Materiały źródłowe

• #1 Hantavirus pulmonary syndrome – Wikipedia

  https://en.wikipedia.org/wiki/Hantavirus_pulmonary_syndrome

  Hantavirus pulmonary syndrome (HPS), also called hantavirus cardiopulmonary syndrome (HCPS), is a severe respiratory disease caused by hantaviruses. The main features of illness are microvascular leakage and acute respiratory distress syndrome. […] Vascular endothelial cells and macrophages are the primary cells infected by hantaviruses, and infection causes abnormalities with blood clotting, all of which results in fluid leakage responsible for the more severe symptoms. […] The main cause of illness is increased vascular permeability, decreased platelet count, and overreaction by the immune system. The increased vascular permeability appears to be the result of infected cells producing vascular endothelial growth factor (VEGF), which activate VEGFR2 receptors on endothelial cells, which increases paracellular permeability.

• #2 Hantavirus Pulmonary Syndrome | Respiratory Therapy

  https://respiratory-therapy.com/disorders-diseases/infectious-diseases/influenza/hantavirus-pulmonary-syndrome/

  The pathogenesis of HPS is unclear, though hantavirus seems to exert a selective attraction of inflammatory cells to injured pulmonary epithelium (in this case, vascular). […] The site of initial infection is unknown, but hantavirus shows a preference for the pulmonary vasculature, thus explaining its respiratory manifestations. […] The lung tissues of HPS patients show heavy edema with serous fluid effusions and a marked increase in vascular permeability, while the respiratory epithelium remains intact. […] Airway distortion is seen in patients who survive the disease for a few days, and this is followed by a thickening of the alveolar septa due to an increased number of type I pneumocytes. […] There is no pneumocyte type II hyperplasia, but there are focal hyaline membranes. […] The pleural cavity is filled with yellow, serous fluid.

• #3 Orthohantavirus – Wikipedia

  https://en.wikipedia.org/wiki/Orthohantavirus

  Hantaviruses in their natural reservoirs usually cause an asymptomatic, persistent infection. In humans, however, hantaviruses cause two diseases: hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). […] For HPS, initial symptoms are flu-like, with fever, headache, and muscle pain, followed by sudden respiratory failure. HPS has a higher case fatality rate than HFRS, at 30-60%. For both HFRS and HPS, illness is the result of increased vascular permeability, decreased platelet count, and overreaction of the immune system. […] The hantavirus genome consists of three single-stranded negative-sense RNA segments that encode one protein each: an RNA-dependent RNA polymerase (RdRp), a spike glycoprotein precursor, and the N protein. […] HPS is mainly caused by two viruses: Andes virus and Sin Nombre virus. The disease has three phases: prodromal (early), cardiopulmonary, and recovery.

• #4 Hantavirus Infection – Infectious Diseases – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/infectious-diseases/arboviruses-arenaviridae-and-filoviridae/hantavirus-infection

  Hantavirus pulmonary syndrome (HPS) occurs in the United States, primarily in the southwestern states, Canada, primarily in western provinces, and in South America and Panama. It begins as a flu-like illness and, within days, causes noncardiogenic pulmonary edema. Diagnosis is with serologic tests and reverse transcriptasepolymerase chain reaction (RT-PCR). The more severe forms have a case fatality rate of up to 50%. Treatment is supportive. […] Hantavirus pulmonary syndrome begins as a nonspecific flu-like illness, with acute fever, myalgia, headache, and gastrointestinal symptoms. Two to 15 days later (median 4 days), patients rapidly develop noncardiogenic pulmonary edema and hypotension. […] Diagnosis of HPS is with serologic testing or reverse transcriptasePCR. […] Treatment of hantavirus pulmonary syndrome is supportive. Mechanical ventilation, meticulous volume control, and vasopressors may be required. For severe cardiopulmonary insufficiency, extracorporal mechanical oxygenation may be lifesaving. […] Patients with HPS who survive the first few days improve rapidly and recover completely over 2 to 3 weeks, often without sequelae. The more severe forms of HPS have a case fatality rate of up to 50%.

• #5 Hantavirus Pulmonary Syndrome – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK513243/

  Hantavirus pulmonary syndrome (HPS) is caused by viruses of the Orthohantavirus genus and the Hantaviridae family. […] The course explores the latest research findings, providing insights into the pathophysiology of HPS and the mechanisms underlying its severe respiratory compromise. […] Hantaviruses infect endothelial, epithelial, dendritic, and lymphocyte cells by attaching the viral glycoprotein to the cell surface receptors. […] Immature dendritic cells likely serve as carriers for the virus through lymphatic tissue and allow further viral replication once at the regional lymph nodes. […] Hantaviruses induce the maturation of infected dendritic cells and elicit a profound T-cell response in the acute infection phase, unlike other hemorrhagic fever viruses that inhibit dendritic cell maturation.

• #6 Human hantavirus infections: epidemiology, clinical features, pathogenesis and immunology

  https://smw.ch/index.php/smw/article/download/1844/2572?inline=1

  The primary target cells of hantavirus infection are endothelial cells of capillaries of various organs, primarily of the lung and kidneys, although infection occurs in a variety of other organs and cell types (endothelial and epithelial cells, macrophages, follicular dendritic cells, lymphocytes, neutrophils and platelets). The main receptor in endothelial cells for pathogenic hantavirus is beta-3-integrin. Infection is followed by impairment of the barrier function of endothelial cells, fluid extravasation and subsequent organ failure. However, although appearance of neutralising antibodies (NAbs) seems to impair the development of disease, the mechanisms for the so-called vascular leak are largely unknown. Notably, infection of endothelial cells by hantavirus is noncytopathic in vitro and in vivo, which has led to the hypothesis that a strong cellular immune response, elicited by cytotoxic CD8+ T cells, may be responsible for hantavirus pathogenesis in man. However, the absence of necrotic endothelial cells despite presence of inflammatory T cells in lung tissue of HCPS patients seemed to argue against T-cell mediated organ damage. A recent paper showing that the N-antigen of hantaviruses protects infected cells from caspase-3-dependent apoptosis may explain this discordant finding. In line with the hypothesis of T-cell mediated immunopathogenesis, early studies in a small number of acute HCPS patients (with SNV infection) pointed towards human leucocyte antigen (HLA) B*35 as a risk factor for a severe HCPS outcome.

• #7 Hantavirus pulmonary syndrome – Wikipedia

  https://en.wikipedia.org/wiki/Hantavirus_pulmonary_syndrome

  Infection begins with 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. […] Pathogenic hantaviruses are able to 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.

• #8 Hantavirus Pulmonary Syndrome – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK513243/

  Critical adhesive receptors, beta-3 integrins, regulate platelet activation and vascular permeability and mediate hantaviruses’ cellular entry. […] Invasion of the endothelium is believed to induce interferon-alpha (IFN-), which is possibly the cause of the prodromal manifestations. […] Once the infection has progressed, immunoblasts may be seen in the peripheral blood smear. […] Capillary endothelial permeability greatly increases after the secretion of tumor necrosis factor-alpha (TNF-), IFN-, and nitric oxide, which results in pulmonary edema. […] Increased viral RNA causes a cytokine storm, ultimately leading to vascular permeability and pulmonary edema. […] Pathophysiology of HPS includes the following: Inhalation of the infectious virus can result in viral deposition in the alveoli or terminal bronchioles. Viremia is likely generated after infection of alveolar macrophages or other primary targets, resulting in widespread infection of the pulmonary capillary endothelium. […] Replication within the vascular endothelium does not have direct cytopathic effects. Instead, tissue injury appears due to the immune response and viral replication. […] Upon the development of pulmonary edema, multiorgan failure may ensue.

• #9

  https://link.springer.com/article/10.1007/s11908-001-0028-1

  Since the first outbreak of hantavirus pulmonary syndrome (HPS) in 1993, understanding of the vast distribution and potential impact of hantaviruses has grown. […] New research has identified the -3 integrins as cellular receptors for hantaviruses and has determined the pivotal role of the immune system in pathogenesis. […] This study identifies the b-3 integrins as the cellular receptors for hantaviruses and investigates the roles of different integrins in facilitating the entry of pathogenic versus nonpathogenic strains of hantavirus. […] Peters CJ, Simpson GL, Levy H: Spectrum of hantavirus infection: hemorrhagic fever with renal syndrome and hantavirus pulmonary syndrome. This is an excellent review of the clinical spectrum of disease and pathogenesis of hantaviral infections.

• #10 Orthohantavirus – Wikipedia

  https://en.wikipedia.org/wiki/Orthohantavirus

  Attachment and entry into the host cell is mediated by the binding of the viral glycoprotein spikes to host cell receptors, particularly 3 integrins. […] 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, which initiates transcription and replication by RdRp.

• #11 Hantavirus Pulmonary Syndrome – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK513243/

  Hantavirus pulmonary syndrome (HPS) is caused by viruses of the Orthohantavirus genus and the Hantaviridae family. […] The course explores the latest research findings, providing insights into the pathophysiology of HPS and the mechanisms underlying its severe respiratory compromise. […] Hantaviruses infect endothelial, epithelial, dendritic, and lymphocyte cells by attaching the viral glycoprotein to the cell surface receptors. […] Immature dendritic cells likely serve as carriers for the virus through lymphatic tissue and allow further viral replication once at the regional lymph nodes. […] Hantaviruses induce the maturation of infected dendritic cells and elicit a profound T-cell response in the acute infection phase, unlike other hemorrhagic fever viruses that inhibit dendritic cell maturation.

• #12 Hantavirus Pulmonary Syndrome – MD Searchlight

  https://mdsearchlight.com/infectious-disease/hantavirus-pulmonary-syndrome/

  Immature cells, specifically dendritic ones, likely act as transporters for the virus into lymphatic tissue and further facilitate the replication of the virus in regional lymph nodes. […] Important receptors, called beta-3 integrins, regulate platelet activation and vessels permeability and aid hantaviruses entry into the cells. […] Invasion of the interior lining of the vessels by the virus likely causes the production of interferon-alpha (IFN-), which could be why prodromal symptoms appear. […] As the infection progresses, specific immune cells called immunoblasts might be seen in a blood smear. T cells become hantavirus-specific. […] Increase in capillary endothelial permeability follows after secretion of substances like tumor necrosis factor-alpha (TNF-), IFN-, and nitric oxide, resulting in fluid buildup in the lungs. […] These same mediators are speculated to cause heart muscle depression in this infection, which results in a state of shock where the heart isnt pumping enough blood to meet the bodys needs.

• #13 Hantavirus Pulmonary Syndrome – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK513243/

  Hantavirus pulmonary syndrome (HPS) is caused by viruses of the Orthohantavirus genus and the Hantaviridae family. […] The course explores the latest research findings, providing insights into the pathophysiology of HPS and the mechanisms underlying its severe respiratory compromise. […] Hantaviruses infect endothelial, epithelial, dendritic, and lymphocyte cells by attaching the viral glycoprotein to the cell surface receptors. […] Immature dendritic cells likely serve as carriers for the virus through lymphatic tissue and allow further viral replication once at the regional lymph nodes. […] Hantaviruses induce the maturation of infected dendritic cells and elicit a profound T-cell response in the acute infection phase, unlike other hemorrhagic fever viruses that inhibit dendritic cell maturation.

• #14 Pathogenesis of the hantavirus pulmonary syndrome – ProQuest

  https://www.proquest.com/scholarly-journals/pathogenesis-hantavirus-pulmonary-syndrome/docview/912286203/se-2

  Human diseases caused by hantaviruses (HVs) are vascular leak syndromes with variations in disease severity and manifestations dependent on the virus strain. […] Pathogenesis must account for three key features of the disease: an organ with a capillary leak; temporal progression; and the fact that this capillary leak syndrome is the most severe observed in clinical medicine. […] The disease progresses as four sequential phases, denoted as the febrile prodrome, cardiopulmonary, diuretic, and convalescent phases.

• #15 Hantavirus Pulmonary Syndrome—The 25th Anniversary of the Four Corners Outbreak – Volume 24, Number 11—November 2018 – Emerging Infectious Diseases journal – CDC

  https://wwwnc.cdc.gov/eid/article/24/11/18-0381_article

  During the spring of 1993, a mysterious respiratory disease struck the Four Corners region of the southwestern United States. […] In the ensuing 25 years, the epidemiology, virology, pathophysiology, clinical course, and treatment of hantavirus pulmonary syndrome have been the focus of ongoing research. […] The virus has a remarkable predilection for pulmonary capillary endothelial cells and a complex and still poorly understood pathogenesis. Infection by inhalation is followed by an incubation period of 15 weeks. A 36-day prodromal period then occurs, during which patients first exhibit fever, with respiratory symptoms notably absent. The development of a cough signals the onset of the fulminant cardiopulmonary phase, which is characterized by severe capillary leak, extraordinary pulmonary edema, and myocardial depression, and lasts for up to 1 week. The current mortality rate during the cardiopulmonary phase is 40%.

• #16 Hantavirus Pulmonary Syndrome—The 25th Anniversary of the Four Corners Outbreak – Volume 24, Number 11—November 2018 – Emerging Infectious Diseases journal – CDC

  https://wwwnc.cdc.gov/eid/article/24/11/18-0381_article

  Most of the damage during the cardiopulmonary phase of HPS is directly related to cell-mediated immunity gone awry. […] During the incubation phase, there is a ubiquitous deposition of the virus within the pulmonary endothelium, with no associated changes in either the structural integrity or permeability of the microenvironment. […] During the relatively brief prodromal phase, circulating immunoblasts appear and humoral antibody is produced. It is during the cardiopulmonary phase that well-differentiated T cells appear on site and participate in the release of soluble mediators (among which tumor necrosis factor- is prominent); massive changes in pulmonary capillary endothelial cell permeability result. […] Fluid loss into the alveolar and pleural spaces is so voluminous that the heart becomes preload deprived and cardiac output decreases. The same soluble mediators are in part responsible for depression of myocardial contractility that often leads to frank cardiovascular collapse.

• #17 About Hantavirus | Hantavirus | CDC

  https://www.cdc.gov/hantavirus/about/index.html

  Hantaviruses can infect and cause serious disease in people worldwide. […] Hantaviruses cause two syndromes. Hantaviruses found in the Western Hemisphere, including here in the U.S., can cause hantavirus pulmonary syndrome (HPS). The most common hantavirus that causes HPS in the U.S. is spread by the deer mouse. […] HPS is a severe and potentially deadly disease that affects the lungs. Symptoms of HPS usually start to show 1 to 8 weeks after contact with an infected rodent. […] Four to 10 days after the initial phase of illness, the late symptoms of HPS appear. These symptoms include coughing and shortness of breath. Patients might experience tightness in the chest, as the lungs fill with fluid. […] HPS can be deadly. Thirty-eight percent of people who develop respiratory symptoms may die from the disease.

• #18 Hantavirus Pulmonary Syndrome—The 25th Anniversary of the Four Corners Outbreak – Volume 24, Number 11—November 2018 – Emerging Infectious Diseases journal – CDC

  https://wwwnc.cdc.gov/eid/article/24/11/18-0381_article

  During the spring of 1993, a mysterious respiratory disease struck the Four Corners region of the southwestern United States. […] In the ensuing 25 years, the epidemiology, virology, pathophysiology, clinical course, and treatment of hantavirus pulmonary syndrome have been the focus of ongoing research. […] The virus has a remarkable predilection for pulmonary capillary endothelial cells and a complex and still poorly understood pathogenesis. Infection by inhalation is followed by an incubation period of 15 weeks. A 36-day prodromal period then occurs, during which patients first exhibit fever, with respiratory symptoms notably absent. The development of a cough signals the onset of the fulminant cardiopulmonary phase, which is characterized by severe capillary leak, extraordinary pulmonary edema, and myocardial depression, and lasts for up to 1 week. The current mortality rate during the cardiopulmonary phase is 40%.

• #19 Hantavirus Pulmonary Syndrome—The 25th Anniversary of the Four Corners Outbreak – Volume 24, Number 11—November 2018 – Emerging Infectious Diseases journal – CDC

  https://wwwnc.cdc.gov/eid/article/24/11/18-0381_article

  Most of the damage during the cardiopulmonary phase of HPS is directly related to cell-mediated immunity gone awry. […] During the incubation phase, there is a ubiquitous deposition of the virus within the pulmonary endothelium, with no associated changes in either the structural integrity or permeability of the microenvironment. […] During the relatively brief prodromal phase, circulating immunoblasts appear and humoral antibody is produced. It is during the cardiopulmonary phase that well-differentiated T cells appear on site and participate in the release of soluble mediators (among which tumor necrosis factor- is prominent); massive changes in pulmonary capillary endothelial cell permeability result. […] Fluid loss into the alveolar and pleural spaces is so voluminous that the heart becomes preload deprived and cardiac output decreases. The same soluble mediators are in part responsible for depression of myocardial contractility that often leads to frank cardiovascular collapse.

• #20 Hantavirus Pulmonary Syndrome—The 25th Anniversary of the Four Corners Outbreak – Volume 24, Number 11—November 2018 – Emerging Infectious Diseases journal – CDC

  https://wwwnc.cdc.gov/eid/article/24/11/18-0381_article

  During the spring of 1993, a mysterious respiratory disease struck the Four Corners region of the southwestern United States. […] In the ensuing 25 years, the epidemiology, virology, pathophysiology, clinical course, and treatment of hantavirus pulmonary syndrome have been the focus of ongoing research. […] The virus has a remarkable predilection for pulmonary capillary endothelial cells and a complex and still poorly understood pathogenesis. Infection by inhalation is followed by an incubation period of 15 weeks. A 36-day prodromal period then occurs, during which patients first exhibit fever, with respiratory symptoms notably absent. The development of a cough signals the onset of the fulminant cardiopulmonary phase, which is characterized by severe capillary leak, extraordinary pulmonary edema, and myocardial depression, and lasts for up to 1 week. The current mortality rate during the cardiopulmonary phase is 40%.

• #21 Hantavirus Pulmonary Syndrome—The 25th Anniversary of the Four Corners Outbreak – Volume 24, Number 11—November 2018 – Emerging Infectious Diseases journal – CDC

  https://wwwnc.cdc.gov/eid/article/24/11/18-0381_article

  Most of the damage during the cardiopulmonary phase of HPS is directly related to cell-mediated immunity gone awry. […] During the incubation phase, there is a ubiquitous deposition of the virus within the pulmonary endothelium, with no associated changes in either the structural integrity or permeability of the microenvironment. […] During the relatively brief prodromal phase, circulating immunoblasts appear and humoral antibody is produced. It is during the cardiopulmonary phase that well-differentiated T cells appear on site and participate in the release of soluble mediators (among which tumor necrosis factor- is prominent); massive changes in pulmonary capillary endothelial cell permeability result. […] Fluid loss into the alveolar and pleural spaces is so voluminous that the heart becomes preload deprived and cardiac output decreases. The same soluble mediators are in part responsible for depression of myocardial contractility that often leads to frank cardiovascular collapse.

• #22 Hantavirus Infection – Infectious Diseases – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/infectious-diseases/arboviruses-arenaviridae-and-filoviridae/hantavirus-infection

  Hantavirus pulmonary syndrome (HPS) occurs in the United States, primarily in the southwestern states, Canada, primarily in western provinces, and in South America and Panama. It begins as a flu-like illness and, within days, causes noncardiogenic pulmonary edema. Diagnosis is with serologic tests and reverse transcriptasepolymerase chain reaction (RT-PCR). The more severe forms have a case fatality rate of up to 50%. Treatment is supportive. […] Hantavirus pulmonary syndrome begins as a nonspecific flu-like illness, with acute fever, myalgia, headache, and gastrointestinal symptoms. Two to 15 days later (median 4 days), patients rapidly develop noncardiogenic pulmonary edema and hypotension. […] Diagnosis of HPS is with serologic testing or reverse transcriptasePCR. […] Treatment of hantavirus pulmonary syndrome is supportive. Mechanical ventilation, meticulous volume control, and vasopressors may be required. For severe cardiopulmonary insufficiency, extracorporal mechanical oxygenation may be lifesaving. […] Patients with HPS who survive the first few days improve rapidly and recover completely over 2 to 3 weeks, often without sequelae. The more severe forms of HPS have a case fatality rate of up to 50%.

• #23 Pathogenesis of the hantavirus pulmonary syndrome – ProQuest

  https://www.proquest.com/scholarly-journals/pathogenesis-hantavirus-pulmonary-syndrome/docview/912286203/se-2

  Human diseases caused by hantaviruses (HVs) are vascular leak syndromes with variations in disease severity and manifestations dependent on the virus strain. […] Pathogenesis must account for three key features of the disease: an organ with a capillary leak; temporal progression; and the fact that this capillary leak syndrome is the most severe observed in clinical medicine. […] The disease progresses as four sequential phases, denoted as the febrile prodrome, cardiopulmonary, diuretic, and convalescent phases.

• #24 Pathophysiology of hantavirus pulmonary syndrome in rhesus macaques

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4024883/

  Hantavirus pulmonary syndrome (HPS) is a rare but often fatal disease caused by infection with New World hantaviruses. […] In this study we describe the characterization of a novel nonhuman primate model of HPS. […] Viremia and hematological abnormalities were the earliest markers of ensuing disease, and the hyperpermeability associated with the onset of respiratory distress coincided with dysregulation of host responses exclusively in the pulmonary endothelium. […] Here we show that rhesus macaques infected with Sin Nombre virus (SNV), the primary etiological agent of HPS in North America, propagated in deer mice develop HPS, which is characterized by thrombocytopenia, leukocytosis, and rapid onset of respiratory distress caused by severe interstitial pneumonia. […] Despite establishing a systemic infection, SNV differentially activated host responses exclusively in the pulmonary endothelium, potentially the mechanism leading to acute severe respiratory distress.

• #25 Hantavirus Pulmonary Syndrome—The 25th Anniversary of the Four Corners Outbreak – Volume 24, Number 11—November 2018 – Emerging Infectious Diseases journal – CDC

  https://wwwnc.cdc.gov/eid/article/24/11/18-0381_article

  Most of the damage during the cardiopulmonary phase of HPS is directly related to cell-mediated immunity gone awry. […] During the incubation phase, there is a ubiquitous deposition of the virus within the pulmonary endothelium, with no associated changes in either the structural integrity or permeability of the microenvironment. […] During the relatively brief prodromal phase, circulating immunoblasts appear and humoral antibody is produced. It is during the cardiopulmonary phase that well-differentiated T cells appear on site and participate in the release of soluble mediators (among which tumor necrosis factor- is prominent); massive changes in pulmonary capillary endothelial cell permeability result. […] Fluid loss into the alveolar and pleural spaces is so voluminous that the heart becomes preload deprived and cardiac output decreases. The same soluble mediators are in part responsible for depression of myocardial contractility that often leads to frank cardiovascular collapse.

• #26 Hantavirus Pulmonary Syndrome – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK513243/

  Critical adhesive receptors, beta-3 integrins, regulate platelet activation and vascular permeability and mediate hantaviruses’ cellular entry. […] Invasion of the endothelium is believed to induce interferon-alpha (IFN-), which is possibly the cause of the prodromal manifestations. […] Once the infection has progressed, immunoblasts may be seen in the peripheral blood smear. […] Capillary endothelial permeability greatly increases after the secretion of tumor necrosis factor-alpha (TNF-), IFN-, and nitric oxide, which results in pulmonary edema. […] Increased viral RNA causes a cytokine storm, ultimately leading to vascular permeability and pulmonary edema. […] Pathophysiology of HPS includes the following: Inhalation of the infectious virus can result in viral deposition in the alveoli or terminal bronchioles. Viremia is likely generated after infection of alveolar macrophages or other primary targets, resulting in widespread infection of the pulmonary capillary endothelium. […] Replication within the vascular endothelium does not have direct cytopathic effects. Instead, tissue injury appears due to the immune response and viral replication. […] Upon the development of pulmonary edema, multiorgan failure may ensue.

• #27 Hantavirus pulmonary syndrome – Wikipedia

  https://en.wikipedia.org/wiki/Hantavirus_pulmonary_syndrome

  Hantavirus pulmonary syndrome (HPS), also called hantavirus cardiopulmonary syndrome (HCPS), is a severe respiratory disease caused by hantaviruses. The main features of illness are microvascular leakage and acute respiratory distress syndrome. […] Vascular endothelial cells and macrophages are the primary cells infected by hantaviruses, and infection causes abnormalities with blood clotting, all of which results in fluid leakage responsible for the more severe symptoms. […] The main cause of illness is increased vascular permeability, decreased platelet count, and overreaction by the immune system. The increased vascular permeability appears to be the result of infected cells producing vascular endothelial growth factor (VEGF), which activate VEGFR2 receptors on endothelial cells, which increases paracellular permeability.

• #28 Hantavirus Pulmonary Syndrome – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK513243/

  Critical adhesive receptors, beta-3 integrins, regulate platelet activation and vascular permeability and mediate hantaviruses’ cellular entry. […] Invasion of the endothelium is believed to induce interferon-alpha (IFN-), which is possibly the cause of the prodromal manifestations. […] Once the infection has progressed, immunoblasts may be seen in the peripheral blood smear. […] Capillary endothelial permeability greatly increases after the secretion of tumor necrosis factor-alpha (TNF-), IFN-, and nitric oxide, which results in pulmonary edema. […] Increased viral RNA causes a cytokine storm, ultimately leading to vascular permeability and pulmonary edema. […] Pathophysiology of HPS includes the following: Inhalation of the infectious virus can result in viral deposition in the alveoli or terminal bronchioles. Viremia is likely generated after infection of alveolar macrophages or other primary targets, resulting in widespread infection of the pulmonary capillary endothelium. […] Replication within the vascular endothelium does not have direct cytopathic effects. Instead, tissue injury appears due to the immune response and viral replication. […] Upon the development of pulmonary edema, multiorgan failure may ensue.

• #29 T Cells and Pathogenesis of Hantavirus Cardiopulmonary Syndrome and Hemorrhagic Fever with Renal Syndrome

  https://www.mdpi.com/1999-4915/3/7/1059

  There are observations suggesting immune-mediated mechanisms in the pathogenesis of the HCPS and HFRS. […] The cytokines detected include tumor necrosis factor (TNF)-α, interleukin (IL)-2, IL-6 and interferon (IFN)-γ, which are produced by T cells and may mediate capillary leakage. […] In vivo the main mechanism for increased permeability may be the release of cytokines, such as TNF-α, by the virus-specific CD8+ T cells rather than direct lysis of endothelial cells. […] In both HCPS and HFRS, CD8+ T cell responses are essential for elimination of virus-infected cells and viral clearance. […] Both too strong and too weak T cell responses may lead to severe disease. […] It is important to clarify the role of T cells in these diseases for better treatment (whether to suppress T cell functions) and protection (vaccine design) which may need to take into account viral factors and the influence of HLA on T cell responses.

• #30 Hantavirus pulmonary syndrome – Wikipedia

  https://en.wikipedia.org/wiki/Hantavirus_pulmonary_syndrome

  Hantavirus pulmonary syndrome (HPS), also called hantavirus cardiopulmonary syndrome (HCPS), is a severe respiratory disease caused by hantaviruses. The main features of illness are microvascular leakage and acute respiratory distress syndrome. […] Vascular endothelial cells and macrophages are the primary cells infected by hantaviruses, and infection causes abnormalities with blood clotting, all of which results in fluid leakage responsible for the more severe symptoms. […] The main cause of illness is increased vascular permeability, decreased platelet count, and overreaction by the immune system. The increased vascular permeability appears to be the result of infected cells producing vascular endothelial growth factor (VEGF), which activate VEGFR2 receptors on endothelial cells, which increases paracellular permeability.

• #31 Uncovering the mysteries of hantavirus infections | Nature Reviews Microbiology

  https://www.nature.com/articles/nrmicro3066?page=6

  Hantaviruses primarily replicate in the endothelium and might use integrins to enter cells. Following entry, the virus synthesizes viral mRNA to produce viral proteins and replicate the genome (comprising small, medium and large segments), although the exact details of these processes remain unclear. […] Disease pathology is characterized by increased permeability of the endothelial cells lining capillaries and is also thought to be mediated by enhanced immune responses, such as increased production of cytokines and expansion of cytotoxic T cells. […] Hantavirus regulation of endothelial cell functions. […] Hantaviruses direct endothelial cell permeability by sensitizing cells to the vascular permeability factor VEGF, while angiopoietin 1 and sphingosine 1-phosphate inhibit hantavirus-directed permeability.

• #32 Endothelial Cell Permeability during Hantavirus Infection Involves Factor XII-Dependent Increased Activation of the Kallikrein-Kinin System | PLOS Pathogens

  https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1003470

  Hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS) are diseases caused by hantavirus infections and are characterized by vascular leakage due to alterations of the endothelial barrier. […] Hantavirus-infected endothelial cells (EC) display no overt cytopathology; consequently, pathogenesis models have focused either on the influx of immune cells and release of cytokines or on increased degradation of the adherens junction protein, vascular endothelial (VE)-cadherin, due to hantavirus-mediated hypersensitization of EC to vascular endothelial growth factor (VEGF). […] Here, we present evidence for a novel mechanism of hantavirus-induced vascular leakage involving activation of the plasma kallikrein-kinin system (KKS). […] We show that incubation of factor XII (FXII), prekallikrein (PK), and high molecular weight kininogen (HK) plasma proteins with hantavirus-infected EC results in increased cleavage of HK, higher enzymatic activities of FXIIa/kallikrein (KAL) and increased liberation of bradykinin (BK).

• #33 Capillary leak-syndrome triggered by Maripa virus in French Guiana: case report and implication for pathogenesis | BMC Infectious Diseases | Full Text

  https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-019-3887-5

  Bradykinin, a potent inflammatory and vasoactive nonapeptide generated by kallikrein at the sites of tissue injury is supposed to be the key mediator of the vascular leakage resulting from hantavirus infection. […] We conclude that HPS secondary to Maripa virus infection in French Guiana can cause severe damages leading to Multi Organ Failure. The severity of the disease may be explained by a dysregulated inflammatory and immune reaction causing a severe capillary leakage without cardiac involvement.

• #34 Hantavirus Pulmonary Syndrome – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK513243/

  Critical adhesive receptors, beta-3 integrins, regulate platelet activation and vascular permeability and mediate hantaviruses’ cellular entry. […] Invasion of the endothelium is believed to induce interferon-alpha (IFN-), which is possibly the cause of the prodromal manifestations. […] Once the infection has progressed, immunoblasts may be seen in the peripheral blood smear. […] Capillary endothelial permeability greatly increases after the secretion of tumor necrosis factor-alpha (TNF-), IFN-, and nitric oxide, which results in pulmonary edema. […] Increased viral RNA causes a cytokine storm, ultimately leading to vascular permeability and pulmonary edema. […] Pathophysiology of HPS includes the following: Inhalation of the infectious virus can result in viral deposition in the alveoli or terminal bronchioles. Viremia is likely generated after infection of alveolar macrophages or other primary targets, resulting in widespread infection of the pulmonary capillary endothelium. […] Replication within the vascular endothelium does not have direct cytopathic effects. Instead, tissue injury appears due to the immune response and viral replication. […] Upon the development of pulmonary edema, multiorgan failure may ensue.

• #35 Endothelial Cell Permeability during Hantavirus Infection Involves Factor XII-Dependent Increased Activation of the Kallikrein-Kinin System | PLOS Pathogens

  https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1003470

  Hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS) are diseases caused by hantavirus infections and are characterized by vascular leakage due to alterations of the endothelial barrier. […] Hantavirus-infected endothelial cells (EC) display no overt cytopathology; consequently, pathogenesis models have focused either on the influx of immune cells and release of cytokines or on increased degradation of the adherens junction protein, vascular endothelial (VE)-cadherin, due to hantavirus-mediated hypersensitization of EC to vascular endothelial growth factor (VEGF). […] Here, we present evidence for a novel mechanism of hantavirus-induced vascular leakage involving activation of the plasma kallikrein-kinin system (KKS). […] We show that incubation of factor XII (FXII), prekallikrein (PK), and high molecular weight kininogen (HK) plasma proteins with hantavirus-infected EC results in increased cleavage of HK, higher enzymatic activities of FXIIa/kallikrein (KAL) and increased liberation of bradykinin (BK).

• #36 Human hantavirus infections: epidemiology, clinical features, pathogenesis and immunology

  https://smw.ch/index.php/smw/article/download/1844/2572?inline=1

  The primary target cells of hantavirus infection are endothelial cells of capillaries of various organs, primarily of the lung and kidneys, although infection occurs in a variety of other organs and cell types (endothelial and epithelial cells, macrophages, follicular dendritic cells, lymphocytes, neutrophils and platelets). The main receptor in endothelial cells for pathogenic hantavirus is beta-3-integrin. Infection is followed by impairment of the barrier function of endothelial cells, fluid extravasation and subsequent organ failure. However, although appearance of neutralising antibodies (NAbs) seems to impair the development of disease, the mechanisms for the so-called vascular leak are largely unknown. Notably, infection of endothelial cells by hantavirus is noncytopathic in vitro and in vivo, which has led to the hypothesis that a strong cellular immune response, elicited by cytotoxic CD8+ T cells, may be responsible for hantavirus pathogenesis in man. However, the absence of necrotic endothelial cells despite presence of inflammatory T cells in lung tissue of HCPS patients seemed to argue against T-cell mediated organ damage. A recent paper showing that the N-antigen of hantaviruses protects infected cells from caspase-3-dependent apoptosis may explain this discordant finding. In line with the hypothesis of T-cell mediated immunopathogenesis, early studies in a small number of acute HCPS patients (with SNV infection) pointed towards human leucocyte antigen (HLA) B*35 as a risk factor for a severe HCPS outcome.

• #37 Capillary leak-syndrome triggered by Maripa virus in French Guiana: case report and implication for pathogenesis | BMC Infectious Diseases | Full Text

  https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-019-3887-5

  We report hereby a severe case of Hantavirus Pulmonary Syndrome (HPS) induced by Maripa virus in French Guiana and describe the mechanism of severity of the human disease. […] The severity of HPS caused by the virus Maripa in French Guiana can be explained by the tropism of hantavirus for the microvascular endothelial cell leading to a CLS. […] The mechanism which may explain the severity of the disease is the tropism of hantavirus for the microvascular endothelial cell. […] This tropism causes microvascular hyperpermeability with fluid and proteins leakage leading to hypovolemia and to a non cardiogenic pulmonary oedema. […] The pathogenesis of capillary leakage remains undefined. Some evidence suggest that hantavirus disease pathogenesis is immunologically mediated by cytotoxic T lymphocytes and other immune cells in target organs producing inflammatory cytokines. Overall, three hypotheses have been reported to explain the mechanism of increased capillary permeability involved in hantavirus infection: a) the attack of infected endothelial cells by virus-specific cytotoxic T lymphocytes (CTLs), b) TNF- production by infected monocyte/macrophages and finally c) the direct effect of the virus on the endothelial cell functions.

• #38 Hantavirus Pulmonary Syndrome—The 25th Anniversary of the Four Corners Outbreak – Volume 24, Number 11—November 2018 – Emerging Infectious Diseases journal – CDC

  https://wwwnc.cdc.gov/eid/article/24/11/18-0381_article

  Most of the damage during the cardiopulmonary phase of HPS is directly related to cell-mediated immunity gone awry. […] During the incubation phase, there is a ubiquitous deposition of the virus within the pulmonary endothelium, with no associated changes in either the structural integrity or permeability of the microenvironment. […] During the relatively brief prodromal phase, circulating immunoblasts appear and humoral antibody is produced. It is during the cardiopulmonary phase that well-differentiated T cells appear on site and participate in the release of soluble mediators (among which tumor necrosis factor- is prominent); massive changes in pulmonary capillary endothelial cell permeability result. […] Fluid loss into the alveolar and pleural spaces is so voluminous that the heart becomes preload deprived and cardiac output decreases. The same soluble mediators are in part responsible for depression of myocardial contractility that often leads to frank cardiovascular collapse.

• #39 Hantavirus pulmonary syndrome – Wikipedia

  https://en.wikipedia.org/wiki/Hantavirus_pulmonary_syndrome

  Infection begins with 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. […] Pathogenic hantaviruses are able to 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.

• #40 Human hantavirus infections: epidemiology, clinical features, pathogenesis and immunology

  https://smw.ch/index.php/smw/article/download/1844/2572?inline=1

  As cellular immune responses may not be sufficient to explain hantavirus pathogenesis, mechanisms based on direct virus-cell interactions come more into focus. In this regard, important contributions come from the group of Mackow et al., who compared pathogenic and nonpathogenic hantaviruses. Whereas pathogenic hantaviruses seem to inhibit innate type I interferon (IFN) responses by infected cells, nonpathogenic viruses, such as Prospect Hill virus, are not capable of doing so. This may be relevant for the pathogenicity of hantaviral infections, since IFN-beta protects from vascular leakage by upregulation of CD73 on endothelial cells. […] However, direct virus-cell interactions may not explain why onset of clinical symptoms occurs so late during infection, usually at a time-point when viral load is already falling, at least in plasma. Likewise, the aetiology of thrombocytopenia, a common feature in hantaviral diseases, is far from being clarified. Several authors have suggested that thrombocytopenia could be due to platelet consumption in response to the damage to the endothelial layer. Others suggested that this may be the direct consequence of the virus interaction with beta-3-integrin receptor on platelets.

• #41 Human hantavirus infections: epidemiology, clinical features, pathogenesis and immunology

  https://smw.ch/index.php/smw/article/download/1844/2572?inline=1

  The primary target cells of hantavirus infection are endothelial cells of capillaries of various organs, primarily of the lung and kidneys, although infection occurs in a variety of other organs and cell types (endothelial and epithelial cells, macrophages, follicular dendritic cells, lymphocytes, neutrophils and platelets). The main receptor in endothelial cells for pathogenic hantavirus is beta-3-integrin. Infection is followed by impairment of the barrier function of endothelial cells, fluid extravasation and subsequent organ failure. However, although appearance of neutralising antibodies (NAbs) seems to impair the development of disease, the mechanisms for the so-called vascular leak are largely unknown. Notably, infection of endothelial cells by hantavirus is noncytopathic in vitro and in vivo, which has led to the hypothesis that a strong cellular immune response, elicited by cytotoxic CD8+ T cells, may be responsible for hantavirus pathogenesis in man. However, the absence of necrotic endothelial cells despite presence of inflammatory T cells in lung tissue of HCPS patients seemed to argue against T-cell mediated organ damage. A recent paper showing that the N-antigen of hantaviruses protects infected cells from caspase-3-dependent apoptosis may explain this discordant finding. In line with the hypothesis of T-cell mediated immunopathogenesis, early studies in a small number of acute HCPS patients (with SNV infection) pointed towards human leucocyte antigen (HLA) B*35 as a risk factor for a severe HCPS outcome.

• #42 Hantavirus-infection Confers Resistance to Cytotoxic Lymphocyte-Mediated Apoptosis | PLOS Pathogens

  https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1003272

  Hantaviruses cause hemorrhagic fever with renal syndrome (HFRS) and hantavirus cardio-pulmonary syndrome (HCPS; also called hantavirus pulmonary syndrome (HPS)), both human diseases with high case-fatality rates. […] An intriguing observation in patients with HFRS and HCPS is that on one hand the virus infection leads to strong activation of CD8 T cells and NK cells, on the other hand no obvious destruction of infected endothelial cells is observed. […] Here, we provide an explanation for this dichotomy by showing that hantavirus-infected endothelial cells are protected from cytotoxic lymphocyte-mediated induction of apoptosis. […] When dissecting potential mechanisms behind this phenomenon, we discovered that the hantavirus nucleocapsid protein inhibits the enzymatic activity of both granzyme B and caspase 3.

• #43 Hantavirus-infection Confers Resistance to Cytotoxic Lymphocyte-Mediated Apoptosis | PLOS Pathogens

  https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1003272

  This provides a tentative explanation for the hantavirus-mediated block of cytotoxic granule-mediated apoptosis-induction, and hence the protection of infected cells from cytotoxic lymphocytes. […] These findings may explain why infected endothelial cells in hantavirus-infected patients are not destroyed by the strong cytotoxic lymphocyte response. […] Here, we show that hantaviruses protect infected endothelial cells from being killed by cytotoxic lymphocytes. […] Hantaviruses inhibit apoptosis in general. […] Interestingly, the nucleocapsid protein was shown to inhibit the enzymatic functions of both granzyme B and caspase 3, two enzymes crucial for cytotoxic lymphocyte-mediated killing of virus-infected cells. […] The finding that hantaviruses inhibited cytotoxic lymphocyte-mediated cell death downstream of degranulation suggested the possibility that these viruses interfere with induction of apoptosis in infected cells.

• #44 Hantavirus Infections in Light of Current Knowledge – Mediterranean Journal of Infection Microbes and Antimicrobials

  https://mjima.org/articles/hantavirus-infections-in-light-of-current-knowledge/doi/mjima.2017.16

  Genetic factors are known to play a role in susceptibility to infection, and some HLA types have been associated with more severe disease course. […] A study by Papa et al. demonstrated the relationship between disease severity and plasma and urine levels of vascular endothelial growth factor (VEGF) and soluble vascular endothelial growth factor receptor 2 (sVEGFR2) in PUUV and DOBV infections, highlighting the dual roles of these molecules in pathogenesis. […] Another study conducted in Sweden reported that the strong inhibition of human umbilical vein endothelial cells due to induction of apoptosis is an important pathogenic mechanism. […] A German study focused on the significance of neutrophil activation and CD8+ T cells in pathogenesis. […] The authors state that acceleration and aggregation of functional CD8+ T cells in particular causes hantavirus-related disease. […] Nucleocapsid proteins control endothelial cell permeability response by interacting with the TSC2 (tuberous sclerosis complex) and Rac/RhoA regulatory proteins.

• #45 Human hantavirus infections: epidemiology, clinical features, pathogenesis and immunology

  https://smw.ch/index.php/smw/article/download/1844/2572?inline=1

  The primary target cells of hantavirus infection are endothelial cells of capillaries of various organs, primarily of the lung and kidneys, although infection occurs in a variety of other organs and cell types (endothelial and epithelial cells, macrophages, follicular dendritic cells, lymphocytes, neutrophils and platelets). The main receptor in endothelial cells for pathogenic hantavirus is beta-3-integrin. Infection is followed by impairment of the barrier function of endothelial cells, fluid extravasation and subsequent organ failure. However, although appearance of neutralising antibodies (NAbs) seems to impair the development of disease, the mechanisms for the so-called vascular leak are largely unknown. Notably, infection of endothelial cells by hantavirus is noncytopathic in vitro and in vivo, which has led to the hypothesis that a strong cellular immune response, elicited by cytotoxic CD8+ T cells, may be responsible for hantavirus pathogenesis in man. However, the absence of necrotic endothelial cells despite presence of inflammatory T cells in lung tissue of HCPS patients seemed to argue against T-cell mediated organ damage. A recent paper showing that the N-antigen of hantaviruses protects infected cells from caspase-3-dependent apoptosis may explain this discordant finding. In line with the hypothesis of T-cell mediated immunopathogenesis, early studies in a small number of acute HCPS patients (with SNV infection) pointed towards human leucocyte antigen (HLA) B*35 as a risk factor for a severe HCPS outcome.

• #46 Human hantavirus infections: epidemiology, clinical features, pathogenesis and immunology

  https://smw.ch/index.php/smw/article/download/1844/2572?inline=1

  The primary target cells of hantavirus infection are endothelial cells of capillaries of various organs, primarily of the lung and kidneys, although infection occurs in a variety of other organs and cell types (endothelial and epithelial cells, macrophages, follicular dendritic cells, lymphocytes, neutrophils and platelets). The main receptor in endothelial cells for pathogenic hantavirus is beta-3-integrin. Infection is followed by impairment of the barrier function of endothelial cells, fluid extravasation and subsequent organ failure. However, although appearance of neutralising antibodies (NAbs) seems to impair the development of disease, the mechanisms for the so-called vascular leak are largely unknown. Notably, infection of endothelial cells by hantavirus is noncytopathic in vitro and in vivo, which has led to the hypothesis that a strong cellular immune response, elicited by cytotoxic CD8+ T cells, may be responsible for hantavirus pathogenesis in man. However, the absence of necrotic endothelial cells despite presence of inflammatory T cells in lung tissue of HCPS patients seemed to argue against T-cell mediated organ damage. A recent paper showing that the N-antigen of hantaviruses protects infected cells from caspase-3-dependent apoptosis may explain this discordant finding. In line with the hypothesis of T-cell mediated immunopathogenesis, early studies in a small number of acute HCPS patients (with SNV infection) pointed towards human leucocyte antigen (HLA) B*35 as a risk factor for a severe HCPS outcome.

• #47 Pathophysiology of hantavirus pulmonary syndrome in rhesus macaques

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4024883/

  This study presents a unique chronological characterization of SNV infection and provides mechanistic data into the pathophysiology of HPS in a closely related surrogate animal model. […] Our results identified a unique combination of virus replication, hematological abnormalities (thrombocytopenia, neutrophilia, eosinophilia, and monocytosis), and the development of uncontrolled, tissue-specific proinflammatory host responses as the mechanisms of HPS pathogenesis. […] The timing of these key parameters overlaps with the rapid progression from minor respiratory disease to severe respiratory distress, which is the hallmark of the cardiopulmonary phase of HPS, and supports their role in the hyperpermeability associated with late-stage disease. […] Viremia was the earliest indicator of disease and was first detected 4-10 d before the onset of respiratory distress and immediately before the observed hematological abnormalities and activated host immune responses. […] The NHP model will help in the future to establish more reliable markers for early treatment against hantavirus infections.

• #48 Hantavirus Pulmonary Syndrome—The 25th Anniversary of the Four Corners Outbreak – Volume 24, Number 11—November 2018 – Emerging Infectious Diseases journal – CDC

  https://wwwnc.cdc.gov/eid/article/24/11/18-0381_article

  A distinctive hematologic laboratory profile offers clues to the diagnosis of HPS. […] Definitive diagnosis of hantavirus infection relies on serologic testing for IgM and IgG, which is highly sensitive and specific, but because of travel times to laboratories performing the assay, it takes 72 hours in most cases to provide results. […] Treatment of HPS is challenging. Because of the severity of endothelial leakage, fluid resuscitation can lead to worsening pulmonary edema. […] HPS is a disease of healthy young persons who have a history of rodent exposure, usually at home or at work. A laboratory examination that demonstrates hemoconcentration, or the presence of immunoblasts on a peripheral blood smear, should raise immediate clinical suspicion. Severe capillary leak with massive pulmonary edema is the hallmark finding of HPS.

• #49 Pathophysiology of hantavirus pulmonary syndrome in rhesus macaques

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4024883/

  This study presents a unique chronological characterization of SNV infection and provides mechanistic data into the pathophysiology of HPS in a closely related surrogate animal model. […] Our results identified a unique combination of virus replication, hematological abnormalities (thrombocytopenia, neutrophilia, eosinophilia, and monocytosis), and the development of uncontrolled, tissue-specific proinflammatory host responses as the mechanisms of HPS pathogenesis. […] The timing of these key parameters overlaps with the rapid progression from minor respiratory disease to severe respiratory distress, which is the hallmark of the cardiopulmonary phase of HPS, and supports their role in the hyperpermeability associated with late-stage disease. […] Viremia was the earliest indicator of disease and was first detected 4-10 d before the onset of respiratory distress and immediately before the observed hematological abnormalities and activated host immune responses. […] The NHP model will help in the future to establish more reliable markers for early treatment against hantavirus infections.

• #50 Human hantavirus infections: epidemiology, clinical features, pathogenesis and immunology

  https://smw.ch/index.php/smw/article/download/1844/2572?inline=1

  As cellular immune responses may not be sufficient to explain hantavirus pathogenesis, mechanisms based on direct virus-cell interactions come more into focus. In this regard, important contributions come from the group of Mackow et al., who compared pathogenic and nonpathogenic hantaviruses. Whereas pathogenic hantaviruses seem to inhibit innate type I interferon (IFN) responses by infected cells, nonpathogenic viruses, such as Prospect Hill virus, are not capable of doing so. This may be relevant for the pathogenicity of hantaviral infections, since IFN-beta protects from vascular leakage by upregulation of CD73 on endothelial cells. […] However, direct virus-cell interactions may not explain why onset of clinical symptoms occurs so late during infection, usually at a time-point when viral load is already falling, at least in plasma. Likewise, the aetiology of thrombocytopenia, a common feature in hantaviral diseases, is far from being clarified. Several authors have suggested that thrombocytopenia could be due to platelet consumption in response to the damage to the endothelial layer. Others suggested that this may be the direct consequence of the virus interaction with beta-3-integrin receptor on platelets.

• #51 Hantavirus Pulmonary Syndrome—The 25th Anniversary of the Four Corners Outbreak – Volume 24, Number 11—November 2018 – Emerging Infectious Diseases journal – CDC

  https://wwwnc.cdc.gov/eid/article/24/11/18-0381_article

  Most of the damage during the cardiopulmonary phase of HPS is directly related to cell-mediated immunity gone awry. […] During the incubation phase, there is a ubiquitous deposition of the virus within the pulmonary endothelium, with no associated changes in either the structural integrity or permeability of the microenvironment. […] During the relatively brief prodromal phase, circulating immunoblasts appear and humoral antibody is produced. It is during the cardiopulmonary phase that well-differentiated T cells appear on site and participate in the release of soluble mediators (among which tumor necrosis factor- is prominent); massive changes in pulmonary capillary endothelial cell permeability result. […] Fluid loss into the alveolar and pleural spaces is so voluminous that the heart becomes preload deprived and cardiac output decreases. The same soluble mediators are in part responsible for depression of myocardial contractility that often leads to frank cardiovascular collapse.

• #52 Hantavirus Pulmonary Syndrome—The 25th Anniversary of the Four Corners Outbreak – Volume 24, Number 11—November 2018 – Emerging Infectious Diseases journal – CDC

  https://wwwnc.cdc.gov/eid/article/24/11/18-0381_article

  Most of the damage during the cardiopulmonary phase of HPS is directly related to cell-mediated immunity gone awry. […] During the incubation phase, there is a ubiquitous deposition of the virus within the pulmonary endothelium, with no associated changes in either the structural integrity or permeability of the microenvironment. […] During the relatively brief prodromal phase, circulating immunoblasts appear and humoral antibody is produced. It is during the cardiopulmonary phase that well-differentiated T cells appear on site and participate in the release of soluble mediators (among which tumor necrosis factor- is prominent); massive changes in pulmonary capillary endothelial cell permeability result. […] Fluid loss into the alveolar and pleural spaces is so voluminous that the heart becomes preload deprived and cardiac output decreases. The same soluble mediators are in part responsible for depression of myocardial contractility that often leads to frank cardiovascular collapse.

• #53 Hantavirus Pulmonary Syndrome | Respiratory Therapy

  https://respiratory-therapy.com/disorders-diseases/infectious-diseases/influenza/hantavirus-pulmonary-syndrome/

  The pathogenesis of HPS is unclear, though hantavirus seems to exert a selective attraction of inflammatory cells to injured pulmonary epithelium (in this case, vascular). […] The site of initial infection is unknown, but hantavirus shows a preference for the pulmonary vasculature, thus explaining its respiratory manifestations. […] The lung tissues of HPS patients show heavy edema with serous fluid effusions and a marked increase in vascular permeability, while the respiratory epithelium remains intact. […] Airway distortion is seen in patients who survive the disease for a few days, and this is followed by a thickening of the alveolar septa due to an increased number of type I pneumocytes. […] There is no pneumocyte type II hyperplasia, but there are focal hyaline membranes. […] The pleural cavity is filled with yellow, serous fluid.

• #54 Hantavirus Pulmonary Syndrome | Respiratory Therapy

  https://respiratory-therapy.com/disorders-diseases/infectious-diseases/influenza/hantavirus-pulmonary-syndrome/

  The pathogenesis of HPS is unclear, though hantavirus seems to exert a selective attraction of inflammatory cells to injured pulmonary epithelium (in this case, vascular). […] The site of initial infection is unknown, but hantavirus shows a preference for the pulmonary vasculature, thus explaining its respiratory manifestations. […] The lung tissues of HPS patients show heavy edema with serous fluid effusions and a marked increase in vascular permeability, while the respiratory epithelium remains intact. […] Airway distortion is seen in patients who survive the disease for a few days, and this is followed by a thickening of the alveolar septa due to an increased number of type I pneumocytes. […] There is no pneumocyte type II hyperplasia, but there are focal hyaline membranes. […] The pleural cavity is filled with yellow, serous fluid.

• #55 Pathophysiology of hantavirus pulmonary syndrome in rhesus macaques

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4024883/

  Hantavirus pulmonary syndrome (HPS) is a rare but often fatal disease caused by infection with New World hantaviruses. […] In this study we describe the characterization of a novel nonhuman primate model of HPS. […] Viremia and hematological abnormalities were the earliest markers of ensuing disease, and the hyperpermeability associated with the onset of respiratory distress coincided with dysregulation of host responses exclusively in the pulmonary endothelium. […] Here we show that rhesus macaques infected with Sin Nombre virus (SNV), the primary etiological agent of HPS in North America, propagated in deer mice develop HPS, which is characterized by thrombocytopenia, leukocytosis, and rapid onset of respiratory distress caused by severe interstitial pneumonia. […] Despite establishing a systemic infection, SNV differentially activated host responses exclusively in the pulmonary endothelium, potentially the mechanism leading to acute severe respiratory distress.

• #56 Pathophysiology of hantavirus pulmonary syndrome in rhesus macaques

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4024883/

  This study presents a unique chronological characterization of SNV infection and provides mechanistic data into the pathophysiology of HPS in a closely related surrogate animal model. […] Our results identified a unique combination of virus replication, hematological abnormalities (thrombocytopenia, neutrophilia, eosinophilia, and monocytosis), and the development of uncontrolled, tissue-specific proinflammatory host responses as the mechanisms of HPS pathogenesis. […] The timing of these key parameters overlaps with the rapid progression from minor respiratory disease to severe respiratory distress, which is the hallmark of the cardiopulmonary phase of HPS, and supports their role in the hyperpermeability associated with late-stage disease. […] Viremia was the earliest indicator of disease and was first detected 4-10 d before the onset of respiratory distress and immediately before the observed hematological abnormalities and activated host immune responses. […] The NHP model will help in the future to establish more reliable markers for early treatment against hantavirus infections.

• #57 T cells are not required for pathogenesis in the Syrian hamster model of hantavirus pulmonary syndrome. | Sigma-Aldrich

  https://www.sigmaaldrich.com/ER/en/tech-docs/paper/601354?srsltid=AfmBOoox-BAcfwejoZeGIX4zFjB7DTfOxA_kL0gII_wfDPaPW88ZMoWT

  T cells are not required for pathogenesis in the Syrian hamster model of hantavirus pulmonary syndrome. […] The mechanism for the massive vascular leakage associated with HPS is poorly understood; however, T cell immunopathology has been implicated on the basis of circumstantial and corollary evidence. […] These data demonstrate, for the first time, that T cells are not required for hantavirus pathogenesis in the hamster model of human HPS. […] Moreover, these data argue for a mechanism of hantavirus-induced vascular permeability that does not involve T cell immunopathology.

• #58 Human hantavirus infections: epidemiology, clinical features, pathogenesis and immunology

  https://smw.ch/index.php/smw/article/download/1844/2572?inline=1

  As cellular immune responses may not be sufficient to explain hantavirus pathogenesis, mechanisms based on direct virus-cell interactions come more into focus. In this regard, important contributions come from the group of Mackow et al., who compared pathogenic and nonpathogenic hantaviruses. Whereas pathogenic hantaviruses seem to inhibit innate type I interferon (IFN) responses by infected cells, nonpathogenic viruses, such as Prospect Hill virus, are not capable of doing so. This may be relevant for the pathogenicity of hantaviral infections, since IFN-beta protects from vascular leakage by upregulation of CD73 on endothelial cells. […] However, direct virus-cell interactions may not explain why onset of clinical symptoms occurs so late during infection, usually at a time-point when viral load is already falling, at least in plasma. Likewise, the aetiology of thrombocytopenia, a common feature in hantaviral diseases, is far from being clarified. Several authors have suggested that thrombocytopenia could be due to platelet consumption in response to the damage to the endothelial layer. Others suggested that this may be the direct consequence of the virus interaction with beta-3-integrin receptor on platelets.

• #59 Human hantavirus infections: epidemiology, clinical features, pathogenesis and immunology

  https://smw.ch/index.php/smw/article/download/1844/2572?inline=1

  As cellular immune responses may not be sufficient to explain hantavirus pathogenesis, mechanisms based on direct virus-cell interactions come more into focus. In this regard, important contributions come from the group of Mackow et al., who compared pathogenic and nonpathogenic hantaviruses. Whereas pathogenic hantaviruses seem to inhibit innate type I interferon (IFN) responses by infected cells, nonpathogenic viruses, such as Prospect Hill virus, are not capable of doing so. This may be relevant for the pathogenicity of hantaviral infections, since IFN-beta protects from vascular leakage by upregulation of CD73 on endothelial cells. […] However, direct virus-cell interactions may not explain why onset of clinical symptoms occurs so late during infection, usually at a time-point when viral load is already falling, at least in plasma. Likewise, the aetiology of thrombocytopenia, a common feature in hantaviral diseases, is far from being clarified. Several authors have suggested that thrombocytopenia could be due to platelet consumption in response to the damage to the endothelial layer. Others suggested that this may be the direct consequence of the virus interaction with beta-3-integrin receptor on platelets.

• #60 Hantavirus Pulmonary Syndrome—The 25th Anniversary of the Four Corners Outbreak – Volume 24, Number 11—November 2018 – Emerging Infectious Diseases journal – CDC

  https://wwwnc.cdc.gov/eid/article/24/11/18-0381_article

  A distinctive hematologic laboratory profile offers clues to the diagnosis of HPS. […] Definitive diagnosis of hantavirus infection relies on serologic testing for IgM and IgG, which is highly sensitive and specific, but because of travel times to laboratories performing the assay, it takes 72 hours in most cases to provide results. […] Treatment of HPS is challenging. Because of the severity of endothelial leakage, fluid resuscitation can lead to worsening pulmonary edema. […] HPS is a disease of healthy young persons who have a history of rodent exposure, usually at home or at work. A laboratory examination that demonstrates hemoconcentration, or the presence of immunoblasts on a peripheral blood smear, should raise immediate clinical suspicion. Severe capillary leak with massive pulmonary edema is the hallmark finding of HPS.

• #61 Hantavirus Pulmonary Syndrome—The 25th Anniversary of the Four Corners Outbreak – Volume 24, Number 11—November 2018 – Emerging Infectious Diseases journal – CDC

  https://wwwnc.cdc.gov/eid/article/24/11/18-0381_article

  A distinctive hematologic laboratory profile offers clues to the diagnosis of HPS. […] Definitive diagnosis of hantavirus infection relies on serologic testing for IgM and IgG, which is highly sensitive and specific, but because of travel times to laboratories performing the assay, it takes 72 hours in most cases to provide results. […] Treatment of HPS is challenging. Because of the severity of endothelial leakage, fluid resuscitation can lead to worsening pulmonary edema. […] HPS is a disease of healthy young persons who have a history of rodent exposure, usually at home or at work. A laboratory examination that demonstrates hemoconcentration, or the presence of immunoblasts on a peripheral blood smear, should raise immediate clinical suspicion. Severe capillary leak with massive pulmonary edema is the hallmark finding of HPS.

• #62 Hantavirus Infection – Infectious Diseases – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/infectious-diseases/arboviruses-arenaviridae-and-filoviridae/hantavirus-infection

  Hantavirus pulmonary syndrome (HPS) occurs in the United States, primarily in the southwestern states, Canada, primarily in western provinces, and in South America and Panama. It begins as a flu-like illness and, within days, causes noncardiogenic pulmonary edema. Diagnosis is with serologic tests and reverse transcriptasepolymerase chain reaction (RT-PCR). The more severe forms have a case fatality rate of up to 50%. Treatment is supportive. […] Hantavirus pulmonary syndrome begins as a nonspecific flu-like illness, with acute fever, myalgia, headache, and gastrointestinal symptoms. Two to 15 days later (median 4 days), patients rapidly develop noncardiogenic pulmonary edema and hypotension. […] Diagnosis of HPS is with serologic testing or reverse transcriptasePCR. […] Treatment of hantavirus pulmonary syndrome is supportive. Mechanical ventilation, meticulous volume control, and vasopressors may be required. For severe cardiopulmonary insufficiency, extracorporal mechanical oxygenation may be lifesaving. […] Patients with HPS who survive the first few days improve rapidly and recover completely over 2 to 3 weeks, often without sequelae. The more severe forms of HPS have a case fatality rate of up to 50%.

• #63 About Hantavirus | Hantavirus | CDC

  https://www.cdc.gov/hantavirus/about/index.html

  There is no specific treatment for hantavirus infection. Patients should receive supportive care, including rest, hydration, and treatment of symptoms. […] HPS can cause breathing difficulties, and patients may need breathing support, such as intubation. Intubation is a medical procedure where a tube is placed in the lungs from the mouth to help the patient get oxygen.

• #64 Endothelial Cell Permeability during Hantavirus Infection Involves Factor XII-Dependent Increased Activation of the Kallikrein-Kinin System | PLOS Pathogens

  https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1003470

  Our data showing that HTNV and ANDV can alter enzyme activation of FXII and PK, cleavage of HK, and liberation of BK, led us to hypothesize that BK would induce profound changes to EC and increase vascular permeability. […] Our findings suggest the possibility of identifying multiple points of intervention using therapeutics.

• #65 Hantavirus Pulmonary Syndrome in the Spotlight: Understanding Risks After Betsy Arakawa’s Tragic Death | NETEC

  https://netec.org/2025/03/10/hantavirus-pulmonary-syndrome-in-the-spotlight-understanding-risks-after-betsy-arakawas-tragic-death/

  Because there is no specific antiviral treatment for HPS, early intensive medical care is essential. […] Most deaths occur within 24-48 hours after the onset of cardiopulmonary symptoms. […] Severe cases often have high levels of lactic acid in the blood and poor heart function. […] To minimize the risk of exposure to hantavirus, individuals should take the following measures: Open and air out buildings such as cabins and sheds, and other areas that may have provided shelter or food, before entering.

• #66 Hantavirus Pulmonary Syndrome in the Spotlight: Understanding Risks After Betsy Arakawa’s Tragic Death | NETEC

  https://netec.org/2025/03/10/hantavirus-pulmonary-syndrome-in-the-spotlight-understanding-risks-after-betsy-arakawas-tragic-death/

  Because there is no specific antiviral treatment for HPS, early intensive medical care is essential. […] Most deaths occur within 24-48 hours after the onset of cardiopulmonary symptoms. […] Severe cases often have high levels of lactic acid in the blood and poor heart function. […] To minimize the risk of exposure to hantavirus, individuals should take the following measures: Open and air out buildings such as cabins and sheds, and other areas that may have provided shelter or food, before entering.

• #67 Capillary leak-syndrome triggered by Maripa virus in French Guiana: case report and implication for pathogenesis | BMC Infectious Diseases | Full Text

  https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-019-3887-5

  Bradykinin, a potent inflammatory and vasoactive nonapeptide generated by kallikrein at the sites of tissue injury is supposed to be the key mediator of the vascular leakage resulting from hantavirus infection. […] We conclude that HPS secondary to Maripa virus infection in French Guiana can cause severe damages leading to Multi Organ Failure. The severity of the disease may be explained by a dysregulated inflammatory and immune reaction causing a severe capillary leakage without cardiac involvement.

• #68

  https://consensus.app/questions/what-symptoms-hantavirus-pulmonary-syndrome/

  Hantavirus pulmonary syndrome (HPS) is a severe respiratory disease caused by hantaviruses, which are transmitted to humans primarily through contact with infected rodent excreta. […] Hantavirus pulmonary syndrome (HPS) is a newly recognized, often fatal disease caused by a previously unrecognized hantavirus, and may be an important cause of severe and fatal adult respiratory distress syndrome. […] Hantavirus pulmonary syndrome (HPS) is a febrile illness characterized by bilateral interstitial pulmonary infiltrates and respiratory compromise, often requiring supplemental oxygen and resembling acute respiratory disease syndrome (ARDS). […] Hantaviruses cause hemorrhagic fever with renal syndrome and hantavirus pulmonary syndrome, both immunopathologic diseases involving inflammatory mediators. […] Hantavirus pulmonary syndrome (HPS) is a fatal viral zoonosis caused by three newly identified hantaviruses, with a febrile prodrome and severe noncardiogenic pulmonary edema.

• #69 Case Study 17: Hantavirus Pulmonary Syndrome: A Clinical Description of 17 Patients with a Newly Recognized Disease | Environmental Medicine: Integrating a Missing Element into Medical Education | The National Academies Press

  https://nap.nationalacademies.org/read/4795/chapter/29

  Infection with a newly described hantavirus causes the hantavirus pulmonary syndrome, which is characterized by a brief prodromal illness followed by rapidly progressive, noncardiogenic pulmonary edema. […] The most likely explanation for the pulmonary findings is an increased permeability of the pulmonary capillaries. […] The pulmonary manifestations of hantavirus pulmonary syndrome may be due to a direct cellular effect of viral infection, the presence of viral antigen in pulmonary-capillary endothelium, or a virus-induced immune-mediated response. […] The absence of a marked local response of the pulmonary inflammatory cells distinguishes this syndrome from a variety of other infectious processes. […] Although the pulmonary findings meet the current criteria for adult respiratory distress syndrome, the atypical histopathologic features, including minimal numbers of neutrophils within the alveolar or interstitial spaces, minimal alveolar epithelial disruption, and limited hyaline-membrane formation, may indicate a distinct pathogenesis. […] An understanding of the pathophysiology of hantavirus infection, especially the mechanisms underlying the increase in pulmonary and systemic endothelial permeability and vascular tone, may lead to targeted therapeutic interventions.

• #70 Hantavirus Pulmonary Syndrome: A Zebra Worth Knowing | AAFP

  https://www.aafp.org/pubs/afp/issues/2002/0915/p1015.html

  Hantavirus pulmonary syndrome (HPS) is a severe cardiopulmonary illness most often caused by the Sin Nombre virus, which is transmitted to humans by inhalation of aerosolized particles of rodent excreta or direct rodent contact. […] The cardiopulmonary phase is heralded by the acute onset of pulmonary edema. Increased pulmonary capillary permeability is central to this process and may be caused by endothelial damage in the lung microvasculature. […] Mortality is related to worsening cardiac depression, progressive respiratory failure, and subsequent acidosis culminating in fatal arrhythmias. […] Our current knowledge of HPS is in its infancy. We know relatively little about disease spectrum, pathogenesis, and potential therapeutic interventions.

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