Cause Of Hemorrhagic Fever Research Articles

Crimean-Congo Hemorragic Fever Outbreak in Pakistan: Emerging Threat.

Crimean-Congo hemorrhagic fever (CCHF) was first recognized in 1944 in the Crimean Peninsula, CCHF virus is the leading cause of hemorrhagic fever in the world. It is a tick borne viral disease of genus Nairovirus, family Bunyaviridae. Ixodid tick is the main reservoir of the virus spreading across globally in more than 40 countries. Average incubation period is 5-7 days of the virus. The onset of symptoms are acute and includes fever, myalgia, photophobia, dizziness, headache, abdominal pain, hepatomegaly and severe bleeding.

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 MESSAGES This 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.

In vitro Anti-Hantavirus Activity of Protein Kinase Inhibitor 8G1 Targeting AKT/mTOR/eIF4E Signaling Pathway.

Hantaan virus (HTNV) is the main cause of hemorrhagic fever with renal syndrome (HFRS) around the world, which results in profound morbidity and mortality. However, there are currently no FDA-approved therapeutics or vaccines against HFRS. To find new anti-HTNV drugs, the inhibitory activity of 901 small molecule kinase inhibitors against HTNV is analyzed. Among these compounds, compound 8G1 inhibits HTNV with a relatively high inhibition rate and lower toxicity. The viral titer and nucleocapsid protein of HTNV are reduced after compound 8G1 treatment in a dose-dependent manner at concentrations ranging from 1 to 20 μM. In addition, the administration of compound 8G1 at the early stage of HTNV infection can inhibit the replication of HTNV. The molecular docking result reveals that compound 8G1 forms interactions with the key amino acid residues of serine/threonine-protein kinase B (Akt), which is responsible for the observed affinity. Then, the mammalian target of rapamycin (mTOR) and eukaryotic translation initiation factor 4E (eIF4E) signaling pathways are inhibited. Our results may help to design novel targets for therapeutic intervention against HTNV infection and to understand the anti-HTNV mechanism of protein kinase inhibitors.

Surveillance of hemorrhagic fever and/or neuroinvasive disease: challenges of diagnosis

ABSTRACTOBJECTIVE To evaluate the performance of post mortem laboratory analysis in identifying the causes of hemorrhagic fever and/or neuroinvasive disease in deaths by arbovirus infection.METHODS Retrospective cross-sectional study based on the differential analysis and final outcome obtained in patients whose samples underwent laboratory testing for arboviruses at the Pathology Center of the Adolfo Lutz Institute, in São Paulo, Brazil.RESULTS Of the 1355 adults clinically diagnosed with hemorrhagic fever and/or neuroinvasive disease, the most commonly attributed cause of death and the most common final outcome was dengue fever. Almost half of the samples tested negative on all laboratory tests conducted.CONCLUSION The failure to identify the causative agent in a great number of cases highlights a gap in the diagnosis of deaths of unknown etiology. Additional immunohistochemical and molecular assessments need to be added to the post-mortem protocol if all laboratory evaluations performed fail to identify a causative agent. While part of our findings may be due to technical issues related to sample fixation, better information availability when making the initial diagnosis is crucial. Including molecular approaches might lead to a significant advancement in diagnostic accuracy.

Three asymptomatic animal infection models of hemorrhagic fever with renal syndrome caused by hantaviruses.

Hantaan virus (HTNV) and Puumala virus (PUUV) are rodent-borne hantaviruses that are the primary causes of hemorrhagic fever with renal syndrome (HFRS) in Europe and Asia. The development of well characterized animal models of HTNV and PUUV infection is critical for the evaluation and the potential licensure of HFRS vaccines and therapeutics. In this study we present three animal models of HTNV infection (hamster, ferret and marmoset), and two animal models of PUUV infection (hamster, ferret). Infection of hamsters with a ~3 times the infectious dose 99% (ID99) of HTNV by the intramuscular and ~1 ID99 of HTNV by the intranasal route leads to a persistent asymptomatic infection, characterized by sporadic viremia and high levels of viral genome in the lung, brain and kidney. In contrast, infection of hamsters with ~2 ID99 of PUUV by the intramuscular or ~1 ID99 of PUUV by the intranasal route leads to seroconversion with no detectable viremia, and a transient detection of viral genome. Infection of ferrets with a high dose of either HTNV or PUUV by the intramuscular route leads to seroconversion and gradual weight loss, though kidney function remained unimpaired and serum viremia and viral dissemination to organs was not detected. In marmosets a 1,000 PFU HTNV intramuscular challenge led to robust seroconversion and neutralizing antibody production. Similarly to the ferret model of HTNV infection, no renal impairment, serum viremia or viral dissemination to organs was detected in marmosets. This is the first report of hantavirus infection in ferrets and marmosets.

Recombinant of PUUV genome S segment isolated from rodents captured in the Republic of Tatarstan, Russia

Purpose: Background: Puumala hantavirus (PUUV) is the main cause of hemorrhagic fever with renal syndrome (HRFS) in Russia. Although known to cause HFRS endemic in the Republic of Tatarstan (RT), little is known about the genetic diversity of PUUV in the Republic. Therefore, we sought to characterize variations in PUUV S-segment in bank voles in the RT. Methods & Materials: Material and methods: Total of 121 bank voles were captured in the north-west regions of RT during the 2014-2015 HFRS outbreak. Total RNA was extracted from lung tissue and used for RT-PCR and sequence analysis. Results: Results: Comparison analysis of viral S segment sequences (564 bp) revealed 92.9-97.3% nucleotide identity between 29 RT PUUV strains and RUS lineage strains, while the lower similarity of 83.7-87.6% was found in strains from FIN lineage. Interestingly, sequence similarity of four RT PUUV strains and RUS strains was lower 85.8-87.6% than that found in the majority of isolates. Surprisingly, these strains had a higher identity (99.6-99.8%) with strain “Sotkamo” of FIN lineage. Phylogenetic analysis demonstrated that the four strains with low similarity to RUS lineage clustered with the FIN strains cluster. Further analysis of the full coding region of strain “032” S-segment, which had more similarity to FIN lineage, revealed that the partial sequence from 242 to 857 nt was 99.5% identical to “Sotkamo” strain, while the segment from 864 to 1341 nt showed 92.1-93.5% identical to RUS lineage strains. Conclusion: Conclusion: Therefore, our data suggest that strain “032” could be the progeny of the recombination between RUS and FIN genetic lineages. It remains to be determined if recombinant PUUV strains could cause different clinical presentation of HFRS. The Russian Government Program of Competitive Growth of Kazan Federal University supported this study. Also, Albert Rizvanov was supported by state assignment 20.5175.2017/6.7 of the Ministry of Education and Science of the Russian Federation.

A potent Lassa virus antiviral targets an arenavirus virulence determinant.

Arenaviruses are a significant cause of hemorrhagic fever, an often-fatal disease for which there is no approved antiviral therapy. Lassa fever in particular generates high morbidity and mortality in West Africa, where the disease is endemic, and a recent outbreak in Nigeria was larger and more geographically diverse than usual. We are developing LHF-535, a small-molecule viral entry inhibitor that targets the arenavirus envelope glycoprotein, as a therapeutic candidate for Lassa fever and other hemorrhagic fevers of arenavirus origin. Using a lentiviral pseudotype infectivity assay, we determined that LHF-535 had sub-nanomolar potency against the viral envelope glycoproteins from all Lassa virus lineages, with the exception of the glycoprotein from the LP strain from lineage I, which was 100-fold less sensitive than that of other strains. This reduced sensitivity was mediated by a unique amino acid substitution, V434I, in the transmembrane domain of the envelope glycoprotein GP2 subunit. This position corresponds to the attenuation determinant of Candid#1, a live-attenuated Junín virus vaccine strain used to prevent Argentine hemorrhagic fever. Using a virus-yield reduction assay, we determined that LHF-535 potently inhibited Junín virus, but not Candid#1, and the Candid#1 attenuation determinant, F427I, regulated this difference in sensitivity. We also demonstrated that a daily oral dose of LHF-535 at 10 mg/kg protected mice from a lethal dose of Tacaribe virus. Serial passage of Tacaribe virus in LHF-535-treated Vero cells yielded viruses that were resistant to LHF-535, and the majority of drug-resistant viruses exhibited attenuated pathogenesis. These findings provide a framework for the clinical development of LHF-535 as a broad-spectrum inhibitor of arenavirus entry and provide an important context for monitoring the emergence of drug-resistant viruses.

Using Satellite Data for the Characterization of Local Animal Reservoir Populations of Hantaan Virus on the Weihe Plain, China

Striped field mice (Apodemus agrarius) are the main host for the Hantaan virus (HTNV), the cause of hemorrhagic fever with renal syndrome (HFRS) in central China. It has been shown that host population density is associated with pathogen dynamics and disease risk. Thus, a higher population density of A. agrarius in an area might indicate a higher risk for an HFRS outbreak. Here, we surveyed the A. agrarius population density between 2005 and 2012 on the Weihe Plain, Shaanxi Province, China, and used this monitoring data to examine the relationships between the dynamics of A. agrarius populations and environmental conditions of crop-land, represented by remote sensing based indicators. These included the normalized difference vegetation index, leaf area index, fraction of photosynthetically active radiation absorbed by vegetation, net photosynthesis (PsnNet), gross primary productivity, and land surface temperature. Structural equation modeling (SEM) was applied to detect the possible causal relationship between PsnNet, A. agrarius population density and HFRS risk. The results showed that A. agrarius was the most frequently captured species with a capture rate of 0.9 individuals per hundred trap-nights, during 96 months of trapping in the study area. The risk of HFRS was highly associated with the abundance of A. agrarius, with a 1–5-month lag. The breeding season of A. agrarius was also found to coincide with agricultural activity and seasons with high PsnNet. The SEM indicated that PsnNet had an indirect positive effect on HFRS incidence via rodents. In conclusion, the remote sensing-based environmental indicator, PsnNet, was highly correlated with HTNV reservoir population dynamics with a 3-month lag (r = 0.46, p &lt; 0.01), and may serve as a predictor of potential HFRS outbreaks.

Phylogenetic analysis based on mitochondrial DNA sequences of wild rats, and the relationship with Seoul virus infection in Hubei, China.

Seoul virus (SEOV), which is predominantly carried by Rattus norvegicus, is one of the major causes of hemorrhagic fever with renal syndrome (HFRS) in China. Hubei province, located in the central south of China, has experienced some of the most severe epidemics of HFRS. To investigate the mitochondrial DNA (mtDNA)-based phylogenetics of wild rats in Hubei, and the relationship with SEOV infection, 664 wild rats were captured from five trapping sites in Hubei from 2000-2009 and 2014-2015. Using reverse-transcription (RT)-PCR, 41 (6.17%) rats were found to be positive for SEOV infection. The SEOV-positive percentage in Yichang was significantly lower than that in other areas. The mtDNA D-loop and cytochrome b (cyt-b) genes of 103 rats were sequenced. Among these animals, 37 were SEOV-positive. The reconstruction of the phylogenetic relationship (based on the complete D-loop and cyt-b sequences) allowed the rats to be categorized into two lineages, R. norvegicus and Rattus nitidus, with the former including the majority of the rats. For both the D-loop and cyt-b genes, 18 haplotypes were identified. The geographic distributions of the different haplotypes were significantly different. There were no significant differences in the SEOVpositive percentages between different haplotypes. There were three sub-lineages for the D-loop, and two for cyt-b. The SEOV-positive percentages for each of the sub-lineages did not significantly differ. This indicates that the SEOV-positive percentage is not related to the mtDNA D-loop or cyt-b haplotype or the sub-lineage of rats from Hubei.

Prevalence of antibodies against hantaviruses in serum and saliva of adults living or working on farms in Yorkshire, United Kingdom.

Hantaviruses are an established cause of haemorrhagic fever with renal syndrome (HFRS) in Europe. Following a confirmed case of HFRS in the UK, in an individual residing on a farm in North Yorkshire and the Humber, a tidal estuary on the east coast of Northern England, and the subsequent isolation of a Seoul hantavirus from rats trapped on the patient’s farm, it was considered appropriate to further investigate the public health risk of this virus in the region. Of a total 119 individuals tested, nine (7.6%) were seropositive for hantavirus antibodies. Seven of the seropositive samples showed a stronger reaction to Seoul and Hantaan compared to other clinically relevant hantaviruses. Observation of rodents during the day, in particular mice, was associated with a reduced risk of seropositivity. In addition to one region known to be at risk following an acute case, five further potential risk areas have been identified. This study supports recently published evidence that hantaviruses are likely to be of public health interest in the region.

The Degree of Leukocytosis and Urine GATA-3 mRNA Levels Are Risk Factors for Severe Acute Kidney Injury in Puumala Virus Nephropathia Epidemica

Puumala hantavirus (PUUV) infection, also known as nephropathia epidemica, is the most common cause of hemorrhagic fever with renal syndrome (HFRS) in Europe. The pathogenesis of PUUV nephropathia epidemica is complex and multifactorial, and the risk factors for severe acute kidney injury (AKI) during acute PUUV infection are not well defined. We conducted a prospective study of hospitalized patients with PUUV infection in Tampere, Finland to identify acute illness risk factors for HFRS severity. Serial daily blood and urine samples were collected throughout acute illness and at 2 week and 6 month convalescent visits. By univariate analyses, the maximum white blood cell count during acute illness was a risk factor for severe AKI. There were no significant associations between PUUV-induced AKI severity and platelet counts, C-reactive protein, or alanine aminotransferase levels. Maximum plasma interleukin (IL)-6, urine IL-6, and urine IL-8 concentrations were positively associated with PUUV-induced AKI. Finally, the maximum urinary sediment GATA-3 mRNA level was positively correlated with the peak fold-change in serum creatinine, regardless of AKI severity classification. By multivariate analyses, we found that the maximum levels of leukocytes and urinary sediment GATA-3 mRNA during acute illness were independent risk factors for severe PUUV-induced AKI. We have identified novel acute illness risk factors for severe PUUV-induced AKI.

Nucleotide Sequence and Phylogenetic Analysis of M and L Segment of Soochong Virus

Hantaan virus (HTNV) and Seoul virus (SEOV) have mainly been known as the cause of hemorrhagic fever with renal syndrome (HFRS) in Korea since HTNV has been isolated from Korean field mouse, Apodemus agrarius in 1976 and SEOV has been isolated from Rattus norvegicus in 1980. Soochong virus-1, -2, -3, -4 (SOOVs) were isolated from lung tissues of four Apodemus peninsulae captured on August 1997 at Mt. Gyebang in Hongcheon-gun, Mt. Gachil, Inje-gun, Gangwon Province, and in September 1998 at Mt. Deogyu, Muju-gun, Jeollabuk Province. Apodemus peninsulae is the second-most dominant field rodent species found throughout Korea. To determine phylogenetic analysis of SOOVs, we entirely identified nucleotide sequences of M and L segments. The length of M segment was 3,615 bp and L segment was 6,533 bp. SOOVs were diverged from HTNV by 22.7~23.3% and SEOV by 36.3~37.2%, in M segment. In addition, L segment was diverged from HTNV by 21.8~22.0% and SEOV by 30.3~30.5%. SOOVs sequence compared with Amur virus (AMRV) in M segment showed that SOOVs were different with AMRV about 14.6~16.2% in nucleotide sequences. Neighbor-joining phylogenetic analysis based on entire sequences of the M and L segment indicated that the SOOVs sequences present a separate lineage with HTNV, SEOV and AMRV. SOOVs constituted an individual cluster on the phylogenetic tree and they composed a phylogenic lineage separately. According to these data, SOOVs could be classified as a new hantavirus.

Ocular features of hantavirus infection

Hantavirus infections are an emerging infectious disease that is beginning to be recognized both worldwide and in India as a cause of hemorrhagic fever that may present as a pulmonary syndrome or as a renal syndrome. Reports of ocular involvement are rare and include transient myopia, low intraocular pressure, conjunctival hemorrhages and changes of intraocular dimensions. Eleven patients (10 males, one female, mean age 37.6 years) were admitted to the intensive care unit for pyrexia of unknown origin or hemorrhagic fever following exposure to flood waters. Five male patients (mean age 31.6 years) were identified as suffering from hantavirus infection. In one patient, dot and blot intraretinal hemorrhages were seen in the macula of one eye and streak hemorrhages of the disc in the other. In the remaining four, no fundus abnormalities were seen. Ophthalmologists should be aware of these features.

Junin virus vaccines.

Argentine hemorrhagic fever (AHF) was recognized as a new clinical entity from the richest farming region of Argentina in the 1950s (Arribalzaga 1955). The etiologic agent of this disease, Junin virus (JUN), was isolated in 1958 (Parodi et al. 1958; Piroski et al. 1959). JUN belongs to the Arenaviridae family, which includes other rodent-borne pathogens which are important causes of hemorrhagic fever in Africa, (Lassa) and South America (Machupo, Guanarito, and Sabia viruses). The Arenaviridae comprises at least 20 recognized members. Arenaviruses are enveloped RNA viruses, and are divided into two groups, with low level antigenic relatedness: the Old World group, and New World group or Tacaribe complex. Two antigenic subgroups were defined within the New World arenaviruses. JUN is contained into the first group, together with Amapari, Latino, Machupo and Tacaribe viruses. Phylogenetic analysis have shown that Old World and New World arenaviruses occupied two distinct clades, and that New World arenaviruses comprise three evolutionary lineages, named A, B, and C. JUN is contained in lineage B, together with the other three agents causing South American hemorrhagic fevers (Enria et al. 1999a).

Hantavirus

Although hantaviruses have been known to exist for over 40 years, they were thought only to be the cause of hemorrhagic fever and renal syndrome (HFRS) in Europe and Asia. Rodents are the primary hosts of hantaviruses, and humans become infected mainly by inhalation of viral particles in the rodent excreta. The United States was thought to be spared from pathologic hantaviruses until the summer of 1993, when an outbreak of acute respiratory distress syndrome occurred in the Four Corners region of the United States, which includes Colorado, New Mexico, Arizona, and Utah. Through serological studies, the etiologic agent of this respiratory disease was found to be a heretofore-unknown hantavirus that was named the Sin Nombre virus. The resulting condition was renamed Hantavirus Pulmonary Syndrome (HPS). HPS begins as a febrile prodrome and quickly progresses to a life-threatening cardiorespiratory failure. A laboratory triad of thrombocytopenia, leucocytosis with bandemia, and immunoblasts is specific to HPS, and enzyme-linked immunosorbent assay remains the gold standard for diagnosis of hantaviruses. The management of both HFRS and HPS is mainly supportive, although ribavirin has been shown to be useful for HFRS. Eliminating exposure to rodents remains the key to prevention of hantavirus infection.

Asymptomatic Ebola Infection: Host Response May Be Key

Ebola virus, one cause of hemorrhagic fever, can kill 70 percent or more of patients in a week or less. Outbreaks expand by person-to-person spread of virus to close contacts in home and health care settings. This study analyzed 24 asymptomatic people who had repeated, unprotected close contact …

Leptospirosis and Ebola virus infection in five gold-panning villages in northeastern Gabon.

An exhaustive epidemiologic and serologic survey was carried out in five gold-panning villages situated in northeastern Gabon to estimate the degree of exposure of to leptospirosis and Ebola virus. The seroprevalence was 15.7% for leptospirosis and 10.2% for Ebola virus. Sixty years after the last seroepidemiologic survey of leptospirosis in Gabon, this study demonstrates the persistence of this infection among the endemic population and the need to consider it as a potential cause of hemorrhagic fever in Gabon. There was no significant statistical correlation between the serologic status of populations exposed to both infectious agents, indicating the lack of common risk factors for these diseases.

Hantaviruses in the United States

HANTAVIRUSES CAUSE chronic infections of rodents and occasionally infect other species as well. Several of the Old World viruses are well known as causes of hemorrhagic fever with renal syndrome (HFRS) in Eurasia. Although HFRS has rarely been described in the United States,¹it is assumed to be underreported. In 1993, an outbreak of febrile disease resembling adult respiratory distress syndrome occurred in the southwestern United States and was found to be caused by a new hantavirus, Sin Nombre virus.² The unique pulmonary syndrome (hantavirus pulmonary syndrome [HPS]) differed from the renal disease so prominent in HFRS. Immunohistologic studies provide evidence of compartmentalization of a selective immune response in the lung in combination with large amounts of viral antigens in the pulmonary microvasculature.³Detailed mechanisms of pathogenesis are not understood, although there are some similarities to HFRS.⁴Selective inflammatory cell recruitment to the lung may occur

Emerging viral diseases of rabbits and rodents: Viral hemorrhagic disease and hantavirus infection

Emerging viruses are viruses that have either newly appeared in a population or have rapidly increased their range, with a corresponding increase in cases of disease. Identifiable sources of emerging viruses are usually existing viruses of animals or humans. Two emerging viruses of significance to exotic animal veterinarians are viral hemorrhagic disease virus of rabbits, and rodent-borne hantaviruses, the cause of hemorrhagic fever with renal syndrome in humans. Viral hemorrhagic disease is highly infectious and rapidly lethal and has killed large numbers of rabbits in Europe and China. It has replaced myxomatosis as the most significant viral disease of rabbits. Hantaviruses are found world-wide in many rodent hosts and are a significant source of “new” zoonoses. A rodent hantavirus was the cause of hantavirus pulmonary syndrome, which killed at least 36 people in 18 United States. Changes in natural environments, often caused by human activity, place both humans and animals in contact with previously inaccessible viruses or natural hosts. Increased international transport of rabbits and increased contact with exotic rodents carrying hantavirus are two such changes. Exotic animal veterinarians are likely to be among the first persons to see the infections and should be aware of the clinical signs and support available if they should encounter these diseases.