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.

中文翻译：

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巴西小头症新生儿和 Oropouche 病毒的潜在垂直传播：病例系列

 背景

奥罗普切热是一种在巴西亚马逊地区流行的正布尼亚病毒疾病，已引起许多发热流行。2024 年，奥罗普切热流行病在巴西蔓延，1 月 1 日至 8 月 31 日期间报告了 7930 多例病例。孕妇感染表明可能存在负面的胎儿后果，因此我们对小头症新生儿进行了已知的先天性病原体和 Oropouche 病毒 （OROV） 检测。

 方法

在本病例系列中，我们评估了出生时患有小头畸形、关节弯曲和其他先天性畸形但原因不明的婴儿的历史病例，以及他们的母亲潜在的 OROV 先天性感染。研究人群包括在巴西出生的婴儿，样本为 2015-21 年和 2024 年。分析了该病例系列的血清和脑脊液 （CSF）：梅毒、弓形虫病、风疹、巨细胞病毒、单纯疱疹病毒、HIV、寨卡病毒、登革热和基孔肯雅热。然后对这些病原体阴性的个体进行 OROV 检测。病原体检测包括抗体的 ELISA 和血凝抑制检测以及病毒 RNA 的 RT-PCR。

 发现

我们测试了来自 65 例先天畸形病史病例的 68 例样本和 2024 年的 3 例样本。所有病例均来自巴西的 10 个州。3 例历史病例的 OROV 检测呈阳性，62 例历史病例检测呈阴性。2024 年的 3 例 OROV 检测均呈阳性。在阳性病例中，5 例为女性，1 例为男性。并非每个病例都检测了所有病原体，有些病例没有可用的母体样本。其中一名新生儿 （病例 6） 在 47 天时死亡，组织样本通过实时 RT-PCR、组织病理学和免疫组织化学测定进行了检测。另一名新生儿于 2016 年死亡，但没有尸检样本。在 5 例新生儿 CSF 标本中的 5 例和 5 例新生儿血清标本中的 5 例中检测到 OROV IgM。5 份母体血清样本中有 4 份呈 OROV IgM 阳性。4 例新生儿 CSF 样本中有 1 例 （病例 6 龄，44 天） 实时 RT 定量 PCR 检测呈 OROV 阳性，4 例新生儿血清样本中有 0 例呈阳性，3 例母体血清样本中有 0 例呈阳性。病例 6 在脑部宏观和显微镜下有主要组织改变，包括神经元、小胶质细胞和星形胶质细胞的坏死和凋亡改变、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;OROV 抗原存在于 CNS 、 肝脏 、 肾脏 、 心脏 和 肺 中，主要存在于神经元和小胶质细胞中，也存在于内皮细胞中，提示血管炎。

 解释

我们在 68 名原因不明的小头畸形新生儿中有 6 名中检测到 OROV IgM。一名死亡的婴儿在包括大脑在内的多个组织中都有 OROV RNA 和抗原。必须紧急调查 OROV 垂直传播的可能性和潜在的胎儿危害。此处提供的证据并未完全证实 OROV 引起的垂直传播或先天性畸形，但对母体或胎儿 OROV 感染的彻底病例发现和详细调查是优先事项。

 资金

Evandro Chagas 研究所、Secretaria de Vigilância em Saúde e Ambiente，以及卫生部和国家新兴和再出现病毒科学技术研究所。