Urgent call for improved diagnostics, treatments, and vaccines against deadly Hantavirus

By Dr. Priyom Bose, Ph.D.Reviewed by Benedette Cuffari, M.Sc.Apr 30 2023

Hantaviruses are found globally and can cause hemorrhagic fevers with renal syndrome (HFRS) and hantavirus cardiopulmonary syndrome (HCPS). Various factors can influence the epidemiology and transmission of hantaviruses, such as the environment, climate, human behavior in epidemic regions, and ecology of rodent hosts.

In a recent The Lancet Infectious Diseases study, scientists review previous publications to better understand the clinical outcomes and management of Hantavirus infection in humans.

Study: Hantavirus in humans: a review of clinical aspects and management. Image Credit: ALPA PROD / Shutterstock.com

What are hantaviruses?

Hantaviruses belong to the family Hantaviridae and the genus Orthohantavirus. These virus particles are between 80-120 nanometers (nm) in diameter and possess a negative-strand ribonucleic acid (RNA) genome.

The viral genome is divided into three segments, including small (S), medium (M), and large (L) segments. The S segment encodes the nucleocapsid protein, whereas the M and L segments encode the envelope glycoproteins and viral RNA-dependent RNA polymerase, respectively.

Although rodents are the natural host for Hantavirus, this virus has also been detected in moles, bats, fish, reptiles, and shrews. Natural hosts infected with Hantavirus do not manifest significant biological effects. Typically, rodents excrete Hantaviruses in urine, saliva, and feces. 

Humans can be infected with Hantaviruses through inhalation of secreted viruses or rodent bites. There remains a lack of research available on the duration of viability of these viruses in the environment.

One previous study indicated that Puumala virus (PUUV) survives at room temperature for five days in a wet environment and 24 hours in dry conditions. Comparatively, the Hantaan virus (HTNV) remains viable in wet conditions for eight days at 20°C and nine days at 37°C.

Pathogenesis and clinical symptoms

Hantaviruses target endothelial cells of capillaries and small vessels to enhance their vascular permeability. In HFRS, changes in endothelial permeability can alter platelet function and coagulation.

Histopathological studies have indicated that HFRS-causing hantaviruses modify renal medulla capillaries, while HCPS-causing hantaviruses affect pulmonary capillaries.

Both HCPS and HFRS are characterized by strong inflammation that affects vascular endothelial cells and contributes to the development of renal failure.

Based on chest X-rays or computed tomography (CT) scans, all patients with HCPS and most with HFRS exhibit respiratory symptoms such as hypoxia. Some of the common symptoms of HFRS include coagulation dysregulation, acute kidney injury, and vascular permeability.

HFRS infection is divided into five stages, beginning with febrile, hypotensive, oliguric, diuretic, and convalescent. The disease progression and severity depend on the type of hantavirus and the individual’s immunity.

After the incubation period of two to six weeks, acute onset of high fever, nausea, headache, abdominal pain, and back pain have been reported. In addition, hypotension is commonly induced due to vascular leakage.

Patients with severe HFRS exhibit menorrhagia, metrorrhagia, petechiae in skin or mucosa, gastrointestinal bleeding, and epistaxis. Both adults and children experience similar clinical manifestations of HFRS.

Both the respiratory and cardiovascular systems are primarily targeted by HCPS-causing hantaviruses. Some of the prominent symptoms of HCPS include headaches, abdominal pain, chills, myalgias, diarrhea, arthralgia, retro-ocular pain, and vomiting. Infrequent respiratory symptoms, such as nasal congestion and odynophagia, have also been reported.

Diagnosis

It is important to differentiate between HFRS and HCPS, particularly in the prodromal phase. Urine dipstick analysis is frequently used to confirm a suspected case of HFRS.

These tests are often followed by serological analysis, such as enzyme-linked immunosorbent assay (ELISA). Here, immunoglobulin M (IgM) antibodies against the Hantavirus nucleocapsid protein are detected at the onset of the febrile prodrome, while IgG antibodies are found at the end of the febrile prodrome. 

Immunochromatographic IgM assays are conducted to detect HFRS caused by PUUV, HTNV, and Dobrava virus (DOBV). Both IgG and IgM ELISAs are used to detect acute infection.

Neutralizing antibody assays are used to determine monoclonal antibody levels, as well as the immunity conferred by both vaccines and natural infection. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) assays are used to diagnose PUUV and DOBV in the early phase of infection. Next-generation sequencing has also been used to study viral genomic epidemiology.

Treatment

To date, no specific antiviral or immunomodulatory treatments are available for Hantavirus infection. One clinical trial conducted in China revealed that intravenous ribavirin reduced mortality linked to HFRS. Another trial contradicted this finding and reported that ribavirin was not effective when HFRS was caused by PUUV.

One clinical trial conducted in Chile revealed that high-dose intravenous methylprednisolone was ineffective against HCPS in the cardiopulmonary phase.

Hantavirus infection can be managed through careful monitoring of clinical symptoms, blood pressure, fluid and electrolyte balance, and urine tests. Common treatments include analgesics, oxygenation against hypoxia, correction of electrolyte imbalances, and intravenous fluids to prevent hypotension. About 15% of patients infected with PUUV require dialysis.

During severe infections that cause kidney failure and acute respiratory distress syndrome, renal replacement therapy and mechanical ventilation might be required. Animal models have revealed that favipiravir could be effective against the Sin Nombre virus (SNV) when administered before the onset of viremia. Icatibant acetate, which is a bradykinin receptor antagonist, was found to be effective in the treatment of severe HFRS.