Hemorrhagic fever with renal syndrome complicated by orchitis

Hemorrhagic fever with renal syndrome (HFRS) is a disease caused by viruses of the family Bunyaviridae,genus Hantavirus.HFRS from Dobrava virus (DOBV) is a seldom reported disease in Albania.Clinically HFRS is manifested as mild,moderate,or severe.Therefore,the number of cases of Hantavirus'infection may be underestimated,and should be included in the differential diagnosis of many acute infections,hematologic diseases,acute abdominal diseases and renal diseases complicated by acute renal failure.We report here an atypical presentation of HFRS from Dobrava virus complicated by orchitis with a positive outcome.     

Hemorrhagic fever with renal syndrome associated with acute pancreatitis

Hemorrhagic fever with renal syndrome (HFRS) is a systemic infectious disease caused by Hantaviruses and characterized by fevers,bleeding tendencies,gastrointestinal symptoms and renal failure.It encom...     

Monocyte subset redistribution from blood to kidneys in patients with Puumala virus caused hemorrhagic fever with renal syndrome

Innate immune cells like monocytes patrol the vasculature and mucosal surfaces, recognize pathogens, rapidly redistribute to affected tissues and cause inflammation by secretion of cytokines. We previously showed that monocytes are reduced in blood but accumulate in the airways of patients with Puumala virus (PUUV) caused hemorrhagic fever with renal syndrome (HFRS). However, the dynamics of monocyte infiltration to the kidneys during HFRS, and its impact on disease severity are currently unknown. Here, we examined longitudinal peripheral blood samples and renal biopsies from HFRS patients and performed in vitro experiments to investigate the fate of monocytes during HFRS. During the early stages of HFRS, circulating CD14–CD16+ nonclassical monocytes (NCMs) that patrol the vasculature were reduced in most patients. Instead, CD14+CD16– classical (CMs) and CD14+CD16+ intermediate monocytes (IMs) were increased in blood, in particular in HFRS patients with more severe disease. Blood monocytes from patients with acute HFRS expressed higher levels of HLA-DR, the endothelial adhesion marker CD62L and the chemokine receptors CCR7 and CCR2, as compared to convalescence, suggesting monocyte activation and migration to peripheral tissues during acute HFRS. Supporting this hypothesis, increased numbers of HLA-DR+, CD14+, CD16+ and CD68+ cells were observed in the renal tissues of acute HFRS patients compared to controls. In vitro, blood CD16+ monocytes upregulated CD62L after direct exposure to PUUV whereas CD16– monocytes upregulated CCR7 after contact with PUUV-infected endothelial cells, suggesting differential mechanisms of activation and response between monocyte subsets. Together, our findings suggest that NCMs are reduced in blood, potentially via CD62L-mediated attachment to endothelial cells and monocytes are recruited to the kidneys during HFRS. Monocyte mobilization, activation and functional impairment together may influence the severity of disease in acute PUUV-HFRS.     

Hemorrhagic fever with renal syndrome: clinical aspects

Hemorrhagic fever with renal syndrome (HFRS) is an acute viral fever which typically progresses through five stages: an acute grippe, followed by hemorrhage and shock, acute renal insufficiency from tubulo-interstitial nephritis, and recovery. Death from circulatory or renal failure occurs in 5%-15% of cases. In mild or abortive forms of the disease, associated with viral strains enzootic in Scandinavia the illness is milder. Hemorrhage and shock occur with lower frequency and the fatality rate is less than 1%. Pathologic examination of HFRS cases from Asia discloses generalized congestion, hyperemia, and hemorrhage, with scattered foci of necrosis in numerous organs. Congestion and hemorrhage are most evident in the kidney medulla. Widespread microscopic evidence of capillary and vascular dysfunction is found, with endothelial cell swelling, perivascular edema, diapadesis of erythrocytes and mononuclear cell infiltration. Hemorrhage and inflammation in the renal interstitium and tubular epithelial degeneration characterize the kidney pathology. Limited data indicate pathogenic roles for cell destruction from viral infection as well as immune mediated mechanisms. No specific therapy is available.     

Cystatin C,a novel urinary biomarker for sensitive detection of acute kidney injury during haemorrhagic fever with renal syndrome

To explore the value of cystatin C for evaluating acute kidney injury (AKI) in haemorrhagic fever with renal syndrome (HFRS), the concentrations of cystatin C in serum and urine samples from HFRS patients were determined. The serum and urinary cystatin C concentrations significantly increased in HFRS patients compared with normal controls (p?<?0.001). In the acute phase of HFRS, urinary cystatin C increased to higher levels than serum creatinine, especially in severe or critical cases in the oliguric stage. Furthermore, higher levels of urinary cystatin C in the acute phase positively correlated with increased severity of the subsequent kidney injury. In conclusion, urinary cystatin C is a more sensitive clinical marker for AKI in HFRS, which may enable us to initiate treatment measures as early as possible.     

Elevated Soluble CD163 Plasma Levels Are Associated with Disease Severity in Patients with Hemorrhagic Fever with Renal Syndrome

Background

Hantaan virus is a major zoonotic pathogen that causesing hemorrhagic fever with renal syndrome (HFRS). Although HFRS pathogenesis has not been entirely elucidated, the importance of host-related immune responses in HFRS pathogenesis has been widely recognized. CD163, a monocyte and macrophage-specific scavenger receptor that plays a vital function in the hosts can reduce inflammation, is shed during activation as soluble CD163 (sCD163). The aim of this study was to investigate the pathological significance of sCD163 in patients with HFRS.

Methods

Blood samples were collected from 81 hospitalized patients in Tangdu Hospital from October 2011 to January 2014 and from 15 healthy controls. The sCD163 plasma levels were measured using a sandwich ELISA, and the relationship between sCD163 and disease severity was analyzed. Furthermore, CD163 expression in 3 monocytes subset was analyzed by flow cytometry.

Results

The results demonstrated that sCD163 plasma levels during the HFRS acute phase were significantly higher in patients than during the convalescent stage and the levels in the healthy controls (P<0.0001). The sCD163 plasma levels in the severe/critical group were higher than those in the mild/moderate group during the acute (P<0.0001). A Spearman correlation analysis indicated that the sCD163 levels were positively correlated with white blood cell, serum creatine, blood urea nitrogen levels, while they were negatively correlated with blood platelet levels in the HFRS patients. The monocyte subsets were significantly altered during the acute stage. Though the CD163 expression levels within the monocyte subsets were increased during the acute stage, the highest CD163 expression level was observed in the CD14++CD16+ monocytes when compared with the other monocyte subsets.

Conclusion

sCD163 may be correlated with disease severity and the disease progression in HFRS patients; however, the underlying mechanisms should be explored further.     

Atmospheric Moisture Variability and Transmission of Hemorrhagic Fever with Renal Syndrome in Changsha City,Mainland China, 1991–2010

Background

The transmission of hemorrhagic fever with renal syndrome (HFRS) is influenced by environmental determinants. This study aimed to explore the association between atmospheric moisture variability and the transmission of hemorrhagic fever with renal syndrome (HFRS) for the period of 1991–2010 in Changsha, China.

Methods and Findings

Wavelet analyses were performed by using monthly reported time series data of HFRS cases to detect and quantify the periodicity of HFRS. A generalized linear model with a Poisson distribution and a log link model were used to quantify the relationship between climate and HFRS cases, highlighting the importance of moisture conditions. There was a continuous annual oscillation mode and multi-annual cycle around 3–4 years from 1994 to 1999. There was a significant association of HFRS incidence with moisture conditions and the Multivariate El Niño–Southern Oscillation Index (MEI). Particularly, atmospheric moisture has a significant effect on the propagation of HFRS; annual incidence of HFRS was positively correlated with annual precipitation and annual mean absolute humidity.

Conclusions

The final model had good accuracy in forecasting the occurrence of HFRS and moisture condition can be used in disease surveillance and risk management to provide early warning of potential epidemics of this disease.     

Hantaviruses: molecular biology, evolution and pathogenesis

Hantaviruses are tri-segmented negative sense single stranded RNA viruses that belong to the family Bunyaviridae. In nature, hantaviruses are exclusively maintained in the populations of their specific rodent hosts. In their natural host species, hantaviruses usually develop a persistent infection with prolonged virus shedding in excreta. Humans become infected by inhaling virus contaminated aerosol. Unlike asymptomatic infection in rodents, hantaviruses cause two acute febrile diseases in humans: hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). The mortality rate varies from 0.1% to 40% depending on the virus involved. Hantaviruses are distributed world wide, with over 150,000 HFRS and HPS cases being registered annually. In this review we summarize current knowledge on hantavirus molecular biology, epidemiology, genetic diversity and co-evolution with rodent hosts. In addition, special attention was given in this review to describing clinical manifestation of HFRS and HPS, and advances in our current understanding of the host immune response, treatment, and prevention.     

Development of small-molecule inhibitors against hantaviruses

Hantavirus (HV), a pathogen of animal infectious diseases that poses a threat to humans, has attracted extensive attention. Clinically, HV can cause hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS), between which HFRS is mostly in Eurasia, and HPS is mostly in the Americas. This paper reviews the research progress of small-molecule inhibitors of HV.     

Hantavirus infection-induced B cell activation elevates free light chains levels in circulation

In humans, orthohantaviruses can cause hemorrhagic fever with renal syndrome (HFRS) or hantavirus pulmonary syndrome (HPS). An earlier study reported that acute Andes virus HPS caused a massive and transient elevation in the number of circulating plasmablasts with specificity towards both viral and host antigens suggestive of polyclonal B cell activation. Immunoglobulins (Igs), produced by different B cell populations, comprise heavy and light chains; however, a certain amount of free light chains (FLCs) is constantly present in serum. Upregulation of FLCs, especially clonal species, associates with renal pathogenesis by fibril or deposit formations affecting the glomeruli, induction of epithelial cell disorders, or cast formation in the tubular network. We report that acute orthohantavirus infection increases the level of Ig FLCs in serum of both HFRS and HPS patients, and that the increase correlates with the severity of acute kidney injury in HFRS. The fact that the kappa to lambda FLC ratio in the sera of HFRS and HPS patients remained within the normal range suggests polyclonal B cell activation rather than proliferation of a single B cell clone. HFRS patients demonstrated increased urinary excretion of FLCs, and we found plasma cell infiltration in archival patient kidney biopsies that we speculate to contribute to the observed FLC excreta. Analysis of hospitalized HFRS patients’ peripheral blood mononuclear cells showed elevated plasmablast levels, a fraction of which stained positive for Puumala virus antigen. Furthermore, B cells isolated from healthy donors were susceptible to Puumala virus in vitro, and the virus infection induced increased production of Igs and FLCs. The findings propose that hantaviruses directly activate B cells, and that the ensuing intense production of polyclonal Igs and FLCs may contribute to acute hantavirus infection-associated pathological findings.     

Dentin matrix protein 1 correlates with the severity of hemorrhagic fever with renal syndrome and promotes hyper-permeability of endothelial cells infected by Hantaan virus

Hantaviruses are the major causative agents of hemorrhagic fever with renal syndrome (HFRS) in humans, which is characterized by increased capillary permeability. Dentin matrix protein 1 (DMP1) has been shown to degrade components of the basal membrane and interendothelial junctions via matrix metalloproteinase-9. To study the changes of serum DMP1 in HFRS, we determined the concentration of DMP1 using sandwich enzyme-linked immunosorbent assay. We found that serum DMP1 concentrations increased significantly, and reached peak value during the oliguric phase and in the critical group in HFRS patients. Moreover, serum DMP1 concentrations were closely related to blood urea nitrogen, creatinine, cystatin C, and vascular endothelial growth factor (VEGF). We further explored the role of DMP1 in HTNV-infected human umbilical vein endothelial cells (HUVECs) model. Data from immunocytochemistry showed that VEGF and tumor necrosis factor-α (TNF-α) promoted the expression of DMP1 on HTNV-infected HUVECs. Results from transwell assays demonstrated that the permeability of HUVECs increased significantly after HTNV infection with the addition of DMP1, VEGF, and TNF-α. This study suggests that elevated DMP1 concentrations may be associated with disease stage, severity, and the degree of acute kidney injury. DMP1 is involved in the regulation of capillary permeability in HFRS caused by hantavirus infection.     

Misdiagnosis of scrub typhus as hemorrhagic fever with renal syndrome and potential co-infection of both diseases in patients in Shandong Province,China, 2013–2014

BackgroundScrub typhus, caused by Orientia tsutsugamushi, an obligate intracellular gram-negative bacterium, along with hemorrhagic fever with renal syndrome (HFRS), caused by hantaviruses, are natural-focus infectious diseases prevalent in Shandong Province, China. Both diseases have similar clinical manifestations in certain disease stages and similar epidemic seasons, which has caused difficulties for physicians in distinguishing them. The aim of this study was to investigate whether misdiagnosis of scrub typhus as HFRS occurred in patients in Shandong Province.MethodsSerum samples (N = 112) of clinically suspected HFRS patients from 2013 to 2014 in Shandong Province were analyzed with enzyme-linked immunosorbent assay (ELISA) for antibodies to both hantavirus and Orientia tsutsugamushi.ResultsELISA showed that 56.3% (63/112) and 8.0% (9/112) of clinically suspected HFRS patients were IgM antibody positive to hantavirus and O. tsutsugamushi, respectively. Among the hantavirus IgM antibody positive patients, 7.9% (5/63) were also IgM antibody positive to O. tsutsugamushi. Among the hantavirus IgM antibody negative sera, 8.2% (4/49) of sera were positive to O. tsutsugamushi.ConclusionsWe concluded that some scrub typhus patients were misdiagnosed as HFRS and co-infection of scrub typhus and HFRS might exist in China. Due to the different treatments for scrub typhus and HFRS, physicians should carefully differentiate between scrub typhus and HFRS and consider administering anti-rickettsia antibiotics if treatment for HFRS alone does not work.     

Wild-Type Puumala Hantavirus Infection Induces Cytokines, C-Reactive Protein, Creatinine, and Nitric Oxide in Cynomolgus Macaques

Hantaviruses cause two severe human diseases: hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). Approximately 200,000 cases are reported annually, and there is to date no specific treatment available. A major obstacle in studying the medical aspects of HFRS and HPS has been the lack of an adequate animal model. Here we show that infection of cynomolgus macaques by wild-type Puumala hantavirus resulted in typical signs of HFRS including lethargy, anorexia, proteinuria, and/or hematuria, in addition to cytokine (interleukin 6 [IL-6], IL-10, and tumor necrosis factor alpha), C-reactive protein, creatinine, and nitric oxide responses. Viral RNA was detected in plasma from days 3 to 7 postinoculation until days 24 to 28 postinoculation, infectious virus was recovered, and the virus-specific immune responses (immunoglobulin M [IgM], IgG, and neutralizing antibodies) mimicked those seen in humans. The results indicated that the monkey model will provide a valuable tool for studies of pathogenesis, candidate vaccines, and antivirals for hantavirus disease.     

东北三省6株肾综合征出血热病毒生物学性状的研究

肾综合征出血热(hemorrhagic fever with renal syndrome,HFRS)是我国重点防治的急性传染病,对于流行于不同地区的汉坦病毒(hanatavirus)进行分离和系统地鉴定,可以为HFRS的防治提供科学依据,特别是对流行株血清型及基因型的确定,是研制疫苗和确定防治重点及对策的重要前提,也为研究我国汉坦病毒的遗传和进化特征奠定了基础。研究对6株流行于东北三省的汉坦病毒进行了全面鉴定,其中H8205、H8207株为人源性汉坦病毒,其余均为鼠源性汉坦病毒。研究表明,6株病毒具有病毒型别明确,抗原性较为广谱,免疫原性好,在Vero细胞上适应能力强及病毒滴度高,以及来源及传代历史清楚等特点,适合作为双价HFRS纯化灭活疫苗候选毒株,并且可建立起完善和合格的生产用毒种库,为我国生产以Vero细胞为基质的双价肾综合征出血热纯化灭活疫苗奠定了坚实的基础。     

Discovery, clinical and etiological characteristic of hemorrhagic fever with renal syndrome in the subtropical zone of Krasnodar region

Twenty-six patients with hemorrhagic fever with renal syndrome (HFRS) were revealed as a result of serological examination of 582 patients with fever living around Sochi town. Etiologic role of Dobrava virus subtype as the cause of HFRS was assessed by immunofluorescent and ELISA assays, and neutralization test. The principal host of this virus and source of infection for humans is Caucasian forest mouse Apodemus ponticus. HFRS morbidity was sporadic and not dependent from patients' occupation and season. Comparative analysis of clinical and laboratory data from HFRS cases caused by DOB/Sochi and DOB/Lipetsk subspecies, as well as Puumala virus showed higher proportion of severe forms of disease in patients with HFRS from Sochi.     

Haemorrhagic fever with renal syndrome: evaluation of ELISA for detection of Puumala-virus-specific IgG and IgM

IgM and IgG ELISA to Puumala virus were evaluated using sera from patients with haemorrhagic fever with renal syndrome (HFRS) from different geographical regions: Sweden, Denmark, Norway, Belgium and the European USSR.IgM ELISA proved useful in the diagnosis of HFRS in patients from all the regions mentioned above. Specific IgM could be detected as early as day 1 post onset of disease, and patients remained IgM-positive for several months. Specific IgG ELISA antibodies were also frequently detected in acute sera, and acute-convalescent serum pairs often failed to show a significant titre rise or increase in optical density (OD) values. This limits the use of IgG ELISA in patient diagnosis. Sera collected 2 years after infection revealed higher IgG ELISA OD readings than convalescent sera, and very high values were still detectable 10 to 20 years postinfection. IgG ELISA is therefore useful for the testing of immunity and in seroepidemiological studies.Acute and convalescent sera from HFRS patients in Korea and the Asian USSR showed no or only very weak reactivity in the Puumala virus IgG and IgM ELISA. These results are consistent with the “one-way” crossing described earlier.     

Changes in Rodent Abundance and Weather Conditions Potentially Drive Hemorrhagic Fever with Renal Syndrome Outbreaks in Xi’an,China, 2005–2012

BackgroundIncreased risks for hemorrhagic fever with renal syndrome (HFRS) caused by Hantaan virus have been observed since 2005, in Xi’an, China. Despite increased vigilance and preparedness, HFRS outbreaks in 2010, 2011, and 2012 were larger than ever, with a total of 3,938 confirmed HFRS cases and 88 deaths in 2010 and 2011.ConclusionsIn addition to a strong seasonal pattern, HFRS incidence was correlated with rodent density and rainfall, indicating that they potentially drive the HFRS outbreaks. Future work should aim to determine the mechanism underlying the seasonal pattern and autocorrelation. However, this model can be useful in risk management to provide early warning of potential outbreaks of this disease.     

Spatiotemporal association of rapid urbanization and water-body distribution on hemorrhagic fever with renal syndrome: A case study in the city of Xi’an,China

Hemorrhagic fever with renal syndrome (HFRS) is a zoonosis characterized by clinical features of high fever, hemorrhage, and renal damage. China has the largest number of HFRS cases worldwide, accounting for over 90% of the total reported cases. In this paper, we used surveyed HFRS data and satellite imagery to conduct geostatistical analysis for investigating the associations of rapid urbanization, water bodies, and other factors on the spatiotemporal dynamics of HFRS from year 2005 to 2018 in Xi’an City, Northwest China. The results revealed an evident epidemic aggregation in the incidence of HFRS within Xi’an City with a phenomenal fluctuation in periodic time series. Rapid urbanization was found to greatly affect the HFRS incidence in two different time phases. HFRS caused by urbanization influences farmers to a lesser extent than it does to non-farmers. The association of water bodies with the HFRS incidence rate was found to be higher within the radii of 696.15 m and 1575.39 m, which represented significant thresholds. The results also showed that geomatics approaches can be used for spatiotemporally investigating the HFRS dynamic characteristics and supporting effective allocations of resources to formulate strategies for preventing epidemics.     

Control of laboratory acquired hemorrhagic fever with renal syndrome (HFRS) in Japan

By the end of 1985, 126 human cases of laboratory acquired hemorrhagic fever with renal syndrome (HFRS) were recorded in Japan. Seroepidemiological studies revealed that laboratory rats exhibited high IFA titers against Hantaan or related viruses at locations where HFRS patients occurred. Laboratory researchers contracted HFRS more frequently than laboratory animal technicians or caretakers, although a laboratory animal caretaker died of the disease. Inhalation of HFRS-virus contaminated air in an animal facility is the likely cause of infection with this virus. Wound infection during animal experiments may be another important route of infection. Infection of laboratory rats can occur by transferring animals from contaminated to other animal facilities. Tissue fragments or cells of transplantable animal tumors are a potential source of spreading the HFRS virus. Eradication of HFRS virus from a contaminated animal facility can be achieved best by elimination of all animals in the room, especially when human HFRS is associated with an infected colony. In some cases, when IFA titers of the sera of the rats tested were low, infection apparently disappeared without instituting any particular control measures other than ordinary procedures for care and management of laboratory animals. HFRS viruses have not yet been eradicated from all animal facilities in Japan. Therefore, serological monitoring of laboratory rats continues.     

NK Cell Activation in Human Hantavirus Infection Explained by Virus-Induced IL-15/IL15Rα Expression

Clinical infection with hantaviruses cause two severe acute diseases, hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). These diseases are characterized by strong immune activation, increased vascular permeability, and up to 50% case-fatality rates. One prominent feature observed in clinical hantavirus infection is rapid expansion of natural killer (NK) cells in peripheral blood of affected individuals. We here describe an unusually high state of activation of such expanding NK cells in the acute phase of clinical Puumala hantavirus infection. Expanding NK cells expressed markedly increased levels of activating NK cell receptors and cytotoxic effector molecules. In search for possible mechanisms behind this NK cell activation, we observed virus-induced IL-15 and IL-15Rα on infected endothelial and epithelial cells. Hantavirus-infected cells were shown to strongly activate NK cells in a cell-cell contact-dependent way, and this response was blocked with anti-IL-15 antibodies. Surprisingly, the strength of the IL-15-dependent NK cell response was such that it led to killing of uninfected endothelial cells despite expression of normal levels of HLA class I. In contrast, hantavirus-infected cells were resistant to NK cell lysis, due to a combination of virus-induced increase in HLA class I expression levels and hantavirus-mediated inhibition of apoptosis induction. In summary, we here describe a possible mechanism explaining the massive NK cell activation and proliferation observed in HFRS patients caused by Puumala hantavirus infection. The results add further insights into mechanisms behind the immunopathogenesis of hantavirus infections in humans and identify new possible targets for intervention.