Viral load in febrile phase rather than the duration of virus associates the severity of hemorrhagic fever with renal syndrome

Viral load in febrile phase rather than the duration of virus associates the severity of hemorrhagic fever with renal syndrome | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Viral load in febrile phase rather than the duration of virus associates the severity of hemorrhagic fever with renal syndrome Lei Shi, Shipu Wang, Fenglan Wang, Xi Zhang, Jie Zheng, Danfeng Ren, and 10 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4576242/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Hemorrhagic fever with renal syndrome (HFRS) was Hantaviruses infectious disease with a mortality rate of 1-10%. In the previous studies, the duration of the virus and the relationship between the virus and the severity of the disease were still unclear. 137 patients with HFRS were enrolled in this study, patients were followed up every three days until the virus load was negative. Virus quantification was performed using RT-PCR method. Of all the 137 patients, 38 patients (28%) were classified as severe/critical cases. We found that the duration of the virus lasted much longer than we thought before. Most patients still have virus during the polyuria phase, and some patients even have virus in recovery phase. We confirmed that viral load in febrile phase rather than the duration of virus associated with the severity of Hantaan virus caused HFRS. This indicates that tissue damage in HFRS may not related to the virus, virus activated immune response in the early stages may responsible for the pathogenesis. Understanding the mechanism of virus in HFRS will provide ideas and guidance for better clinical treatment. Health sciences/Diseases/Infectious diseases/Viral infection Health sciences/Health care/Therapeutics/Drug therapy HFRS Hantaan virus HTNV RNA disease severity Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Introduction Hantaviruses are negative-sense, single-stranded RNA viruses which belong to the order Bunyavirales, family Hantaviridae and genus Orthohantavirus 1 . Hantaviruses can cause two acute febrile diseases in humans: Hantavirus pulmonary syndrome (HPS) and hemorrhagic fever with renal syndrome (HFRS) 2 , HFRS could be caused by Hantaan virus (HTNV), Amur virus(AMV), Seoul virus (SEOV), Dobrava virus (DOBV), and Puumala virus (PUUV). HFRS are endemic in many Asian countries, most number of cases reported in China, South Korea, and the Far Eastern Federal District of Russia, cases in China account for 40-50% of all the HFRS case 2-4 . In recent years, almost 200,000 people were affected by Hantaviruses annually, with a fatality of 1-15% for HFRS around the world 5 . However, the pathogenesis has not been fully elucidated, and there is no specific treatment 6,7 . Studies have demonstrated Hantaviruses RNA can be detected in the serum up to two weeks before the onset of the disease 8,9 . These data indicate that the body’s reaction to Hantaviruses infection is delayed. As no virus replication-associated cell death has been reported in tissues collected postmortem from HFRS and HPS cases 10,11 , and these viruses are non-cytopathic in vitro 12,13 , it seems that the process of disease is not directly caused by the virus. But viruses are the initiating factors for the occurrence and development of the disease, the dynamic changes of Hantaviruses RNA and its roles with disease are still unclear. The aim of our study was to investigate the dynamic changes of HTNV RNA and its relationship with disease severity of HFRS. Results Demographics and baseline characteristics All genotypes were Hantaan viruses type, this is coincide with the studys before 14 . 137 HFRS patients (n = 99 mild/medium and n = 38, severe/critical, 28%) were consecutively enrolled in this study. Baseline characteristics of the 137 patients were shown in Fig. 1. Of all the patients, 61% were men, and the average age was 47 (± 3.9) years. WBC counts (< 0.0001), PLT counts (< 0.001), Hg(< 0.01), CRP(< 0.001), PCT (< 0.001), Cr (< 0.01) and BUN (< 0.01) have statistic difference at baseline between mild/medium and severe/critical groups. Dynamic changes of Hantavirus load from onset day HTNV RNA load in 137 patients were followed up every three days from until the hantavirus load turned negative (Fig. 2). The viral load was highest in fever phase and then gradually decreases. In most patients, the virus turned negative after 2 weeks. Patients with longer fever phase also have a longer duration of virus. Dynamic changes of Hantavirus load in different phase Hantavirus replicated all cross the disease, fever, hypotensive-shock/oliguric, polyuria, and recovery phase (Fig. 3). Most patients still have viral replication during polyuria phase, some patients even have viruses replication in convalescent phase. Relationship of HTNV RNA load with the severity of HFRS Comparison of HTNV load in fever and unfever phase with disease severity of HFRS. We found the severity of HFRS was only associated with the HTNV RNA load in fever phase rather than unfever phase (Fig. 4). Relationship of duration of HTNV with the severity of HFRS Comparison of the duration of HTNV between patients with mild/medium and severe/critical HFRS. We found the severity of HFRS has no relationship with the duration of HTNV (Fig. 5). Discussion The aim of our study was to investigate the dynamic changes of HTNV RNA and its relationship with disease severity of HFRS, to gain further knowledge of disease pathogenesis and possible treatment strategies. Data showed in PUUV-caused HFRS, The PUUV RNA was detected in a majority of patient plasma samples up to 9 days after disease onset, the viral load was highest in the early stage of the disease 15 . In DOBV-caused HFRS, the viral RNA varied according to the day of illness 16 . In HTNV-caused HFRS, The viral RNA could only be detected in plasma samples from patients in febrile, hypotensive, and oliguric stage 17 . In our study, we found the virus lasted much longer than we thought before. Most patients still have viral replication in polyuria phase, some patients even have viruses in convalescent phase. The viral load was highest at the very beginning of the disease, and then decreases gradually, for most patients the virus turned negative after 2 weeks. Patients with longer fever phase have a longer duration of virus. Because the virus lasts for a long time, we further explored if there is a relationship between viral load and disease severity. In previous studies, there were different opinions on whether virus load was related to disease severity. PUUV RNA load or duration of viraemia were not significantly associated with disease severity 15 . Dobrava virus load might be associated with the severity of disease, the patients with severe disease had higher viral RNA loads than patients with a milder course of disease (P =0 .053) 16 . In our study, we found that HTNV load at 1-3 days, 4-6 days, and 7-9 days have no relationship with the severity of disease, but when combined all 1-9 days data in febrile phase, HTNV load was associated with disease severity. We also found that HTNV load in non-febrile phase and the duration of virus have no correlation with the severity of HFRS. So it is possible that the virus activated immune in the febrile phase, and virus-induced immune response may responsible for the subsequent tissue damage. This requires further expanding size study to observe the relationship between viral load and disease severity at the very early stage of HFRS. We also found higher WBC, Hg, PCT, CRP, BUN, Cr and lower PLT were significantly associated with the severity of HFRS. We then studied if there is a relationship between virus loads and the clinical indicators. The results showed that HTNV load has no correlation with white blood cell, hemoglobin, procalcitonin, C-reactive protein, urea nitrogen, and creatinine (Data not show). As viruses are non-cytopathic 10,11 and it turns out that inflammation caused by HTNV plays an important role in the pathogenesis of HFRS, further exploration of inflammation in HFRS is needed. There were several limitations in this study. First, the number of cases was relatively small. Second, since the hypotensive-shock phase lasted only a few hours and the condition of patients was really critical, there was no data on the shock phase in this study. Third, though this was a multi-center research, all the patients were from west-north of China, cases out of China were needed to verify the role of cytokine in HFRS patients. Methods Study population Patients with HFRS were recruited from the First Affiliated Hospital of Xi'an Jiaotong University, the Eighth Hospital of Xi’an and the Central Hospital of Weinan in Shaanxi Province in China from January 2022 to December 2023. Patients who were pregnancy or younger than 18 years, patients with serious chronic disease were excluded from the study. 137 patients with HFRS were followed up from the day of hospitalization. Virus quantification was performed using RT-PCR method. Statistical analysis was conducted using SPSS 27 software. The protocol was approved by the Ethics Committee of the First Affiliated Hospital of Xi’an Jiaotong University and was performed in accordance with relevant guidelines and regulations. Informed consent was obtained from all the patients. Diagnostic criteria: HFRS RNA positive and IgM positive. 169 patients with suspected HFRS were recruited at first, 26 patients with positive IgM but negative HTNV RNA were excluded. Among all the 137 patients confirmed HFRS, 15 cases were negative IgM but positive HTNV RNA at admission ( Less than 4 days of onset) and then confirmed by IgM and IgG positive in the subsequent follow-up. IgM/IgG detection using colloidal gold method (Figure 6). The typical clinical course of HFRS includes five phases: febrile phase, hypotensive-shock phase, oliguric phase, polyuric phase and convalescent phase. Furthermore, in severe cases, the first two or three phases may overlap, while in moderate cases, hypotension shock and/or oliguric phase may be missing. According to the severity of the disease, HFRS can be divided into 4 kinds of clinical types 18 : Mild type: urinary protein is “+ to + +”, and there is no oliguria and hypotension shock. Medium type: bulbar conjunctival edema is obvious, and the systolic blood pressure is lower than 90mmHg or pulse pressure difference less than 30mmhg, oliguria, urinary protein is “++ to +++”. Severe type: with neurological symptoms, shock, oliguria up to 5 days or no urine within 2 days. Critical type: one of the following situations occurs on the basis of severe patients, refractory shock, bleeding of important organs, no urine for more than 2 days, others serious complications such as heart failure, pulmonary edema, respiratory failure, coma, subsequent severe infection. Data management and laboratory parameters Demographic and clinical data were collected from the HFRS patients. Variables collected at hospital admission included serum white blood cell (WBC) counts, hemoglobin (Hg), platelet (PLT) counts, C-reactive protein(CRP), procalcitonin (PCT), urea nitrogen( BUN) and creatinine (Cr). Blood sampling After obtaining informed consent, venous blood was collected from HFRS patients and was taken for virus quantification testing immediately. 345 blood samples from 137 patients were obtained in this study. Patients were followed up every three days, from the day of hospitalization in febrile phase, until the virus quantitative test was negative. HTNV RNA detection HTNV RNA detection using RT-PCT described as before. The minimum detection limit for virus quantification is 100 copies/ml. Linear range for detection is 1.0 × 10 3 copies/mL to 1.0 × 10 7 copies/ml. Detectable genotyping: Hantaan type or Seoul type 19 . Statistics All analyses were done using SPSS V.27. For descriptive analyses, categorical variables were reported with absolute and relative frequencies and continuous variables with mean and SD. All virus quantification were standardized using log transformation to enable comparable data in the downstream analyses. Declarations Acknowledgements. We would like to acknowledge the patients and their families, the physicians and research staff for their dedication and contributions to the study. We also thank Dr. Wei Hou and Dr. Tianhui Li for primer design and data analyzing support. Author contributions LS and TYC designed research; LS, SPW, FLW, XZ, DFR and TTT followed-up patients and collected data; LS, SPW, FLW, JZ, HBL, YPL, YWW and JSH conducted data analysis and prepared figures and tables; LS, SPW and FLW wrote the manuscript with input from all the authors. YLH, SML, ZWL, YRZ and TYC revised the manuscript. TYC acquired the funding and provided overall supervision. Funding This work was supported by the National Science and Technology Projects (Project No. 2017ZX10305501-002-002); the Natural Science Research Project of Shaanxi Province (Project No. 2020JM-363); and the Research Fund of Xi’an Jiaotong University (Project No. 2019ZYTS-09). Competing Interests All authors declare no competing interests. Additional information Availability of data and materials The datasets analyzed in the current study will be available from the corresponding author upon reasonable request. References Kuhn, J. H. & Schmaljohn, C. S. A Brief History of Bunyaviral Family Hantaviridae. Diseases 11 (2023). https://doi.org/10.3390/diseases11010038 Sehgal, A. et al. Hemorrhagic Fever with Renal Syndrome in Asia: History, Pathogenesis, Diagnosis, Treatment, and Prevention. Viruses 15 (2023). https://doi.org/10.3390/v15020561 Jiang, H. et al. Hantavirus infection: a global zoonotic challenge. Virol Sin 32, 32–43 (2017). https://doi.org/10.1007/s12250-016-3899-x Lv, C. L. et al. Dual seasonal pattern for hemorrhagic fever with renal syndrome and its potential determinants in China. Sci Total Environ 859 (2023). https://doi.org/ARTN 10.1016/j.scitotenv.2022.160339 Singh, S. et al. Epidemiology, virology and clinical aspects of hantavirus infections: an overview. Int J Environ Health Res 32, 1815–1826 (2022). https://doi.org/10.1080/09603123.2021.1917527 Afzal, S. et al. Hantavirus: an overview and advancements in therapeutic approaches for infection. Front Microbiol 14, 1233433 (2023). https://doi.org/10.3389/fmicb.2023.1233433 Malinin, O. V. & Platonov, A. E. Insufficient efficacy and safety of intravenous ribavirin in treatment of haemorrhagic fever with renal syndrome caused by Puumala virus. Infect Dis (Lond) 49, 514–520 (2017). https://doi.org/10.1080/23744235.2017.1293841 Galeno, H. et al. First human isolate of Hantavirus (Andes virus) in the Americas. Emerg Infect Dis 8, 657–661 (2002). https://doi.org/10.3201/eid0807.010277 Ferres, M. et al. Prospective evaluation of household contacts of persons with hantavirus cardiopulmonary syndrome in chile. The Journal of infectious diseases 195, 1563–1571 (2007). https://doi.org/10.1086/516786 Zaki, S. R. et al. Hantavirus pulmonary syndrome. Pathogenesis of an emerging infectious disease. Am J Pathol 146, 552–579 (1995). Temonen, M. et al. Cytokines, adhesion molecules, and cellular infiltration in nephropathia epidemica kidneys: an immunohistochemical study. Clin Immunol Immunopathol 78, 47–55 (1996). https://doi.org/10.1006/clin.1996.0007 Temonen, M. et al. Susceptibility of human cells to Puumala virus infection. The Journal of general virology 74 (Pt 3), 515–518 (1993). https://doi.org/10.1099/0022-1317-74-3-515 Khaiboullina, S. F., Netski, D. M., Krumpe, P. & St Jeor, S. C. Effects of tumor necrosis factor alpha on sin nombre virus infection in vitro. Journal of virology 74, 11966–11971 (2000). https://doi.org/10.1128/jvi.74.24.11966-11971.2000 Lv, C. L. et al. Dual seasonal pattern for hemorrhagic fever with renal syndrome and its potential determinants in China. Sci Total Environ 859, 160339 (2023). https://doi.org/10.1016/j.scitotenv.2022.160339 Pettersson, L. et al. Viral load and humoral immune response in association with disease severity in Puumala hantavirus-infected patients-implications for treatment. Clin Microbiol Infec 20, 235–241 (2014). https://doi.org/10.1111/1469-0691.12259 Saksida, A., Duh, D., Korva, M. & Avsic-Zupanc, T. Dobrava virus RNA load in patients who have hemorrhagic fever with renal syndrome. Journal of Infectious Diseases 197, 681–685 (2008). https://doi.org/10.1086/527485 Yi, J. et al. Hantaan Virus RNA Load in Patients Having Hemorrhagic Fever With Renal Syndrome: Correlation With Disease Severity. Journal of Infectious Diseases 207, 1457–1461 (2013). https://doi.org/10.1093/infdis/jis475 Hong J et al. Expert Consensus on the Prevention and Treatment of Hemorrhagic Fever with Renal Syndrome. Infectious Diseases & Immunity 2, 224–232 (2022). https://doi.org/10.1097/ID9.0000000000000054 Chen, X. P. et al. Lack of association between integrin αβ gene polymorphisms and hemorrhagic fever with renal syndrome in Han Chinese from Hubei, China. Virologica Sinica 32, 73–79 (2017). https://doi.org/10.1007/s12250-016-3888-0 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4576242","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":324799828,"identity":"c29aa995-1256-441d-ab86-b7db49cb142b","order_by":0,"name":"Lei Shi","email":"","orcid":"","institution":"First Affiliated Hospital of Xi'an Jiaotong University","correspondingAuthor":false,"prefix":"","firstName":"Lei","middleName":"","lastName":"Shi","suffix":""},{"id":324799830,"identity":"4952db71-d65c-43b3-8054-84a3cd9ec869","order_by":1,"name":"Shipu Wang","email":"","orcid":"","institution":"Weinan Central 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12:38:24","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4576242/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4576242/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":60623338,"identity":"b3155275-bd12-406f-815a-c5e276176fde","added_by":"auto","created_at":"2024-07-18 21:48:53","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":300225,"visible":true,"origin":"","legend":"\u003cp\u003eComparison of clinical testing (WBC, PLT, CRP, PCT, CRE, BUN and HG) between patients with mild/medium (n=99)and severe/critical (n=38) HFRS.\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4576242/v1/0298067830ccc9643f62c0a3.jpg"},{"id":60623337,"identity":"671eb50b-fb67-43cb-a0c7-e2589e3ed7f3","added_by":"auto","created_at":"2024-07-18 21:48:53","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":106887,"visible":true,"origin":"","legend":"\u003cp\u003eThe kinetics of HTNV RNA load from patients with mild/medium(n=99) versus moderate/severe (n=38) HFRS. The figure represents mean values for each time interval and the error bars are standard error of the mean (SEM). In total, 345 plasma samples from the 137 patients were analyzed. The proportions of samples from patients with mild/medium versus severe/critical illness were: (1-3 days) 6 vs 6 samples, (4-6 days) 59 vs 23, (7-9 days) 53 vs 17, (10-12 days) 48 vs 17, (13-15 days) 43 vs 20, (16-18 days) 35 vs 14, (19-21 days) 2 vs 0, and (22-25 days) 2 vs 0.\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4576242/v1/d90013107831947a58a9610a.jpg"},{"id":60623896,"identity":"8e6d1b6f-f33f-4a45-ba8d-87146d7fe186","added_by":"auto","created_at":"2024-07-18 21:56:53","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":106420,"visible":true,"origin":"","legend":"\u003cp\u003eComparison of HTNV RNA load among patients in different phases of HFRS. Data were obtained from samples collected in the febrile (n=101), hypotensive/oliguric (n=39), polyuric (n=156) or convalescent phase (n=49) .\u003c/p\u003e","description":"","filename":"Figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4576242/v1/152a4157058ee34b17fe15cd.jpg"},{"id":60623339,"identity":"f3edfa6c-7bda-4cd2-b205-6cf54cc63df4","added_by":"auto","created_at":"2024-07-18 21:48:53","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":221540,"visible":true,"origin":"","legend":"\u003cp\u003eComparison of HTNV RNA load with the severity of HFRS in course of fever and unfever phase. The proportions of samples from patients with mild/medium versus severe/critical illness were: (A) fever phase 77 vs 24 samples and (B) unfever phase 233 vs 69 samples.\u003c/p\u003e","description":"","filename":"Figure4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4576242/v1/f73a22f5f267d6c54c9ff3e6.jpg"},{"id":60623343,"identity":"dce3bfbd-96a3-4443-97cb-522f3d3c9e22","added_by":"auto","created_at":"2024-07-18 21:48:53","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":76506,"visible":true,"origin":"","legend":"\u003cp\u003eComparison of the duration of HTNV between patients with mild/medium and severe/critical HFRS.\u003c/p\u003e","description":"","filename":"Figure5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4576242/v1/fef3569b3ccea45e751c97d0.jpg"},{"id":60623341,"identity":"3f01b4b7-be57-4fa3-b5e1-851df3e37338","added_by":"auto","created_at":"2024-07-18 21:48:53","extension":"jpg","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":244853,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart of the study\u003c/p\u003e","description":"","filename":"Figure6.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4576242/v1/04c31e0042763b246fd6ce7c.jpg"},{"id":75144953,"identity":"1a53d6cc-ad70-426f-a7ed-0be22fad4e77","added_by":"auto","created_at":"2025-01-31 06:23:47","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1623241,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4576242/v1/87aad3e4-2f34-4a0c-bd42-4dcf019f6158.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Viral load in febrile phase rather than the duration of virus associates the severity of hemorrhagic fever with renal syndrome","fulltext":[{"header":"Introduction","content":"\u003cp\u003eHantaviruses are negative-sense, single-stranded RNA viruses which belong to the order Bunyavirales, family Hantaviridae and genus Orthohantavirus\u003csup\u003e1\u003c/sup\u003e. Hantaviruses can\u0026nbsp;cause two acute febrile diseases in humans: Hantavirus pulmonary syndrome (HPS) and hemorrhagic fever with renal syndrome (HFRS)\u003csup\u003e2\u003c/sup\u003e, HFRS could be caused by Hantaan virus (HTNV), Amur virus(AMV), Seoul virus (SEOV), Dobrava virus (DOBV), and Puumala virus (PUUV).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eHFRS are endemic in many Asian countries, most number of cases reported in China, South Korea, and the Far Eastern Federal District of Russia, cases in China account for 40-50% of all the HFRS case\u0026nbsp;\u003csup\u003e2-4\u003c/sup\u003e.\u0026nbsp;In recent years, almost 200,000 people were affected by Hantaviruses annually, with a fatality of 1-15% for HFRS around the world\u003csup\u003e5\u003c/sup\u003e. However, the pathogenesis has not been fully elucidated, and there is no specific treatment\u003csup\u003e6,7\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eStudies have demonstrated Hantaviruses RNA can be detected in the serum up to two weeks before the onset of the disease\u003csup\u003e8,9\u003c/sup\u003e. These data indicate that the body\u0026rsquo;s reaction to Hantaviruses infection is delayed. As no virus replication-associated cell death has been reported in tissues collected postmortem from HFRS and HPS cases\u003csup\u003e10,11\u003c/sup\u003e, and these viruses are non-cytopathic in vitro\u003csup\u003e12,13\u003c/sup\u003e, it seems that the process of disease is not directly caused by the virus. But viruses are the initiating factors for the occurrence and development of the disease, the dynamic changes of Hantaviruses RNA and its roles with disease are still unclear. The aim of our study was to investigate the dynamic changes of HTNV RNA and its relationship with disease severity of HFRS.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eDemographics and baseline characteristics\u003c/h2\u003e \u003cp\u003eAll genotypes were Hantaan viruses type, this is coincide with the studys before\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. 137 HFRS patients (n\u0026thinsp;=\u0026thinsp;99 mild/medium and n\u0026thinsp;=\u0026thinsp;38, severe/critical, 28%) were consecutively enrolled in this study. Baseline characteristics of the 137 patients were shown in Fig.\u0026nbsp;1. Of all the patients, 61% were men, and the average age was 47 (\u0026plusmn;\u0026thinsp;3.9) years. WBC counts (\u0026lt;\u0026thinsp;0.0001), PLT counts (\u0026lt;\u0026thinsp;0.001), Hg(\u0026lt;\u0026thinsp;0.01), CRP(\u0026lt;\u0026thinsp;0.001), PCT (\u0026lt;\u0026thinsp;0.001), Cr (\u0026lt;\u0026thinsp;0.01) and BUN (\u0026lt;\u0026thinsp;0.01) have statistic difference at baseline between mild/medium and severe/critical groups.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eDynamic changes of Hantavirus load from onset day\u003c/h2\u003e \u003cp\u003eHTNV RNA load in 137 patients were followed up every three days from until the hantavirus load turned negative (Fig.\u0026nbsp;2). The viral load was highest in fever phase and then gradually decreases. In most patients, the virus turned negative after 2 weeks. Patients with longer fever phase also have a longer duration of virus.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eDynamic changes of Hantavirus load in different phase\u003c/h2\u003e \u003cp\u003eHantavirus replicated all cross the disease, fever, hypotensive-shock/oliguric, polyuria, and recovery phase (Fig.\u0026nbsp;3). Most patients still have viral replication during polyuria phase, some patients even have viruses replication in convalescent phase.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eRelationship of HTNV RNA load with the severity of HFRS\u003c/h2\u003e \u003cp\u003eComparison of HTNV load in fever and unfever phase with disease severity of HFRS. We found the severity of HFRS was only associated with the HTNV RNA load in fever phase rather than unfever phase (Fig.\u0026nbsp;4).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eRelationship of duration of HTNV with the severity of HFRS\u003c/h2\u003e \u003cp\u003eComparison of the duration of HTNV between patients with mild/medium and severe/critical HFRS. We found the severity of HFRS has no relationship with the duration of HTNV (Fig.\u0026nbsp;5).\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe aim of our study was to investigate the dynamic changes of HTNV RNA and its relationship with disease severity of HFRS, to gain further knowledge of disease pathogenesis and possible treatment strategies.\u003c/p\u003e\n\u003cp\u003eData showed in\u0026nbsp;PUUV-caused HFRS,\u0026nbsp;The PUUV RNA was detected in a majority of patient plasma samples up to 9 days after disease onset, the viral load was highest in the early stage of the disease\u003csup\u003e15\u003c/sup\u003e.\u0026nbsp;In DOBV-caused HFRS, the viral RNA varied according to the day of illness\u003csup\u003e16\u003c/sup\u003e. In\u0026nbsp;HTNV-caused HFRS, The viral RNA could only be detected in plasma samples from patients in febrile, hypotensive, and oliguric stage\u003csup\u003e17\u003c/sup\u003e. In our study, we found the virus lasted much longer than we thought before. Most patients still have viral replication in polyuria phase, some patients even have viruses in convalescent phase. The viral load was highest at the very beginning of the disease, and then decreases gradually, for most patients the virus turned negative after 2 weeks. Patients with longer fever phase have a longer duration of virus.\u003c/p\u003e\n\u003cp\u003eBecause the virus lasts for a long time, we further explored if there is a relationship between viral load and disease severity. In previous studies, there were different opinions on whether virus load was related to disease severity. PUUV RNA load or duration of viraemia were not significantly associated with disease severity\u003csup\u003e15\u003c/sup\u003e.\u0026nbsp;Dobrava virus load might be associated with the severity of disease,\u0026nbsp;the patients with severe disease had higher viral RNA loads than patients with a milder course of disease (P =0 .053)\u003csup\u003e16\u003c/sup\u003e. In our study, we found that HTNV load at 1-3 days, 4-6 days, and 7-9 days have no relationship with the severity of disease, but when combined all 1-9 days data in febrile phase, HTNV load was associated with disease severity. We also found that HTNV load in non-febrile phase and the duration of virus have no correlation with the severity of HFRS. So it is possible that the virus activated immune in the febrile phase, and virus-induced immune response may responsible for the subsequent tissue damage. This requires further expanding size study to observe the relationship between viral load and disease severity at the very early stage of HFRS.\u003c/p\u003e\n\u003cp\u003eWe also found higher WBC, Hg, PCT, CRP, BUN, Cr and lower PLT were significantly associated with the severity of HFRS. We then studied if there is a relationship between virus loads and the clinical indicators. The results showed that HTNV load has no correlation with white blood cell, hemoglobin, procalcitonin, C-reactive protein, urea nitrogen, and\u0026nbsp;creatinine (Data not show).\u0026nbsp;As viruses are non-cytopathic\u003csup\u003e10,11\u003c/sup\u003e and it turns out that inflammation caused by HTNV plays an important role in the pathogenesis of HFRS, further exploration of inflammation in HFRS is needed.\u003c/p\u003e\n\u003cp\u003eThere were several limitations in this study. First, the number of cases was relatively small. Second, since the hypotensive-shock phase lasted only a few hours and the condition of patients was really critical, there was no data on the shock phase in this study. Third, though this was a multi-center research, all the patients were from west-north of China, cases out of China were needed to verify the role of cytokine in HFRS patients.\u0026nbsp;\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003eStudy population\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients with HFRS were recruited from the First Affiliated Hospital of Xi'an Jiaotong University, the Eighth Hospital of Xi\u0026rsquo;an and the Central Hospital of Weinan in Shaanxi Province in China from January 2022 to December 2023. Patients who were pregnancy or younger than 18 years, patients with serious chronic disease were excluded from the study. 137 patients with HFRS were followed up from the day of hospitalization. Virus quantification was performed using RT-PCR method. Statistical analysis was conducted using SPSS 27 software. The protocol was approved by the Ethics Committee of the First Affiliated Hospital of Xi\u0026rsquo;an Jiaotong University and was performed in accordance with relevant guidelines and regulations. Informed consent was obtained from all the patients.\u003c/p\u003e\n\u003cp\u003eDiagnostic criteria: HFRS RNA positive and IgM positive. 169 patients with suspected HFRS were recruited at first, 26 patients with positive IgM but negative HTNV RNA were excluded. Among all the 137 patients confirmed HFRS, 15 cases were negative IgM but positive HTNV RNA at admission ( Less than 4 days of onset) and then confirmed by IgM and IgG positive in the subsequent follow-up. IgM/IgG detection using colloidal gold method (Figure 6).\u003c/p\u003e\n\u003cp\u003eThe typical clinical course of HFRS includes five phases: febrile phase, hypotensive-shock phase, oliguric phase, polyuric phase and convalescent phase. Furthermore, in severe cases, the first two or three phases may overlap, while in moderate cases, hypotension shock and/or oliguric phase may be missing. According to the severity of the disease, HFRS can be divided into 4 kinds of clinical types\u003csup\u003e18\u003c/sup\u003e:\u003c/p\u003e\n\u003col\u003e\n\u003cli\u003eMild type: urinary protein is \u0026ldquo;+ to + +\u0026rdquo;, and there is no oliguria and hypotension shock.\u003c/li\u003e\n\u003cli\u003eMedium type: bulbar conjunctival edema is obvious, and the systolic blood pressure is lower than 90mmHg or pulse pressure difference less than 30mmhg, oliguria, urinary protein is \u0026ldquo;++ to +++\u0026rdquo;.\u003c/li\u003e\n\u003cli\u003eSevere type: with neurological symptoms, shock, oliguria up to 5 days or no urine within 2 days.\u003c/li\u003e\n\u003cli\u003eCritical type: one of the following situations occurs on the basis of severe patients, refractory shock, bleeding of important organs, no urine for more than 2 days, others serious complications such as heart failure, pulmonary edema, respiratory failure, coma, subsequent severe infection.\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003e\u003cstrong\u003eData management and laboratory parameters \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDemographic and clinical data were collected from the HFRS patients. Variables collected at hospital admission included serum white blood cell (WBC) counts, hemoglobin (Hg), platelet (PLT) counts, C-reactive protein(CRP), procalcitonin (PCT), urea nitrogen( BUN) and creatinine (Cr).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBlood sampling\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAfter obtaining informed consent, venous blood was collected from HFRS patients and was taken for virus quantification testing immediately. 345 blood samples from 137 patients were obtained in this study. Patients were followed up every three days, from the day of hospitalization in febrile phase, until the virus quantitative test was negative.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHTNV RNA detection\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHTNV RNA detection using RT-PCT described as before. The minimum detection limit for virus quantification is 100 copies/ml. Linear range for detection is 1.0 \u0026times; 10\u003csup\u003e3 \u003c/sup\u003ecopies/mL to 1.0 \u0026times; 10\u003csup\u003e7 \u003c/sup\u003ecopies/ml. Detectable genotyping: Hantaan type or Seoul type\u003csup\u003e19\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll analyses were done using SPSS V.27. For descriptive analyses, categorical variables were reported with absolute and relative frequencies and continuous variables with mean and SD. All virus quantification were standardized using log transformation to enable comparable data in the downstream analyses.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements. \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to acknowledge the patients and their families, the physicians and research staff for their dedication and contributions to the study.\u0026nbsp;We also thank Dr. Wei Hou and Dr. Tianhui Li for primer design and data analyzing support.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLS and TYC designed research; LS, SPW, FLW, XZ, DFR and TTT followed-up patients and collected data; LS, SPW, FLW, JZ, HBL, YPL, YWW and JSH conducted data analysis and\u0026nbsp;prepared figures and tables; LS, SPW and FLW wrote the manuscript with input from all the authors. YLH, SML, ZWL, YRZ and TYC revised the manuscript.\u0026nbsp;TYC acquired the funding and provided overall supervision.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by the National Science and Technology Projects (Project No. 2017ZX10305501-002-002); the Natural Science Research Project of Shaanxi Province (Project No. 2020JM-363); and the Research Fund of Xi\u0026rsquo;an Jiaotong University (Project No. 2019ZYTS-09).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAdditional information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets analyzed in the current study will be available from the corresponding author upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eKuhn, J. H. \u0026amp; Schmaljohn, C. S. A Brief History of Bunyaviral Family Hantaviridae. \u003cem\u003eDiseases\u003c/em\u003e 11 (2023). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3390/diseases11010038\u003c/span\u003e\u003cspan address=\"10.3390/diseases11010038\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSehgal, A. \u003cem\u003eet al.\u003c/em\u003e Hemorrhagic Fever with Renal Syndrome in Asia: History, Pathogenesis, Diagnosis, Treatment, and Prevention. Viruses 15 (2023). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3390/v15020561\u003c/span\u003e\u003cspan address=\"10.3390/v15020561\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJiang, H. \u003cem\u003eet al.\u003c/em\u003e Hantavirus infection: a global zoonotic challenge. Virol Sin 32, 32\u0026ndash;43 (2017). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/s12250-016-3899-x\u003c/span\u003e\u003cspan address=\"10.1007/s12250-016-3899-x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLv, C. L. \u003cem\u003eet al.\u003c/em\u003e Dual seasonal pattern for hemorrhagic fever with renal syndrome and its potential determinants in China. Sci Total Environ 859 (2023). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/ARTN\u003c/span\u003e\u003cspan address=\"https://doi.org/ARTN\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.scitotenv.2022.160339\u003c/span\u003e\u003cspan address=\"10.1016/j.scitotenv.2022.160339\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSingh, S. \u003cem\u003eet al.\u003c/em\u003e Epidemiology, virology and clinical aspects of hantavirus infections: an overview. Int J Environ Health Res 32, 1815\u0026ndash;1826 (2022). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1080/09603123.2021.1917527\u003c/span\u003e\u003cspan address=\"10.1080/09603123.2021.1917527\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAfzal, S. \u003cem\u003eet al.\u003c/em\u003e Hantavirus: an overview and advancements in therapeutic approaches for infection. Front Microbiol 14, 1233433 (2023). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3389/fmicb.2023.1233433\u003c/span\u003e\u003cspan address=\"10.3389/fmicb.2023.1233433\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMalinin, O. V. \u0026amp; Platonov, A. E. Insufficient efficacy and safety of intravenous ribavirin in treatment of haemorrhagic fever with renal syndrome caused by Puumala virus. Infect Dis (Lond) 49, 514\u0026ndash;520 (2017). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1080/23744235.2017.1293841\u003c/span\u003e\u003cspan address=\"10.1080/23744235.2017.1293841\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGaleno, H. \u003cem\u003eet al.\u003c/em\u003e First human isolate of Hantavirus (Andes virus) in the Americas. Emerg Infect Dis 8, 657\u0026ndash;661 (2002). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3201/eid0807.010277\u003c/span\u003e\u003cspan address=\"10.3201/eid0807.010277\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFerres, M. \u003cem\u003eet al.\u003c/em\u003e Prospective evaluation of household contacts of persons with hantavirus cardiopulmonary syndrome in chile. The Journal of infectious diseases 195, 1563\u0026ndash;1571 (2007). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1086/516786\u003c/span\u003e\u003cspan address=\"10.1086/516786\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZaki, S. R. \u003cem\u003eet al.\u003c/em\u003e Hantavirus pulmonary syndrome. Pathogenesis of an emerging infectious disease. Am J Pathol 146, 552\u0026ndash;579 (1995).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTemonen, M. \u003cem\u003eet al.\u003c/em\u003e Cytokines, adhesion molecules, and cellular infiltration in nephropathia epidemica kidneys: an immunohistochemical study. Clin Immunol Immunopathol 78, 47\u0026ndash;55 (1996). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1006/clin.1996.0007\u003c/span\u003e\u003cspan address=\"10.1006/clin.1996.0007\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTemonen, M. \u003cem\u003eet al.\u003c/em\u003e Susceptibility of human cells to Puumala virus infection. The Journal of general virology 74 (Pt 3), 515\u0026ndash;518 (1993). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1099/0022-1317-74-3-515\u003c/span\u003e\u003cspan address=\"10.1099/0022-1317-74-3-515\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKhaiboullina, S. F., Netski, D. M., Krumpe, P. \u0026amp; St Jeor, S. C. Effects of tumor necrosis factor alpha on sin nombre virus infection in vitro. Journal of virology 74, 11966\u0026ndash;11971 (2000). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1128/jvi.74.24.11966-11971.2000\u003c/span\u003e\u003cspan address=\"10.1128/jvi.74.24.11966-11971.2000\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLv, C. L. \u003cem\u003eet al.\u003c/em\u003e Dual seasonal pattern for hemorrhagic fever with renal syndrome and its potential determinants in China. Sci Total Environ 859, 160339 (2023). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.scitotenv.2022.160339\u003c/span\u003e\u003cspan address=\"10.1016/j.scitotenv.2022.160339\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePettersson, L. \u003cem\u003eet al.\u003c/em\u003e Viral load and humoral immune response in association with disease severity in Puumala hantavirus-infected patients-implications for treatment. Clin Microbiol Infec 20, 235\u0026ndash;241 (2014). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1111/1469-0691.12259\u003c/span\u003e\u003cspan address=\"10.1111/1469-0691.12259\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSaksida, A., Duh, D., Korva, M. \u0026amp; Avsic-Zupanc, T. Dobrava virus RNA load in patients who have hemorrhagic fever with renal syndrome. Journal of Infectious Diseases 197, 681\u0026ndash;685 (2008). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1086/527485\u003c/span\u003e\u003cspan address=\"10.1086/527485\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYi, J. \u003cem\u003eet al.\u003c/em\u003e Hantaan Virus RNA Load in Patients Having Hemorrhagic Fever With Renal Syndrome: Correlation With Disease Severity. Journal of Infectious Diseases 207, 1457\u0026ndash;1461 (2013). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1093/infdis/jis475\u003c/span\u003e\u003cspan address=\"10.1093/infdis/jis475\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHong J \u003cem\u003eet al.\u003c/em\u003e Expert Consensus on the Prevention and Treatment of Hemorrhagic Fever with Renal Syndrome. Infectious Diseases \u0026amp; Immunity 2, 224\u0026ndash;232 (2022). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1097/ID9.0000000000000054\u003c/span\u003e\u003cspan address=\"10.1097/ID9.0000000000000054\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChen, X. P. \u003cem\u003eet al.\u003c/em\u003e Lack of association between integrin αβ gene polymorphisms and hemorrhagic fever with renal syndrome in Han Chinese from Hubei, China. Virologica Sinica 32, 73\u0026ndash;79 (2017). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/s12250-016-3888-0\u003c/span\u003e\u003cspan address=\"10.1007/s12250-016-3888-0\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"HFRS, Hantaan virus, HTNV RNA, disease severity","lastPublishedDoi":"10.21203/rs.3.rs-4576242/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4576242/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eHemorrhagic fever with renal syndrome (HFRS) was Hantaviruses infectious disease with a mortality rate of 1-10%. In the previous studies, the duration of the virus and the relationship between the virus and the severity of the disease were still unclear. 137 patients with HFRS were enrolled in this study, patients were followed up every three days until the virus load was negative. Virus quantification was performed using RT-PCR method. Of all the 137 patients, 38 patients (28%) were \u0026nbsp;classified as severe/critical cases. We found that the duration of the virus lasted much longer than we thought before. Most patients still have virus during the polyuria phase, and some patients even have virus in recovery phase. We confirmed that viral load in febrile phase rather than the duration of virus associated with the severity of Hantaan virus caused HFRS. This indicates that tissue damage in HFRS may not related to the virus, virus activated immune response in the early stages may responsible for the pathogenesis. Understanding the mechanism of virus in HFRS will provide ideas and guidance for better clinical treatment.\u003c/p\u003e","manuscriptTitle":"Viral load in febrile phase rather than the duration of virus associates the severity of hemorrhagic fever with renal syndrome","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-18 21:48:48","doi":"10.21203/rs.3.rs-4576242/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"22a86a91-a9e8-4b65-ae98-e549fe9f8415","owner":[],"postedDate":"July 18th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":34356003,"name":"Health sciences/Diseases/Infectious diseases/Viral infection"},{"id":34356004,"name":"Health sciences/Health care/Therapeutics/Drug therapy"}],"tags":[],"updatedAt":"2025-01-31T06:23:28+00:00","versionOfRecord":[],"versionCreatedAt":"2024-07-18 21:48:48","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4576242","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4576242","identity":"rs-4576242","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}