Rare case of intracranial hemorrhage associated with seoul virus infection diagnosed by metagenomic next‐generation sequencing

Abstract Background Seoul virus (SEOV) is a Hantavirus and the causative pathogen of Hemorrhagic Fever with Renal Syndrome (HFRS). Diagnosing SEOV infection is difficult because the clinical presentations are often undistinguishable from other viral or bacterial infections. In addition, diagnostic tools including serological and molecular assays are not readily available in the clinical settings. Case Report A 57‐year‐old male presented with fever and a sudden loss of consciousness in November 2019. Computed tomography (CT) scan showed subdural hematoma, subfalcine herniation, and brain infarction. He developed thrombocytopenia and elevated transaminases, but no rashes or obvious kidney damage. He reported having a rat bite. HFRS was suspected. The Hantavirus IgG was positive, and the metagenomic next‐generation sequencing (mNGS) detected SEOV sequences directly in the blood. Conclusion This report highlights the importance of suspecting SEOV infection in febrile patients with thrombocytopenia and elevated liver enzymes despite the absence of hemorrhagic manifestations of skin and renal syndromes. Next‐generation sequencing is a powerful tool for pathogen detection. Intracranial hemorrhage and brain infarction as extrarenal manifestations of HFRS are rare but possible as demonstrated in this case.

harbored by Rattus norvegicus and R.rattus rats, is one of major causative etiologies of Hemorrhagic Fever with Renal Syndrome (HFRS) in China. 2 Clinically, the typical HFRS manifestations include five consecutive phases: febrile, hypotensive shock, oliguric, polyuric, and convalescent. 3 The general clinical features include fever, myalgias, hemorrhage, thrombocytopenia, leukocytosis, renal failure, and shock in most severe cases. Elevation of liver enzymes is characteristic of HFRS caused by SEOV. 4 But these presentations are non-specific for HFRS, which are often undistinguishable from other viral or bacterial infections. The serological assays to detect Hantavirus IgM and IgG offered by the state or regional Centers for Disease Control and Prevention (CDC) can confirm HFRS, but are not specific to SEOV. Molecular assays to detect SEOV viral RNA is also not available in most hospitals. Metagenomic next-generation sequencing (mNGS) is a powerful tool for the detection and identification of pathogens directly from the specimen. In this report, we describe a highly unusual case of SEOV infection diagnosed by mNGS in a patient with intracranial hemorrhage but without typical hemorrhagic manifestations of skin or renal syndromes.

| C A S E REP ORT
A 57-year-old previously healthy male was transferred to our hospital in November 2019 after a sudden loss of consciousness. Four days prior, the patient developed fever (maximum temperature 39°C) of unknown origin. He was admitted to a local hospital and was diagnosed with Dengue fever after the Dengue virus IgM was tested weakly positive. During the hospitalization, he suddenly lost consciousness and started vomiting. He had no significant medical history (particularly no anti-platelet or anticoagulant history), no recent travel history, and no history of cerebral trauma. Physical examination showed blood pressure of 161/82 mmHg, heart rate of 97 beats/minutes, respiratory rate of 25/minutes, and temperature of 37.8℃. He was in a coma and did not response to voice. The Glasgow Coma Scale (GCS) score was 6 points. The diameter of his left and right pupil was 3.0mm and 4.0mm, respectively. The direct and indirect light reflex was slow. Limb movement was observed, and his chest, cardiac, and abdominal examination was normal. There were no rashes, petechia, ecchymoses, or other skin lesions. Blood tests

| D ISCUSS I ON
The initial differential diagnosis in this case was very challenging, as our patient presented with intracranial hemorrhage but without the three common causes including head trauma, hypertension, and arterial malformations. 5 His presentation of fever, thrombocy-   8 cerebral edema and small subarachnoid, epidural and focal brain stem hemorrhages, 9 and brain infarction. 7 Unfortunately, in our case, the hematoma tissue and cerebrospinal fluid were not saved for serological and molecular tests for further investigation, which is the major limitation of this study.

| CON CLUS ION
This report highlights the importance of suspecting SEOV infection in febrile patients with thrombocytopenia and elevated liver enzymes despite the absence of hemorrhagic manifestations of skin and mucosal membrane and renal syndromes. mNGS can be a powerful tool to detect SEOV directly in the blood. Intracranial hemorrhage and brain infarction as extrarenal manifestations of HFRS are rare. Clinicians should be aware of various extrarenal manifestations of SEOV infections.

ACK N OWLED G M ENTS
We thank IngeniGen XMK Biotechnologies Inc (Hangzhou, Zhejiang, China) for providing the technical assistance.

CO N FLI C T O F I NTE R E S T
The authors declare no conflict of interest.