Hantavirus in humans: a review of clinical aspects and management.

Hantavirus infections are part of the broad group of viral haemorrhagic fevers. They are also recognised as a distinct model of an emergent zoonotic infection with a global distribution. Many factors influence their epidemiology and transmission, such as climate, environment, social development, ecology of rodent hosts, and human behaviour in endemic regions. Transmission to humans occurs by exposure to infected rodents in endemic areas; however, Andes hantavirus is unique in that it can be transmitted from person to person. As hantaviruses target endothelial cells, they can affect diverse organ systems; increased vascular permeability is central to pathogenesis. The main clinical syndromes associated with hantaviruses are haemorrhagic fever with renal syndrome (HFRS), which is endemic in Europe and Asia, and hantavirus cardiopulmonary syndrome (HCPS), which is endemic in the Americas. HCPS and HFRS are separate clinical entities, but they share several features and have many overlapping symptoms, signs, and pathogenic alterations. For HCPS in particular, clinical outcomes are highly associated with early clinical suspicion, access to rapid diagnostic testing or algorithms for presumptive diagnosis, and prompt transfer to a facility with critical care units. No specific effective antiviral treatment is available.

First wave of SARS-CoV-2 in Santiago Chile: Seroprevalence, asymptomatic infection and infection fatality rate.

BACKGROUND: The first wave of SARS-CoV-2 infection in Chile occurred during the cold season reaching a peak by the end of June 2020, with 80 % of the cases concentrated in its capital, Santiago. The main objective of this study was to estimate the attack rate during this first wave of SARS-CoV-2 in a large, densely populated city with more than seven million inhabitants. Since the number of confirmed cases provides biased information due to individuals' potential self-selection, mostly related to asymptomatic patients and testing access, we measured antibodies against SARS-CoV-2 to assess infection prevalence during the first wave in the city, as well as estimate asymptomatic cases, and infection fatality ratio. To our knowledge this is one of the few population-based cross-sectional serosurvey during the first wave in a highly affected emerging country. The challenges of pandemic response in urban settings in a capital city like Santiago, with heterogeneous subpopulations and high mobility through public transportation, highlight the necessity of more accurate information regarding the first waves of new emerging diseases. METHODS: From April 24 to June 21, 2020, 1326 individuals were sampled from a long-standing panel of household representatives of Santiago. Immunochromatographic assays were used to detect IgM and IgG antibody isotypes. RESULTS: Seroprevalence reached 6.79 % (95 %CI 5.58 %-8.26 %) in the first 107 days of the pandemic, without significant differences among sex and age groups; this figure indicates an attack rate 2.8 times higher than the one calculated with registered cases. It also changes the fatality rate estimates, from a 2.33 % case fatality rate reported by MOH to an estimated crude 1.00 % (CI95 % 0.97-1.03) infection fatality rate (adjusted for test performance 1.66 % [CI95 % 1.61-1.71]). Most seropositive were symptomatic (81,1 %). CONCLUSIONS: Despite the high number of cases registered, mortality rates, and the stress produced over the health system, the vast majority of the people remained susceptible to potential new epidemic waves. We contribute to the understanding of the initial spread of emerging epidemic threats. Consequently, our results provide better information to design early strategies that counterattack new health challenges in urban contexts.

Proteinuria in Hantavirus Cardiopulmonary Syndrome: A Frequent Finding Linked To Mortality.

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.

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

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.

Correction: Indirect Immunofluorescence Assay for the Simultaneous Detection of Antibodies against Clinically Important Old and New World Hantaviruses.

[This corrects the article DOI: 10.1371/journal.pntd.0002157.].

Comparison of VSV Pseudovirus and Focus Reduction Neutralization Assays for Measurement of Anti-Andes orthohantavirus Neutralizing Antibodies in Patient Samples.

Andes orthohantavirus (ANDV) is the etiologic agent of hantavirus cardiopulmonary syndrome (HCPS), which has a case fatality rate around 35%, with no effective treatment or vaccine available. ANDV neutralizing antibody (NAb) measurements are important for the evaluation of the immune response following infection, vaccination, or passive administration of investigational monoclonal or polyclonal antibodies. The standard assay for NAb measurement is a focus reduction neutralization test (FRNT) featuring live ANDV and must be completed under biosafety level (BSL)-3 conditions. In this study, we compared neutralization assays featuring infectious ANDV or vesicular stomatitis virus (VSV) pseudovirions decorated with ANDV glycoproteins for their ability to measure anti-ANDV NAbs from patient samples. Our studies demonstrate that VSV pseudovirions effectively measure NAb from clinical samples and have greater sensitivity compared to FRNT with live ANDV. Importantly, the pseudovirus assay requires less labor and sample materials and can be conducted at BSL-2.

Hemodynamic and Pulmonary Permeability Characterization of Hantavirus Cardiopulmonary Syndrome by Transpulmonary Thermodilution.

Hantavirus cardiopulmonary syndrome (HCPS) is characterized by capillary leak, pulmonary edema (PE), and shock, which leads to death in up to 40% of patients. Treatment is supportive, including mechanical ventilation (MV) and extracorporeal membrane oxygenation (ECMO). Hemodynamic monitoring is critical to titrate therapy and to decide ECMO support. Transpulmonary thermodilution (TPTD) provides hemodynamic and PE data that have not been systematically used to understand HCPS pathophysiology. We identified 11 HCPS patients monitored with TPTD: eight on MV, three required ECMO. We analyzed 133 measurements to describe the hemodynamic pattern and its association with PE. The main findings were reduced stroke volume, global ejection fraction (GEF), and preload parameters associated with increased extravascular lung water and pulmonary vascular permeability compatible with hypovolemia, myocardial dysfunction, and increased permeability PE. Lung water correlated positively with heart rate (HR, r = 0.20) and negatively with mean arterial pressure (r = -0.27) and GEF (r = -0.36), suggesting that PE is linked to hemodynamic impairment. Pulmonary vascular permeability correlated positively with HR (r = 0.31) and negatively with cardiac index (r = -0.49), end-diastolic volume (r = -0.48), and GEF (r = -0.40), suggesting that capillary leak contributes to hypovolemia and systolic dysfunction. In conclusion, TPTD data suggest that in HCPS patients, increased permeability leads to PE, hypovolemia, and circulatory impairment.

A 19 Year Analysis of Small Mammals Associated with Human Hantavirus Cases in Chile.

Small mammals present in areas where hantavirus cardiopulmonary syndrome (HCPS) cases had occurred in central and southern Chile were captured and analyzed to evaluate the abundance of rodents and seroprevalence rates of antibodies to Andes orthohantavirus (ANDV). Sampling areas ranged from the Coquimbo to Aysén regions (30-45° S approx.) regions. Ninety-two sites in peridomestic and countryside areas were evaluated in 19 years of sampling. An antibody against ANDV was detected by strip immunoassay in 58 of 1847 specimens captured using Sherman traps. Of the eleven species of rodents sampled, Abrothrix olivacea, Oligoryzomys longicaudatus and Abrothrix hirta were the most frequently trapped. O. longicaudatus had the highest seropositivity rate, and by logistic regression analysis, O. longicaudatus of at least 60 g had 80% or higher probability to be seropositive. Sex, age and wounds were significantly related to seropositivity only for O. longicaudatus. Across administrative regions, the highest seropositivity was found in the El Maule region (34.8-36.2° S), and the highest number of HCPS cases was registered in the Aysén region. Our results highlight the importance of long term and geographically extended studies, particularly for highly fluctuating pathogens and their reservoirs, to understand the implications of the dynamics and transmission of zoonotic diseases in human populations.

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.

Molecular method for the detection of Andes hantavirus infection: validation for clinical diagnostics.

Hantavirus cardiopulmonary syndrome is a severe disease caused by exposure to New World hantaviruses. Early diagnosis is difficult due to the lack of specific initial symptoms. Antihantavirus antibodies are usually negative until late in the febrile prodrome or the beginning of cardiopulmonary phase, while Andes hantavirus (ANDV) RNA genome can be detected before symptoms onset. We analyzed the effectiveness of quantitative reverse transcription polymerase chain reaction (RT-qPCR) as a diagnostic tool detecting ANDV-Sout genome in peripheral blood cells from 78 confirmed hantavirus patients and 166 negative controls. Our results indicate that RT-qPCR had a low detection limit (~10 copies), with a specificity of 100% and a sensitivity of 94.9%. This suggests the potential for establishing RT-qPCR as the assay of choice for early diagnosis, promoting early effective care of patients, and improving other important aspects of ANDV infection management, such as compliance of biosafety recommendations for health personnel in order to avoid nosocomial transmission.

A non-randomized multicentre trial of human immune plasma for treatment of hantavirus cardiopulmonary syndrome caused by Andes virus.

BACKGROUND: In Chile, Andes virus (ANDV) is the sole aetiological agent of hantavirus cardiopulmonary syndrome (HCPS) with mean annual incidence of 55 cases, 32% case fatality rate (CFR) and no specific treatment. Neutralizing antibody (NAb) titres at hospital admission correlate inversely with HCPS severity. We designed an open trial to explore safety and efficacy and evaluate pharmacokinetics of immune plasma as a treatment strategy for this disease. METHODS: We performed plasmapheresis on donors at least 6 months after HCPS and measured NAb titres through a focus-reduction neutralization test. Subjects admitted to 10 study sites with suspected/confirmed HCPS were eligible for treatment with immune plasma by intravenous infusion at an ANDV NAb dose of 5,000 U/kg. HCPS was confirmed through immunoglobulin M serology or reverse transcriptase-PCR. The main outcome was mortality within 30 days. RESULTS: From 2008-2012, we enrolled and treated 32 cases and confirmed HCPS in 29. CFR of hantavirus plasma-treated cases was 4/29 (14%); CFR of non-treated cases in the same period in Chile was 63/199 (32%; P=0.049, OR=0.35, CI=0.12, 0.99); CFR of non-treated cases at the same study sites between 2005-2012 was 18/66 (27%; (P=0.15, OR=0.43, CI=0.14, 1.34) and CFR in a previous methylprednisolone treatment study was 20/60 (33%; P=0.052, OR=0.32, CI=0.10, 1.00). We detected no serious adverse events associated to plasma infusion. Plasma NAb titres reached in recipients were variable and viral load remained stable. CONCLUSIONS: Human ANDV immune plasma infusion appears safe for HCPS. We observed a decrease in CFR in treated cases with borderline significance that will require further studies for confirmation.

Person-to-person household and nosocomial transmission of andes hantavirus, Southern Chile, 2011.

Andes hantavirus (ANDV) causes hantavirus cardiopulmonary syndrome in Chile and is the only hantavirus for which person-to-person transmission has been proven. We describe an outbreak of 5 human cases of ANDV infection in which symptoms developed in 2 household contacts and 2 health care workers after exposure to the index case-patient. Results of an epidemiologic investigation and sequence analysis of the virus isolates support person-to-person transmission of ANDV for the 4 secondary case-patients, including nosocomial transmission for the 2 health care workers. Health care personnel who have direct contact with ANDV case-patients or their body fluids should take precautions to prevent transmission of the virus. In addition, because the incubation period of ANDV after environmental exposure is longer than that for person-to-person exposure, all persons exposed to a confirmed ANDV case-patient or with possible environmental exposure to the virus should be monitored for 42 days for clinical symptoms.

High-dose intravenous methylprednisolone for hantavirus cardiopulmonary syndrome in Chile: a double-blind, randomized controlled clinical trial.

BACKGROUND: Andes virus (ANDV)-related hantavirus cardiopulmonary syndrome (HCPS) has a 35% case fatality rate in Chile and no specific treatment. In an immunomodulatory approach, we evaluated the efficacy of intravenous methylprednisolone for HCPS treatment, through a parallel-group, placebo-controlled clinical trial. METHODS: Patients aged >2 years, with confirmed or suspected HCPS in cardiopulmonary stage, admitted to any of 13 study sites in Chile, were randomized by study center in blocks of 4 with a 1:1 allocation and assigned through sequentially numbered envelopes to receive placebo or methylprednisolone 16 mg/kg/day (≤1000 mg) for 3 days. All personnel remained blinded except the local pharmacist. Infection was confirmed by immunoglobulin M antibodies or ANDV RNA in blood. The composite primary endpoint was death, partial pressure of arterial oxygen/fraction of inspired oxygen ratio ≤55, cardiac index ≤2.2, or ventricular tachycardia or fibrillation within 28 days. Safety endpoints included the number of serious adverse events (SAEs) and quantification of viral RNA in blood. Analysis was by intention to treat. RESULTS: Infection was confirmed in 60 of 66 (91%) enrollees. Fifteen of 30 placebo-treated patients and 11 of 30 methylprednisolone-treated patients progressed to the primary endpoint (P = .43). We observed no significant difference in mortality between treatment groups (P = .41). There was a trend toward more severe disease in placebo recipients at entry. More subjects in the placebo group experienced SAEs (P = .02). There were no SAEs clearly related to methylprednisolone administration, and methylprednisolone did not increase viral load. CONCLUSIONS: Although methylprednisolone appears to be safe, it did not provide significant clinical benefit to patients. Our results do not support the use of methylprednisolone for HCPS. CLINICAL TRIALS REGISTRATION: NCT00128180.

Indirect immunofluorescence assay for the simultaneous detection of antibodies against clinically important old and new world hantaviruses.

In order to detect serum antibodies against clinically important Old and New World hantaviruses simultaneously, multiparametric indirect immunofluorescence assays (IFAs) based on biochip mosaics were developed. Each of the mosaic substrates consisted of cells infected with one of the virus types Hantaan (HTNV), Puumala (PUUV), Seoul (SEOV), Saaremaa (SAAV), Dobrava (DOBV), Sin Nombre (SNV) or Andes (ANDV). For assay evaluation, serum IgG and IgM antibodies were analyzed using 184 laboratory-confirmed hantavirus-positive sera collected at six diagnostic centers from patients actively or previously infected with the following hantavirus serotypes: PUUV (Finland, n=97); SEOV (China, n=5); DOBV (Romania, n=7); SNV (Canada, n=23); ANDV (Argentina and Chile, n=52). The control panel comprised 89 sera from healthy blood donors. According to the reference tests, all 184 patient samples were seropositive for hantavirus-specific IgG (n=177; 96%) and/or IgM (n=131; 72%), while all control samples were tested negative. In the multiparametric IFA applied in this study, 183 (99%) of the patient sera were IgG and 131 (71%) IgM positive (accordance with the reference tests: IgG, 96%; IgM, 93%). Overall IFA sensitivity for combined IgG and IgM analysis amounted to 100% for all serotypes, except for SNV (96%). Of the 89 control sera, 2 (2%) showed IgG reactivity against the HTNV substrate, but not against any other hantavirus. Due to the high cross-reactivity of hantaviral nucleocapsid proteins, endpoint titrations were conducted, allowing serotype determination in >90% of PUUV- and ANDV-infected patients. Thus, multiparametric IFA enables highly sensitive and specific serological diagnosis of hantavirus infections and can be used to differentiate PUUV and ANDV infection from infections with Murinae-borne hantaviruses (e.g. DOBV and SEOV).

Pandemic influenza A (H1N1) 2009 with neurological manifestations, a case series.

OBJECTIVES: Describe a series of atypical presentations of pandemic influenza A (H1N1) 2009. METHODS: Description of case series using hospital records. RESULTS: Six patients aged 1 to 65 years with confirmed pandemic influenza A (H1N1) 2009 infection presented with neurological complications within 2 to 5 days after the first signs of influenza-like illness. All six were admitted with seizures or altered mental status. No abnormalities were found in brain scans or cerebral spinal fluid studies of any of the six. All were discharged without sequelae within days of admission. CONCLUSIONS: This is only the second report of pandemic influenza presenting with neurological manifestations. Clinicians caring for patients when pandemic influenza is prevalent in their communities should maintain a high level of awareness of the potential atypical presentations with which this disease can appear.

Ecology, genetic diversity, and phylogeographic structure of andes virus in humans and rodents in Chile.

Andes virus (ANDV) is the predominant etiologic agent of hantavirus cardiopulmonary syndrome (HCPS) in southern South America. In Chile, serologically confirmed human hantavirus infections have occurred throughout a wide latitudinal distribution extending from the regions of Valparaíso (32 to 33 degrees S) to Aysén (46 degrees S) in southern Patagonia. In this study, we found seropositive rodents further north in the Coquimbo region (30 degrees S) in Chile. Rodent seroprevalence was 1.4%, with Oligoryzomys longicaudatus displaying the highest seroprevalence (5.9%), followed by Abrothrix longipilis (1.9%) and other species exhibiting

Incubation period of hantavirus cardiopulmonary syndrome.

The potential incubation period from exposure to onset of symptoms was 7-39 days (median 18 days) in 20 patients with a defined period of exposure to Andes virus in a high-risk area. This period was 14-32 days (median 18 days) in 11 patients with exposure for <48 hours.

Diagnosis and treatment of new world hantavirus infections.

PURPOSE OF REVIEW: The purpose of this review is to summarize the current knowledge regarding the diagnosis and treatment of indigenous new world hantavirus infections. RECENT FINDINGS: Recent studies have defined the incubation period of new world hantavirus infections, provided additional evidence for person-to-person transmission of Andes virus, described a rapid method for the presumptive diagnosis of infection in the cardiopulmonary phase through a review of the peripheral smear, and suggested that intravenous ribavirin is probably not effective for the treatment of new world hantavirus infections when started in the cardiopulmonary phase. SUMMARY: Presumptive diagnosis may be made by a review of the peripheral blood smear after the onset of the cardiopulmonary phase. Critical care management includes the avoidance of fluid overload, pressors to maintain cardiac output, and the use of extracorporeal membrane oxygenation in the most severe cases, but treatment with intravenous ribavirin is probably not effective.