Complete Genome and Phylogeny of Puumala Hantavirus Isolates Circulating in France

Puumala virus (PUUV) is the agent of nephropathia epidemica (NE), a mild form of hemorrhagic fever with renal syndrome (HFRS) in Europe. NE incidence presents a high spatial variation throughout France, while the geographical distribution of the wild reservoir of PUUV, the bank vole, is rather continuous. A missing piece of the puzzle is the current distribution and the genetic variation of PUUV in France, which has been overlooked until now and remains poorly understood. During a population survey, from 2008 to 2011, bank voles were trapped in eight different forests of France located in areas known to be endemic for NE or in area from where no NE case has been reported until now. Bank voles were tested for immunoglobulin (Ig)G ELISA serology and two seropositive animals for each of three different areas (Ardennes, Jura and Orleans) were then subjected to laboratory analyses in order to sequence the whole S, M and L segments of PUUV. Phylogenetic analyses revealed that French PUUV isolates globally belong to the central European (CE) lineage although isolates from Ardennes are clearly distinct from those in Jura and Orleans, suggesting a different evolutionary history and origin of PUUV introduction in France. Sequence analyses revealed specific amino acid signatures along the N protein, including in PUUV from the Orleans region from where NE in humans has never been reported. The relevance of these mutations in term of pathophysiology is discussed.     

Hantavirus Research in Finland: Highlights and Perspectives

Finland has the highest incidence of hantavirus infections globally, with a significant impact on public health. The large coverage of boreal forests and the cyclic dynamics of the dominant forest rodent species, the bank vole Myodes glareolus, explain most of this. We review the relationships between Puumala hantavirus (PUUV), its host rodent, and the hantavirus disease, nephropathia epidemica (NE), in Finland. We describe the history of NE and its diagnostic research in Finland, the seasonal and multiannual cyclic dynamics of PUUV in bank voles impacting human epidemiology, and we compare our northern epidemiological patterns with those in temperate Europe. The long survival of PUUV outside the host and the life-long shedding of PUUV by the bank voles are highlighted. In humans, the infection has unique features in pathobiology but rarely long-term consequences. NE is affected by specific host genetics and risk behavior (smoking), and certain biomarkers can predict the outcome. Unlike many other hantaviruses, PUUV causes a relatively mild disease and is rarely fatal. Reinfections do not exist. Antiviral therapy is complicated by the fact that when symptoms appear, the patient already has a generalized infection. Blocking vascular leakage measures counteracting pathobiology, offer a real therapeutic approach.     

First Molecular Evidence for Puumala Hantavirus in Poland

Puumala virus (PUUV) causes mild to moderate cases of haemorrhagic fever with renal syndrome (HFRS), and is responsible for the majority of hantavirus infections of humans in Fennoscandia, Central and Western Europe. Although there are relatively many PUUV sequences available from different European countries, little is known about the presence of this virus in Poland. During population studies in 2009 a total of 45 bank voles were trapped at three sites in north-eastern Poland, namely islands on Dejguny and Dobskie Lakes and in a forest near Mikołajki. S and M segment-specific RT-PCR assays detected PUUV RNA in three animals from the Mikołajki site. The obtained partial S and M segment sequences demonstrated the highest similarity to the corresponding segments of a PUUV strain from Latvia. Analysis of chest cavity fluid samples by IgG ELISA using a yeast-expressed PUUV nucleocapsid protein resulted in the detection of two seropositive samples, both being also RT-PCR positive. Interestingly, at the trapping site in Mikołajki PUUV-positive bank voles belong to the Carpathian and Eastern genetic lineages within this species. In conclusion, we herein present the first molecular evidence for PUUV in the rodent reservoir from Poland.     

Prevalence of Hantaviruses Harbored by Murid Rodents in Northwestern Ukraine and Discovery of a Novel Puumala Virus Strain

In Europe, two species of hantaviruses, Puumala orthohantavirus (PUUV) and Dobrava orthohantavirus (DOBV), cause hemorrhagic fever with renal syndrome in humans. The rodent reservoirs for these viruses are common throughout Ukraine, and hence, the goal of this study was to identify the species and strains of hantaviruses circulating in this region. We conducted surveillance of small rodent populations in a rural region in northwestern Ukraine approximately 30 km from Poland. From the 424 small mammals captured, we identified nine species, of which the most abundant were Myodes glareolus, the bank vole (45%); Apodemus flavicollis, the yellow-necked mouse (29%); and Apodemus agrarius, the striped field mouse (14.6%) Using an indirect immunofluorescence assay, 15.7%, 20.5%, and 33.9% of the sera from M. glareolus, A. glareolus, and A. flavicollis were positive for hantaviral antibodies, respectively. Additionally, we detected antibodies to the hantaviral antigen in one Microtus arvalis, one Mus musculus, and one Sorex minutus. We screened the lung tissue for hantaviral RNA using next-generation sequencing and identified PUUV sequences in 25 small mammals, including 23 M. glareolus, 1 M. musculus, and 1 A. flavicollis, but we were unable to detect DOBV sequences in any of our A. agrarius specimens. The percent identity matrix and Bayesian phylogenetic analyses of the S-segment of PUUV from 14 M. glareolus lungs suggest the highest similarity (92–95% nucleotide or 99–100% amino acid) with the Latvian lineage. This new genetic information will contribute to future molecular surveillance of human cases in Ukraine.     

Muju Virus,Harbored by Myodes regulus in Korea,Might Represent a Genetic Variant of Puumala Virus,the Prototype Arvicolid Rodent-Borne Hantavirus

The genome of Muju virus (MUJV), identified originally in the royal vole (Myodes regulus) in Korea, was fully sequenced to ascertain its genetic and phylogenetic relationship with Puumala virus (PUUV), harbored by the bank vole (My. glareolus), and a PUUV-like virus, named Hokkaido virus (HOKV), in the grey red-backed vole (My. rufocanus) in Japan. Whole genome sequence analysis of the 6544-nucleotide large (L), 3652-nucleotide medium (M) and 1831-nucleotide small (S) segments of MUJV, as well as the amino acid sequences of their gene products, indicated that MUJV strains from different capture sites might represent genetic variants of PUUV, the prototype arvicolid rodent-borne hantavirus in Europe. Distinct geographic-specific clustering of MUJV was found in different provinces in Korea, and phylogenetic analyses revealed that MUJV and HOKV share a common ancestry with PUUV. A better understanding of the taxonomic classification and pathogenic potential of MUJV must await its isolation in cell culture.     

Variations in the mitochondrial DNA markers in the Anopheles (Cellia) sundaicus population from the Andaman and Nicobar Islands, India

Four sibling species in the Anopheles sundaicus complex have earlier been reported, including species D from the Andaman and Nicobar Islands of India where it constitutes 58% of all Anopheles population and is a major malaria vector. Earlier, we have reported the identical sequences for ribosomal DNA markers among the specimens of A. sundaicus from Andaman and Nicobar islands irrespective of their habitat. These ITS2 sequences were also identical to the reported sequence of variant III of Southeast Asian A. sundaicus. In the present study, we describe variations in three mitochondrial DNA markers among these specimens from Andaman and Nicobar islands. There were two different genotypes for each locus of COI and COII, and three genotypes for cytochrome-b (Cyt-b) locus resulting in three different combined genotypes (genotypes I, II and III) in the population. Specimens with combined genotype I (59%, n = 100) were found only among the A. sundaicus population breeding in fresh water whereas two different multi-loci genotypes i.e. genotype II (25%, n = 100) and genotype III (16%, n = 100) were present in the population breeding in brackish water. Thus, the A. sundaicus population breeding in fresh water was homogenous with single multi-loci genotype and can be distinguished from the heterogenous mosquito population breeding in brackish water with these markers. These Cyt-b and COI sequences of A. sundaicus species D were also different from the reported Southeast Asian species of A. sundaicus.     

Serum Markers Associated with Disease Severity in a Bosnian Hemorrhagic Fever with Renal Syndrome Cohort

Puumala orthohantavirus (PUUV) is endemic in Europe and can cause hemorrhagic fever with renal syndrome (nephropathia epidemica). Disease features include fever, thrombocytopenia, and acute kidney injury (AKI). This retrospective cohort study of forty PUUV patients aims to characterize associations of serum immunological, hemostatic or kidney injury markers to disease severity. While interleukin-18 (IL-18) was significantly increased in severely thrombocytopenic patients (<100 × 10⁹ platelets/L) compared to patients with higher platelet counts, RANTES was significantly decreased in these patients. These data suggest that patients with significant thrombocytopenia might have experienced pronounced Th1 immune responses. When kidney dysfunction was used as the primary disease outcome, recently identified AKI biomarkers (Cystatin C, insulin-like growth factor-binding protein 7, Nephrin, and trefoil factor 3) were significantly upregulated in patients with severe PUUV infection, defined as the estimated glomerular filtration rate (eGFR) below 30 m/min/1.73 m². The increased expression of these markers specifically indicates pathology in glomeruli and proximal tubuli. Furthermore, E-selectin was significantly higher while interferon gamma-induced protein 10 (IP-10) was significantly lower in PUUV patients with more severe kidney dysfunction compared to patients with higher eGFR-values. Increased E-selectin illustrates the central role of endothelial cell activation, whereas decreased IP-10 could indicate a less important role of this cytokine in the pathogenesis of kidney dysfunction.     

Genetic Characterization of Echinococcus granulosus from a Large Number of Formalin-Fixed,Paraffin-Embedded Tissue Samples of Human Isolates in Iran

Cystic echinococcosis (CE), caused by the larval stage of Echinococcus granulosus, presents an important medical and veterinary problem globally, including that in Iran. Different genotypes of E. granulosus have been reported from human isolates worldwide. This study identifies the genotype of the parasite responsible for human hydatidosis in three provinces of Iran using formalin-fixed paraffin-embedded tissue samples. In this study, 200 formalin-fixed paraffin-embedded tissue samples from human CE cases were collected from Alborz, Tehran, and Kerman provinces. Polymerase chain reaction amplification and sequencing of the partial mitochondrial cytochrome c oxidase subunit 1 gene were performed for genetic characterization of the samples. Phylogenetic analysis of the isolates from this study and reference sequences of different genotypes was done using a maximum likelihood method. In total, 54.4%, 0.8%, 1%, and 40.8% of the samples were identified as the G1, G2, G3, and G6 genotypes, respectively. The findings of the current study confirm the G1 genotype (sheep strain) to be the most prevalent genotype involved in human CE cases in Iran and indicates the high prevalence of the G6 genotype with a high infectivity for humans. Furthermore, this study illustrates the first documented human CE case in Iran infected with the G2 genotype.     

Immunogenetic Factors Affecting Susceptibility of Humans and Rodents to Hantaviruses and the Clinical Course of Hantaviral Disease in Humans

We reviewed the associations of immunity-related genes with susceptibility of humans and rodents to hantaviruses, and with severity of hantaviral diseases in humans. Several class I and class II HLA haplotypes were linked with severe or benign hantavirus infections, and these haplotypes varied among localities and hantaviruses. The polymorphism of other immunity-related genes including the C4A gene and a high-producing genotype of TNF gene associated with severe PUUV infection. Additional genes that may contribute to disease or to PUUV infection severity include non-carriage of the interleukin-1 receptor antagonist (IL-1RA) allele 2 and IL-1β (-511) allele 2, polymorphisms of plasminogen activator inhibitor (PAI-1) and platelet GP1a. In addition, immunogenetic studies have been conducted to identify mechanisms that could be linked with the persistence/clearance of hantaviruses in reservoirs. Persistence was associated during experimental infections with an upregulation of anti-inflammatory responses. Using natural rodent population samples, polymorphisms and/or expression levels of several genes have been analyzed. These genes were selected based on the literature of rodent or human/hantavirus interactions (some Mhc class II genes, Tnf promoter, and genes encoding the proteins TLR4, TLR7, Mx2 and β3 integrin). The comparison of genetic differentiation estimated between bank vole populations sampled over Europe, at neutral and candidate genes, has allowed to evidence signatures of selection for Tnf, Mx2 and the Drb Mhc class II genes. Altogether, these results corroborated the hypothesis of an evolution of tolerance strategies in rodents. We finally discuss the importance of these results from the medical and epidemiological perspectives.     

Mercadeo Virus: A Novel Mosquito-Specific Flavivirus from Panama

Viruses in the genus Flavivirus (family Flaviviridae) include many arthropod-borne viruses of public health and veterinary importance. However, during the past two decades an explosion of novel insect-specific flaviviruses (ISFs), some closely related to vertebrate pathogens, have been discovered. Although many flavivirus pathogens of vertebrates have been isolated from naturally infected mosquitoes in Panama, ISFs have not previously been reported from the country. This report describes the isolation and characterization of a novel ISF, tentatively named Mercadeo virus (MECDV), obtained from Culex spp. mosquitoes collected in Panama. Two MECDV isolates were sequenced and cluster phylogenetically with cell-fusing agent virus (CFAV) and Nakiwogo virus (NAKV) to form a distinct lineage within the insect-specific group of flaviviruses.     

Phylogeographic population structure of Red-winged Blackbirds assessed by mitochondrial DNA

A continent-wide survey of restriction-site variation in mitochondrial DNA (mtDNA) of the Red-winged Blackbird (Agelaius phoeniceus) was conducted to assess the magnitude of phylogeographic population structure in an avian species. A total of 34 mtDNA genotypes was observed among the 127 specimens assayed by 18 restriction endonucleases. Nonetheless, population differentiation was minor, as indicated by (i) small genetic distances in terms of base substitutions per nucleotide site between mtDNA genotypes (maximum P ≈ 0.008) and by (ii) the widespread geographic distributions of particular mtDNA clones and phylogenetic arrays of clones. Extensive morphological differentiation among redwing populations apparently has occurred in the context of relatively little phylogenetic separation. A comparison between mtDNA data sets for Red-winged Blackbirds and deermice (Peromyscus maniculatus) also sampled from across North America shows that intraspecific population structures of these two species differ dramatically. The lower phylogeographic differentiation in redwings is probably due to historically higher levels of gene flow.     

Identification of FactorsInfluencing the Puumala Virus Seroprevalence within Its Reservoir in aMontane Forest Environment

Puumala virus (PUUV) is a major cause of mild to moderate haemorrhagic fever with renal syndrome and is transmitted by the bank vole (Myodes glareolus). There has been a high cumulative incidence of recorded human cases in South-eastern Germany since 2004 when the region was first recognized as being endemic for PUUV. As the area is well known for outdoor recreation and the Bavarian Forest National Park (BFNP) is located in the region, the increasing numbers of recorded cases are of concern. To understand the population and environmental effects on the seroprevalence of PUUV in bank voles we trapped small mammals at 23 sites along an elevation gradient from 317 to 1420m above sea level. Generalized linear mixed effects models(GLMEM) were used to explore associations between the seroprevalence of PUUV in bank voles and climate and biotic factors. We found that the seroprevalence of PUUV was low (6%–7%) in 2008 and 2009, and reached 29% in 2010. PUUV seroprevalence was positively associated with the local species diversity and deadwood layer, and negatively associated with mean annual temperature, mean annual solar radiation, and herb layer. Based on these findings, an illustrative risk map for PUUV seroprevalence prediction in bank voles was created for an area of the national park. The map will help when planning infrastructure in the national park (e.g., huts, shelters, and trails).     

Investigation of the thoracic aorta in cholesterol embolism by transoesophageal echocardiography

Objectives—To examine the thoracic aorta of patients with severe cholesterol embolism (CE) by transoesophageal echocardiography (TOE).
Methods—The thoracic aorta of 20 consecutive patients with CE was compared with that in a control population matched for age and risk factors by TOE. Patients were prescribed steroids after CE was diagnosed. Follow up is reported and compared with results in the literature.
Results—Aortic plaques and debris were more common in patients with CE than in the control population (p < 0.001 and p < 0.0001, respectively). The mean (SD) number of aortic plaques in the CE patients was 2.6 (0.7). This aortic atheroma was found predominantly in the descending aorta. One patient died during a mean (SD) follow up of 24 (10) months.
Conclusions—Aortic atheroma, as detected by TOE, should be considered as the main source of CE. In addition, the prognosis in our series, in which steroids were systematically prescribed, is much better than in others reported in the literature.

Keywords: aortic atheroma;  transoesophageal echocardiography;  cholesterol embolism     

Detection of Human Hantavirus Infections in Lithuania

Abstract Background: In Europe certain hantaviruses are known to cause hemorrhagic fever with renal syndrome of different severity. The objective of the present investigation was to study the presence of hantavirus infections in Lithuania. Material and Methods: Two different serum panels from cancer patients (n = 438) and blood donors (n = 299) from Lithuania were tested by monoclonal antibody capture IgG ELISA using yeast-expressed recombinant nucleocapsid (rN) proteins of Puumala virus (PUUV), Hantaan virus (HTNV) and Dobrava virus (DOBV). The reactivity of ELISA-positive sera was proven in Western blot tests using various hantavirus rN proteins. Selected serum samples were further analyzed by focus reduction neutralization assays. Results: In the IgG ELISA 39 sera from the cancer patients and four sera from blood donors were found to be reactive with at least one of the rN proteins. By immunoblot using the three yeast-expressed rN proteins, the ELISA reactivity of 36 of 39 and two of four serum samples from cancer patients and blood donors, respectively, was confirmed; this corresponds to a seroprevalence of 8.2% and 0.7%, respectively. In ELISA, the majority of the samples reacted exclusively with rN proteins of HTNV and DOBV (31 of 36 and one of two in the two groups). In the group of sera selected for serotyping by focus reduction neutralization assay, this dominance was confirmed by the identification of eight DOBV but only four PUUV infections. No infection by HTNV or another hantavirus besides DOBV and PUUV was verified. Anti-hantavirus-positive human sera were detected in all seven investigated counties of Lithuania. Conclusion: In Lithuania at least two hantaviruses, DOBV and PUUV, circulate and cause human infections. Additional investigations are needed to study the seroprevalence more precisely and to search for clinical cases of hantavirus infections.     

Geographic differences in low-dose aspirin-associated gastroduodenal mucosal injury

Aspirin, even at low doses, has been known to cause upper gastro-intestinal complications, such as gastroduodenal ulcers, despite the definite benefits from its antithrombotic effects. Helicobacter pylori (H. pylori) is major pathogen responsible for gastroduodenal ulcer formation. There have been conflicting results about the potential interaction between these two ulcerogenic factors and the geographic areas involved. In Western countries, the prevalence of gastroduodenal ulcers is consistently higher in H. pylori-positive low-dose aspirin (LDA) users than in H. pylori-negative ones, suggesting that H. pylori infection exacerbates LDA-induced gastroduodenal mucosal injury in these geographic areas. Meanwhile, previous studies from Japan have generally reported a similar prevalence of LDA-induced gastroduodenal mucosal injury regardless of the presence of H. pylori infection, indicating that the infection is not an overall exacerbating factor for drug-induced injury. H. pylori infection could have a synergistic or antagonistic interaction with LDA use in adverse gastroduodenal events depending on gastric acid secretion. It is well-recognized that the net effect of H. pylori infection on gastric acid secretion shows considerable geographic variation at the population level. While gastric acid secretion levels were not decreased and were well-preserved in most patients with H. pylori infection from Western countries, the majority of Japanese patients with H. pylori infection exhibited decreased gastric acid secretion. Such large geographic differences in the net effect of H. pylori infection on gastric acid secretion could be at least partly responsible for the geographically distinct interaction between LDA use and H. pylori infection on adverse gastroduodenal lesions.     

From the Cover: Patterns of genome evolution that have accompanied host adaptation in Salmonella

Many bacterial pathogens are specialized, infecting one or few hosts, and this is often associated with more acute disease presentation. Specific genomes show markers of this specialization, which often reflect a balance between gene acquisition and functional gene loss. Within Salmonella enterica subspecies enterica, a single lineage exists that includes human and animal pathogens adapted to cause infection in different hosts, including S. enterica serovar Enteritidis (multiple hosts), S. Gallinarum (birds), and S. Dublin (cattle). This provides an excellent evolutionary context in which differences between these pathogen genomes can be related to host range. Genome sequences were obtained from ∼60 isolates selected to represent the known diversity of this lineage. Examination and comparison of the clades within the phylogeny of this lineage revealed signs of host restriction as well as evolutionary events that mark a path to host generalism. We have identified the nature and order of events for both evolutionary trajectories. The impact of functional gene loss was predicted based upon position within metabolic pathways and confirmed with phenotyping assays. The structure of S. Enteritidis is more complex than previously known, as a second clade of S. Enteritidis was revealed that is distinct from those commonly seen to cause disease in humans or animals, and that is more closely related to S. Gallinarum. Isolates from this second clade were tested in a chick model of infection and exhibited a reduced colonization phenotype, which we postulate represents an intermediate stage in pathogen–host adaptation.The central importance of horizontal acquisition of mobile genetic elements in the development of virulence in bacteria has been well described. It has frequently been observed that, as pathogens acquire virulence determinants, they become increasingly adapted to a specific host (1, 2). Exquisitely host-restricted pathogens also often exhibit extensive genome decay, through insertion sequence element proliferation, genomic rearrangement, and/or pseudogene formation (1, 3, 4). Investigating mechanisms involved in host adaptation is key to an understanding of pathogen evolution and has directly translatable relevance to the epidemiology and potentially the control of human and zoonotic infectious disease.By concentrating upon individual pathogenic clades, insights have been obtained into specific adaptations relating to specific hosts; however, comparative analysis is relatively rare. By broadening this approach to examine multiple human and animal pathogens, derived from a single closely related lineage but with differing host specializations, there is an opportunity to understand the fundamental evolutionary processes involved in host adaptation. Lineage-specific changes that have become fixed can then be distinguished from those stochastic changes that differentiate individual isolates.A single lineage within Salmonella enterica presents such an opportunity. S. enterica is a leading cause of foodborne gastroenteritis, globally responsible for 80 million cases annually (5). Differentiation of S. enterica is largely based upon somatic (O) and flagellar (H) antigens, but it is increasingly being typed by genomic methods, such as multilocus sequence typing (MLST). Somatic serogrouping and MLST have identified a single lineage with closely related members that exhibit a range of different host specializations (6–9). These include two of the most important Salmonella pathogens: S. Enteritidis and S. Gallinarum. In addition to the contribution of S. Enteritidis to human disease, in many countries both of these pathogens are notifiable diseases in poultry farming and egg production. Despite their close phylogenetic relatedness, they exhibit strikingly different host ranges, with S. Enteritidis capable of infecting multiple host species, whereas S. Gallinarum is restricted to infection in galliforme birds. This lineage also includes S. Gallinarum biovar Pullorum (hereafter S. Pullorum), also restricted to galliformes, and S. Dublin, which is strongly associated with infection of cattle and more rarely that of humans (10). The Salmonella pathogens adapted to particular hosts are associated with a much more invasive disease than generalists like S. Enteritidis, which tend to cause enteritis.Fifty-nine isolates of this Salmonella lineage were selected to capture the diversity of sequence types, phage types, and geographical and temporal spread available at the time. Through genome sequencing, we generated a phylogeny to act as a framework with which to reconstruct the evolutionary history of the lineage, onto which observed gene loss and acquisition could be plotted.This dataset provides a compelling record of the degradation of common metabolic pathways during host specialization to date. We have documented the order of events during the evolution of an entire Salmonella lineage. To link this specifically to host adaptation, we have tested isolates occupying key positions in the phylogeny in their cognate host to assess the effects of gene degradation on the manner and severity of disease caused.     

The Clinical Presentation of Puumala Hantavirus Induced Hemorrhagic Fever with Renal Syndrome Is Related to Plasma Glucose Concentration

Puumala hantavirus (PUUV) causes a hemorrhagic fever with renal syndrome characterized by thrombocytopenia, increased capillary leakage, and acute kidney injury (AKI). As glucosuria at hospital admission predicts the severity of PUUV infection, we explored how plasma glucose concentration associates with disease severity. Plasma glucose values were measured during hospital care in 185 patients with PUUV infection. They were divided into two groups according to maximum plasma glucose concentration: P-Gluc < 7.8 mmol/L (n = 134) and P-Gluc ≥ 7.8 mmol/L (n = 51). The determinants of disease severity were analyzed across groups. Patients with P-Gluc ≥7.8 mmol/L had higher hematocrit (0.46 vs. 0.43; p < 0.001) and lower plasma albumin concentration (24 vs. 29 g/L; p < 0.001) than patients with P-Gluc < 7.8 mmol/L. They presented with higher prevalence of pulmonary infiltrations and pleural effusion in chest radiograph, higher prevalence of shock and greater weight change during hospitalization. Patients with P-Gluc ≥ 7.8 mmol/L were characterized by lower platelet count (50 vs. 66 × 10⁹/L; p = 0.001), more severe AKI (plasma creatinine 272 vs. 151 µmol/L; p = 0.001), and longer hospital treatment (8 vs. 6 days; p < 0.001) than patients with P-Gluc < 7.8 mmol/L. Plasma glucose level is associated with the severity of capillary leakage, thrombocytopenia, inflammation, and AKI in patients with acute PUUV infection.