Logistic regression analysis of risk factors for hemorrhagic fever with renal syndrome complicated with acute pancreatitis.

BACKGROUND: Hantavirus infection is the main cause of hemorrhagic fever with renal syndrome (HFRS), which is common in Asia and Europe. There is a considerable risk of morbidity and mortality from the uncommon Hantavirus complication known as acute pancreatitis (AP). METHODS: Retrospective analysis of the medical records of individuals with HFRS was performed. Relevant variables were assessed by univariate analyses and the variables with a p value <.05 were entered into the multivariable regression analysis. RESULTS: In this study, 114 individuals with HFRS in total were included, and 30 of them (26.32%) had AP. The univariate analyses showed that living in Xuancheng city (Anhui Province); an alcohol consumption history; white blood cell (WBC) count; lymphocyte (lym%) and eosinophil percentages (EO%); neutrophil (neut), eosinophil (EO), and red blood cell (RBC) counts; hemoglobin (Hb); hematocrit (HCT); proteinuria; hematuria; albumin (ALB), blood urea nitrogen (BUN), creatinine (Cr), uric acid (UA), cystatin-C (Cys-C) levels; carbon dioxide-combining power (CO2CP); fibrinogen degradation products (FDPs); and D-dimer level were significantly associated with HFRS complicated with AP (p < .05). In the multivariable regression analysis, an alcohol consumption history, lym%, proteinuria, FDPs and D-dimer level were found to be risk factors for HFRS complicated with AP (p < .05). CONCLUSION: Our findings indicate that HFRS patients with a history of consuming alcohol, a high lym%, intense proteinuria, high levels of FDPs, and a low level of D-dimer might be more prone to the development of AP.KEY MESSAGESThis is the first report employing Logistic regression analysis methods for exploring the risk factors for HFRS complicated with AP in China.Many factors (most are laboratory parameters) were significantly associated with HFRS complicated with AP.We found that HFRS patients with a history of consuming alcohol, a high lym%, intense proteinuria, high levels of FDPs, and a low level of D-dimer might be more prone to the development of AP.

Infección por hantavirus en la Provincia de Buenos Aires-Argentina. Comportamiento de la serie temporal 1997-2021 / Hantavirus infection in the Province of Buenos Aires-Argentina. Characteristics of the time series 1997-2021

INTRODUCCIÓN: La infección por hantavirus es endémica en América del Sur, con un amplio espectro de gravedad y una letalidad que varía entre 17 y 40 por ciento. El presente estudio recoge información de 25 años de vigilancia epidemiológica en Buenos Aires, Argentina. OBJETIVO: Caracterizar el comportamiento de la serie temporal 1997-2021, observando tendencia y estacionalidad. MÉTODOS: La función de serie temporal utilizada empleó la media móvil centrada según periodos trimestrales, de forma que cada año se dividió en cuartiles. Se consideró un modelo multiplicativo. RESULTADOS: Con una tasa de mortalidad de la serie de 0,15 por 100 mil y de letalidad de 22,6, la razón varones : mujeres fue de 3,4:1. La distribución sindrómica mostró mayor compromiso renal, siendo la tasa de mortalidad prácticamente igual en ambos sexos. CONCLUSIÓN: Como enfermedad infecciosa, la infección por hantavirus reflejó en los últimos 25 años un comportamiento, recurrente y estacional, endémico y compartido en sus características clínicas con el resto de la región andina.

BACKGROUND: Hantavirus infection is endemic in South America, with a wide spectrum of severity and a fatality rate that varies between 17-40 percent. This study collects information from 25 years of epidemiological surveillance in Buenos Aires, Argentina. AIM: To characterize the behavior of the 1997-2021 time series, observing trends and seasonality. METHODS: The time series function used the moving average centered according to quarterly periods, so that each year was divided into quartiles. A multiplicative model is missed. RESULTS: With a mortality rate for the series of 0.15 per 100,000 and a fatality rate of 22.6, the male : female ratio was 3.4:1. The syndromic distribution showed greater renal involvement, with the mortality rate being practically the same in both sexes. CONCLUSION: As an infectious disease, hantavirus has reflected in the last 25 years a behavior, recurrent and seasonal, endemic and shared in its clinical characteristics with the rest of the Andean region.

Risk of lymphoid malignancies increased after Puumala virus infection in Finland, 2009-2019: A retrospective register-based cohort study.

OBJECTIVES: The Puumala virus (PUUV) is a hantavirus that causes hemorrhagic fever with renal syndrome. Studies showing an increased risk of lymphoid malignancies after hantavirus infection, together with the observation that PUUV infects B cells, motivated us to study the risk of lymphoid malignancies after PUUV infection. METHODS: We linked data from the Finnish Cancer Registry and National Infectious Diseases Register for 2009-2019. We used a time-dependent Cox regression model to evaluate the hazard of the lymphoid malignancies grouped according to the HAEMACARE classification. RESULTS: We identified 68 cases of lymphoid malignancies after PUUV infection among 16,075 PUUV-infected individuals during 61,114,826 person-years of observation. A total of 10 cases occurred within 3-<12 months and 38 within 1-<5 years after PUUV infection, and the risk of lymphoid malignancies increased with hazard ratios (HRs) of 2.0 (95% confidence interval [CI], 1.1-3.7) and 1.6 (95% CI, 1.2-2.3), respectively. The group of mature B cell neoplasms showed an increased risk 3-<12 months and 1-<5 years after PUUV infection, HR 2.2 (95% CI, 1.2-4.3) and HR 1.8 (95% CI, 1.3-2.5), respectively. CONCLUSION: PUUV infection is associated with lymphoid malignancies in the Finnish population, supporting the earlier studies. Further research is required to understand the pathophysiological mechanisms behind this association.

Association between haemorrhagic fever with renal syndrome and cancers.

OBJECTIVES: To investigate the risk of haematologic and solid organ malignancies in patients with haemorrhagic fever with renal syndrome (HFRS) compared with the general population. METHODS: This propensity-score-matched cohort study was conducted using data collected from the Korean national health insurance service (NHIS) between January 2003 and December 2017. The HFRS cohort included 5888 newly diagnosed cases of HFRS, and 412,804 general participants from the NHIS database were included as the control cohort. The incidence rate of malignancies was assessed and compared between the HFRS and control cohorts. RESULTS: There were 64 cases of haematologic malignancy in 236,286 person-years of observation, and 1245 cases of solid organ cancer in 209,333 person-years. The risks of haematologic malignancy and solid organ cancer were significantly higher in the HFRS cohort [adjusted hazards ratio (aHR) 4.10, 95% confidence interval (CI) 2.36-7.14] than the control cohort [aHR 2.97, 95% CI 2.60-3.38). In subgroup analysis, the HFRS cohort was associated with high hazard ratios for leukaemia and non-Hodgkin lymphoma. The HFRS cohort also had increased aHRs for all types of solid organ cancer. CONCLUSIONS: Patients with HFRS are at increased risk of both haematologic and solid organ malignancies compared with the general population, and this increased proportionally over time. Careful monitoring for malignancy after the onset of HFRS may be necessary.

Population-based seroprevalence of Puumala hantavirus in Finland: smoking as a risk factor.

Puumala hantavirus (PUUV) causes hemorrhagic fever with renal syndrome in humans, that is an endemic disease in Finland. We estimated the seroprevalence of PUUV in Finland and explored risk factors and disease associations by using unique survey data with health register linkage. A total of 2000 sera from a nationwide health survey from 2011, representative of the adult population, were screened for PUUV IgG by immunofluorescence assay. We performed statistical analysis adjusting for stratified cluster design and taking into account sampling weights. In total, 254 sera among 2000 tested were PUUV-IgG-positive resulting in a weighted seroprevalence of 12.5%, (95% CI 10.9-14.4), mirroring known age and regional variation in reported incidence. No associations between PUUV-seropositivity and chronic diseases including cardiovascular (including hypertension), pulmonary, kidney disease and cancer were observed. Smoking was significantly associated with seropositivity (adjusted OR 1.54; 95% CI 1.16-2.04). In addition, significant dose-response relations were found for the number of cigarettes smoked daily (OR 1.14; 95% CI 1.12-1.28). The results are important for disease burden assessment and guide intervention strategies, highlighting also the role of smoking prevention.

Hemorrhagic fever with renal syndrome (HFRS) in Poland

Hemorrhagic fever with renal syndrome (HFRS) is an acute viral zoonosis occurring due to the hantavirus infection. On the territory it constitutes the only case of viral hemorrhagic fever. The infections occurring in Poland are mainly caused by the Puumala and Dobrava serotypes. The pathogenetic influence of other Hanta serotypes such as Boginia, Nova and Seewis on humans is still unknown. The endemic territory of the occurrence of the hantavirus infections in Poland is the Podkarpacie region. The morbidity is not high and ranges between 0.02 and 0.14 in every 100 000 but professional literature suggests that the data concerning the territory of Poland is underestimated. So far hantavirus infections have not been reported in other areas of Poland yet the presence of the virus may be excluded. In view of literature and the significant occurrence of Hanta antibodies in patients included in the risk group, it may be claimed that the diseases caused by Hanta virus constitute a significant factor influencing the medical status of the group in focus all over the country.

Clinical characterization of two severe cases of hemorrhagic fever with renal syndrome (HFRS) caused by hantaviruses Puumala and Dobrava-Belgrade genotype Sochi.

BACKGROUND: Hantavirus disease belongs to the emerging infections. The clinical picture and severity of infections differ between hantavirus species and may even vary between hantavirus genotypes. The mechanisms that lead to the broad variance of severity in infected patients are not completely understood. Host- and virus-specific factors are considered. CASE PRESENTATION: We analyzed severe cases of hantavirus disease in two young women. The first case was caused by Puumala virus (PUUV) infection in Germany; the second case describes the infection with Dobrava-Belgrade virus (DOBV) in Russia. Symptoms, laboratory parameters and cytokine levels were analyzed and compared between the two patients. Serological and sequence analysis revealed that PUUV was the infecting agent for the German patient and the infection of the Russian patient was caused by Dobrava-Belgrade virus genotype Sochi (DOBV-Sochi). The symptoms in the initial phase of the diseases did not differ noticeably between both patients. However, deterioration of laboratory parameter values was prolonged and stronger in DOBV-Sochi than in PUUV infection. Circulating endothelial progenitor cells (cEPCs), known to be responsible for endothelial repair, were mobilized in both infections. Striking differences were observed in the temporal course and level of cytokine upregulation. Levels of angiopoietin-2 (Ang-2), vascular endothelial growth factor (VEGF), and stromal derived factor-1 (SDF-1α) were increased in both infections; but, sustained and more pronounced elevation was observed in DOBV-Sochi infection. CONCLUSIONS: Severe hantavirus disease caused by different hantavirus species did not differ in the general symptoms and clinical characteristics. However, we observed a prolonged clinical course and a late and enhanced mobilization of cytokines in DOBV-Sochi infection. The differences in cytokine deregulation may contribute to the observed variation in the clinical course.

Human Puumala hantavirus infection in northern Sweden; increased seroprevalence and association to risk and health factors.

BACKGROUND: The rodent borne Puumala hantavirus (PUUV) causes haemorrhagic fever with renal syndrome in central and northern Europe. The number of cases has increased and northern Sweden has experienced large outbreaks in 1998 and 2006-2007 which raised questions regarding the level of immunity in the human population. METHODS: A randomly selected population aged between 25 and 74 years from northern Sweden were invited during 2009 to participate in a WHO project for monitoring of trends and determinants in cardiovascular disease. Health and risk factors were evaluated and sera from 1,600 participants were available for analysis for specific PUUV IgG antibodies using a recombinant PUUV nucleocapsid protein ELISA. RESULTS: The overall seroprevalence in the investigated population was 13.4 %, which is a 50 % increase compared to a similar study only two decades previously. The prevalence of PUUV IgG increased with age, and among 65-75 years it was 22 %. More men (15.3 %) than women (11.4 %) were seropositive (p < 0.05). The identified risk factors were smoking (OR = 1.67), living in rural areas (OR = 1.92), and owning farmland or forest (OR = 2.44). No associations were found between previous PUUV exposure and chronic lung disease, diabetes, hypertension, renal dysfunction, stroke or myocardial infarction. CONCLUSIONS: PUUV is a common infection in northern Sweden and there is a high life time risk to acquire PUUV infection in endemic areas. Certain risk factors as living in rural areas and smoking were identified. Groups with increased risk should be targeted for future vaccination when available, and should also be informed about appropriate protection from rodent secreta.

Landscape features and helminth co-infection shape bank vole immunoheterogeneity, with consequences for Puumala virus epidemiology.

Heterogeneity in environmental conditions helps to maintain genetic and phenotypic diversity in ecosystems. As such, it may explain why the capacity of animals to mount immune responses is highly variable. The quality of habitat patches, in terms of resources, parasitism, predation and habitat fragmentation may, for example, trigger trade-offs ultimately affecting the investment of individuals in various immunological pathways. We described spatial immunoheterogeneity in bank vole populations with respect to landscape features and co-infection. We focused on the consequences of this heterogeneity for the risk of Puumala hantavirus (PUUV) infection. We assessed the expression of the Tnf-α and Mx2 genes and demonstrated a negative correlation between PUUV load and the expression of these immune genes in bank voles. Habitat heterogeneity was partly associated with differences in the expression of these genes. Levels of Mx2 were lower in large forests than in fragmented forests, possibly due to differences in parasite communities. We previously highlighted the positive association between infection with Heligmosomum mixtum and infection with PUUV. We found that Tnf-α was more strongly expressed in voles infected with PUUV than in uninfected voles or in voles co-infected with the nematode H. mixtum and PUUV. H. mixtum may limit the capacity of the vole to develop proinflammatory responses. This effect may increase the risk of PUUV infection and replication in host cells. Overall, our results suggest that close interactions between landscape features, co-infection and immune gene expression may shape PUUV epidemiology.

The pathogenesis of nephropathia epidemica: new knowledge and unanswered questions.

Puumala virus (PUUV) causes an acute hemorrhagic fever with renal syndrome (HFRS), a zoonosis also called nephropathia epidemica (NE). The reservoir host of PUUV is the bank vole (Myodes glareolus). Herein we review the main clinical manifestations of NE, acute kidney injury, increased vascular permeability, coagulation abnormalities as well as pulmonary, cardiac, central nervous system and ocular manifestations of the disease. Several biomarkers of disease severity have recently been discovered: interleukin-6, pentraxin-3, C-reactive protein, indoleamine 2,3-dioxygenase, cell-free DNA, soluble urokinase-type plasminogen activator, GATA-3 and Mac-2 binding protein. The role of cytokines, vascular endothelial growth hormone, complement, bradykinin, cellular immune response and other mechanisms in the pathogenesis of NE as well as host genetic factors will be discussed. Finally therapeutic aspects and directions for further research will be handled.

Uso e ocupação do solo e a disseminação da hantavirose na região de São Sebastião, Distrito Federal: 2004 - 2008 / Land use and occupation and hantavirosis dissemination in the São Sebastião region, Federal District: 2004 - 2008

INTRODUÇÃO: As hantaviroses apresentam distribuição mundial e constituem importante problema de saúde pública. A epidemiologia da hantavirose no Brasil mostra que vem aumentando a cada ano o número de casos que são notificados e de variantes que têm sido descobertas em diversos estados e no Distrito Federal. Neste contexto, o estudo tem como objetivo principal analisar o uso e da ocupação do solo na disseminação da hantavirose no Distrito Federal, no período de 2004 a 2008. MÉTODOS: Para a realização desta pesquisa, foram utilizados dados epidemiológicos e do uso da terra com fins de elaborar tabelas e cartogramas para detalhar a espacialização da hantavirose no território. RESULTADOS: Dos 40 locais prováveis de infecção (LPIs) plotados no Mapa de Cobertura e Uso da Terra, 19 (47 por cento) ocorreram em áreas de pastagens, 10 (25 por cento) em área urbana (periurbana), 6 (15 por cento) em áreas utilizadas para a agricultura e 5 (12 por cento) em espaços de cerrado. CONCLUSÕES: Sendo assim, as atividades agrícolas e a expansão urbana em direção às áreas de cerrado vêm favorecendo a disseminação da hantavirose no Distrito Federal e em especialmente em São Sebastião.

INTRODUCTION: Hantavirosis has worldwide distribution and is an important public health problem. The epidemiology of hantavirosis in Brazil shows that the number of cases notified and the number of variants discovered in several states and the Federal District have been increasing year by year. Within this context, the main objective of this study was to examine land use and occupation in relation to the spread of hantavirosis in the Federal District, between 2004 and 2008. METHODS: To carry out this investigation, epidemiological and land use data were used to drafting tables and cartograms in order to detail the special spread of hantavirosis in this area. RESULTS: Out of the 40 likely infection sites plotted on the coverage and land use map, 19 (47 percent) were in pasture areas, 10 (25 percent) in urban areas (periurban), 6 (15 percent) in areas used for agriculture and 5 (12 percent) in savanna areas. CONCLUSIONS: It can thus be seen that agricultural activities and urban expansion towards the savanna areas have favored the spread of hantavirosis in the Federal District and especially in São Sebastião.

Specific humoral reaction of hemorrhagic fever with renal syndrome (HFRS) patients in China to recombinant nucleocapsid proteins from European hantaviruses.

Hemorrhagic fever with renal syndrome (HFRS) is endemic in East Asia and Europe. This study was initiated to investigate the reactivity of antibodies in sera of Chinese HFRS patients with the recombinant nucleocapsid proteins (rNPs) of Hantaan virus (HTNV), Dobrava-Belgrade virus (DOBV), and Puumala virus (PUUV), which are the prevalent hantavirus strains in Europe. Forty-eight pairs of acute and convalescent sera were collected from HFRS patients in Hubei, China (1985-2002) and tested by indirect IgG, IgA, and IgM enzyme-linked immunosorbent assays with six rNPs of European hantaviruses as coated antigens, respectively. The results showed that the sensitivity of rNPs against IgG was HTNV-rNP > DOBV-rNP > PUUV-rNP, while the sensitivity against IgA was DOBV-rNP > HTNV-rNP > PUUV-rNP. Quantitative analysis revealed both acute and convalescent sera from HFRS patients predominantly exhibit high levels of IgA. Although PUUV-rNPs showed very weak reactivity to the three kinds of immunoglobulins in all samples, three pairs of sera unexpectedly cross-reacted strongly to all three PUUV-rNP subtypes. We first observe that HFRS patients' sera from Hubei Province show new prevalent characteristics of cross-reacting with PUUV-rNPs and continued high level of IgA in convalescent phase, as well as in China.

Case-control study on Puumala virus infection: smoking is a risk factor.

Puumala hantavirus (PUUV) is apparently transmitted to humans by inhalation of aerosolized secretions of carrier rodents (bank voles). The means of transmission and the associated risk factors are poorly defined. An epidemiological study during the peak of an epidemic season in Finland was conducted based on 282 acute clinical PUUV infections and 204 controls without PUUV infection or immunity. The main risk factors adjusted by age, sex and living environment were cigarette smoking [odds ratio (OR) 3.6, 95% confidence interval (CI) 2.1-5.9, P<0.0001] and buildings with holes allowing rodents to enter (OR 3.3, 95% CI 2.0-5.6); these results were similar in two subsets. Further, use of rodent traps (OR3.5, 95% CI 2.2-5.7) and handling firewood (OR 2.7, 95% CI 1.6-4.4) were associated with a risk. The risk attributed to smoking also remained high using simulated population controls with average smoking habits. The results suggest that hantavirus transmission occurs by inhalation mainly indoors and is dependent on the condition of the respiratory tract.

Inhibition of TNF-alpha-induced activation of NF-kappaB by hantavirus nucleocapsid proteins.

Hantaviruses cause two human diseases thought to be immune-mediated: hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). We recently reported that the nucleocapsid (N) protein of HFRS-causing Hantaan virus (HTNV) inhibits tumor necrosis factor-alpha (TNF-alpha) activation of nuclear factor-kappaB (NF-kappaB). Here we measured the ability of other hantaviral N proteins to similarly interfere with the inflammatory process of TNF-alpha. We found that like HTNV N, the N proteins of HFRS-causing Seoul and Dobrava viruses inhibited TNF-alpha activation of NF-kappaB and translocation of the NF-kappaB p65 subunit, but did not interfere with degradation of inhibitor of NF-kappaB (IkappaB). In contrast, the HFRS-causing Puumala virus and the HPS-causing Andes and Sin Nombre viruses did not prevent TNF-alpha activation of NF-kappaB or nuclear translocation of p65. These studies provide evidence that hantaviruses differ in their abilities to interfere with host innate immune responses.

Serological and genetic evidence for the presence of Seoul hantavirus in Rattus norvegicus in Flanders, Belgium.

Seoul hantavirus (SEOV), carried by Rattus rattus (black rat) and R. norvegicus (Norway, brown rat), was reported to circulate as well as cause HFRS cases in Asia. As Rattus sp. are present worldwide, SEOV has the potential to cause human disease worldwide. In Europe however, only SEOV prevalence in rats from France was reported and no confirmed cases of SEOV infection were published. We here report genetic and serological evidence for the presence of SEOV virus in brown rat populations in Belgium. We also serologically screened an at-risk group that was in contact with R. norvegicus on a daily basis and found no evidence for SEOV infection.

Situation of hantavirus infections and haemorrhagic fever with renal syndrome in European countries as of December 2006.

Hantavirus infections are widely distributed in Europe with the exception of the far north and the Mediterranean regions. The underlying causes of varying epidemiological patterns differ among regions: in western and central Europe epidemics of haemorrhagic fever with renal syndrome (HFRS) caused by hantavirus infections follow mast years with increased seed production by oak and beech trees followed by increased rodent reproduction. In the northern regions, hantavirus infections and HFRS epidemics occur in three to four year cycles and are thought to be driven by prey - predator interactions. Hantavirus infections and HFRS seem to be on the increase in Europe, partly because of better diagnostics, partly perhaps due to environmental changes. Unfortunately, hantavirus infections are still heavily under-diagnosed in many European countries. Here we report the results of a survey conducted in 2007 amongst the member laboratories of the European Network for diagnostics of Imported Viral Diseases (ENIVD).

Hantavirus nephropathy.

Pathogenic rodent-borne hantaviruses cause in humans generalized infections that involve the peripheral vascular bed and severely affect their permeability. We describe a 30-yr-old male patient with clinical symptoms characterizing five conventional phases of hemorrhagic fever with renal syndrome after an uncommonly severe hantavirus infection with the Puumala strain. Renal biopsy in this situation typically demonstrates acute hemorrhagic interstitial nephritis, particularly pronounced in the outer medulla. Hantaviruses are not cytopathic for most cells, and their interactions with endothelial cells that activate immune mechanisms play a key role in the pathogenesis of vascular dysfunction characterizing this disease.

Molecular diversity and phylogeny of Hantaan virus in Guizhou, China: evidence for Guizhou as a radiation center of the present Hantaan virus.

To gain further insight into the molecular epidemiology of Hantaan virus (HTNV) in Guizhou, China, rodents were captured in this region in 2004 and 2005. In addition, serum samples were collected from four patients. Ten hantaviruses were isolated successfully in cell culture from four humans, two Apodemus agrarius, three Rattus norvegicus and one Rattus nitidus. The nucleotide sequences for their small (S), medium (M) and partial large (L) segments were determined. Phylogenetic analysis of the S and M segment sequences revealed that all of these isolates belong to the species HTNV, suggesting a spillover of HTNV from A. agrarius to Rattus rats. All available isolates from Guizhou were divided into four distinct groups either in the S segment tree or in the M segment tree. The clustering pattern of these isolates in the S segment tree was not in agreement with that in the M or L segment tree, showing that genetic reassortment between HTNV had occurred naturally. Analysis of the S segment sequences from available HTNV strains indicated that they formed three clades. The first clade, which comprised only viruses from Guizhou, was the outgroup of clades II and III. The viruses in the second clade were found in Guizhou and mainly in the far-east Asian region, including China. However, the viruses in the third clade were found in most areas of China, including Guizhou, in which haemorrhagic fever with renal syndrome (HFRS) is endemic. Our results reveal that the highest genetic diversity of HTNV is in a limited geographical region of Guizhou, and suggest that Guizhou might be a radiation centre of the present form of HTNV.