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Hantaan virus (HTNV) causes hemorrhagic fever with renal syndrome (HFRS), which is a zoonosis endemic in eastern Asia, especially in China. The reservoir host of HTNV is field mouse (Apodemus agraricus). The main manifestation of HFRS, including acute kidney injury, increases vascular permeability, and coagulation abnormalities. In this paper, we review the current knowledge of the pathogenesis of HFRS including virus factor, immunity factor and host genetic factors. Furthermore, the treatment and prevention will be discussed.

Thromboelostograms (TEG) are indicators that reflect the dynamic changes in blood coagulation objectively. Compared with traditional coagulation tests, TEG are easy to perform; imparting a head start in determining patients'coagulation status. The aim of this study was to explore the role of thromboelastography as an early predictor of disease severity and as a prognostic factor in patients with haemorrhagic fever of renal syndrome (HFRS). This was a retrospective study in which we collected clinical data from 342 patients with HFRS who were hospitalized from January 2017 to January 2021. The predictive value of laboratory parameters for HFRS criticalization was assessed via receiver operating characteristic (ROC) curves. After that, a model of criticalization was developed using stepwise analysis, subsequently, the model was evaluated and validated internally as well as externally. This study was approved by the Ethics Committee of the Hospital. The study population was categorized into critical and noncritical groups according to their condition during hospitalization, with a median age of 52.00 (39.00-61.50) years for the critical group and 39.00 (16.00-53.25) years for the noncritical group. Both groups had a large proportion of male patients (65.3% and 72.3%, respectively). The median duration of hospitalization was 15.00 (3.50-25.00) days in the critical group and 13.00 (10.00-17.25) days in noncritical group. In the critical group 40.8% of patients died. The incidence of bleeding was greater in critical patients (51.0%) than in noncritical patients (15.1%). The coagulation indices: CI, K, MA, R and angle were significantly different between the two groups (p < 0.05). Critical patients had higher levels of K and R and lower levels of CI, MA and angle. Multivariate analysis revealed that K, ALB, CK, SCR, angle, WBC and LYM were independently associated with disease severity in patients with HFRS. ROC curve analysis revealed that the criticality model equation had an AUC of 0.9058, a sensitivity of 88.9% and a specificity of 80.2%, which were better than that of any single parameter in predicting the patient's outcome. The internal validation C index was 0.866, the GOF P value was 0.825, and the external validation AUC was 0.762, with a sensitivity of 71.4% and a specificity of 74.2%. The results of the calibration plots indicated that there was some agreement between the model-estimated HFRS critical illness rates and the final observed critical illness rates in the study population. Decision curve analysis indicated that the model had significant clinical utility and comparable net benefit over a range of threshold probabilities. Critical HFRS have significantly abnormal coagulation function and high incidence of bleeding associated with poor outcome. A criticalization prediction model constructed on the basis of thromboelastography indices in early stages of the disease has a good predictive ability and may be helpful in the early identification of critically ill patients for timely clinical intervention and treatment.

Hantavirus causes hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). Strong inflammatory responses and vascular leakage are important hallmarks of these often fatal diseases. The mechanism behind pathogenesis is unknown and no specific treatment is available. IL-6 was recently highlighted as a biomarker for HPS/HFRS severity. IL-6 signaling is complex and context dependent: while classical signaling generally provide protective responses, trans-signaling can cause severe pathogenic responses. Here, we investigated a potential role for IL-6 trans-signaling in hantavirus pathogenesis. Effects of IL-6 trans-signaling during in vitro hantavirus infection were assessed using primary human endothelial cells treated with recombinant soluble IL-6 receptor (sIL-6R). Plasma from Puumala orthohantavirus-infected HFRS patients (n=28) were analyzed for IL-6 trans-signaling potential and its associations to severity. In vitro, sIL-6R treatment of infected cells enhanced IL-6 and CCL2 secretion, upregulated ICAM-1, and affected VE-cadherin leading to a disrupted cell barrier integrity. HFRS patients showed altered plasma levels of sIL-6R and soluble gp130 (sgp130) resulting in an increased sIL-6R/sgp130 ratio suggesting enhanced IL-6 trans-signaling potential. Plasma sgp130 levels negatively correlated with number of interventions and positively with albumin levels. Patients receiving oxygen treatment displayed a higher sIL-6R/sgp130 ratio compared to patients that did not. IL-6 trans-signaling is linked to hantavirus pathogenesis. Targeting IL-6 trans-signaling might provide a therapeutic strategy for treatment of severe HFRS and perhaps also HPS.

Scrub typhus and Hemorrhagic fever with renal syndrome (HFRS) are prevalent infectious diseases in South Korea. This study compared the clinical and laboratory characteristics associated with scrub typhus and HFRS treated at Chosun University Hospital, South Korea. A retrospective cross-sectional study was conducted by reviewing the medical records of patients diagnosed with scrub typhus and HFRS between 2010 and 2023. Diagnoses were confirmed through molecular and serological testing. A total of 156 patients with scrub typhus and 45 patients with HFRS were included. Among patients with scrub typhus, 136 (87.18%) patients had Boryong strain, 4 (2.56%) had Taguchi strain, 3 (1.93%) had Karp strain, and 1 (0.64%) had Kanda strain. Most cases of scrub typhus and HFRS occurred in individuals aged ≥65 years. The common clinical features of scrub typhus included fever, fatigue, skin rash, and eschar. In contrast, HFRS commonly presented with fever, gastrointestinal symptoms, and hemorrhagic manifestations. The mean hospital stay was significantly longer for HFRS (14.09 ± 7.67 days) compared to scrub typhus (7.89 ± 7.56 days, p < 0.001). A higher proportion of patients with HFRS (15, 33.33%) required intensive care unit admission compared to patients with scrub typhus (14, 8.97%, p < 0.001). Among patients with scrub typhus, the adjusted odds of presenting with a skin rash, eschar, or lymphopenia (<1500/µL) were 1.37 (95% confidence interval [CI]: 1.18-1.59, p < 0.001), 1.25 (95% CI: 1.11-1.40, p < 0.001), and 1.83 (95% CI: 1.34-2.49, p < 0.001), respectively. While scrub typhus and HFRS share overlapping clinical features, skin rash, eschar, and lymphopenia were more commonly associated with scrub typhus. Further studies are warranted to characterize clinical features and outcomes of various hantavirus subtypes.

Hemorrhagic fever with renal syndrome (HFRS) is the result of acute, zoonotic, natural foci hantavirus infections. It has serious social and medical importance due to its widespread distribution and the disease’s severity. There is a lack of effective etiotropic therapy and specific prophylaxis available. The aim of this review is to observe the etiological, clinical, and epidemiological features of nosologic HFRS forms in Russia, as well as differences and similarities with hantavirus pulmonary syndrome (HPS). The various clinical HFRS manifestations characterized diseases associated with Puumala, Kurkino, and Sochi hantaviruses in the Russian European part, and with Hantaan, Amur, and Seoul hantaviruses in the Russian Far East. Differences were observed for HFRS foci types based on biological characteristics and natural host population dynamics. As a result of clinical and epidemiological analysis six nosological forms were established, all of which were classified as “hemorrhagic fever with renal syndrome” according to the WHO’s expert recommendation from 1983 year. The study showed comparable taxonomic characteristics and determined the mechanism of human infection course for HFRS and HPS. The accumulated knowledge of this study allows for the combination of HFRS and HPS names into a common logical disease name “Hantavirus fever”.

Background Hemorrhagic fever with renal syndrome (HFRS) is an endemic disease occurring in various parts of the world. Prompt access to care with proper treatment is essential for preventing patients from developing renal failure and unfavorite outcomes. This study aimed to elucidate laboratory parameters associated with HFRS severity and prognosis to predict disease course and initiate prompt clinical management. Methods Retrospective analysis of laboratory data was performed on HFRS patients from December 2016 to January 2022 in Baoji City of Shaanxi Province in China using different statistical methods. Results The WBC and neutrophils in peripheral blood, RBC in urine sediments, blood, protein, and glucose in urine, PT/INR, aPTT, TT, AST, ALT, AST/ALT, MAO, AD, urea, creatinine, cystatin C, CK‐MB, LDH, α‐HBDH, mAST, triglycerides, glucose, amylase, ferritin, and PCT in serum increased in HFRS patients along with disease severity, while the lymphocytes, monocytes, platelets, plateletcrit, fibrinogen, serum total protein, albumin, HDL‐c, magnesium, complement C3 and C4, IgG, triiodothyronine, thyroxine, and free triiodothyronine were reduced. Results also indicated that in uncured HFRS patients, the NEUT%, CRP, cast, PT/INR, aPTT, D‐dimer, AST/ALT, CK‐MB, LDH, α‐HBDH, m‐AST, ferritin, and PCT were significantly higher than in cured patients, while platelets, C3, and C4 in uncured patients were significantly lower than in cured patients. The NEUT%, CRP, AST/ALT, and LDH were associated with patients' prognosis. Conclusions Laboratory data are helpful in predicting HFRS patients' progress, severity, and prognosis, thus, these parameters are useful in guiding prompt clinical management of patients. Prompt access to care with proper treatment is essential for preventing patients from developing renal failure and unfavorable outcomes. This study aimed to elucidate laboratory parameters associated with HFRS severity and prognosis to predict disease course and initiate prompt clinical management. Retrospective analysis of laboratory data was performed on HFRS patients from December 2016 to January 2022 in Baoji City of Shaanxi Province in China using different statistical methods. Multiple abnormal laboratory results were found in patients with HFRS when compared with healthy subjects. The WBC and neutrophils in peripheral blood, RBC in urine sediments, blood, protein, and glucose in urine, PT/INR, aPTT, TT, AST, ALT, AST/ALT, MAO, AD, urea, creatinine, cystatin C, CK‐MB, LDH, α‐HBDH, mAST, triglycerides, glucose, amylase, ferritin, and PCT in serum increased along with disease severity, while the lymphocytes, monocytes, platelets, plateletcrit, fibrinogen, serum total protein, albumin, HDL‐c, magnesium, complement C3 and C4, IgG, triiodothyronine, thyroxine, and free triiodothyronine were reduced. Results also indicated that in uncured HFRS patients, the NEUT%, CRP, cast, PT/INR, aPTT, D‐dimer, AST/ALT, CK‐MB, LDH, α‐HBDH, m‐AST, ferritin, and PCT were significantly higher than in cured patients, while platelets, C3, and C4 in uncured patients were significantly lower than in cured patients. The NEUT%, CRP, AST/ALT, and LDH were associated with patients' prognosis. Laboratory data are helpful in predicting HFRS patients' progress, severity, and prognosis; thus, these parameters are useful in guiding prompt clinical management of patients.

Hantaan virus (HTNV) infects humans and causes hemorrhagic fever with renal syndrome (HFRS). The development of well-characterized animal models of HFRS could accelerate the testing of vaccine candidates and therapeutic agents and provide a useful tool for studying the pathogenesis of HFRS. Because NLRC3 has multiple immunoregulatory roles, we investigated the susceptibility of Nlrc3 −/− mice to HTNV infection in order to establish a new model of HFRS. Nlrc3 −/− mice developed weight loss, renal hemorrhage, and tubule dilation after HTNV infection, recapitulating many clinical symptoms of human HFRS. Moreover, infected Nlrc3 −/− mice showed higher viral loads in serum, spleen, and kidney than wild type C57BL/6 (WT) mice, and some of them manifested more hematological disorders and significant pathological changes within multiple organs than WT mice. Our results identify that HTNV infected Nlrc3 −/− mice can develop clinical symptoms and pathological changes resembling patients with HFRS, suggesting a new model for studying the pathogenesis and testing of candidate vaccines and therapeutics.

Hantaviruses, zoonotic RNA viruses belonging to the order Bunyavirales, cause two severe acute diseases in humans, hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). Hantavirus-infected patients show strong cytotoxic lymphocyte responses and hyperinflammation; however, infected cells remain mostly intact. Hantaviruses were recently shown to inhibit apoptosis in infected cells. By inhibiting granzyme B- and TRAIL-mediated apoptosis, hantaviruses specifically and efficiently inhibit cytotoxic lymphocyte-mediated killing of infected cells. Hantaviruses also strongly inhibit apoptosis triggered intrinsically; i.e., initiated through intracellular activation pathways different from those used by cytotoxic lymphocytes. However, insights into the latter mechanisms are currently largely unknown. Here, we dissected the mechanism behind how hantavirus infection, represented by the HFRS-causing Hantaan virus and the HPS-causing Andes virus, results in resistance to staurosporine-induced apoptosis. Less active caspase-8 and caspase-9, and consequently less active caspase-3, was observed in infected compared to uninfected staurosporine-exposed cells. While staurosporine-exposed uninfected cells showed massive release of pro-apoptotic cytochrome C into the cytosol, this was not observed in infected cells. Further, hantaviruses prevented activation of BAX and mitochondrial outer membrane permeabilization (MOMP). In parallel, a significant increase in levels of the pro-survival factor BCL-2 was observed in hantavirus-infected cells. Importantly, direct inhibition of BCL-2 by the inhibitor ABT-737, as well as silencing of BCL-2 by siRNA, resulted in apoptosis in staurosporine-exposed hantavirus-infected cells. Overall, we here provide a tentative mechanism by which hantaviruses protect infected cells from intrinsic apoptosis at the mitochondrial level by inducing an increased expression of the pro-survival factor BCL-2, thereby preventing MOMPs and subsequent activation of caspases. The variety of mechanisms used by hantaviruses to ensure survival of infected cells likely contribute to the persistent infection in natural hosts and may play a role in immunopathogenesis of HFRS and HPS in humans.

Podocyte injury has recently been described as unifying feature in idiopathic nephrotic syndromes (INS). Puumala hantavirus (PUUV) infection represents a unique RNA virus-induced renal disease with significant proteinuria. The underlying pathomechanism is unclear. We hypothesized that PUUV infection results in podocyte injury, similar to findings in INS. We therefore analyzed standard markers of glomerular proteinuria (e.g. immunoglobulin G [IgG]), urinary nephrin excretion (podocyte injury) and serum levels of the soluble urokinase plasminogen activator receptor (suPAR), a proposed pathomechanically involved molecule in INS, in PUUV-infected patients. Hantavirus patients showed significantly increased urinary nephrin, IgG and serum suPAR concentrations compared to healthy controls. Nephrin and IgG levels were significantly higher in patients with severe proteinuria than with mild proteinuria, and nephrin correlated strongly with biomarkers of glomerular proteinuria over time. Congruently, electron microcopy analyses showed a focal podocyte foot process effacement. suPAR correlated significantly with urinary nephrin, IgG and albumin levels, suggesting suPAR as a pathophysiological mediator in podocyte dysfunction. In contrast to INS, proteinuria recovered autonomously in hantavirus patients. This study reveals podocyte injury as main cause of proteinuria in hantavirus patients. A better understanding of the regenerative nature of hantavirus-induced glomerulopathy may generate new therapeutic approaches for INS.

This study aimed to investigate the Thrombomodulin (TM) levels in patients who suffered hemorrhagic fever with renal syndrome (HFRS) of varying severities, and to evaluate the predictive properties of TM for the seriousness of HFRS, thereby providing a clue for the monitoring and management of this patients in the future. Chemiluminescence was used to determine the concentrations of TM in 196 patients with HFRS and 49 healthy controls. Conventional testing techniques were used to test the basic clinical reference values for leukocytes, platelets (PLT), C-reactive protein (CRP), creatine (Cr), uric acid (UA), and urea, and the values for activated partial thromboplastin time, prothrombin time, and fibrinogen. The colloidal gold method was used to measure HFRS antibody levels in the patients. The correlation of TM with conventional parameters was assessed using Spearman correlation analysis, and ordinal logistic regression analysis was used to analyze the severity risk factors. The predictive potency of TM for HFRS patients' severity was evaluated by receiver operating characteristics (ROC) curve analysis. The concentrations of TM increased with disease severity and peaked in the critical type patients. In addition, plasma levels of TM were proportionally correlated with the levels of leukocytes ( = 0.4218; <0.01), creatine ( = 0.3797; <0.01), urea ( = 0.3763; <0.01), uric acid ( = 0.3624; <0.01), and C-reactive protein ( = 0.2767; <0.01). Conversely, there was an inverse correlation between TM, platelet counts ( = -0.4509; <0.01), and fibrinogen levels ( = -0.2431; <0.01). Furthermore, TM demonstrated significant predictive value for the severity of HFRS with an area under the ROC curve (AUC) of 0.872(95% : 0.822-0.921, <0.001). TM levels are associated with HFRS severity, suggesting that TM detection might be beneficial for monitoring the status and effective management of HFRS patients.