Hantavirus hemorrhagic fever with renal syndrome

Hantavirus hemorrhagic fever with renal syndrome (HFRS) is characterized by five phases: febrile, hypotensive, low urine production (oliguria), high urine production (polyuria or diuretic), and recovery. Symptoms usually occur 12–16 days after exposure to the virus, but may appear as early as 5 days or as late as 42 days after exposure. A hallmark of HFRS is acute kidney disease with kidney swelling, excess protein in urine (proteinuria), and blood in urine (hematuria). Other symptoms include headache, lower back pain, impaired vision, nausea, vomiting, diarrhea, and bloody stool. These early symptoms last 3–7 days. Hemorrhagic symptoms include the appearance of red, purple, or brown spots on the skin (petechiae) and mucosa within 3–4 days after the onset of symptoms, and Dobrava-Belgrade varies depending on genotype. During the hypotensive phase, which lasts 1–3 days, there is a sudden onset of lower blood pressure and shock due to microvascular leakage, which can result in sudden death. The oliguric or diuretic phase, which lasts 2–6 days, and inflammation of the gallbladder (cholecystitis), the pericardium (pericarditis), the brain (encphalitis), Infection with Puumala virus or Dobrava-Belgrade virus often causes a mild form of HFRS known as nephropathia epidemica (NE). For pregnant women and fetuses, symptoms are more severe, In more mild cases, the different phases of illness may be hard to distinguish, or some phases may be absent, while in more severe cases, the phases may overlap. Some symptoms are associated with specific hantaviruses: Puumala virus often causes ocular symptoms such as blurry vision and nearsightedness, Hantaan virus can affect the pituitary gland and cause empty sella syndrome, and Dobrava-Belgrade virus commonly causes ARDS. ==Virology==

, a hantavirus. Genome and structure The genome of hantaviruses is segmented into three parts: the large (L), medium (M), and small (S) segments. Each part is a single-stranded negative-sense RNA strand, consisting of 10,000–15,000 nucleotides in total. The segments form into circles via non-covalent bonding of the ends of the genome. The L segment is about 6.6 kilobases (kb) in length and encodes RNA-dependent RNA polymerase (RdRp), which mediates transcription and replication of viral RNA. The M segment, about 3.7 kb in length, of some hantaviruses also encodes the non-structural protein NS that inhibits interferon production in host cells. The untranslated regions at the ends of the genome are highly conserved and participate in the replication and transcription of the genome. or tubular. Life cycle Vascular endothelial cells and macrophages are the primary cells infected by hantaviruses. After entering a cell, virions form vesicles that are transported to early endosomes, then late endosomes and lysosomal compartments. A decrease in pH then causes the viral envelope to fuse with the endosome or lysosome. Because hantaviruses have segmented genomes, they are capable of genetic recombination and reassortment in which segments from different viruses can combine to form new viruses. This occurs often in nature and facilitates the adaptation of hantaviruses to multiple hosts and ecosystems. Within species, geography has also affected the evolution of hantaviruses. For example, Hantaan virus and Seoul virus have both formed multiple lineages corresponding to their geographic distribution. ==Mechanism==

Transmission Rodents transmit hantaviruses that cause illness in humans. In rodents, hantaviruses usually cause an asymptomatic, persistent infection. Infected animals can spread the virus to uninfected animals through aerosols or droplets from their feces, urine, saliva, through consumption of contaminated food, from virus particles shed from skin or fur, Living in a rural environment, in unhygienic settings, and interacting with environments shared with hosts are the biggest risk factors for infection, especially people who are hikers, and zoology. Research has also shown that pigs can be infected with Hantaan virus without severe symptoms and sows can transmit the virus to offspring through the placenta. Pig-to-human transmission may also be possible, as one swine breeder was infected with hantavirus with no contact with rodents or mites. Hantaan virus and Puumala virus have been detected in cattle, deer, and rabbits, and antibodies to Seoul virus have been detected in cats and dogs. The role of these hosts for hantaviruses is unknown. Sewers and stormwater drainage systems may be inhabited by rodents, especially in areas with poor solid waste management. Maritime trade and travel have also been implicated in the spread of hantaviruses. Oxygenation problems and bradykinin are also thought to play a role in increased vascular permeability during infection. Coagulation abnormalities may also occur. Virus particles cluster on the surface of endothelial cells, which causes a misallocation of platelets to infected endothelial cells. Disseminated coagulating without signs of hemorrhaging, major blood clots, and damage to vascular endothelial cells during infection may negatively affect coagulation and platelet levels and promote further vascular leaking and hemorrhaging. Infection begins with the interaction of the viral glycoproteins Gn and Gc and β-integrin receptors on target cell membranes. Immature dendritic cells near endothelial cells transport virions from lymphatic vessels to local lymph nodes to infect more endothelial cells. These cells produce antigens to induce an immune response, especially those of macrophages and CD8+ T lymphocytes. After activation of the immune system, cytotoxic T lymphocytes produce pro-inflammatory cytokines that can damage infected endothelial cells, which can lead to increased vascular permeability and inflammatory reactions. These cytokines include interferon (IFN), interleukins (IL-1, IL-6, and IL-10), and tumor necrosis factor-α (TNF-α). Elevated IL-6 levels are associated with low platelet count and renal failure. HFRS mainly affects the kidneys and blood vessels, though other parts of the body, such as the nervous system, spleen, and liver, can also be affected. While most major organs become infected, organ failure does not occur in most, as pathology is different from organ to organ. In the tubular epithelium of the kidneys, tight junction proteins are redistributed, and tubular necrosis occurs, which impairs the kidney tubules and causes proteinuria and hematuria. Glomerular endothelium infection in the kidneys causes decreased function of glomerular ZO-1 expression, which reduces the function of the glomerulus as a molecular filter by increasing glomerular permeability, which causes proteinuria and hematuria. Liver infection does not lead to significant dysfunction since hepatic blood vessels are already relatively permeable. In the spleen, infection of immune cells can cause over-activation of immature lymphocytes elsewhere and facilitate prolonged spread of the virus throughout the body. Immunology The innate immune system recognizes hantavirus infection by the detection of viral RNA. This triggers production of interferons, immune cytokines, and chemokines and activation of signaling pathways to respond to viral infection. Monocytes respond to infection by using phagocytosis to consume virus particles. IgM antibodies to the viral surface glycoproteins are created to bind to and disable virus particles. During infection, the anti-Gc IgM response is stronger than the anti-Gn IgM response. Long term, the anti-Gc IgG response is stronger than the anti-Gn IgG response. Anti-N antibodies are produced during infection but are not involved in neutralizing virions. Long non-coding RNA and microRNA are involved in inhibiting hantavirus infection. Pathogenic hantaviruses can modify the immune response and evade interferon-mediated antiviral signaling pathways in various ways, including by inhibiting interferon activation, inhibiting the activation of transcription factors, and inhibiting downstream JAK/STAT signaling. They can also regulate cell death to aid in completing their life cycle through autophagy, apoptosis, and pyroptosis. Hantaan virus infection and NP and GP protein expression have been shown to promote the production of microRNAs that reduce the expression of pro-inflammatory cytokines. Furthermore, hantaviruses appear to induce cell stress via endoplasmic reticulum stress while inhibiting the cellular response to stress, which helps the virus escape host stress signaling. ==Prevention==

Reducing the risk of exposure to rodents at home, one's workplace, and when camping People at high risk of infection, including pest exterminators, people who work in agriculture, forestry, and animal husbandry can take preventive measures such as wearing masks to prevent exposure to hantaviruses. but is associated with reduced disease severity. Due to a diminishing vaccine-induced antibody response, frequent booster doses are required. A similar vaccine was approved for use in China in 2005, which provides immunity for up to 33 months. Other vaccines have been researched in animal models such as recombinant vaccines, DNA vaccines, virus-like particle (VLP) vaccines, recombinant vector vaccines, and subunit vaccines. These vaccines have shown varying degrees of effectiveness. ==Diagnosis==

Initial diagnosis of hantavirus infection can be made based on epidemiological information and clinical symptoms. Confirmation of infection also includes detection of hantavirus nucleic acid, proteins, or hantavirus-specific antibodies. Key findings of laboratory findings include thrombocytopenia, leukocytosis, hemoconcentration, elevated serum creatinine levels, hematuria, and proteinuria. Hantavirus-specific IgM and IgG antibodies are usually present at the onset of symptoms. IgM is detectable in the acute phase of infection but declines over a period of 2–6 months. The response of IgG antibodies is low during infection but grows over time and lasts for one's lifetime. Neutralization tests, immunofluorescent assays (IFAs), and enzyme-linked immunosorbent assays (ELISAs) can be used to detect antibodies to hantavirus infection in blood, usually anti-N or anti-Gc antibodies. ELISA is inexpensive and can be used at any point during the illness, but results may need to be confirmed by other methods. Rapid immunochromatographic IgM antibody tests can also be used for diagnosis as they are simple to carry out and inexpensive. Western blotting can detect hantavirus antigen in tissue samples, but is costly and time consuming. Both traditional and real-time polymerase chain reaction (PCR) tests of blood, saliva, BAL fluids, and tissue samples can be used. There is a possibility of false negatives with PCR if there are low levels of virus in the blood, and PCR testing is prone to cross-contamination, but when performed during the onset of infection, it may predict disease severity. PCR can also be used for postmortem diagnosis and for analysis of organ involvement, and it can be used to sequence the virus's genome to identify which specific virus is causing illness. ==Management==

Treatment of HFRS is supportive in nature. The specific form of treatment depends on the phase of the disease and clinical presentation. Intravenous hydration and electrolyte therapy are essential to maintain blood pressure and electrolyte balance. Platelet transfusions can be used to reduce mortality in cases of severe thrombocytopenia and disseminated intravascular coagulation to control bleeding. If acute kidney injury occurs, then intermittent hemodialysis is used as the first option, and continuous renal replacement therapy in critical HFRS cases. No specific antiviral drugs exist for hantavirus infection, but ribavirin and favipiravir have shown varying efficacy and safety. Prophylactic use of ribavirin and favipiravir in early infection or post-exposure shows some efficacy, and both have shown some anti-hantavirus activity in vivo and in vitro. Ribavirin is effective in the early treatment of HFRS with some limitations, such as toxicity at high doses and the potential to cause hemolytic anemia. Anemia is reversible upon completion of ribavirin treatment. In some instances, ribavirin may cause excess bilirubin in the blood (hyperbilirubinemia), abnormally slow heartbeat (sinus bradycardia), and rashes. Administering ribavirin after the onset of the cardiopulmonary phase of HPS is not an effective treatment, and currently there is no recommendation for the use of ribavirin to treat HFRS or HPS. Favipiravir has greater efficacy than ribavirin, without anemia as a side effect. In hamster models, oral administration of favipiravir twice per day of 100 mg/kg significantly reduced viral load in the blood and antigen load in the lungs. Oral administration before viremia prevented HPS, but not after this. Several other approaches have been researched as potential anti-hantavirus treatments, including small-molecule compounds that target the virus or host, peptides, alligator weed, antibodies, and classical antiviral drugs, tested mainly to block hantavirus entry into cells or restrain virus replication. Host-targeting medicines are designed to improve vascular function or rebuild homeostasis. ==Prognosis==

Prognosis is good in most cases. The case fatality rate ranges from less than 1% to 15%, In South Korea, the case fatality rate is 1–2%. Death is also associated with lower platelet count, elevated white blood cell count, and higher aspartate aminotransferase and alanine aminotransferase. The antibody response to hantavirus infection is strong and long-lasting. Early production of neutralizing antibodies (nAbs) that target the surface glycoproteins is directly associated with increased likelihood of survival. High nAb counts can be detected as long as ten years after infection. Higher levels of IL-6, in contrast, are associated with more severe disease, and deceased individuals have higher IL-6 levels than survivors. Genetic susceptibility to severe illness is related to one's human leukocyte antigen (HLA) type, which also depends on the hantavirus, as increased susceptibility to different hantaviruses is associated with different HLA haplogroups. ==Epidemiology==

Most cases of HFRS are caused by just four viruses: Hantaan virus, Seoul virus, Puumala virus, and Dobrava-Belgrade virus. The geographic distribution of individual hantaviruses is directly tied to the geographic distribution of their natural reservoir. In South Korea, 400–600 cases occur each year. More than 10,000 cases of NE are diagnosed annually. In some places, such as South Korea, routine trapping of wild rodents is performed to surveil hantavirus circulation. Infections are more common in the wet season than the dry season. Low rainfall and drought are associated with decreased incidence since such conditions result in a smaller rodent population, but displacement of rodent populations via drought or flood can lead to an increase in rodent-human interactions and infections. In Europe, however, no association between rainfall and incidence has been observed. Temperature has varying effects on hantavirus transmission. Higher temperatures create unfavorable environments for virus survival, but it can cause rodents to seek shelter from heat in human settings and are beneficial for aerosol production. Lower temperature can prolong virus survival outside a host. Higher average winter temperature is associated with reduced survival of bank voles, the natural reservoir of Puumala virus, but increased survival of striped field mice in China, the natural reservoirs of Hantaan virus. Extreme temperatures, whether hot or cold, are associated with lower disease incidence. ==History==

Hantavirus hemorrhagic disease was likely first described in the Yellow Emperor's Internal Canon in Imperial China during the Warring States Period of 475-221 BCE. ==See also==