巴西新生儿小头畸形与奥罗普切病毒的潜在垂直传播：一个病例系列

IF 36.4 1区医学 Q1 INFECTIOUS DISEASES

Lancet Infectious Diseases Pub Date : 2024-10-16 DOI:10.1016/s1473-3099(24)00617-0

Fernanda Eduarda das Neves Martins, Jannifer Oliveira Chiang, Bruno Tardelli Diniz Nunes, Bethania de Freitas Rodrigues Ribeiro, Lívia Carício Martins, Lívia Medeiros Neves Casseb, Daniele Freitas Henriques, Consuelo Silva de Oliveira, Ethel Leonor Noia Maciel, Rafael da Silva Azevedo, Layna de Cássia Campos Cravo, André Rodrigues Façanha Barreto, André Luiz Santos Pessoa, Arnaldo Jorge Martins Filho, Jorge Rodrigues de Sousa, Lavinia Schuler-Faccini, Juarez Antônio Simões Quaresma, Pedro Fernando da Costa Vasconcelos, Raimunda do Socorro da Silva Azevedo

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引用次数: 0

摘要

背景奥罗普切热是巴西亚马逊地区流行的一种正布尼亚病毒病，曾多次引发发热性流行病。2024 年，奥罗普切热在巴西流行，1 月 1 日至 8 月 31 日期间报告的病例超过 7930 例。因此，我们对患有小头畸形的新生儿进行了已知先天性病原体和奥罗普切病毒（OROV）的检测。在这一病例系列中，我们对患有小头畸形、关节发育不良和其他先天性畸形但未确诊病因的历史病例及其母亲进行了评估，以确定是否存在潜在的奥罗普切病毒先天性感染。研究对象包括 2015-21 年和 2024 年在巴西出生的婴儿样本。对该病例系列的血清和脑脊液（CSF）进行了分析，以检测梅毒、弓形虫病、风疹、巨细胞病毒、单纯疱疹病毒、艾滋病病毒、寨卡病毒、登革热和基孔肯雅病毒。然后对这些病原体检测呈阴性的个体进行 OROV 检测。病原体检测包括针对抗体的 ELISA 和血凝抑制检测，以及针对病毒 RNA 的 RT-PCR 检测。所有病例均来自巴西的十个州。三个历史病例的 OROV 检测结果呈阳性，62 个历史病例的 OROV 检测结果呈阴性。2024 年的三个病例均检测出 OROV 阳性。在阳性病例中，五例为女性，一例为男性。并非每个病例都检测了所有病原体，有些病例没有母体样本。其中一名新生儿（病例 6）在 47 天后死亡，组织样本通过实时 RT-PCR、组织病理学和免疫组化检测进行了检测。另有一名新生儿于 2016 年死亡，但没有尸检样本。五份新生儿脑脊液样本中有五份检测到 OROV IgM，五份新生儿血清样本中有五份检测到 OROV IgM。五份母体血清样本中有四份检出 OROV IgM 阳性。通过实时 RT 定量 PCR 检测，4 份新生儿脑脊液样本中有 1 份（病例 6，44 天）呈 OROV 阳性，4 份新生儿血清样本中有 0 份呈阳性，3 份母体血清样本中有 0 份呈阳性。病例 6 的大脑组织在宏观和微观上都发生了重大变化，包括神经元、小胶质细胞和星形胶质细胞的坏死和凋亡、空泡化和组织萎缩。在脑、肺、肾、脑脊液和胸腔积液中检测到 OROV RNA；在中枢神经系统、肝脏、肾脏、心脏和肺中发现 OROV 抗原，主要存在于神经元和小胶质细胞中，也存在于血管内皮细胞中，提示为血管炎。一名死亡婴儿的多个组织（包括大脑）中都有 OROV RNA 和抗原。必须紧急调查 OROV 垂直传播的可能性和对胎儿的潜在危害。本文提供的证据并不能完全证实奥罗莫病毒导致的垂直传播或先天性畸形，但对母体或胎儿感染奥罗莫病毒进行彻底的病例调查和详细的调查是当务之急。

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Newborns with microcephaly in Brazil and potential vertical transmission of Oropouche virus: a case series

Background

Oropouche fever, an orthobunyavirus disease endemic in Brazilian Amazon, has caused many febrile epidemics. In 2024, an epidemic of Oropouche fever spread in Brazil, with more than 7930 cases reported between Jan 1 and Aug 31. Infections in pregnant people have suggested the possibility of negative fetal consequences, therefore we tested newborns with microcephaly for known congenital pathogens and Oropouche virus (OROV).

Methods

In this case series, we assessed historical cases of infants born with microcephaly, arthrogryposis, and other congenital malformations without a confirmed cause and their mothers for potential OROV congenital infections. The study population consisted of infants born in Brazil with samples from 2015–21 and 2024. Serum and cerebrospinal fluid (CSF) from this case series were analysed for: syphilis, toxoplasmosis, rubella, cytomegalovirus, herpes simplex, HIV, Zika, dengue, and chikungunya. Individuals that were negative for these pathogens were then tested for OROV. Pathogen testing included ELISA and haemagglutination inhibition testing for antibodies and RT-PCR for virus RNA.

Findings

We tested 68 samples from 65 historical cases of congential malformations and three cases from 2024. All cases were from ten states in Brazil. Three historical cases tested positive for OROV and 62 historical cases tested negative. The three cases from 2024 all tested positive for OROV. Of the positive cases, five were female and one was male. Not all pathogens were tested for each case, and some did not have maternal samples available. One of the newborns (case 6) died aged 47 days and tissue samples were tested by real-time RT-PCR, histopathology, and immunohistochemistry assays. One other newborn died in 2016 but no post-mortem samples were available. OROV IgM was detected in five of five newborn CSF samples, and five of five newborn serum samples. Four of five maternal serum samples were positive for OROV IgM. One of four newborn CSF samples (case 6 at age 44 days) was OROV positive by real-time RT-quantitative PCR and 0 of four newborn serum samples were positive, as were 0 of three maternal serum samples. Case 6 had major tissue changes of the brain macroscopically and microscopically, including necrotic and apoptotic changes of neurons, microglia and astrocytes, vacuolisation, and tissue atrophy. OROV RNA was detected in brain, lungs, kidney, CSF, and pleural fluid; OROV antigens were found in CNS, liver, kidney, heart, and lung, mainly in neurons and microglia and also in endothelial cells, suggesting vasculitis.

Interpretation

We detected OROV IgM in six of 68 newborns with microcephaly of unknown cause. One infant who died had OROV RNA and antigen in several tissues, including the brain. The possibility of OROV vertical transmission and potential fetal harm must be investigated with urgency. The evidence presented here does not completely confirm vertical transmission or congenital malformations due to OROV, but thorough case finding and detailed investigation of maternal or fetal OROV infection is a priority.

Funding

Evandro Chagas Institute, Secretaria de Vigilância em Saúde e Ambiente, and Ministry of Health and National Institute of Science and Technology for Emerging and Reemerging Viruses.

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来源期刊

Lancet Infectious Diseases 医学-传染病学

CiteScore

60.90

自引率

0.70%

发文量

1064

审稿时长

6-12 weeks

期刊介绍： The Lancet Infectious Diseases was launched in August, 2001, and is a lively monthly journal of original research, review, opinion, and news covering international issues relevant to clinical infectious diseases specialists worldwide.The infectious diseases journal aims to be a world-leading publication, featuring original research that advocates change or sheds light on clinical practices related to infectious diseases. The journal prioritizes articles with the potential to impact clinical practice or influence perspectives. Content covers a wide range of topics, including anti-infective therapy and immunization, bacterial, viral, fungal, and parasitic infections, emerging infectious diseases, HIV/AIDS, malaria, tuberculosis, mycobacterial infections, infection control, infectious diseases epidemiology, neglected tropical diseases, and travel medicine. Informative reviews on any subject linked to infectious diseases and human health are also welcomed.