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Infectious disease AND Hemorrhagic fever Hantavirus [keywords]
- Hantavirus immunology of rodent reservoirs: current status and future directions. [Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't]
- Viruses 2014; 6(3):1317-35.
Hantaviruses are hosted by rodents, insectivores and bats. Several rodent-borne hantaviruses cause two diseases that share many features in humans, hemorrhagic fever with renal syndrome in Eurasia or hantavirus cardiopulmonary syndrome in the Americas. It is thought that the immune response plays a significant contributory role in these diseases. However, in reservoir hosts that have been closely examined, little or no pathology occurs and infection is persistent despite evidence of adaptive immune responses. Because most hantavirus reservoirs are not model organisms, it is difficult to conduct meaningful experiments that might shed light on how the viruses evade sterilizing immune responses and why immunopathology does not occur. Despite these limitations, recent advances in instrumentation and bioinformatics will have a dramatic impact on understanding reservoir host responses to hantaviruses by employing a systems biology approach to identify important pathways that mediate virus/reservoir relationships.
- Elevated Serum IL-21 Levels in Hantavirus-Infected Patients Correlate with the Severity of the Disease. [JOURNAL ARTICLE]
- Inflammation 2014 Feb 9.
Hemorrhagic fever with renal syndrome (HFRS) is an acute viral infection caused by Hantavirus (HTV). Capillary leakage is one of the hallmarks of HTV infection. The mechanisms underlying the pathogenesis of HFRS are not completely understood. However, it has been suggested that immune mechanisms, including cytokines, might have an important role in HFRS pathogenesis. In this study, we investigated the potential role of interleukin-21 (IL-21) which is a newly discovered cytokine that stimulates T-cell and B-cell responses in the pathogenesis of HFRS. Serum samples were collected from 58 patients hospitalized with laboratory-verified HTV infection and 20 healthy controls. Serum IL-21 concentration was measured using an enzyme-linked immunosorbent assay. Serum IL-21 levels began to increase in the fever phase when renal damage appeared. The highest serum IL-21 level was detected in oliguric phase along with the peak degree of urinary renal impairment. When entering the polyuric phase, with gradual increase in urine and recovered renal function, the serum IL-21 level was observed to fall, returning to normal level after the renal function recovered in the convalescent phase. The serum IL-21 level was positively correlated with blood urea nitrogen (BUN) and creatinine (Cr), suggesting that the serum IL-21 level is associated with the disease severity of HFRS. This study indicated that IL-21 may act as an important inflammatory mediator in the immunopathogenesis of HFRS. The strategy to control IL-21 may hamper the immune response in patients with HFRS.
- Discovery of hantaviruses in bats and insectivores and the evolution of the genus Hantavirus. [JOURNAL ARTICLE]
- Virus Res 2014 Feb 6.
Hantaviruses are among the most important zoonotic pathogens of humans, causing either hemorrhagic fever with renal syndrome (HFRS) or hantavirus pulmonary syndrome (HPS). From the period 1964-2006 almost all hantaviruses had been identified in rodents, with the exception of Thottapalayam virus (TPMV) isolated from shrews sampled in India. As a consequence, rodents were considered as the natural reservoir hosts. However, over the past seven years, most of the newly found hantavirus genotypes have been from either shrews or moles. Remarkably, in recent years divergent hantaviruses have also been identified in bats sampled from both Africa and Asia. All these data indicate that hantaviruses have a broad range of natural reservoir hosts. Phylogenetic analyses of the available sequences of hantaviruses suggest that hantaviruses might have first appeared in Chiroptera (bats) or Soricomorpha (moles and shrews), before emerging in rodent species. Although rodent hantaviruses cluster according to whether their hosts are members of the Murinae and Cricetidae, the phylogenetic histories of the viruses are not always congruent with those of their hosts, indicating that cross-species transmission events have occurred at all taxonomic levels. In sum, both cross-species transmission and co-divergence have produced the high genetic diversity of hantaviruses described to date.
- [Prognostic factors in hantavirus infections]. [English Abstract, Journal Article, Review]
- Mikrobiyol Bul 2014 Jan; 48(1):179-87.
The hantaviruses classified in Hantavirus genus of Bunyaviridae family, may cause two different types of clinical conditions, namely hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). Mortality may reach up to 40% in these infections. Hantavirus subtypes (Sin Nombre, Hantaan, Seoul, Puumala, Dobrava, etc) with different virulences represent one of the most significant factors affecting the mortality. Additionally, many other factors including age, gender, humoral immune response, genetic factors, patient's clinical and laboratory findings, transfusion, mechanical ventilation requirement, antiviral treatment and immunotherapy administered to the patient are prognostically important. Increasing age had an unfavorable effect on mortality. While the disease is commonly observed in the male gender, mortality rate is higher in the female gender. The higher the emergent neutralizing antibody response, the virus spread, the number of the infected cells and the cytotoxic T lymphocyte-mediated injury will be lower. The requirement for dialysis is reported to be higher with a poorer prognosis in individuals with HLA-B8, -DR3, -DQ2 alleles, and those with HLA-B27 allele usually experience a milder clinical course. Clinically, the risk of mortality increases in patients with multiple, central nervous system hemorrhage, sepsis, disseminated intravascular coagulation (DIC) and secondary infection. The presence of adult respiratory distress syndrome (ARDS), the requirement for mechanical ventilation, the presence of dyspnea and hemoconcentration in HPS are reported to be the most important prognostic factors associated with death. The correlation of severity and the transfusion requirement with mortality was demonstrated. High serum levels of white blood cells, blood urea nitrogen (BUN), creatinine phophokinase (CPK), C-reactive protein (CRP), prothrombin time (PT), activated partial thromboplastin time (aPTT), D-dimer and INR (International normalized ratio) are prognostic factors that increase the mortality risk. Hemodialysis support is particularly important in cases infected with Hantaan and Dobrava viruses. Respiratory support and mechanical ventilation can be life-saving in HPS cases. Extracorporeal membrane oxygenation support has been demonstrated to have a favorable contribution to the patient survival in HPS. While there are some human and animal trials showing that ribavirin reduces the severity of HFRS, hemodialysis requirement and mortality, its efficacy for HPS has not yet been demonstrated. As a result, a proper evaluation of the prognostic factors will provide physicians a perspective with respect to the disease course and the necessary treatment approach.
- HFRS and hantaviruses in the Balkans/South-East Europe. [JOURNAL ARTICLE]
- Virus Res 2014 Jan 26.
Hemorrhagic fever with renal syndrome is endemic in the Balkans with epidemic outbreaks and sporadic cases that have been recorded yearly since the disease was first recognized. The incidence of Balkan HFRS is modest, with approximately one hundred cases reported in most years. Seroepidemiological investigations conducted in several Balkan countries revealed an overall seroprevalence of 6% in Bosnia and Herzegovina, 1.6% in Croatia, 4% in Greece and 1.7% in Slovenia, respectively. The complex ecology of the Balkan Peninsula supports the existence of diverse rodent and insectivore species which harbor several pathogenic and non-pathogenic hantaviruses. Among them only Dobrava (DOBV) and Puumala (PUUV) viruses are associated with disease in humans. Comprehensive clinical studies compared clinical signs and symptoms between patients infected with either virus. A spectrum of clinical picture of the disease ranges from mild illness typical of PUUV infections to a severe form with fulminant hemorrhagic fever and an overall mortality rate of 9.8% among DOBV infected patients. While severe DOBV cases are recognized from Slovenia in the North to Greece in the South, PUUV infections are more frequent in northern part of the area. Balkans represent an area with a potential need for hantavirus vaccines, but due to co-existence of DOBV and PUUV causing HFRS in the same region, a universal vaccine is required.
- Old World hantaviruses: Aspects of pathogenesis and clinical course of acute renal failure. [JOURNAL ARTICLE]
- Virus Res 2014 Jan 8.
Hantavirus-associated diseases represent emerging infections that are ranked in the highest priority group of communicable diseases for surveillance and epidemiological research. In the last years, several novel hantavirus species were described and the number of host reservoir species harboring hantaviruses is also increasing. Reports of cases with severe or atypical clinical courses become also more frequent. These facts raise more and more questions concerning host reservoir specificity, pathogenicity and molecular mechanism of pathogenesis. Hantavirus disease is characterized by vascular leakage due to increased capillary permeability. The infection manifests often in the lung (hantaviral cardiopulmonary syndrome; HCPS) or in the kidney (hemorrhagic fever with renal syndrome, HFRS). The underlying mechanisms of both syndromes are probably similar despite the difference in organ tropism. Characterization of hantaviral replication cycle and of patient-specific determinants will help to identify factors responsible for the clinical symptoms and course.
- Increased risk of acute myocardial infarction and stroke during hemorrhagic fever with renal syndrome: a self-controlled case series study. [Journal Article, Research Support, Non-U.S. Gov't]
- Circulation 2014 Mar 25; 129(12):1295-302.
We recently observed that cardiovascular causes of death are common in patients with hemorrhagic fever with renal syndrome (HFRS), which is caused by hantaviruses. However, it is not known whether HFRS is a risk factor for the acute cardiovascular events of acute myocardial infarction (AMI) and stroke.Personal identification numbers from the Swedish HFRS patient database (1997-2012; n=6643) were cross-linked with the National Patient Register from 1987 to 2011. Using the self-controlled case series method, we calculated the incidence rate ratio of AMI/stroke in the 21 days after HFRS against 2 different control periods either excluding (analysis 1) or including (analysis 2) fatal AMI/stroke events. The incidence rate ratios for analyses 1 and 2 for all AMI events were 5.53 (95% confidence interval [CI], 2.6-11.8) and 6.02 (95% CI, 2.95-12.3) and for first AMI events were 3.53 (95% CI, 1.25-9.96) and 4.64 (95% CI, 1.83-11.77). The incidence rate ratios for analyses 1 and 2 for all stroke events were 12.93 (95% CI, 5.62-29.74) and 15.16 (95% CI, 7.21-31.87) and for first stroke events were 14.54 (95% CI, 5.87-36.04) and 17.09 (95% CI, 7.49-38.96). The majority of stroke events occurred in the first week after HFRS. Seasonal effects were not observed, and apart from 1 study, neither sex nor age interacted with the associations observed in this study.There is a significantly increased risk for AMI and stroke in the immediate time period after HFRS. Therefore, HFRS patients should be carefully monitored during the acute phase of disease to ensure early recognition of symptoms of impending AMI or stroke.
- Ongoing spillover of Hantaan and Gou hantaviruses from rodents is associated with hemorrhagic fever with renal syndrome (HFRS) in China. [Journal Article, Research Support, Non-U.S. Gov't]
- PLoS Negl Trop Dis 2013; 7(10):e2484.
Longquan City, Zhejiang province, China, has been seriously affected by hemorrhagic fever with renal syndrome (HFRS) since the first cases were registered in 1974. To understand the epidemiology and emergence of HFRS in Longquan, which may be indicative of large parts of rural China, we studied long-term incidence patterns and performed a molecular epidemiological investigation of the causative hantaviruses in human and rodent populations.During 1974-2011, 1866 cases of HFRS were recorded in Longquan, including 20 deaths. In 2011, the incidence of HFRS remained high, with 19.61 cases/100,000 population, despite the onset of vaccination in 1997. During 1974-1998, HFRS cases in Longquan occurred mainly in winter, while in the past decade the peak of HFRS has shifted to the spring. Notably, the concurrent prevalence of rodent-borne hantaviruses in the region was also high. Phylogenetic analyses of viral sequences recovered from rodents in Longquan revealed the presence of novel genetic variants of Gou virus (GOUV) in Rattus sp. rats and Hantaan virus (HTNV) in the stripe field mice, respectively. Strikingly, viral sequences sampled from infected humans were very closely related to those from rodents.HFRS represents an important public health problem in Longquan even after years of preventive measures. Our data suggest that continual spillover of the novel genetic variant of GOUV and the new genetic lineage of HTNV are responsible for the high prevalence of HFRS in humans. In addition, this is the first report of GOUV associated with human HFRS cases, and our data suggest that GOUV is now the major cause of HFRS in this region.
- No gender-related differences in the severity of nephropathia epidemica, Germany. [Journal Article]
- BMC Infect Dis 2013.:457.
The number of cases of hantavirus disease caused by Puumala virus is increasing enormously in Germany within the last years. Men are overrepresented in hantavirus disease and differences in course and symptoms in relation to gender were reported from several countries. This study was conducted to define possible gender-specific risk factors and aspects of severity in hantavirus infections occurring in Germany.Characteristics, clinical parameters and symptoms were recorded in a retrospective analysis of 108 patients with serologically confirmed hantavirus infection treated in our department. This cohort corresponds in regard to age, time of infection and gender ratio to the characteristics of the overall cases reported in Germany.The frequency of characteristic symptoms of hantavirus disease did not differ between males and females. The median of nadir and peak levels of clinical parameters did not exhibit relevant differences that would point to a more severe course in males or females. The clinical course and duration of hospitalization were similar for both sexes. No relevant differences in renal and pulmonary findings were observed. Males with hantavirus disease exhibited more cardiac findings than females.To compare the unequal gender distribution of the rodent-borne Puumala hantavirus disease with the gender ratio of other infectious diseases, we analyzed the gender ratio for notifiable infections according to their mode of transmission. Our data revealed a general overrepresentation of men in infections carried by arthropods and rodents.In contrast to reports from other countries, no crucial differences in the symptoms, course or severity of hantavirus disease between infected men and female were observed in our cohort. However behavioural differences may account for the fact that men are more often affected by certain infectious diseases than females.
- Elevated plasma soluble Sema4D/CD100 levels are associated with disease severity in patients of hemorrhagic fever with renal syndrome. [Journal Article, Research Support, Non-U.S. Gov't]
- PLoS One 2013; 8(9):e73958.
Hantaan virus (HTNV) could cause a severe lethal hemorrhagic fever with renal syndrome (HFRS) in humans. Despite a limited understanding of the pathogenesis of HFRS, the importance of host-related immune responses in the pathogenesis of HFRS has been widely recognized. CD100/Sema4D has been demonstrated to play an important role in physiological and pathological immune responses, but the functional role of CD100 in infectious diseases has only been inadequately reported. The aim of this study was to investigate the pathological significance of CD100 in patients after HTNV infection.Blood samples were collected from 99 hospitalized patients in Tangdu Hospital and 27 health controls. The level of soluble CD100 (sCD100) in plasma were quantified by ELISA and the relationship between sCD100 and the disease course or severity were analyzed. The expressions of membrane CD100 on various subpopulations of peripheral blood mononuclear cell (PBMC) were analyzed by flow cytometry. The results showed that sCD100 level in acute phase of HFRS was significantly higher in patients than that in healthy controls (P<0.0001) and the sCD100 level declined in convalescent phase. Multivariate model analysis showed that platelet count, white blood cell count, serum creatinine level and blood urea nitrogen level were associated with sCD100 levels and contributed independently to the elevated sCD100 levels. The expression of membrane CD100 on PBMCs decreased in the acute phase of HFRS patients compared with that of the normal controls and recovered in the convalescent phase.We reported the elevated level of plasma sCD100 in HFRS patients and the elevated level might be a result from the shedding of membrane CD100 on PBMC. The elevated level of sCD100 was associated with disease severity, suggesting that sCD100 might be a cause or a consequence of progression of HFRS. The underlying mechanisms should be explored further.