The main transmission pathway from rodents to humans is aerosolized excreta inhalation and contact infection. Person-to-person transmission has not been found. Forest workers, shepherds, woodcutters and military personnel also have high occupational hazard from HTNV infection in that epidemiologic investigations have linked virus exposure to such activities as heavy farm work, threshing, sleeping on the ground and military exercises Schmaljohn and Hjelle, HFRS mostly occurs in the period from the late autumn to the next spring, with two incidence peaks Liu et al.
The starting time of HFRS incidence peak depends on the type of pathogenic hantavirus and also coincides with increased human outdoor activities in spring and fall. The scale of rodent populations may also affect the disease outbreaks in humans Khaiboullina et al.
SEOV is the major hantavirus that circulates in the domestic rats and causes human infection in urban areas. The clinical course of HFRS is primarily characterized by fever, circulatory collapse with hypotension, hemorrhage, and acute kidney injury AKI.
Additionally, some of these phases frequently overlap in severe cases, and one or two phases are frequently absent in some mild cases. Laboratory findings during acute stage of the disease are anemia, leukocytosis, thrombocytopenia, elevated liver enzymes, and serum creatinine renal dysfunction , as well as proteinuria and hematuria.
Most of the cases can recover completely, while some severe cases still have some sequelaes including headache, insomnia, hyperhidrosis, hemorrhage, and hyperdiuresis. Kidney injury frequently occurs in HFRS and the most prominent pathological presentation is acute tubulointerstitial nephritis following the infiltration of inflammatory cells Kim et al. The elderly patients often develop severe AKI and are more likely to have shock, hematuria, thrombocytopenia and leukocytosis.
The patients with severe AKI usually need dialysis or continuous blood purification and stay longer in hospital than non-AKI patients Wang et al. Thrombocytopenia, which is one of the factors that cause the increase of blood vessel permeability, is related to severe AKI among patients with acute HTNV infection.
Acute thrombocytopenia is a common symptom of HFRS and persists throughout hantavirus infection. Pulmonary, cardiac, endocrinological, central nervous system, and ocular findings are also major manifestations of HFRS.
The febrile, hypotensive, and oliguric phases can overlap in some severe cases. In this condition, acute progressive noncardiogenic pulmonary edema, which often presents as acute respiratory distress syndrome ARDS , is likely to happen, and, thus, results in a high fatality rate. It was demonstrated that the agitation, conjunctival hemorrhage, coma, were also negatively correlated with survival outcome Du et al.
The diagnosis of HFRS is based on exposure history, typical clinical manifestations, and serum test results, such as the detection of IgM or IgG antibodies against hantavirus in patient serum by enzyme-linked immunosorbent assay ELISA and colloidal gold method. A safe, rapid and specific serotyping method for diagnosis was developed by using the recombinant hantavirus nucleocapsid protein NP as antigen Li et al. It has been demonstrated that the detection of NP-specific IgM antibodies in clinical samples is a good indicator of a recent hantavirus infection Peters and Khan, The detection of hantavirus-specific IgM in an ELISA format is the most valuable and widely used method for diagnosing acute hantavirus infections Li et al.
Truncated recombinant NP detection has been shown to be more specific to differentiate the involved hantavirus serotype Araki et al. However, ELISA and other serological tests cannot be used to assess the replication of the virus in patient's blood.
Several methods for detection of HTNV in cell culture supernatant or blood sample have also been developed. Plaque assay is a classical method to titrate virus.
However, it usually takes 5—7 days for the formation of the viral plaques. HFRS has been widely believed as one type of systemic inflammatory response syndrome, and the patient's pathophysiologic manifestations of the hypotensive phase are similar to those of typical distributive shock. Vascular endothelial dysfunction is the basic pathological change, which is characterized by dramatic increase in vascular permeability Grvrilovskaya et al.
Increased vascular permeability leads to plasma exosmosis and even hemorrhage, which is associated with lots of clinical features in HFRS, such as hemoconcentration, hypotension, shock, and abdominal pains Hayasaka et al. So far, it is difficult to explain the pathogenesis in a single factor. Studies have suggested that HFRS may be developed via indirect mechanisms including the virus factors, immune factors and host genetic factors.
Left side: Normal endothelial cells EC , no vascular leakage occurs. Right side: EC were infected with hantaviruses. High hantavirus RNA load result in severe vascular leakage. HFRS is characterized by increased vascular permeability and coagulation disorders. It was recognized that human endothelial cells isolated from both adult and fetal veins are highly susceptible to the HTNV infection.
However, in vitro infection with HTNV does not cause any noticeable cytopathic effect, as judged by both phase microscopy and electron microscopy Pensiero et al. Therefore, hantavirus is considered to be a non-cytopathogenic virus which targets primarily vascular endothelial cells Guhl et al.
It has been demonstrated that there is an association between the hantavirus RNA load and disease severity in some recent studies. An increased Sin Nombre viral load is likely to produce a more severe clinical outcome Xiao et al. Close correlation between viral load and disease severity were also found in cases of DOBV Saksida et al. It has been suggested that the cell permeability induced by hantavirus infection is associated with impaired barrier structure.
It was reported that increased secreted vascular endothelial growth factor VEGF and concomitant decreased VE-cadherin were detected during the early stages in human primary lung endothelial cells infected by Andes virus Shrivastava-Ranjan et al.
The study also found that active virus replication could produce increased permeability and decreased the integrity of the endothelial cell barrier. Wang et al. Similar to the effects of many other pathogenic viruses, HFRS is mainly medicated by the efforts of the immune system, both innate, and adaptive, to clear the infection. Therefore, it has been widely accepted that HFRS pathogenesis is largely immune mediated, including immune complexes, complement activation, T cell response, B cell response, and HTNV-induced cytokine production Khaiboullina et al.
The humoral pattern recognition receptor PTX3 and antibodies activate complement. Activated complement components induce cytoskeletal rearrangement in EC further increasing dysfunction of the EC barrier. TLRs recognize Hantavirus and mediate the innate response. B cells produce several subclass antibodies, while only the neutralizing antibodies against G1 and G2 is beneficial to decrease the viruses, then decrease vascular leakage. Innate immunity works like a sentinel against microbial pathogen invasion.
Innate immunity can be activated immediately following the recognition of diverse Pathogen-associated molecular patterns PAMPs by various Pattern-recognition receptors PRRs. Among the different receptors that participate in the recognition of microbial invaders, Toll-like receptors TLRs play important roles in mediating the innate response Akira et al.
TLRs can produce effective immune responses and trigger the release of inflammatory cytokines and type I interferon for host defense Beutler, Handke et al. In Jiang et al. Zhang et al. Vaheri et al. Increased levels of cytokines and chemokines and an imbalance in their production contribute to increasing vascular endothelial permeability and a severe clinical course in patients with HFRS. In Linderholm et al. However, Khaiboullina et al. Moreover, elevated levels of VEGF have correlation with the severity and degree of kidney damage Li et al.
Thus, regulating the early IFN response is necessary for hantaviruses to replicate in human endothelial cells and to be pathogenic. MxA inhibits representative members of the Bunyaviridae family by interacting with an early step of virus replication.
When constitutively expressed in stably transfected Vero cells, MxA prevented the accumulation of viral transcripts and proteins of Hantaan virus Frese et al. It was suggested that MxA endogenously expressed in response to type I or type II IFNs does not play a pivotal role in the antiviral process against HTNV and that there is more than one mechanism by which cellular defense blocks hantavirus replication Oelschlegel et al. Khaiboullina et al. Several other cytokines also have relationship with the symptoms of HFRS.
On the one hand, they are helpful in eliminating viruses directly or indirectly by inducing innate effector functions and antigen presentation of viral epitopes to T cells. It has been proposed that the complement system is associated with hantavirus-induced immunopathology.
The soluble form of the terminal complement membrane attack complex, SC5b-9, can increase the permeability of cultured endothelial cells Bossi et al. In the acute phase of PUUV infection, the complement system becomes activated and the severity of disease varies directly as the levels of complement activation Sane et al.
The acute phase protein pentraxin-related protein 3 PTX3 , which mediated the complement activation in the course of hantavirus infection, is increased during the acute phase of PUUV infection Outinen et al. Monocytes and Macrophages put up a bridge between innate and adaptive immunity. High expression of cytokines activating in the early phase of HFRS contribute to the immune-mediated pathogenesis Mustonen et al.
IgM response. IgM antibody is against all the three structural proteins of hantavirus. Symptoms of HFRS usually develop within 1 to 2 weeks after exposure to infectious material, but in rare cases, they may take up to 8 weeks to develop. Initial symptoms begin suddenly and include intense headaches, back and abdominal pain, fever, chills, nausea, and blurred vision.
Individuals may have flushing of the face, inflammation or redness of the eyes, or a rash. Later symptoms can include low blood pressure, acute shock, vascular leakage, and acute kidney failure, which can cause severe fluid overload. The severity of the disease varies depending upon the virus causing the infection.
Hantaan and Dobrava virus infections usually cause severe symptoms, while Seoul, Saaremaa, and Puumala virus infections are usually more moderate. Complete recovery can take weeks or months. Several laboratory tests are used to confirm a diagnosis of HFRS in patients with a clinical history compatible with the disease. Such patients are determined to have HFRS if they have serologic test results positive for hantavirus infection, evidence of hantavirus antigen in tissue by immunohistochemical staining and microscope examination, or evidence of hantavirus RNA sequences in blood or tissue.
Supportive therapy is the mainstay of care for patients with hantavirus infections. Dialysis may be required to correct severe fluid overload. Intravenous ribavirin, an antiviral drug, has been shown to decrease illness and death associated with HFRS if used very early in the disease.
Rodent control is the primary strategy for preventing hantavirus infections. Find articles by Ji Yun Noh. Find articles by Jaehun Jung. Find articles by Jin-Won Song. Author information Article notes Copyright and License information Disclaimer. Corresponding author. Corresponding Author: Jin-Won Song. Received Jun This article has been corrected.
See Infect Chemother. This article has been cited by other articles in PMC. Keywords: Family hantaviridae, Hemorrhagic fever with renal syndrome, Hantavirus, Epidemiology. Discovery and Epidemiology A. Open in a separate window.
Figure 1. Figure 2. Regions affected by the hemorrhagic fever with renal syndrome epidemic, including Hantaan River. Types of virus Hantaviruses are known as rodent-transmitted viruses, and each species of this family is associated with a unique wild rodent as a carrier.
Table 1 Major Hantaviruses in Korea. HFRS, hemorrhagic fever with renal syndrome. Incidence and epidemiology The Old World Hantaviruses, which are usually found in East Asia and Europe, are generally transmitted to humans via the respiratory pathway during dry seasons, usually in late spring and fall.
Figure 3. Incidence of hemorrhagic fever with renal syndrome in Korea since Disease characteristics A. Clinical course The typical clinical course of HFRS is classified into five phases: febrile, hypotensive, oliguric, diuretic, and convalescent [ 8 ]. Pathological findings In a pathology report on a case of death by HFRS in late , bleeding in the renal medulla, right atrium, and submucosa of gastrointestinal tract; necrosis in the renal medulla, anterior pituitary lobe, and adrenal gland; and monocyte infiltration in the myocardium, pancreas, spleen, and liver were reported as characteristic findings [ 15 ].
Preventive measures and management A. Prior to the discovery of the Hantaan virus Epidemic hemorrhagic fever in Korea was first officially reported in the medical community in Figure 4. Preventive measures for and management of HFRS since the s 1 Promotion of effective vaccination and development of a new vaccine Because HFRS outbreaks mostly occur in regions near the truce line in Korea, vaccination is virtually the only protection against the virus among military personnel working in such regions and local residents-particularly farmers.
Data curation: JJ. Formal analysis: JJ. Investigation: JYN. Methodology: JYN. Project administration: JWS. Resources: JWS. Supervision: JWS.
References 1. Smadel JE. Epidemic hemorrhagic fever. Am J Public Health. Brown WL. Trench nephritis. A review of Soviet viral hemorrhagic fevers, J Infect Dis. In this report, we demonstrate that the cellular entry of HFRS-associated hantaviruses is facilitated by specific integrins expressed on platelets, endothelial cells, and macrophages.
In addition, PH infectivity was not inhibited by alphavbeta3-specific sera or vitronectin but was blocked by alpha5beta1-specific sera and the integrin ligand fibronectin.
0コメント