Clinical and genomic characterisation of a fatal Puumala orthohantavirus case with low levels of neutralising antibodies.

Orthohantaviruses are rodent-borne emerging viruses that cause hemorrhagic fever with renal syndrome (HFRS) in Eurasia and hantavirus pulmonary syndrome in America. Transmission between humans have been reported and the case-fatality rate ranges from 0.4–40 % depending on virus strain. There is no specific and efficient treatment for patients with severe HFRS. Here, we characterized a fatal case of HFRS and sequenced the causing Puumala orthohantavirus (PUUV). PUUV RNA and virus specific neutralizing antibodies were quantified in plasma samples from the fatal case and other patients with non-fatal PUUV infection. To investigate if the causing PUUV strain was different from previously known strains, Sanger sequencing was performed directly from the patient’s plasma. Biopsies obtained from autopsy were stained for immunohistochemistry. The patient had approximately tenfold lower levels of PUUV neutralizing antibodies and twice higher viral load than was normally seen for patients with less severe PUUV infection. We could demonstrate unique mutations in the S and M segments of the virus that could have had an impact on the severity of infection. Due to the severe course of infection, the patient was treated with the bradykinin receptor inhibitor icatibant to reduce bradykinin-mediated vessel permeability and maintain vascular circulation. Our data suggest that bradykinin receptor inhibitor may not be highly efficient to treat patients that are at an advanced stage of HFRS. Low neutralizing antibodies and high viral load at admission to the hospital were associated with the fatal outcome and may be useful for future predictions of disease outcome.

正汉坦病毒是由啮齿动物传播的新兴病毒，在欧亚大陆引起肾综合征出血热（HFRS），在美国引起汉坦病毒肺综合征。据报道存在人传人情况，病死率因病毒株而异，在0.4% - 40%之间。对于重症肾综合征出血热患者，没有特效且高效的治疗方法。 在此，我们对一例肾综合征出血热致死病例进行了特征分析，并对致病的普马拉正汉坦病毒（PUUV）进行了测序。 对该致死病例以及其他非致死性普马拉病毒感染患者的血浆样本中的普马拉病毒RNA和病毒特异性中和抗体进行了定量检测。为了研究致病的普马拉病毒株是否与先前已知的毒株不同，直接从患者血浆中进行了桑格测序。对尸检获取的活检组织进行了免疫组化染色。 该患者的普马拉病毒中和抗体水平比一般轻症普马拉病毒感染患者低约十倍，病毒载量则高两倍。我们能够证明病毒的S和M片段存在独特突变，这些突变可能对感染的严重程度产生了影响。由于感染过程严重，患者接受了缓激肽受体抑制剂艾替班特治疗，以降低缓激肽介导的血管通透性并维持血管循环。 我们的数据表明，缓激肽受体抑制剂对于治疗处于肾综合征出血热晚期的患者可能不是非常有效。入院时中和抗体水平低和病毒载量高与致命结局相关，可能对未来疾病预后的预测有用。