developmental delay ( n = 3), and failure to thrive ( n = 2). Infection was found in all cases. Six infants were admitted with fever. One patient had clinical dysentery and group C Salmonella sepsis; the others had mild infection: acute gastroenteritis ( n = 2); upper respiratory infection ( n = 2); and bronchopneumonia, acute bronchitis, and viral infection ( n = 1 each). Two infants were treated with antibiotics. Three infants had neurologic symptoms of ophthalmoplegia with bilateral abduction deficit with or without upbeat nystagmus. All 3 had blood lactic acidosis, and 2 had high cerebrospinal fluid lactate levels. Patient 1, our index case, was hospitalized for upbeat nystagmus and ophthalmoplegia, in addition to daily vomiting episodes since 4 months of age and weight loss of 0.5 kg. Findings on brain computed tomography were normal. Blood lactate levels were high, and TPPE was 37.8%. Brain magnetic resonance imaging (MRI) revealed no abnormalities. Patient 2, who presented at 5 months with lethargy, vomiting, grunting, and abdominal tenderness, was found to have intussusception on abdominal ultrasound and underwent 2 attempts at reduction with air enema several hours apart. However, the lethargy failed to resolve and ophthalmoplegia appeared the next day, leading to suspicions of Wernicke's encephalopathy. Laboratory tests showed severe thiamine deficiency ( TPPE 31.2%). In patients 1 and 2, treatment led to complete resolution of symptoms. The third infant, a 5-month-old girl, was admitted on October 10, 2003, well before the outbreak was recognized, with vomiting, fever, and ophthalmoplegia. Her condition deteriorated to seizures, apnea, and coma. Brain MRI showed a bilateral symmetrical hyperintense signal in the basal ganglia, mamillary bodies, and periaqueductal gray matter. Suspecting a metabolic disease, vitamins were added to the intravenous solution, including thiamine 250 mg twice a day. Clinical improvement was noted 1 day later. TPPE assay performed after treatment with thiamine was started was still abnormal (17.6%). Her formula was substituted after 4 weeks, after the announcement about the thiamine deficiency. Although the MRI findings improved 5 weeks later, the infant had sequelae of ophthalmoplegia and motor abnormalities and is currently receiving physiotherapy. All 3 patients with neurologic manifestations were fed exclusively with the soy-based formula for 2 to 3.5 months, whereas the others had received solid food supplements. Longer administration of the formula (ie, chronic thiamine deficiency) was associated with failure to thrive. For example, one 12-month-old girl who received the defective formula for 8 months presented with refusal to eat, vomiting, failure to thrive (75th to < 5th percentile), hypotonia, weakness, and motor delay. Extensive workup was negative for malabsorption and immunodeficiency. On admission, the patient had Salmonella gastroenteritis and sepsis and was treated with antibiotics. After thiamine deficiency was diagnosed, she received large doses of thiamine ( 50 mg/day) for 2 weeks. Like the other 5 infants without neurologic involvement, her clinical signs and symptoms disappeared completely within 2 to 3 weeks of treatment, and TPPE levels normalized within 1 to 7 days. There were no side effects. As part of its investigation, the Israel Ministry of Health screened 156 infants who were fed the soy-based formula for thiamine defHowever, by that time, most were already being fed alternative formulas and had begun oral thiamine treatment. Abnormal TPPE results (> 15%) were noted in 8 infants, 3 male and 5 female, all > 1 year old, who were receiving solid food supplements. Although their parents failed to notice any symptoms, irritability, lethargy, vomiting, anorexia, failure to thrive, and developmental delay were documented by the examining physicians. None had signs of neurologic involvement. Treatment consisted of oral thiamine supplements for 2 weeks.Conclusions. Clinician awareness of the possibility of thiamine deficiency even in well-nourished infants is important for early recognition and prevention of irreversible brain damage. Therapy with large doses of thiamine should be initiated at the earliest suspicion of vitamin depletion, even before laboratory evidence is available and before neurologic or cardiologic symptoms appear.