Severe Hantavirus Cardiopulmonary Syndrome Research Articles

Assessing Pulmonary Epithelial Damage in Hantavirus Cardiopulmonary Syndrome: Challenging the Predominant Role of Vascular Endothelium through sRAGE as a Potential Biomarker.

Hantavirus cardiopulmonary syndrome (HCPS) is a severe respiratory illness primarily associated with microvascular endothelial changes, particularly in the lungs. However, the role of the pulmonary epithelium in HCPS pathogenesis remains unclear. This study explores the potential of soluble Receptors for Advanced Glycation End-products (sRAGE) as a biomarker for assessing pulmonary epithelial damage in severe HCPS, challenging the prevailing view that endothelial dysfunction is the sole driver of this syndrome. We conducted a cross-sectional study on critically ill HCPS patients, categorizing them into mild HCPS, severe HCPS, and negative control groups. Plasma sRAGE levels were measured, revealing significant differences between the severe HCPS group and controls. Our findings suggest that sRAGE holds promise as an indicator of pulmonary epithelial injury in HCPS and may aid in tracking disease progression and guiding therapeutic strategies. This study brings clarity on the importance of investigating the pulmonary epithelium's role in HCPS pathogenesis, offering potential avenues for enhanced diagnostic precision and support in this critical public health concern.

Two point mutations in protocadherin-1 disrupt hantavirus recognition and afford protection against lethal infection

Andes virus (ANDV) and Sin Nombre virus (SNV) are the etiologic agents of severe hantavirus cardiopulmonary syndrome (HCPS) in the Americas for which no FDA-approved countermeasures are available. Protocadherin-1 (PCDH1), a cadherin-superfamily protein recently identified as a critical host factor for ANDV and SNV, represents a new antiviral target; however, its precise role remains to be elucidated. Here, we use computational and experimental approaches to delineate the binding surface of the hantavirus glycoprotein complex on PCDH1’s first extracellular cadherin repeat domain. Strikingly, a single amino acid residue in this PCDH1 surface influences the host species-specificity of SNV glycoprotein-PCDH1 interaction and cell entry. Mutation of this and a neighboring residue substantially protects Syrian hamsters from pulmonary disease and death caused by ANDV. We conclude that PCDH1 is a bona fide entry receptor for ANDV and SNV whose direct interaction with hantavirus glycoproteins could be targeted to develop new interventions against HCPS.

Therapeutic Efficacy of Human Monoclonal Antibodies against Andes Virus Infection in Syrian Hamsters.

Andes virus, an orthohantavirus endemic to South America, causes severe hantavirus cardiopulmonary syndrome associated with human-to-human transmission. No approved treatments or vaccines against this virus are available. We show that a combined treatment with 2 monoclonal antibodies protected Syrian hamsters when administered at midstage or late-stage disease.

Targeted high volume hemofiltration could avoid extracorporeal membrane oxygenation in some patients with severe Hantavirus cardiopulmonary syndrome.

BackgroundHantavirus cardiopulmonary syndrome (HCPS) has a high lethality. Severe cases may be rescued by venoarterial extracorporeal membrane oxygenation (VA ECMO), alongside substantial complications. High volume hemofiltration (HVHF) is a depurative technique that provides homeostatic balance allowing hemodynamic stabilization in some critically ill patients.MethodsWe implemented HVHF before VA ECMO consideration in the last five severe HCPS patients requiring mechanical ventilation and vasoactive drugs admitted to our intensive care unit. Patients were considered HVHF‐responders if VA ECMO was avoided and HVHF‐nonresponders if VA ECMO support was needed despite HVHF. A targeted‐HVHF strategy compounded by aggressive hyperoncotic albumin, sodium bicarbonate, and calcium supplementation plus ultrafiltration to avoid fluid overload was implemented on three patients.ResultsPatients had maximum serum lactate of 8.8 (8.7–12.8) mmol/L and a lowest cardiac index of 1.8 (1.8–1.9) L/min/m2. The first two required VA ECMO. They were connected later to HVHF, displayed progressive tachycardia and declining stroke volume. The opposite was true for HVHF‐responders who received targeted‐HVHF. All patients survived, but one of the VA ECMO patients suffered a vascular complication.ConclusionHVHF may contribute to support severe HCPS patients avoiding the need for VA ECMO in some. Early connection and targeted‐HVHF may increase the chance of success.

Sociodemographic risk factors of hantavirus cardiopulmonary syndrome

Hantavirus cardiopulmonary syndrome (HCPS) is caused by new world hantaviruses, among which Andes hantavirus (ANDV) is endemic to Chile and Southern Argentina. The disease caused by ANDV produces plasma leakage leading to enhanced vascular permeability and has a high case fatality rate (35%), mainly due to respiratory failure, pulmonary edema and myocardial dysfunction, hypoperfusion and shock. Host sociodemographic and genetic factors might influence the course and outcome of the disease. Yet, they have not been thoroughly characterized. To evaluate sociodemographic factors as risk factors in severity of HCPS. Study period: 2004-20013, attending in eight collaborative centers, etiological diagnosis was performed by serology or molecular biology, mild and severe HCPS were compared.139 Chilean patients were analyzed, 64 (46%) with severe disease among which 12 (19 %) died. European ethnicity had 5,1 times higher risk than Amerindian ethnic group to develop a severe HCPS, greater seriousness that was also associated with an urban residence. It was observed that ethnicity and type of residence were significant risk factors for HCPS severity. Hypotheses explaining these findings are discussed.

Platelet Count in Patients with Mild Disease at Admission is Associated with Progression to Severe Hantavirus Cardiopulmonary Syndrome.

Background: Hantavirus cardiopulmonary syndrome (HCPS) has a mortality up to 35–40% and its treatment is mainly supportive. A variable to predict progression from mild to severe disease is unavailable. This study was performed in patients with documented infection by Andes orthohantavirus, and the aim was to find a simple variable to predict progression to moderate/severe HCPS in patients with mild disease at admission. Methods: We performed a retrospective analysis of 175 patients between 2001 and 2018. Patients were categorized into mild, moderate, and severe disease according to organ failure and advanced support need at hospital admission (e.g., mechanical ventilation, vasopressors). Progression to moderate/severe disease was defined accordingly. Clinical and laboratory variables associated with progression were explored. Results: Forty patients with mild disease were identified; 14 of them progressed to moderate/severe disease. Only platelet count was different between those who progressed versus those that did not (37 (34–58) vs. 83 (64–177) K/mm3, p < 0.001). A ROC curve analysis showed an AUC = 0.889 (0.78–1.0) p < 0.001, with a platelet count greater than 115K /mm3 ruling out progression to moderate/severe disease. Conclusions: In patients with mild disease at presentation, platelet count could help to define priority of evacuation to tertiary care centers.

Deletions in Genes Participating in Innate Immune Response Modify the Clinical Course of Andes Orthohantavirus Infection.

Andes orthohantavirus (ANDV) is an important human pathogen causing hantavirus cardiopulmonary syndrome (HCPS) with a fatality rate of 30% in Chile. Around 60% of all cases have a severe clinical course, while the others have a mild clinical course. The main goal of this study was to understand if the genetic variation of patients is associated with the clinical course they develop after ANDV infection. For this, the frequency of copy number variants (CNVs, i.e., deletions and duplications) was studied in 195 patients, 88 with mild and 107 with severe HCPS. CNVs were called from intensity data of the Affymetrix Genome-Wide SNP Array 6.0. The analysis of the data was performed with PennCNV, ParseCNV and R softwares; Results: a deletion of 19, 416 bp in the q31.3 region of chromosome 1 is found more frequently in severe patients (p < 0.05). This region contains Complement Factor H Related (CFHR1) and CFHR3 genes, regulators of the complement cascade. A second deletion of 1.81 kb located in the p13 region of chr20 was significantly more frequent in mild patients (p < 0.05). This region contains the SIRPB1 gene, which participates in the innate immune response, more specifically in neutrophil trans-epithelial migration. Both deletions are associated with the clinical course of HCPS, the first being a risk factor and the second being protective. The participation of genes contained in both deletions in ANDV infection pathophysiology deserves further investigation.

Elevated cytokines, thrombin and PAI-1 in severe HCPS patients due to Sin Nombre virus.

Sin Nombre Hantavirus (SNV, Bunyaviridae Hantavirus) is a Category A pathogen that causes Hantavirus Cardiopulmonary Syndrome (HCPS) with case fatality ratios generally ranging from 30% to 50%. HCPS is characterized by vascular leakage due to dysregulation of the endothelial barrier function. The loss of vascular integrity results in non-cardiogenic pulmonary edema, shock, multi-organ failure and death. Using Electric Cell-substrate Impedance Sensing (ECIS) measurements, we found that plasma samples drawn from University of New Mexico Hospital patients with serologically-confirmed HCPS, induce loss of cell-cell adhesion in confluent epithelial and endothelial cell monolayers grown in ECIS cultureware. We show that the loss of cell-cell adhesion is sensitive to both thrombin and plasmin inhibitors in mild cases, and to thrombin only inhibition in severe cases, suggesting an increasing prothrombotic state with disease severity. A proteomic profile (2D gel electrophoresis and mass spectrometry) of HCPS plasma samples in our cohort revealed robust antifibrinolytic activity among terminal case patients. The prothrombotic activity is highlighted by acute ≥30 to >100 fold increases in active plasminogen activator inhibitor (PAI-1) which, preceded death of the subjects within 48 h. Taken together, this suggests that PAI-1 might be a response to the severe pathology as it is expected to reduce plasmin activity and possibly thrombin activity in the terminal patients.

Extracorporeal membrane oxygenation support improves survival of patients with severe Hantavirus cardiopulmonary syndrome

Extracorporeal membrane oxygenation support improves survival of patients with severe Hantavirus cardiopulmonary syndrome

Case report: T‐cell responses during clearance of andes virus from blood cells 2 months after severe hantavirus cardiopulmonary syndrome

Hantavirus Cardiopulmonary Syndrome (HCPS) due to Andes virus (ANDV) is endemic in Chile and Argentina and currently demonstrates a case-fatality rate of 37% in humans. By contrast to the chronically infected rodents, it is believed that ANDV in humans is cleared during the acute phase. Moreover, to date, both magnitude and quality of human T-cell responses during ANDV infection and clearance are unknown. Using IFN-gamma and granzyme B ELISPOT assays as well as flow cytometry, we prospectively studied the ANDV-specific T-cell responses in a 56-year-old convalescing survivor of severe HCPS, whose blood cells remained PCR-positive for ANDV-RNA until day 53 after hospital admission, that is, 67 days after infection and 42 days after discharge. PCR-negativity was closely related to the increase and function of (Gn(46-60))-specific IFN-gamma(+) granzyme B(+) CD8(+) T-cells, but not to neutralizing antibody titers. Concurrently, the phenotype of CD45RA(+)CCR7(-) Gn(46-60)-specific T-cells shifted from a CD28(-)CD27(+) "intermediate" to a CD28(-) CD27(-) "late" effector memory beyond day 53 after hospital admission. This is the first report that shows that ANDV can persist in the human hosts for more than 2 months. Moreover, the kinetics of T-cell responses during ANDV clearance may indicate a major role of T-cells for clearance of ANDV and human immunity to this pathogen.

Extracorporeal membrane oxygenation support improves survival of patients with severe Hantavirus cardiopulmonary syndrome

The purposes of this study are to evaluate the outcome of extracorporeal membrane oxygenation support in a subgroup of patients with Hantavirus cardiopulmonary syndrome who had a predicted mortality of 100% and to assess the complications associated with this treatment modality and with different cannulation techniques. Thirty-eight patients with severe Hantavirus cardiopulmonary syndrome were supported with extracorporeal membrane oxygenation between April 1994 and June 2006. Cannulation of the femoral vessels was performed on an emergency basis by a percutaneous approach in 15 (39.5%) and by an open technique in 23 (60.5%) patients. Duration of extracorporeal membrane oxygenation averaged 132 hours (range: 5-276 hours). Complications from percutaneous cannulation occurred in 4 (26.6%) of 15 patients: retroperitoneal hematoma in 2 (13.3%) and lower extremity ischemia in 2 (13.3%) patients, which resolved after insertion of a distal perfusion cannula. Complications from open femoral cannulation occurred in 8 (34.8%) of 23 patients: severe bleeding in 7 (30.4%) patients and lower extremity ischemia in 1 (4.3%) patient who required a leg amputation. The overall survival was 60.5% (23/38 patients). Six (40%) of the 15 patients cannulated percutaneously and 9 (39.1%) of 23 patients who had open cannulation died. All survivors recovered completely and were discharged from the hospital after a mean hospital stay of 20.8 days (range: 10-39 days). Almost two thirds of the patients with severe Hantavirus cardiopulmonary syndrome who were supported with extracorporeal circulation survived and recovered completely. The complications associated with both types of femoral cannulation may be attributed to the fact that all patients were in shock or in full cardiac arrest, and the procedure had to be done expeditiously. Earlier institution of extracorporeal membrane oxygenation may decrease the complication rates and improve the overall survival.

Can Modeling of Fine-Scale Spatial Patterns of Environmental Markers of Zoonotic Infections Enhance Disease Prevention and Clinical Outcomes?

When evaluating patients with an undiagnosed infectious disease, physicians in general (and infectious disease specialists in particular) are trained to obtain a history of factors such as recent travel, location of residence, country of birth, occupation, and contact with animals. These factors are taken into account when generating a ranked differential diagnosis. For example, a history of work as a professional landscaper in the setting of a compatible clinical presentation would likely trigger specific diagnostic testing and presumptive treatment of tularemia. 1 Unfortunately, physicians generally lack the expertise to identify factors such as specific ecotones associated with risk of zoonotic infections. On the other hand, infectious disease ecologists and epidemiologists consider the role of the environment to be critical in vector-borne and zoonotic disease transmission, 2–4 and they are increasingly aware of the need to consider the effective range of transmission overlap of several pathogens, model the potential benefits of integrated control, and define the environmentally appropriate level for control efforts. 5,6 In this issue, Eisen and others 7 report the development of a fine-scale model to predict the risk of plague and hantavirus infection in humans in northwestern New Mexico and northeastern Arizona. The environmental risk of plague was related to precipitation and distance to pinon-juniper ecotones, whereas the risk of hantavirus infection was related to precipitation and elevation; half the area had risk for both zoonotic infections. The authors suggest that fine-scale identification of areas of increased disease risk would be useful for targeting education activities, resulting in improved disease prevention and management. Targeting disease prevention activities for these significant, rodent-borne infections should at a minimum lead to more efficient use of public health funding, which in turn could lead to more effective prevention activities. Education of healthcare providers also might lead to some improvement in disease management, but it is not clear whether targeted education with training on fine-scale identification of areas of increased disease risk or targeting training in areas of increased risk would be more effective than general, regional educational activities without this training. Early initiation of appropriate antibiotic therapy for plague reduces mortality; management by an experienced critical care team in a tertiary care center, including extracorporeal membrane oxygenation (ECMO) in some centers, reduces mortality in severe hantavirus cardiopulmonary syndrome (HCPS), also known as hantavirus pulmonary syndrome. 8–10