Hantavirus infection-related acute inflammatory demyelinative polyradiculoneuropathy: A case report and literature review.

RATIONALE: Hemorrhagic fever with renal syndrome (HFRS) is a common infectious disease in China. As a complication of post-Hantavirus infection, Guillain-Barre syndrome (GBS) was rarely previously reported. Here, we described a case of acute inflammatory demyelinative polyradiculoneuropathy secondary to Hantavirus infection in spring of 2023. We also made a summary of the clinical features from previous reported cases. PATIENT CONCERNS: A young male patient complained a fever with headache, who was subsequently diagnosed with HFRS with positive serum Hantavirus antibody IgM. Two weeks later, he presented sustained back pain, obvious numbness located in 4 extremities, chest and abdomen, facial dyskinesia and 4 extremities muscle weakness. DIAGNOSIS, INTERVENTIONS, AND OUTCOMES: He was rapidly diagnosed with GBS by typical cerebrospinal fluid change and the electromyography examination presentation, which was verified associated with hantavirus infection. He was treated with intravenous immunoglobulin infusion followed by rehabilitation treatment. He got a complete recovery within 4 months after disease onset. LESSONS: GBS was an uncommon manifestation of Hantavirus infection. GBS should be considered when acute limb weakness happens in cases with HFRS. A multidisciplinary team could make a rapid diagnosis and optimal treatment when nervous system disorders occurred.

Favorable course of leptospirosis and hantavirus-induced acute tubulointerstitial nephritis under corticosteroid treatment.

BACKGROUND: We present two children with acute tubulointerstitial nephritis (ATIN) caused by leptospirosis in a 12-year-old boy and hantavirus in a 10-year-old girl. The role of glucocorticoids in the management of ATIN triggered by infectious agents is unclear. CASE-DIAGNOSIS/TREATMENT: Both children were hospitalized with jaundice, elevated serum creatinine, and thrombocytopenia. There was no oliguria or hypertension. Urine analysis revealed tubular proteinuria. Kidney biopsy was performed on one patient and showed tubulointerstitial inflammation with mild mesangial proliferation. Both patients were treated with glucocorticoids in view of deteriorating kidney function with respective serum creatinine values of 5.2 and 4.1 mg/dl. Both children exhibited an excellent clinical and biochemical response to treatment. Neither of the patients required dialysis. Positive serology test results indicated a recent leptospirosis and hantavirus infection. CONCLUSIONS: Leptospirosis and hantavirus associated ATIN share common clinical and biochemical features. Due to the low incidence in Europe these infectious causes of kidney dysfunction may be overlooked. Glucocorticoids may be considered in the management of ATIN.

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.

Chloroquine, an Anti-Malaria Drug as Effective Prevention for Hantavirus Infections.

We investigated whether chloroquine can prevent hantavirus infection and disease in vitro and in vivo, using the Hantaan virus newborn C57BL/6 mice model and the Syrian hamster model for Andes virus. In vitro antiviral experiments were performed using Vero E6 cells, and Old World and New World hantavirus species. Hantavirus RNA was detected using quantitative RT-PCR. For all hantavirus species tested, results indicate that the IC50 of chloroquine (mean 10.2 ± 1.43 µM) is significantly lower than the CC50 (mean 260 ± 2.52 µM) yielding an overall selectivity index of 25.5. We also investigated the potential of chloroquine to prevent death in newborn mice after Hantaan virus infection and its antiviral effect in the hantavirus Syrian hamster model. For this purpose, C57Bl/6 mother mice were treated subcutaneously with daily doses of chloroquine. Subsequently, 1-day-old suckling mice were inoculated intracerebrally with 5 x 102 Hantaan virus particles. In litters of untreated mothers, none of the pups survived challenge. The highest survival rate (72.7% of pups) was found when mother mice were administered a concentration of 10 mg/kg chloroquine. Survival rates declined in a dose-dependent manner, with 47.6% survival when treated with 5 mg/kg chloroquine, and 4.2% when treated with 1 mg/kg chloroquine. Assessing the antiviral therapeutic and prophylactic effect of chloroquine in the Syrian hamster model was done using two different administration routes (intraperitoneally and subcutaneously using an osmotic pump system). Evaluating the prophylactic effect, a delay in onset of disease was noted and for the osmotic pump, 60% survival was observed. Our results show that chloroquine can be highly effective against Hantaan virus infection in newborn mice and against Andes virus in Syrian hamsters.

Identification of Novel Antiviral Compounds Targeting Entry of Hantaviruses.

Hemorrhagic fever viruses, among them orthohantaviruses, arenaviruses and filoviruses, are responsible for some of the most severe human diseases and represent a serious challenge for public health. The current limited therapeutic options and available vaccines make the development of novel efficacious antiviral agents an urgent need. Inhibiting viral attachment and entry is a promising strategy for the development of new treatments and to prevent all subsequent steps in virus infection. Here, we developed a fluorescence-based screening assay for the identification of new antivirals against hemorrhagic fever virus entry. We screened a phytochemical library containing 320 natural compounds using a validated VSV pseudotype platform bearing the glycoprotein of the virus of interest and encoding enhanced green fluorescent protein (EGFP). EGFP expression allows the quantitative detection of infection and the identification of compounds affecting viral entry. We identified several hits against four pseudoviruses for the orthohantaviruses Hantaan (HTNV) and Andes (ANDV), the filovirus Ebola (EBOV) and the arenavirus Lassa (LASV). Two selected inhibitors, emetine dihydrochloride and tetrandrine, were validated with infectious pathogenic HTNV in a BSL-3 laboratory. This study provides potential therapeutics against emerging virus infection, and highlights the importance of drug repurposing.

Acute angle-closure glaucoma with choroidal effusion revealing a hantavirus infection: Description of ultrasound biomicroscopy imagery and optical coherence tomography Visante.

PURPOSE: To report a case of bilateral angle-closure associated with systemic hantavirus infection. MATERIALS AND METHODS: A 32-year-old Caucasian man was referred with blurred vision, fever, cough, dyspnea and thrombocytopenia. Ophthalmologic examination revealed myopic shift, elevated intraocular pressure (30 mmHg right eye and 24 mmHg left eye), corneal edema, iridocorneal angle closure and shallow anterior chamber. Ciliochoroidal effusion was detected on anterior segment optical coherence tomography and ultrasound biomicroscopy. Serologic test and polymerase chain reaction confirmed the diagnosis of hantavirus infection and the serotype Puumala. On the sixth day after he started topical anti-glaucoma and cycloplegic medications, the anterior chamber and iridocorneal angles were normalized with disappearance of ciliochoroidal effusion. CONCLUSION: Puumala hantavirus infection is an exceptional cause of acute bilateral angle-closure combined with ciliochoroidal effusion.

Guia para el manejo terapéutico de la infección por hantavirus andes sur / Guide for the therapeutic management of andes sur hantavirus infection

El panel priorizó la posibilidad de una reducción significativa en la mortalidad por sobre la incertidumbre en los efectos de la intervención (muy baja certeza en la evidencia), los efectos adversos del tratamiento y la carga del tratamiento en términos de utilización de recursos necesarios para implementar la intervención. La evidencia en estudios en humanos con infección por hantavirus con síndrome cardiopulmonar muestra que el tratamiento con ribavirina en humanos podria reducir el riesgo de muerte en etapa asintomatica o prodromica (RR 0.28; IC 95%: 0,08 a 1). En ensayos en modelos animales infectados con hantavirus en fase asintomatica (hasta 7 dias luego de la inoculacion del virus) mostró una disminución de la mortalidad entre el 12% y el 81% (RR 0.41; 0.19 a 0.88. Sin embargo, no es posible determinar el impacto sobre la mortalidad, ya que la certeza en la evidencia sobre este desenlace resultó muy baja por lo que existe incertidumbre sobre el efecto de ribavirina en pacientes con infección por hantavirus en etapas asintomática o prodrómica. La incidencia de efectos adversos que llevaron a discontinuar el tratamiento fue de 4%. El efecto adverso más frecuentemente reportado fue anemia hemolítica con una incidencia de 14% (la mayoría de los casos no fueron severos). Otros efectos adversos menos frecuentes fueron nefrotoxicidad, pancreatitis, rash y hepatotoxicidad. Existe una incertidumbre en relación al riesgo de efectos adversos severos asociados a la ribavirina dada la muy baja certeza de la evidencia, que se basa en estudios observacionales. La ribavirina probablemente se asocie con anemia con un 57.8% más (25.3 más a 111.9 más) en la rama intervención.

Progress on the Prevention and Treatment of Hantavirus Disease.

Hantaviruses, members of the order Bunyavirales, family Hantaviridae, have a world-wide distribution and are responsible for greater than 150,000 cases of disease per year. The spectrum of disease associated with hantavirus infection include hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS) also known as hantavirus cardiopulmonary syndrome (HCPS). There are currently no FDA-approved vaccines or treatments for these hantavirus diseases. This review provides a summary of the status of vaccine and antiviral treatment efforts including those tested in animal models or human clinical trials.

Use of ribavirin in viruses other than hepatitis C. A review of the evidence. / Uso de ribavirina en virus distintos de la hepatitis C. Una revisión de la evidencia.

Ribavirin is a molecule with antiviral activity against different viruses. In clinical practice, it has made its niche almost exclusively for the treatment of the hepatitisC virus. However, there are other diseases in which it could be of benefit and it has the advantage of being suitable for oral, intravenous and inhaled administration. We conducted a review of the indications of the main drug agencies (Spanish, European and American) and other possible indications, mainly haemorrhagic fevers and coronavirus.

Two recombinant human monoclonal antibodies that protect against lethal Andes hantavirus infection in vivo.

Andes hantavirus (ANDV) is an etiologic agent of hantavirus cardiopulmonary syndrome (HCPS), a severe disease characterized by fever, headache, and gastrointestinal symptoms that may progress to hypotension, pulmonary failure, and cardiac shock that results in a 25 to 40% case-fatality rate. Currently, there is no specific treatment or vaccine; however, several studies have shown that the generation of neutralizing antibody (Ab) responses strongly correlates with survival from HCPS in humans. In this study, we screened 27 ANDV convalescent HCPS patient sera for their capacity to bind and neutralize ANDV in vitro. One patient who showed high neutralizing titer was selected to isolate ANDV-glycoprotein (GP) Abs. ANDV-GP-specific memory B cells were single cell sorted, and recombinant immunoglobulin G antibodies were cloned and produced. Two monoclonal Abs (mAbs), JL16 and MIB22, potently recognized ANDV-GPs and neutralized ANDV. We examined the post-exposure efficacy of these two mAbs as a monotherapy or in combination therapy in a Syrian hamster model of ANDV-induced HCPS, and both mAbs protected 100% of animals from a lethal challenge dose. These data suggest that monotherapy with mAb JL16 or MIB22, or a cocktail of both, could be an effective post-exposure treatment for patients infected with ANDV-induced HCPS.

A High-Throughput Flow Cytometry Screen Identifies Molecules That Inhibit Hantavirus Cell Entry.

Hantaviruses cause hemorrhagic fever with renal syndrome (HFRS) and hantavirus cardiopulmonary syndrome (HCPS), which infects more than 200,000 people worldwide. Sin Nombre virus (SNV) and Andes virus (ANDV) cause the most severe form of HCPS, with case fatality ratios of 30%-40%. There are no specific therapies or vaccines for SNV. Using high-throughput flow cytometry, we screened the Prestwick Chemical Library for small-molecule inhibitors of the binding interaction between UV-inactivated and fluorescently labeled SNVR18 particles, and decay-accelerating factor (DAF) expressed on Tanoue B cells. Eight confirmed hit compounds from the primary screen were investigated further in secondary screens that included infection inhibition, cytotoxicity, and probe interference. Antimycin emerged as a bona fide hit compound that inhibited cellular infection of the major HCPS (SNV)- and HCPS (Hantaan)-causing viruses. Confirming our assay's ability to detect active compounds, orthogonal testing of the hit compound showed that antimycin binds directly to the virus particle and blocks recapitulation of physiologic integrin activation caused by SNV binding to the integrin PSI domain.

Development of High-Throughput Screening Assay for Antihantaviral Therapeutics.

Humans acquire hantavirus infection by the inhalation of aerosolized excreta of infected rodent hosts. There is no treatment for hantavirus diseases at present. Therapeutic intervention during early stages of viral infection can improve the outcome of this zoonotic viral illness. The interaction between an evolutionary conserved sequence at the 5' terminus of hantaviral genomic RNA and hantavirus nucleocapsid protein plays a critical role in the hantavirus replication cycle. This unique interaction is a novel target for therapeutic intervention of hantavirus disease. We developed a very sensitive, tractable, and cost-effective fluorescence-based assay to monitor the interaction between the nucleocapsid protein and the target RNA sequence. The assay was optimized for high-throughput screening of chemical libraries to identify molecules that interrupt this RNA-protein interaction. The assay was validated using a library of 6880 chemical compounds. This validation screen demonstrated the reproducibility and validity of required statistical criteria for high-throughput screening. The assay is ready to use for high-throughput screening of large chemical libraries to identify antihantaviral therapeutic molecules and can be amenable to similar targets in other viruses.

Antiviral therapy and prevention against hantavirus infections.

Hantaviruses are emerging zoonoses hosted by small mammals. In humans, they cause two diseases. Hemorrhagic fever with renal syndrome is mainly caused by Dobrava-Belgrade virus, Puumala virus, Seoul virus and Hantaan virus in Asia and Europe. On the other hand, the most important causes of hantavirus cardiopulmonary syndrome are Sin Nombre virus and Andes virus in Americas. Ribavirin yet remains the only licensed drug against the hantavirus infections, but its sufficient antiviral activity remains an issue under discussion. There are still no available vaccines against hantaviruses except of some inactivated virus vaccines licensed only in East-Asian countries. Some of the vaccines are under development in pre-clinical stages. The review discuses about specific compounds with approved antiviral activity against hantaviruses. Other approaches such as development of vaccines, are compiled as well.

Targeting a Novel RNA-Protein Interaction for Therapeutic Intervention of Hantavirus Disease.

An evolutionarily conserved sequence at the 5' terminus of hantaviral genomic RNA plays an important role in viral transcription initiation and packaging of the viral genome into viral nucleocapsids. Interaction of viral nucleocapsid protein (N) with this conserved sequence facilitates mRNA translation by a unique N-mediated translation strategy. Whereas this evolutionarily conserved sequence facilitates virus replication with the assistance of N in eukaryotic hosts having multifaceted antiviral defense, we demonstrate its interaction with N presents a novel target for therapeutic intervention of hantavirus disease. Using a high throughput screening approach, we identified three lead inhibitors that bind and induce structural perturbations in N. The inhibitors interrupt N-RNA interaction and abrogate both viral genomic RNA synthesis and N-mediated translation strategy without affecting the canonical translation machinery of the host cell. The inhibitors are well tolerated by cells and inhibit hantavirus replication with the same potency as ribavarin, a commercially available antiviral. We report the identification of a unique chemical scaffold that disrupts a critical RNA-protein interaction in hantaviruses and holds promise for the development of the first anti-hantaviral therapeutic with broad spectrum antiviral activity.

Meeting report: Tenth International Conference on Hantaviruses.

The 10th International Conference on Hantaviruses, organized by the International Society on Hantaviruses, was held from May 31-June 3, 2016 at Colorado State University, Fort Collins, CO, USA. These conferences have been held every three years since 1980. The current report summarizes research presented on all aspects of hantavirology: ecology and epidemiology, virus replication, phylogeny, pathogenesis, immune response, clinical studies, vaccines and therapeutics.

Successful treatment of severe hantavirus nephritis with corticosteroids: a case report and literature review.

Hantaviruses can be associated with severe form of hemorrhagic fever with renal syndrome although there are only a few cases reporting chronic kidney disease after hantavirus infection. We report a severe nonresolving chronic renal failure after protracted Dobrava hantavirus infection successfully treated with corticosteroids. Ten days after working in a basement a 33-year-old man fell seriously ill, with high fever, chills, diffuse myalgia, headache and abdominal pain. After hospital admission a diagnosis of hemorrhagic fever with renal syndrome caused by Dobrava hantavirus was made. Acute oliguric kidney injury developed in the first 3 days after admission, in a few days diuresis restored and he became polyuric. Nevertheless renal failure persisted and he needed hemodialysis. Because of nonresolving kidney failure, nephrogenic diabetes insipidus and renoparenchymal arterial hypertension persisting 2 months after onset of symptoms, a kidney biopsy was performed, showing severe necrotizing tubulointerstitial nephritis. High dose methylprednisolone therapy was started and his renal function significantly improved. Two months later a second renal biopsy showed persisting elements of active necrotizing tubulointerstitial nephritis. We decided to stop corticosteroid treatment and introduced aldosterone antagonist eplerenon as anti-fibrotic agent, and his renal function further improved and remained stable. Nine months later his serum creatinine concentration was 227 µmol/L, proteinuria 0.156 g/day and well controlled nephrogenic diabetes insipidus.

A severe case of Puumala hantavirus infection successfully treated with bradykinin receptor antagonist icatibant.

A patient with severe capillary leakage syndrome caused by a Puumala hantavirus infection was treated with a single dose of icatibant, a bradykinin receptor antagonist, with a dramatic positive response. We suggest that this drug should be tested in a larger number of patients with severe hantavirus infection.

[Hantavirus infection due to Dobrava-Belgrade virus in a third trimester pregnant woman]. / Hantavirusinfektion durch Dobrava-Belgrad-Virus bei einer schwangeren Patientin im 3. Trimenon.

HISTORY AND ADMISSION FINDINGS: A 20-year-old woman was admitted to our hospital because of acute renal failure. She was pregnant in the third trimester. She reported on nausea, feeling of sickness, vomiting, abdominal pain and consecutively gross hematuria and sinustachycardia. Under suspicion of premature labour the patient was admitted to an external hospital. An antibiotic therapy with intravenous ampicillin/sulbactam was initiated. Because of acute kidney injury the patient was transferred firstly to the university women's hospital and finally to the department of nephrology. Obesity, the clinical signs of pregnancy, dehydration and small edema of the lower legs were the main medical findings on examination. INVESTIGATIONS: Laboratory tests revealed hyperuricemia, virological tests detected an acute infection with Dobrava-Belgrade virus. The ultrasonography demonstrated a pregnancy in good condition and a dilated (physiological) renal pelvis but otherwise normal renal morphology. DIAGNOSIS, TREATMENT AND COURSE: A Hantavirus associated acute kidney failure due to infection with the Dobrava-Belgrade virus was diagnosed. The course of the acute renal failure was characterised by remission of all symptoms. Intermittent evaluation by an obstetrician and a nephrologist were done to diagnose maternal and/or fetal complications. A renal replacement therapy was not necessary. At the 41st week of gestation a healthy male infant was born. The development of the newborn was age-appropriate. CONCLUSION: Hantavirus infections should be considered in cases of pregnancy-associated acute kidney injury.

In vitro and in vivo activity of ribavirin against Andes virus infection.

Pathogenic hantaviruses are a closely related group of rodent-borne viruses which are responsible for two distinct diseases in humans, hemorrhagic fever with renal syndrome and hantavirus pulmonary syndrome (HPS, otherwise known as hantavirus cardiopulmonary syndrome, HCPS). The antiviral effect of ribavirin against Old World hantaviruses, most notably Hantaan virus, is well documented; however, only a few studies have addressed its inhibitory effect on New World hantaviruses. In the present study, we demonstrate that ribavirin is highly active against Andes virus (ANDV), an important etiological agent of HPS, both in vitro and in vivo using a lethal hamster model of HPS. Treatment of ANDV infected Vero E6 cells with ribavirin resulted in dose-dependent reductions in viral RNA and protein as well as virus yields with a half maximal inhibitory concentration between 5 and 12.5 µg ml(-1). In hamsters, treatment with as little as 5 mg kg(-1) day(-1) was 100% effective at preventing lethal HPS disease when therapy was administered by intraperitoneal injection from day 1 through day 10 post-infection. Significant reductions were observed in ANDV RNA and antigen positive cells in lung and liver tissues. Ribavirin remained completely protective when administered by intraperitoneal injections up to three days post-infection. In addition, we show that daily oral ribavirin therapy initiated 1 day post-infection and continuing for ten days is also protective against lethal ANDV disease, even at doses of 5 mg kg(-1) day(-1). Our results suggest ribavirin treatment is beneficial for postexposure prophylaxis against HPS-causing hantaviruses and should be considered in scenarios where exposure to the virus is probable. The similarities between the results obtained in this study and those from previous clinical evaluations of ribavirin against HPS, further validate the hamster model of lethal HPS and demonstrate its usefulness in screening antiviral agents against this disease.