Hantavirus hemorrhagic fever with renal syndrome (HFRS) is a hemorrhagic fever caused by hantavirus infection. Symptoms usually occur 2 weeks after exposure to the hantavirus and come in five distinct clinical stages: febrile (toxic), hypotensive, low urine production (oliguric), high urine production (diuretic), and recovery. Early symptoms include headache, lower back pain, nausea, vomiting, diarrhea, bloody stool, the appearance of spots on the skin, bleeding in the respiratory tract, and renal symptoms such as kidney swelling, proteinuria, and hematuria. During the hypotensive phase, blood pressure lowers due to microvascular leakage. Renal failure then causes the oliguric phase, before recovering and increasing urine production as disease progression improves. The severity of symptoms varies depending on which virus causes HFRS and ranges from mild illness to severe. The case fatality rate likewise varies by virus, from less than 1% up to 15%.
HFRS is caused mainly by four viruses in Asia and Europe: Hantaan virus, Seoul virus, Puumala virus, and Dobrava-Belgrade virus. In East Asia, Hantaan virus is the most common cause of HFRS, causes a severe form of HFRS, and is spread by striped field mice. The Seoul virus accounts for about a quarter of HFRS cases, causes a moderate form of the disease, and is found worldwide due to the global distribution of its natural reservoir, the brown rat. Puumala virus is the most common cause of HFRS in Russia and northern and central Europe, usually causes a mild form of HFRS, and is transmitted by the bank vole. The Dobrava-Belgrade virus is the most common cause of HFRS in southern Europe, and varies in disease severity and natural reservoir depending on its genotype. A mild form of HFRS, often called nephropathia epidemica (NE), is caused by the Puumala virus and Dobrava-Belgrade virus. Transmission occurs mainly through inhalation of aerosols that contain rodent saliva, urine, or feces but can also occur through contaminated food, bites, and scratches. Vascular endothelial cells and macrophages are the primary cells infected by hantaviruses, and infection causes abnormalities with blood clotting, all of which result in fluid leakage responsible for the more severe symptoms. Recovery from infection likely confers lifelong protection.
The main way to prevent HFRS is to avoid or minimize contact with rodents that carry hantaviruses. Removing sources of food for rodents, safely cleaning up after them, and preventing them from entering one's house are all important means of protection. People who are at risk of interacting with infected rodents can wear masks to protect themselves. Bivalent vaccines that protect against Hantaan virus and Seoul virus are in use in China and South Korea. Initial diagnosis of infection can be made based on epidemiological information and symptoms. Confirmation of infection can be done by testing for hantavirus nucleic acid, proteins, or hantavirus-specific antibodies. Treatment of HFRS is supportive and depends on the phase of the disease and clinical presentation. Intravenous hydration, electrolyte therapy, and platelet transfusions may be performed, as well as intermittent hemodialysis for renal failure and continuous renal replacement therapy in critical cases. No specific antiviral drugs exist for hantavirus infection.
More than 100,000 cases of HFRS occur each year. China is the most affected country in Asia, while Finland is the most affected country in Europe. More than 10,000 cases of NE are diagnosed annually. The distribution of viruses that cause HFRS is directly tied to the distribution of their natural reservoirs. Transmission is also greatly influenced by environmental factors such as rainfall, temperature, and humidity, which affect the rodent population and virus transmissibility. Outbreaks of HFRS have occurred throughout history, especially among soldiers during wartime who live in poor conditions. During the Korean War in the 1950s, an epidemic of HFRS occurred among United Nations soldiers stationed near the Hantan river. The outbreak was determined in the 1970s and 1980s to be caused by the Hantaan virus, which was named after the river and which was the first hantavirus discovered. Other HFRS epidemics include an outbreak in Finland in World War Two among German and Finnish soldiers, caused by the Puumala virus, and an outbreak in Croatia during the Balkan Wars, caused by the Puumala virus and the Dobrava-Belgrade virus.
Signs and symptoms
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, coughing up blood or blood-stained mucus or airway bleeding (hemoptysis); congestion of the conjunctiva in the eye; gastrointestinal bleeding, and intracranial bleeding. In severe cases, excess blood clotting throughout the body, called disseminated intravascular coagulation (DIC), can occur. The severity of symptoms varies depending on the virus: Hantaan virus causes severe HFRS; Seoul virus, moderate HFRS; Puumala virus, mild HFRS; 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. Urine production and platelet count decrease, white blood cell count in blood increases, and hemorrhaging begins during the hypotensive phase. The oliguric or diuretic phase, which lasts 2–6 days, is caused by renal failure with oliguria and proteinuria. During the polyuria phase, which lasts about 1–2 weeks, renal functions gradually recover, which leads to increased urine production. Complete renal function can be restored after a long recovery process, about 2–6 months, but chronic renal failure, endocrine dysfunction, and hypertension may occur. Extra-renal complications include acute respiratory distress syndrome (ARDS), pituitary gland injury or insufficient pituitary gland hormone production, and inflammation of the gallbladder (cholecystitis), the pericardium (pericarditis), the brain (encephalitis), and the pancreas (pancreatitis).
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, whereas for children symptoms are milder with greater frequency of abdominal symptoms. Serological surveys suggest that many HFRS infections go unnoticed, either as asymptomatic infections or as a mild flu-like illness with symptoms such as high fever, malaise, and muscle pain. 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. While HFRS is typically associated with renal disease, symptoms sometimes include cardiopulmonary symptoms associated with hantavirus pulmonary syndrome (HPS). 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. Repeated infections of hantaviruses have not been observed, so recovering from infection likely grants life-long immunity.
Virology
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, encodes a glycoprotein precursor that is co-translated and cleaved into Gn and Gc. Gn and Gc bind to cell receptors, regulate immune responses, and induce protective antibodies. The S segment is around 2.1 kb in length and encodes the N protein, which binds to and protects viral RNA. An open reading frame in the N gene on the S segment 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.
Individual hantavirus particles (virions) are usually spherical, but may be oval, pleomorphic, or tubular. The diameter of the virion is 70–350 nanometers (nm). The lipid envelope is about 5 nm thick. Embedded in the envelope are the surface spike glycoproteins Gn and Gc, which are arranged in a lattice pattern. Each surface spike is composed of a tetramer of Gn and Gc (four units each) that has four-fold rotational symmetry, extending about 10 nm out from the envelope. Gn forms the stalk of the spike and Gc the head. Inside the envelope are helical nucleocapsids made of many copies of the nucleocapsid protein N, which interact with the virus's genome and RdRp. Hantaviruses do not encode matrix proteins to assist with structuring the virion, so how surface proteins organize into a sphere with a symmetrical lattice is not yet known.
Life cycle Vascular endothelial cells and macrophages are the primary cells infected by hantaviruses. Podocytes, tubular cells, dendritic cells, and lymphocytes can also be infected. Attachment and entry into the host cell is mediated by the binding of the viral glycoprotein spikes to host cell receptors, particularly β1 and β3 integrins. Decay acceleration factors and complement receptors have also been proposed to be involved in attachment. After attachment, hantaviruses rely on several ways to enter a cell, including micropinocytosis, clathrin-independent receptor-mediated endocytosis and cholesterol- or caveolae-dependent endocytosis. Old World hantaviruses use clathrin-dependent endocytosis while New World hantaviruses use clathrin-independent endocytosis.
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. This fusion releases viral ribonucleoprotein complexes into the cell cytoplasm, initiating transcription and replication by RdRp. RdRp transcribes viral -ssRNA into complementary positive-sense strands, then snatches 5′ ("five prime") ends of host messenger RNA (mRNA) to prepare mRNA for translation by host ribosomes to produce viral proteins. Complementary RNA strands are also used to produce copies of the genome, which are encapsulated by N proteins to form RNPs.