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Background: In the United States (U.S.), hantavirus pulmonary syndrome (HPS) and non-HPS hantavirus infection are nationally notifiable diseases. Criteria for identifying human cases are based on clinical symptoms (HPS or non-HPS) and acute diagnostic results (IgM+, rising IgG+ titers, RT-PCR+, or immunohistochemistry (IHC)+). Here we provide an overview of diagnostic testing and summarize human Hantavirus disease occurrence and genotype distribution in the U.S. from 2008 to 2020. Methods: Epidemiological data from the national hantavirus registry was merged with laboratory diagnostic testing results performed at the CDC. Residual hantavirus-positive specimens were sequenced, and the available epidemiological and genetic data sets were linked to conduct a genomic epidemiological study of hantavirus disease in the U.S. Findings: From 1993 to 2020, 833 human hantavirus cases have been identified, and from 2008 to 2020, 335 human cases have occurred. Among New World (NW) hantavirus cases detected at the CDC diagnostic laboratory (representing 29.2% of total cases), most (85.0%) were detected during acute disease, however, some convalescent cases were detected in states not traditionally associated with hantavirus infections (Connecticut, Missouri, New Jersey, Pennsylvania, Tennessee, and Vermont). From 1993 to 2020, 94.9% (745/785) of U.S. hantaviruses cases were detected west of the Mississippi with 45.7% (359/785) in the Four Corners region of the U.S. From 2008 to 2020, 67.7% of NW hantavirus cases were detected between the months of March and August. Sequencing of RT-PCR-positive cases demonstrates a geographic separation of Orthohantavirus sinnombreense species [Sin Nombre virus (SNV), New York virus, and Monongahela virus]; however, there is a large gap in viral sequence data from the Northwestern and Central U.S. Finally, these data indicate that commercial IgM assays are not concordant with CDC-developed assays, and that "concordant positive" (i.e., commercial IgM+ and CDC IgM+ results) specimens exhibit clinical characteristics of hantavirus disease. Interpretation: Hantaviral disease is broadly distributed in the contiguous U.S, viral variants are localised to specific geographic regions, and hantaviral disease infrequently detected in most Southeastern states. Discordant results between two diagnostic detection methods highlight the need for an improved standardised testing plan in the U.S. Hantavirus surveillance and detection will continue to improve with clearly defined, systematic reporting methods, as well as explicit guidelines for clinical characterization and diagnostic criteria. Funding: This work was funded by core funds provided to the Viral Special Pathogens Branch at CDC.

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Hantavirus cardiopulmonary syndrome is a severe illness transmitted by rodent excretions. We describe a case of a 24-year-old man who presented to the emergency department with cough, shortness of breath, chills, myalgias, nausea, and diarrhea. Physical examination and laboratory analysis revealed signs of respiratory distress and thrombocytopenia. The trajectory of his illness led to acute respiratory distress syndrome (ARDS) and hemodynamic instability. Serum testing was positive for hantavirus IgM and IgG antibodies. The patient was managed with supportive care and improved. This case highlights the importance of considering hantavirus when managing patients who develop thrombocytopenia, ARDS, and hemodynamic instability in the appropriate clinical setting.

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Orthohantaviruses are zoonotic pathogens that cause acute and severe syndromes in humans. This review was performed to estimate the occurrence of human orthohantaviruses in South America between 2010 and 2022. A careful evaluation of the eligibility and quality of the articles was carried out after a systematic bibliographic search of four databases. The pooled frequency of human orthohantaviruses was calculated using a random effects model meta-analysis. The heterogeneity of estimates (resulting from the chi2 test and I2 statistics) was investigated by subgroup analysis and meta-regression. 1,962 confirmed cases of orthohantavirus infections were diagnosed among 35,548 individuals from seven South American countries. The general occurrence of orthohantaviruses was estimated to be 4.4% (95% confidence interval: 2.9-6.2%) based on general pooling of human cases from 32 studies. In a subgroup analysis considering the study design and method of diagnosis, the percentages of diagnosed orthohantavirus infections differed substantially (I2 = 97.8%, p = 0.00) among South American countries. Four genetic variants of orthohantavirus have been identified circulating in Argentina, Brazil, Bolivia, Chile, Colombia, and Peru. Although laboratory diagnosis of orthohantaviruses is not performed in many countries in South America, there is evidence that four different orthohantaviruses are circulating in the region. The pooled occurrence of viral infection was approximately 4.0% in more than half of the South American countries. Updated information on the occurrence of human infections is essential for monitoring the territorial spread and determining the frequency of this zoonosis.

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Hantaviruses, members of the Bunyaviridae family, can cause two patterns of disease in humans, hantavirus hemorrhagic fever with renal syndrome (HFRS) and cardiopulmonary syndrome (HCPS), being the latter hegemonic on the American continent. Andesvirus is one of the strains that can cause HCPS and is endemic in Chile. Its transmission occurs through direct or indirect contact with infected rodents' urine, saliva, or feces and inhalation of aerosol particles containing the virus. HCPS rapidly evolves into acute but reversible multiorgan dysfunction. The hemodynamic pattern of HCPS is not identical to that of cardiogenic or septic shock, being characterized by hypovolemia, systolic dysfunction, and pulmonary edema secondary to increased permeability. Given the lack of specific effective therapies to treat this viral infection, the focus of treatment lies in the timely provision of intensive care, specifically hemodynamic and respiratory support, which often requires veno-arterial extracorporeal membrane oxygenation (VA-ECMO). This narrative review aims to provide insights into specific ICU management of HCPS based on the available evidence and gathered experience in Chile and South America including perspectives of pathophysiology, organ dysfunction kinetics, timely life support provision, safe patient transportation, and key challenges for the future.

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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.

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Several occurrences of human-to-human transmission of Andes virus, an etiological agent of hantavirus cardiopulmonary syndrome, are documented. Syrian hamsters consistently model human hantavirus cardiopulmonary syndrome, yet neither transmission nor shedding has been investigated. We demonstrate horizontal virus transmission and show that Andes virus is shed efficiently from both inoculated and contact-infected hamsters.

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Hantaviridae currently encompasses seven genera and 53 species. Multiple hantaviruses such as Hantaan virus, Seoul virus, Dobrava-Belgrade virus, Puumala virus, Andes virus, and Sin Nombre virus are highly pathogenic to humans. They cause hemorrhagic fever with renal syndrome (HFRS) and hantavirus cardiopulmonary syndrome or hantavirus pulmonary syndrome (HCPS/HPS) in many countries. Some hantaviruses infect wild or domestic animals without causing severe symptoms. Rodents, shrews, and bats are reservoirs of various mammalian hantaviruses. Recent years have witnessed significant advancements in the study of hantaviruses including genomics, taxonomy, evolution, replication, transmission, pathogenicity, control, and patient treatment. Additionally, new hantaviruses infecting bats, rodents, shrews, amphibians, and fish have been identified. This review compiles these advancements to aid researchers and the public in better recognizing this zoonotic virus family with global public health significance.

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Background: Hantaviruses - dichotomized into New World (i.e. Andes virus, ANDV; Sin Nombre virus, SNV) and Old-World viruses (i.e. Hantaan virus, HTNV) - are zoonotic viruses transmitted from rodents to humans. Currently, no FDA-approved vaccines against hantaviruses exist. Given the recent breakthrough to human-human transmission by the ANDV, an essential step is to establish an effective pandemic preparedness infrastructure to rapidly identify cell tropism, infective potential, and effective therapeutic agents through systematic investigation. Methods: We established human cell model systems in lung (airway and distal lung epithelial cells), heart (pluripotent stem cell-derived (PSC-) cardiomyocytes), and brain (PSC-astrocytes) cell types and subsequently evaluated ANDV, HTNV and SNV tropisms. Transcriptomic, lipidomic and bioinformatic data analyses were performed to identify the molecular pathogenic mechanisms of viruses in different cell types. This cell-based infection system was utilized to establish a drug testing platform and pharmacogenomic comparisons. Results: ANDV showed broad tropism for all cell types assessed. HTNV replication was predominantly observed in heart and brain cells. ANDV efficiently replicated in human and mouse 3D distal lung organoids. Transcriptomic analysis showed that ANDV infection resulted in pronounced inflammatory response and downregulation of cholesterol biosynthesis pathway in lung cells. Lipidomic profiling revealed that ANDV-infected cells showed reduced level of cholesterol esters and triglycerides. Further analysis of pathway-based molecular signatures showed that, compared to SNV and HTNV, ANDV infection caused drastic lung cell injury responses. A selective drug screening identified STING agonists, nucleoside analogues and plant-derived compounds that inhibited ANDV viral infection and rescued cellular metabolism. In line with experimental results, transcriptome data shows that the least number of total and unique differentially expressed genes were identified in urolithin B- and favipiravir-treated cells, confirming the higher efficiency of these two drugs in inhibiting ANDV, resulting in host cell ability to balance gene expression to establish proper cell functioning. Conclusions: Overall, our study describes advanced human PSC-derived model systems and systems-level transcriptomics and lipidomic data to better understand Old and New World hantaviral tropism, as well as drug candidates that can be further assessed for potential rapid deployment in the event of a pandemic.

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Purpose: The purpose of this study was to investigate the impact of a new arterial intravascular pump on the hemodynamic surroundings within the aorta. Methods: A new arterial intravascular pump was placed in the descending aorta, and the effects of three positions within the aorta, as well as the number (n = 1 to 3) of pumps, on arterial flow features, organ perfusion, and blood trauma were investigated using a computational fluid dynamics (CFD) method. Results: It was found that as the pump position was moved backward, the perfusion in the three bifurcated vessels of the aorta arch increased and the pump suction flow decreased, resulting in a reduced high shear stress and decreased residence time in the three branches of the aortic arch. The further posterior the location of the pump, the better the blood flow perfusion to the kidneys, while the perfusion at the bifurcation of the abdominal aorta was reduced, due to the pump suction effect. Compared to the condition with single pump support, the multi-pump assist model can significantly reduce the pump rotating speed, while keeping the same flow patterns, leading to a decreased volume of high shear stress and flow loss. When increasing the number of pumps, the perfusion to the three branches of the aortic arch increased, accompanied by a diminished residence time, and the perfusion to the other aortic branches was decreased. However, the perfusion to the other aortic branches, especially for the renal arteries and even under a three-pump condition, was close to that without pump assistance. Conclusion: The placement of an intravascular pump near the beginning of the suprarenal abdominal aorta was considered the optimal location, in order to improve the hemodynamic surroundings. Increasing the number of pumps can significantly reduce the rotational speed, while maintaining the same flowrate, with a decreased fluid energy loss and a reduced high shear stress. This arterial intravascular pump can effectively improve renal blood flow.

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We demonstrate that 6 distinct Peromyscus rodent species are permissive to experimental infection with Sin Nombre orthohantavirus (SNV). Viral RNA and SNV antibodies were detected in members of all 6 species. P. leucopus mice demonstrated markedly higher viral and antibody titers than P. maniculatus mice, the established primary hosts for SNV.

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Hantavirus-induced diseases are emerging zoonoses with endemic appearances and frequent outbreaks in different parts of the world. In humans, hantaviral pathology is characterized by the disruption of the endothelial cell barrier followed by increased capillary permeability, thrombocytopenia due to platelet activation/depletion and an overactive immune response. Genetic vulnerability due to certain human leukocyte antigen haplotypes is associated with disease severity. Typically, two different hantavirus-caused clinical syndromes have been reported: hemorrhagic fever with renal syndrome (HFRS) and hantavirus cardiopulmonary syndrome (HCPS). The primarily affected vascular beds differ in these two entities: renal medullary capillaries in HFRS caused by Old World hantaviruses and pulmonary capillaries in HCPS caused by New World hantaviruses. Disease severity in HFRS ranges from mild, e.g. Puumala virus-associated nephropathia epidemica, to moderate, e.g. Hantaan or Dobrava virus infections. HCPS leads to a severe acute respiratory distress syndrome with high mortality rates. Due to novel insights into organ tropism, hantavirus-associated pathophysiology and overlapping clinical features, HFRS and HCPS are believed to be interconnected syndromes frequently involving the kidneys. As there are no specific antiviral treatments or vaccines approved in Europe or the USA, only preventive measures and public awareness may minimize the risk of hantavirus infection. Treatment remains primarily supportive and, depending on disease severity, more invasive measures (e.g., renal replacement therapy, mechanical ventilation and extracorporeal membrane oxygenation) are needed.

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OBJECTIVES: Navajo Nation is disproportionately affected by hantavirus cardiopulmonary syndrome (HCPS), a severe respiratory disease that can quickly progress to respiratory failure and cardiogenic shock. The initial signs and symptoms of HCPS are indistinguishable from coronavirus disease 2019 (COVID-19). However, this distinction is critical, as the disease course differs greatly, with most patients with COVID-19 experiencing mild to moderate illness. We set out to determine if the evaluation of peripheral blood smears for five hematopathologic criteria previously identified as hallmarks of hantavirus infection, or "the hantavirus 5-point screen," could distinguish between COVID-19 and HCPS. METHODS: The hantavirus 5-point screen was performed on peripheral blood smears from 139 patients positive for COVID-19 seeking treatment from Tséhootsooí Medical Center and two Emory University hospitals. RESULTS: Of these 139 individuals, 136 (98%) received a score of 3/5 or below, indicating low suspicion for HCPS. While thrombocytopenia, one of the key signs of HCPS, was seen in the patients with COVID-19, it was generally mild and remained stable on repeat specimens collected 12 to 24 hours later. CONCLUSIONS: Given these findings, the 5-point screen remains a useful rapid screening tool for potential HCPS cases and may be useful to distinguish early HCPS from COVID-19 in HCPS endemic regions.

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BACKGROUND: Frequent outbreaks around the globe and endemic appearance in different parts of the world emphasize the substantial risk of hantavirus diseases. Increasing incidence rates, trends of changing distribution of hantavirus species and new insights into clinical courses of hantavirus diseases call for multinational surveillance. Furthermore, evidence-based guidelines for the management of hantavirus diseases and scoring systems, which allow stratification of patients into risk categories, are lacking. METHODS: Hantavirus registry (HantaReg) is a novel registry platform facilitating multinational research of hantavirus-caused diseases, such as haemorrhagic fever with renal syndrome (HFRS) and hantavirus cardiopulmonary syndrome (HCPS). HantaReg provides an electronic case report form and uses the General Data Protection Regulation compliant platform clinicalsurveys.net, which can be accessed from any internet browser in the world. Having a modular structure, the registry platform is designed to display or hide questions and items according to the documented case (e.g. patient with HFRS versus HCPS) to facilitate fast, but standardized, data entry. Information categories documented in HantaReg are demographics, pre-existing diseases, clinical presentation, diagnostic and therapeutic approaches, as well as outcome. CONCLUSIONS: HantaReg is a novel, ready-to-use platform for clinical and epidemiological studies on hantavirus diseases and facilitates the documentation of the disease course associated with hantavirus infections. HantaReg is expected to promote international collaboration and contributes to improving patient care through the analysis of diagnostic and treatment pathways for hantavirus diseases, providing evidence for robust treatment recommendations. Moreover, HantaReg enables the development of prognosis-indicating scoring systems for patients with hantavirus disease.

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Hantaviruses are viral pathogens usually endemic in rodent populations. Human exposure follows inhalation of dusts contaminated with rodent excreta, and most individuals have been infected in occupational settings heavily contaminated with rodent droppings, such as agricultural and forestry. To date, knowledge, attitudes and practices of medical professionals, especially occupational physicians (OP), regarding hantavirus disease in at-risk workers have been scarcely investigated. We investigated these topics through a structured questionnaire administered through an online survey of 223 medical professionals (42.2% of them working as OP). Adequate general knowledge of hantavirus disease was found in 48.9% of respondents, with OP exhibiting a better understanding of clinical features of human hantavirus infections. OP aware of the endemic status of hantavirus in North-Eastern Italy exhibited higher risk perception for agricultural workers (odds ratio 21,193, 95% confidence interval 3.666-122.505). On the contrary, a better knowledge of hantaviruses was association with acknowledging an increased risk of hantavirus infection in forestry workers (odds ratio 5.880, 95% confidence interval 1.620-21.343). Hantavirus in Italy represent an often-overlooked biological risk in occupational settings. The lack of preventive immunization, the inappropriate risk perception and the unsatisfying awareness of hantavirus issues collectively stress the importance of appropriate information campaigns among health care providers.

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Hantavirus cardiopulmonary syndrome is an emerging zoonosis in Argentina, which has low incidence but high death rates. No specific pharmacological therapy is available and symptomatic therapy is the only current alternative. This article presents the pathogenesis of hantavirus cardiopulmonary syndrome through a review of clinical experiences in neighbor South American countries, mainly Chile, and the experience acquired at the Infectious Diseases Hospital Francisco Javier Muñiz, Buenos Aires, Argentina. The role of early corticosteroid therapy is discussed taking into account that there is insufficient evidence favoring its use in the hantavirus cardiopulmonary syndrome.

El síndrome cardiopulmonar por hantavirus es una zoonosis emergente en la Argentina, que presenta baja incidencia, pero elevada mortalidad. No existe tratamiento farmacológico especifico y la única alternativa actual es la terapia de apoyo. En este artículo se expone la patogenia del síndrome cardiopulmonar por hantavirus a través de la revisión de las experiencias clínicas de otros países de Sudamérica, en particular Chile, y la adquirida en el Hospital de Infecciosas Francisco Javier Muñiz de Buenos Aires, Argentina. Se discute sobre la administración temprana de corticoides en este síndrome, teniendo en cuenta que la evidencia a favor de su uso es insuficiente.

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Resumen El síndrome cardiopulmonar por hantavirus es una zoonosis emergente en la Argentina, que presenta baja incidencia, pero elevada mortalidad. No existe tratamiento farmacológico especifico y la única alternativa actual es la terapia de apoyo. En este artículo se expone la patogenia del síndrome cardiopulmonar por hantavirus a través de la revisión de las experiencias clínicas de otros países de Sudamérica, en particular Chile, y la adquirida en el Hospital de Infecciosas Francisco Javier Muñiz de Buenos Aires, Argentina. Se discute sobre la administración temprana de corticoides en este síndrome, teniendo en cuenta que la evidencia a favor de su uso es insuficiente.

Abstract Hantavirus cardiopulmonary syndrome is an emerging zoonosis in Argentina, which has low incidence but high death rates. No specific pharmacological therapy is available and symptomatic therapy is the only current alterna tive. This article presents the pathogenesis of hantavirus cardiopulmonary syndrome through a review of clinical experiences in neighbor South American countries, mainly Chile, and the experience acquired at the Infectious Diseases Hospital Francisco Javier Muñiz, Buenos Aires, Argentina. The role of early corticosteroid therapy is discussed taking into account that there is insufficient evidence favoring its use in the hantavirus cardiopulmonary syndrome.

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In Brazil, the first confirmed cases of hantavirus cardiopulmonary syndrome in Indigenous populations occurred in 2001. The purpose of this study was to determine the seroprevalence of orthohantavirus infections in the Utiariti Indigenous land located in the southeastern region of the Brazilian Amazon. In December 2014 and 2015, a survey was conducted using an enzyme-linked immunosorbent assay in nine villages belonging to the Haliti-Paresí Indigenous communities. A total of 301 participants were enrolled in the study. Of the two study cohorts, the one from 2014 showed a prevalence of 12.4%, whereas the one from 2015 had a serum prevalence of 13.4%. Analysis of the paired samples of 110 Indigenous people who participated in both stages of the study enabled identification of four individuals who had seroconverted during the study period. Identifying the circulation of orthohantaviruses in the Utiariti Indigenous land highlights a serious public health problem in viral expansion and highlights the need to implement preventive measures appropriate to the sociocultural reality of these communities.

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OBJECTIVES: To determine the relative frequency and prognosis value of proteinuria in hantavirus cardiopulmonary syndrome (HCPS) due to Andes virus. METHODS: This observational analytical study prospectively obtained data from patients admitted to 12 health centers in nine Chilean cities between 2001 and 2018. Only patients with confirmed Andes virus HCPS and laboratory characterization that included qualitative proteinuria determination at admission were considered. RESULTS: The database involved 175 patients, 95 of them had a measurement of urine protein at the time of hospital admission. They were mainly male (71%) and the median age was 35 [22-47] years. Median duration of the febrile prodromal time was 5 [4-7] days. Hospital length of stay and hospital mortality rate were 10 [7-14] days and 21.1%, respectively. Seventy-three patients (77%) were identified with proteinuria at admission, which was associated with increased mortality rate (26% versus 5%, p=0.036) and the relative risk was 1.3 [1.1-1.6], p=0.002. CONCLUSIONS: Proteinuria is a frequent finding in patients with HCPS, which is associated with a higher mortality rate.

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BACKGROUND: Hantavirus 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. METHODS: We 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. RESULTS: Patients 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. CONCLUSION: HVHF 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.

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Orthohantaviruses, previously named hantaviruses, cause two emerging zoonotic diseases: haemorrhagic fever with renal syndrome (HFRS) in Eurasia and hantavirus cardiopulmonary syndrome (HCPS) in the Americas. Overall, over 200 000 cases are registered every year worldwide, with a fatality rate ranging between 0·1% and 15% for HFRS and between 20% and 40% for HCPS. No specific treatment or vaccines have been approved by the U.S. Food and Drug Administration (FDA) to treat or prevent hantavirus-caused syndromes. Currently, little is known about the mechanisms at the basis of hantavirus-induced disease. However, it has been hypothesized that an excessive inflammatory response plays an essential role in the course of the disease. Furthermore, the contributions of the cellular immune response to either viral clearance or pathology have not been fully elucidated. This article discusses recent findings relative to the immune responses elicited to hantaviruses in subjects suffering HFRS or HCPS, highlighting the similarities and differences between these two clinical diseases. Also, we summarize the most recent data about the cellular immune response that could be important for designing new vaccines to prevent this global public health problem.

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