Upregulation of P2Y2R, Active uPA, and PAI-1 Are Essential Components of Hantavirus Cardiopulmonary Syndrome.

Sin Nombre virus (SNV) causes hantavirus cardiopulmonary pulmonary syndrome (HCPS) with the loss of pulmonary vascular endothelial integrity, and pulmonary edema without causing cytopathic effects on the vascular endothelium. HCPS is associated primarily with a dysregulated immune response. We previously found occult signs of hemostatic imbalance in the form of a sharp >30-100 fold increase in the expression of plasminogen activator inhibitor type 1 (PAI-1), in serial blood plasma draws of terminal stage-patients. However, the mechanism of the increase in PAI-1 remains unclear. PAI-1 is a primary inhibitor of fibrinolysis caused by tissue plasminogen activator (tPA) and urokinase plasminogen activator plasma (uPA). Here, we investigate factors that contribute to PAI-1 upregulation during HCPS. Using zymography, we found evidence of PAI-1-refractory uPA activity and no tPA activity in plasma samples drawn from HCPS patients. The sole prevalence of uPA activity suggested that severe inflammation drove PAI-1 activity. We have recently reported that the P2Y2 receptor (P2Y2R) mediates SNV infectivity by interacting in cis with ß3 integrins, which activates the latter during infection. P2Y2R is a known effector for several biological processes relevant to HCPS pathogenesis, such as upregulation of tissue factor (TF), a primary initiator of the coagulation cascade, stimulating vascular permeability and leukocyte homing to sites of infection. As P2Y2R is prone to upregulation under conditions of inflammation, we compared the expression level of P2Y2R in formalin fixed tissues of HCPS decedents using a TaqMan assay and immunohistochemistry. Our TaqMan results show that the expression of P2Y2R is upregulated significantly in HCPS cases compared to non- HCPS controls (P < 0.001). Immunohistochemistry showed that lung macrophages were the primary reservoir of high and coincident localization of P2Y2R, uPA, PAI-1, and TF antigens. We also observed increased staining for SNV antigens in the same tissue segments where P2Y2R expression was upregulated. Conversely, sections of low P2Y2R expression showed weak manifestations of macrophages, SNV, PAI-1, and TF. Coincident localization of P2Y2R and PAI-1 on macrophage deposits suggests an inflammation-dependent mechanism of increasing pro-coagulant activity in HCPS in the absence of tissue injury.

A 44-Year-Old Man With Sore Throat and Fatigue After Using an Old Camper Van.

A 44-year-old man from Connecticut with no significant past medical history presented to the ED with a 2-week history of sore throat and fatigue, subsequently developing cough, dyspnea, fevers, and chills. The patient reported buying an old camper van and noticed a large infestation of rodent droppings, which he had cleaned thoroughly from the cabin. He used the camper van on several camping trips in Vermont, and symptoms started on his return.

Pathophysiology of hantavirus pulmonary syndrome in rhesus macaques.

The pathophysiology of hantavirus pulmonary syndrome (HPS) remains unclear because of a lack of surrogate disease models with which to perform pathogenesis studies. Nonhuman primates (NHP) are considered the gold standard model for studying the underlying immune activation/suppression associated with immunopathogenic viruses such as hantaviruses; however, to date an NHP model for HPS has not been described. 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. 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. We anticipate this model will advance our understanding of HPS pathogenesis and will greatly facilitate research toward the development of effective therapeutics and vaccines against hantaviral diseases.

Hantavirus pulmonary syndrome clinical findings: evaluating a surveillance case definition.

Clinical cases of hantavirus pulmonary syndrome (HPS) can be challenging to differentiate from other acute respiratory diseases, which can lead to delays in diagnosis, treatment, and disease reporting. Rapid onset of severe disease occurs, at times before diagnostic test results are available. This study's objective was to examine the clinical characteristics of patients that would indicate HPS to aid in detection and reporting. Test results of blood samples from U.S. patients suspected of having HPS submitted to the Centers for Disease Control and Prevention from 1998-2010 were reviewed. Patient information collected by case report forms was compared between HPS-confirmed and test-negative patients. Diagnostic sensitivity, specificity, predictive values, and likelihood ratios were calculated for individual clinical findings and combinations of variables. Of 567 patients included, 36% were HPS-confirmed. Thrombocytopenia, chest x-rays with suggestive signs, and receiving supplemental oxygenation were highly sensitive (>95%), while elevated hematocrit was highly specific (83%) in detecting HPS. Combinations that maximized sensitivity required the presence of thrombocytopenia. Using a national sample of suspect patients, we found that thrombocytopenia was a highly sensitive indicator of HPS and should be included in surveillance definitions for suspected HPS. Using a sensitive suspect case definition to identify potential HPS patients that are confirmed by highly specific diagnostic testing will ensure accurate reporting of this disease.

High-resolution computed tomography findings in hantavirus pulmonary syndrome.

The hantavirus pulmonary syndrome (HPS) is an acute, rapidly progressive disease transmitted by rodent excreta, with endothelial damage playing a central role in the pathophysiology. It usually affects rural workers. The lung itself is the target organ and reflects all the patterns of endothelial involvement of this disease. The radiologic findings of HPS are vast and range from a mild interstitial involvement to total obliteration of the airspaces with or without pleural effusion. There are no specific findings on high-resolution computed tomography in HPS; nevertheless, findings of thickening of interlobular septa, ground-glass opacities, and occasionally small ill-defined nodular opacities have been described. The authors report a fulminant case of HPS and discuss its varied high-resolution computed tomography findings. To our knowledge, the "crazy-paving" pattern has not been seen previously in such cases.

Treatment of hantavirus pulmonary syndrome.

Viruses in the genus Hantavirus can cause one of two serious illnesses when transmitted from rodents to humans: hemorrhagic fever with renal syndrome (HFRS) or hantavirus pulmonary syndrome (HPS). Of the two diseases, HPS is more severe with an approximate 40% mortality across the Americas. The high rate of mortality could be reduced if effective therapeutics could be discovered for treatment of this illness. Herein we review approaches being explored for the discovery of therapeutics for HPS and how they could be employed in treatment and prevention of disease.

Hantavirus pulmonary syndrome: high-resolution CT findings in one patient.

Physical examination demonstrated petechiae, leg oedema and mild dyspnoea. Chest radiograph showed minimal bilateral hazy increased opacification, mainly on the right side, and small bilateral pleural effusions. High-resolution CT demonstrated extensive bilateral ground-glass opacities most severe in the middle and lower lung zones. Also noted were a few slightly thickened interlobular septa, a few poorly defined small nodules, bronchial wall thickening and small bilateral pleural effusions. Blood tests revealed high leukocyte and low platelet counts. Renal function was normal. Serological test (ELISA) for hantavirus using SNV (Sin Nombre virus) antigen was positive. The patient received supportive treatment, gradually improved, and was discharged 10 days after hospital admission. His symptoms completely resolved and follow-up radiographs returned to normal.

Corticosteroids combined with continuous veno-venous hemodiafiltration for treatment of hantavirus pulmonary syndrome caused by Puumala virus infection.

Reported here are two cases of hantavirus pulmonary syndrome caused by Puumala virus infection, which rapidly resolved after initiation of corticosteroid treatment combined with continuous veno-venous hemodiafiltration. These cases emphasize the role of the inflammatory response in the pathogenesis of hantavirus pulmonary syndrome.

Viral pneumonias in adults: radiologic and pathologic findings.

Numerous viruses, including influenza virus, measles virus, Hantavirus, adenovirus, herpesviruses, varicella-zoster virus, cytomegalovirus, and Epstein-Barr virus, can cause lower respiratory tract infection in adults. Viral pneumonia in adults can be classified into two clinical groups: so-called atypical pneumonia in otherwise healthy hosts and viral pneumonia in immunocompromised hosts. Influenza virus types A and B cause most cases of viral pneumonia in immunocompetent adults. Immunocompromised hosts are susceptible to pneumonias caused by cytomegalovirus, herpesviruses, measles virus, and adenovirus. The radiographic findings, which consist mainly of patchy or diffuse ground-glass opacity with or without consolidation and reticular areas of increased opacity, are variable and overlapping. Computed tomographic findings, which are also overlapping, consist of poorly defined centrilobular nodules, ground-glass attenuation with a lobular distribution, segmental consolidation, or diffuse ground-glass attenuation with thickened interlobular septa. The radiologic findings reflect the variable extents of the histopathologic features: diffuse alveolar damage (intraalveolar edema, fibrin, and variable cellular infiltrates with a hyaline membrane), intraalveolar hemorrhage, and interstitial (intrapulmonary or airway) inflammatory cell infiltration. Clinical information such as patient age, immune status, community outbreaks, symptom onset and duration, and presence of a rash remain important aids in diagnosis of viral causes.

Radiographic findings in 20 patients with Hantavirus pulmonary syndrome correlated with clinical outcome.

OBJECTIVE: Hantavirus is a rare rodent-borne pathogen responsible for the Hantavirus pulmonary syndrome. The objective of this study was to review the clinical and radiographic findings of patients presenting with Hantavirus pulmonary syndrome in northern Alberta, Canada. MATERIALS AND METHODS: We retrospectively reviewed the cases of 20 patients who presented with Hantavirus pulmonary syndrome from 1989 to 1999. RESULTS: Two patterns of presentation were identified. One group (13/20 patients) presented with fulminant clinical and radiographic findings and required intensive care support. Six (46%) of the 13 died within a few days of presentation. Some presented in respiratory failure with bilateral parenchymal infiltrates or a rapid progression from mild bilateral interstitial changes to bilateral interstitial and alveolar infiltrates with pleural effusions. The radiographic findings paralleled these clinical symptoms. The second group (7/20) consisted of patients whose clinical course was more limited, as were their corresponding radiographic findings. These patients had a limited hospital stay, and only minimal changes were identified on radiographs. None of the second group of patients died. CONCLUSION: Clearly, in our study, the patients with Hantavirus pulmonary syndrome presented as two groups: those with the fulminant form of the illness and those with the limited type. Of the patients we studied, the group with the fulminant form presented with severe clinical symptoms and radiographic signs of pulmonary disease and had a 46% mortality rate. The group with the limited form presented with mild clinical symptoms and minimal radiographic changes and had no mortalities.

Hantavirus pulmonary syndrome in Brazil: clinical aspects of three new cases.

Hantavirus pulmonary syndrome (HPS) has been recognized recently in Brazil, where 28 cases have been reported as of September 1999. We report here the clinical and laboratory findings of three cases whose diagnoses were confirmed serologically. All the patients were adults who presented a febrile illness with respiratory symptoms that progressed to respiratory failure that required artificial ventilation in two of them. Laboratory findings were most of the time consistent with those reported in the United States in patients infected with the Sin Nombre virus, and included elevated hematocrit and thrombocytopenia; presence of atypical lymphocytes was observed in one patient. The chest radiological findings observed in all the patients were bilateral, diffuse, reticulonodular infiltrates. Two patients died. Histopathological examination of the lungs of these patients revealed interstitial and alveolar edema, alveolar hemorrhage, and mild interstitial pneumonia characterized by infiltrate of immunoblasts and mononuclear cells. In the epidemiologic investigation of one of the cases, serologic (ELISA) tests were positive in 3 (25%) out of 12 individuals who shared the same environmental exposure. HPS should be included in the differential diagnosis of interstitial pneumonia progressing to acute respiratory failure.

Hantaviruses: an overview and radiographic correlation.

This article describes Hantaviruses and the infections they cause. Routes of transmission, disease phases and radiographic manifestations are discussed, along with recommendations for prevention and the radiologic technologist's role in prompt diagnosis.

Distinguishing hantavirus pulmonary syndrome from acute respiratory distress syndrome by chest radiography: are there different radiographic manifestations of increased alveolar permeability?

Hantavirus infection may cause diffuse air space disease, termed hantavirus pulmonary syndrome (HPS). The authors sought to determine if chest radiographs could differentiate HPS from typical acute respiratory distress syndrome (ARDS). The authors identified patients with either HPS (n = 11) or acute ARDS (n = 32) and selected the earliest chest radiograph showing diffuse airspace disease, and a chest radiograph taken 24 to 48 hours previously. Thoracic and general radiologists first viewed the chest radiograph showing diffuse air space disease, and ranked the likelihood that each case represented HPS versus ARDS. Afterward, readers viewed earlier chest radiographs and rescored each case. Receiver operating characteristic (ROC) curves from both scoring sessions were generated. The mean areas under the ROC curves for the entire group was 0.83 +/- 0.12 initially, and improved to 0.87 +/- 0.09 (p < 0.05) after viewing prior chest radiographs. Receiver operating characteristic curves of thoracic radiologists described greater areas than those of general radiologists both before and after viewing prior chest radiographs; 0.95 +/- 0.01 versus 0.78 +/- 0.08 (p < 0.05) and 96 +/- 0.02 versus 0.80 +/- 0.05 (p < 0.05). The mean sensitivity and specificity of chest radiograph interpretation for HPS was 86 +/- 13% and 74 +/- 11%, respectively. Chest radiographs can differentiate HPS from ARDS. Accuracy is improved by the use of serial radiographs and more highly trained readers. The chest radiograph findings may represent differences in the extent of alveolar epithelial damage seen in HPS and ARDS.

Bayou virus-associated hantavirus pulmonary syndrome in Eastern Texas: identification of the rice rat, Oryzomys palustris, as reservoir host.

We describe the third known case of hantavirus pulmonary syndrome (HPS) due to Bayou virus, from Jefferson County, Texas. By using molecular epidemiologic methods, we show that rice rats (Oryzomys palustris) are frequently infected with Bayou virus and that viral RNA sequences from HPS patients are similar to those from nearby rice rats. Bayou virus is associated with O. palustris; this rodent appears to be its predominant reservoir host.

Pleural fluid characteristics in hantavirus pulmonary syndrome.

Hantavirus pulmonary syndrome (HPS), is a rodent-borne, acute, often fulminant cardiorespiratory illness. Noncardiogenic pulmonary edema is prominent in HPS as is cardiac dysfunction. Pleural effusions are commonly noted in patients with HPS and have been thought to be exudative. This report describes the prevalence and characteristics of pleural effusions by an assessment of chest radiographs for the presence of pleural fluid and reviews all pleural fluid specimens obtained from patients with HPS. Of 23 patients treated at the University of New Mexico Hospital for HPS, 22 had evidence of pleural fluid while 4 had sampling of their pleural fluid. Two samples met criteria for an exudate by pleural fluid protein to serum protein ratio of more than 0.5; one was clearly a transudate and the other had inconsistent characteristics. The two exudative samples were obtained 7 days after admission, while the other 2 were obtained within 1 day of admission. Pleural fluid cultures were sterile, and the total of nucleated cells was less than 170/mm3, and predominately mononuclear. A hypothesis may be formulated that the pleural fluid in HPS is initially transudative, consistent with the observed cardiopulmonary dysfunction. However, following aggressive resuscitative efforts and as the acute illness resolves, fluid shifts occur as cardiac function normalizes; the pleural fluid may take on characteristics of an exudate.

Pulmonary involvement in nephropathia epidemica: radiological findings and their clinical correlations.

Nephropathia epidemica (NE) is a hemorrhagic fever with renal syndrome (HFRS) normally taking a benign clinical course. The etiologic agent, Puumala hantavirus is genetically closely related to Sin Nombre virus, which causes a frequently lethal febrile syndrome with pulmonary involvement (hantavirus pulmonary syndrome, HPS). HPS is characterized by acute respiratory distress, non-cardiogenic pulmonary edema and severe and hypotension, but usually no significant renal involvement. Pulmonary involvement and respiratory symptoms also occur in NE. To understand the mechanisms of pulmonary involvement in NE, we studied the clinical records and chest X-rays of 125 hospital-treated acutely ill NE patients. Twenty-eight percent of the patients had disease-related changes in their chest radiographs. Pleural effusion and atelectasis were the most common X-ray findings, whereas frank pulmonary edema was rare. The patients with pathologic X-ray findings had a more marked hypoproteinemia (lowest measured serum protein concentration 54 +/- 1 g/l) than those with normal X-ray (62.1 +/- 0.9 g/l, p < 0.001) and leukocytosis (highest measured blood leukocyte count 14.1 +/- 0.9 x 10(9)/l vs. 10.6 +/- 0.6 x 10(9)/l, p < 0.001) and more severe renal insufficiency (highest measured serum creatinine 590 +/- 60 mumol/l vs. 356 +/- 29 mumol/l, p < 0.05). Hypoproteinemia best predicted the occurrence of abnormal chest X-ray findings in NE. This suggests, that capillary leakage and inflammation may play a role in the pathogenesis of NE lung involvement, similarly as in HPS. Differently from HPS, the fluid volume overload associated with renal insufficiency seemed to contribute strongly to the chest X-ray changes in NE.