Hantavirus infection medical therapy
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1], Associate Editor(s)-in-Chief: Basir Gill, M.B.B.S, M.D.[2] Seyedmahdi Pahlavani, M.D. [3]
Overview
There is no specific approved antiviral treatment, cure, or vaccine for hantavirus infection in Europe or the Americas.[1][2] Treatment is primarily supportive. Infected individuals who are recognized early and receive medical care in an intensive care unit (ICU) may have improved outcomes. ICU management includes careful assessment, monitoring, and adjustment of volume status and cardiac function, including inotropic and vasopressor support as needed. Extracorporeal membrane oxygenation (ECMO) is effective in the treatment of refractory hantavirus cardiopulmonary syndrome (HCPS), with venoarterial ECMO achieving 80% survival in one series of 25 patients with predicted 100% mortality.[3] Intravenous ribavirin reduced mortality in one controlled trial for hemorrhagic fever with renal syndrome (HFRS) caused by Hantaan virus, but was ineffective against HFRS caused by Puumala virus and showed no survival benefit for HCPS.[1][4] Convalescent immune plasma has shown a promising reduction in case fatality rate (CFR) in a non-randomized trial for HCPS caused by Andes virus.[5]
Medical Therapy
General Principles
There is no specific approved antiviral or immunomodulatory treatment for hantavirus infection. Early diagnosis, hospitalization, and supportive therapy are the fundamentals of treatment.[1] If there is a high degree of clinical suspicion for HCPS, patients should be immediately transferred to an emergency department or ICU with access to ECMO for close monitoring and care.[1][6] Patients should receive appropriate broad-spectrum antibiotic therapy while awaiting confirmation of a diagnosis of HCPS, along with antipyretics and analgesia as needed.[7]
Supportive Therapy for Hantavirus Cardiopulmonary Syndrome (HCPS)
The pathophysiology of HCPS is characterized by pulmonary capillary leak with non-cardiac pulmonary edema, low preload, progressive hypovolemia, cardiac index impairment, and high systemic vascular resistance index in severe disease. This hemodynamic pattern is distinct from classic cardiogenic shock or septic shock.[6][1]
Key principles of supportive care for HCPS include:
Volume management: Volume resuscitation should be avoided, as it can exacerbate pulmonary edema and increase mortality.[1]
Hemodynamic monitoring: When clinical hypoperfusion (mottling, slow capillary refill time) or hyperlactatemia is present, hemodynamic monitoring of cardiac index should be initiated promptly. Cardiac index can be monitored by thermodilution-based techniques, including transpulmonary thermodilution or pulmonary artery catheterization, or by serial echocardiography where trained staff are continuously available.[1]
Inotropic support: Inotropic drugs (dobutamine or epinephrine) are the main strategy for improving cardiac index.[1]
Oxygenation and ventilation: Supplemental oxygen should be administered if patients become hypoxic. Equipment and materials for intubation and mechanical ventilation should be readily available since onset of respiratory failure may be precipitous. However, intubation should be delayed when feasible until vascular access for ECMO has been established.[1][7]
Vasopressor support: Vasopressor agents may be required for refractory hypotension.[7]
Supportive Therapy for Hemorrhagic Fever with Renal Syndrome (HFRS)
Management strategies for HFRS include:[1][2]
- Careful monitoring of clinical signs, fluid and electrolyte balance, blood pressure, and urine output.
- Analgesic drugs for pain management.
- Intravenous fluids for hypotension, with vasoactive drugs for shock.
- Oxygen therapy for hypoxia.
- Correction of electrolyte imbalances.
- Dialysis is required in approximately 15% of patients with Dobrava virus (DOBV) infection, but in less than 5% of patients with Puumala virus (PUUV) infection[1].
- Mechanical ventilation and renal replacement therapy may be necessary in severe cases with acute respiratory distress syndrome (ARDS) and overt kidney failure[1].
Extracorporeal Membrane Oxygenation (ECMO)
When shock is refractory to inotropic drug support, or respiratory support does not provide adequate gas exchange, early connection to venoarterial (VA) ECMO should be considered.[1][6]
Outcomes:
In a study by Wernly et al. (2011), 51 patients with refractory HCPS were supported with ECMO between 1994 and 2010. Overall survival was 66.6% (34 of 51 patients). In the second cohort (2003–2010, n=25), survival was significantly higher at 80% (20/25, P=0.048) compared to 56% (14/26) in the earlier cohort (1994–2000). All survivors recovered completely and were discharged after a mean hospital stay of 19.8 days (range: 10–39 days).[3]
In an earlier report by Dietl et al. (2008), 38 patients with severe HCPS supported with ECMO had an overall survival of 60.5% (23/38). Average ECMO duration was 132 hours (range: 5–276 hours).[8]
The improved survival in the later cohort was attributed to a strategy of early insertion of vascular sheaths based on presumptive or definitive HCPS diagnosis, with delay of intubation until it could be performed almost concurrently with ECMO vascular access placement. Tailored high-volume hemofiltration was used before ECMO in five patients, thereby avoiding ECMO in three patients.[3][1]
Indications for ECMO: Good candidates for ECMO are patients with a cardiac index of <2.5 L/min/m2 despite attempts to resuscitate with pressors and inotropic agents.[9][10]
Antiviral Therapy
Ribavirin
Ribavirin, a guanosine analogue, is the only antiviral agent that has been evaluated in clinical trials for hantavirus infection.
HFRS (Hantaan virus): In a prospective, double-blind, placebo-controlled trial of 242 patients with serologically confirmed HFRS in China, intravenous ribavirin (loading dose 33 mg/kg, then 16 mg/kg every 6 hours for 4 days, then 8 mg/kg every 8 hours for 3 days) resulted in a sevenfold decrease in the risk of mortality (P=0.01). Ribavirin therapy also significantly reduced the risk of entering the oliguric phase and experiencing hemorrhage. The only ribavirin-related side effect was a fully reversible anemia after completion of therapy.[11]
HFRS (Puumala virus): In a randomized, open-label trial of 73 patients with HFRS caused by PUUV in Russia, intravenous ribavirin showed insufficient efficacy. Viral load kinetics were similar in both treatment groups. Significantly more patients receiving ribavirin experienced adverse effects: low hemoglobin (95% vs 36%), hyperbilirubinemia (81% vs 3%), sinus bradycardia (43% vs 14%), and rash (19% vs 0%).[4]
HCPS: A small, placebo-controlled trial of intravenous ribavirin for HCPS in the cardiopulmonary phase in North America suggested no survival benefit.[1]
Dosing regimen (when used for HFRS):
Ribavirin IV infusion: 33 mg/kg loading dose, then 16 mg/kg every 6 hours for 4 days, then 8 mg/kg every 8 hours for 3 days[11]
Methylprednisolone
High-dose intravenous methylprednisolone was ineffective in a controlled trial for HCPS in the cardiopulmonary phase in Chile.[1]
Convalescent Immune Plasma
An association has been shown between low concentrations of specific neutralizing antibodies in serum during the acute phase and severe or fatal outcomes in patients infected with PUUV, ANDV, or SNV.[1][12]
In an open, non-randomized multicenter trial in Chile (2008–2012), 29 confirmed HCPS patients caused by Andes virus were treated with human immune plasma at an ANDV neutralizing antibody dose of 5,000 U/kg. The CFR of plasma-treated cases was 14% (4/29) compared to 32% (63/199) in non-treated cases during the same period (P=0.049, OR=0.35, CI=0.12–0.99). No serious adverse events were associated with plasma infusion. Plasma neutralizing antibody titers reached in recipients were variable, and viral load remained stable.[5]
Investigational Therapies
Favipiravir (T-705)
Favipiravir (T-705), a broad-spectrum antiviral agent that inhibits RNA-dependent RNA polymerase, has shown promising preclinical activity against hantaviruses. In vitro, T-705 potently inhibited both Sin Nombre virus (SNV) and Andes virus (ANDV), with an IC90 estimated at ≤5 μg/mL (≤31.8 μM) for both viruses. In the lethal ANDV hamster model, daily oral T-705 at 50 or 100 mg/kg significantly improved survival rates when treatment was initiated prior to the onset of viremia.[13] Favipiravir also demonstrates potent activity against Hantaan virus (HTNV) in vitro, and combination with ribavirin enhances efficacy.[14] No human clinical trials for hantavirus have been completed. Evaluation of early post-exposure treatment with favipiravir (before viremia) may be considered for close household contacts of ANDV cases, high-risk laboratory exposures, or super-spreader events.[1]
Icatibant
Icatibant acetate, a bradykinin B2 receptor antagonist, has been used in several patients with severe HFRS. Randomized clinical trials are warranted to evaluate its efficacy.[1]
Investigational Monoclonal and Polyclonal Antibodies
Several antibody-based therapeutics are under preclinical development:
- SAB-163: A fully human, quadrivalent polyclonal antibody produced from transchromosomic bovines vaccinated with DNA plasmids encoding the major glycoproteins of ANDV, SNV, HTNV, and PUUV. SAB-163 has potent neutralizing antibodies (PRNT50 >200,000) against all four targeted hantaviruses and cross-neutralization against several heterotypic hantaviruses. At a dosage of 10 mg/kg, SAB-163 protected all hamsters from lethal ANDV disease when administered 1 day before or 5 days after exposure. SAB-163 is investigational new drug (IND)-enabled for phase 1 clinical trials.[15]
- ADI-42898: A human monoclonal antibody recognizing a quaternary Gn/Gc epitope on the hantavirus glycoprotein spike. ADI-42898 blocked cell entry of seven HCPS- and HFRS-associated hantaviruses and protected Syrian hamsters and bank voles against lethal ANDV and PUUV challenge with a single dose.[16] An optimized variant with improved potency against Andes virus has been engineered.[17]
- MIB22 and JL16: Two recombinant human monoclonal antibodies isolated from an HCPS-recovered individual. Both potently neutralized ANDV and protected 100% of Syrian hamsters from lethal ANDV challenge when administered as monotherapy or in combination post-exposure.[18]
- SNV-53: A broadly neutralizing human monoclonal antibody targeting the Gn/Gc interface that cross-protects against Old World Hantaan virus when administered pre- or post-exposure in animal models.[19]
Summary of Therapeutic Evidence
| Agent | Syndrome | Evidence Level | Outcome |
|---|---|---|---|
| Ribavirin IV | HFRS (Hantaan virus) | Prospective, double-blind, placebo-controlled trial (n=242) | Sevenfold decrease in mortality risk (P=0.01); reduced oliguria and hemorrhage |
| Ribavirin IV | HFRS (Puumala virus) | Randomized, open-label trial (n=73) | Ineffective; significant adverse effects (anemia, hyperbilirubinemia, bradycardia) |
| Ribavirin IV | HCPS | Small placebo-controlled trial | No survival benefit |
| Methylprednisolone IV | HCPS | Controlled trial | Ineffective |
| Convalescent immune plasma | HCPS (Andes virus) | Non-randomized multicenter trial (n=29) | CFR 14% vs 32% (P=0.049, OR=0.35) |
| VA-ECMO | HCPS (refractory) | Case series (n=25, second cohort) | 80% survival (P=0.048 vs earlier cohort) |
| Favipiravir (T-705) | HCPS (ANDV/SNV) | Animal models only | Protective when given pre-viremia; IC90 ≤5 μg/mL |
| Icatibant | HFRS | Case reports | Under investigation; RCTs warranted |
| SAB-163 (polyclonal Ab) | Pan-hantavirus | Animal models; IND-enabled | Phase 1 clinical trial pending |
| ADI-42898 (monoclonal Ab) | Pan-hantavirus | Animal models | Preclinical; optimized variant engineered |
| MIB22 / JL16 (monoclonal Abs) | HCPS (Andes virus) | Animal models | 100% protection in lethal hamster model |
Vaccines
No vaccines are approved for hantavirus infection in Europe or the Americas. Inactivated HTNV and SEOV vaccines are used in Asia (South Korea, China); case numbers decreased following implementation, but clear evidence of vaccine efficacy is absent.[1][20] DNA vaccines, mRNA vaccines, virus-like particle (VLP) vaccines, and viral vector vaccines are under investigation.[20][21]
Post-Exposure Prophylaxis Considerations
Evaluation of early post-exposure treatment with favipiravir (before viremia), ribavirin (with viremia), or neutralizing antibodies may be considered for:[1]
Close household contacts of Andes virus cases (given documented person-to-person transmission)
High-risk laboratory exposures
Super-spreader events
References
- ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14 1.15 1.16 1.17 1.18 1.19 1.20 Vial PA, Ferrés M, Vial C, Rabagliati R, Castillo C, Ossa G, Mertz GJ, Enria D, López R, Padula P, Pini N, Ramírez E, Godoy P, Calvo M, Valdivieso F (2023). "Hantavirus in humans: a review of clinical aspects and management". Lancet Infect Dis. 23 (9): e371–e382. doi:10.1016/S1473-3099(23)00128-7. PMID 37105214 Check
|pmid=value (help). - ↑ 2.0 2.1 Abdoler EA, Malani PN (2025). "What is hantavirus?". JAMA. 334 (1): 98. doi:10.1001/jama.2025.5014.
- ↑ 3.0 3.1 3.2 Wernly JA, Dietl CA, Tabe CE, Pett SB, Giles C, Giles BW, Crowley MR (2011). "Extracorporeal membrane oxygenation support improves survival of patients with hantavirus cardiopulmonary syndrome refractory to medical treatment". Eur J Cardiothorac Surg. 40 (6): 1334–40. doi:10.1016/j.ejcts.2011.01.089. PMID 21900022.
- ↑ 4.0 4.1 Malinin OV, Platonov AE (2017). "Insufficient efficacy and safety of intravenous ribavirin in treatment of haemorrhagic fever with renal syndrome caused by Puumala virus". Infect Dis (Lond). 49 (7): 514–520. doi:10.1080/23744235.2017.1293841. PMID 28276794.
- ↑ 5.0 5.1 Vial PA, Valdivieso F, Calvo M, Rioseco ML, Riquelme R, Araneda A, Tomicic V, Graf J, Paredes L, Florenzano M, Bidart T, Cuiza A, Marco C, Hjelle B, Ye C, Hanfelt-Goade D, Vial C, Rivera JC, Delgado I, Mertz GJ (2015). "A non-randomized multicentre trial of human immune plasma for treatment of hantavirus cardiopulmonary syndrome caused by Andes virus". Antivir Ther. 20 (4): 377–86. doi:10.3851/IMP2875. PMID 25316807.
- ↑ 6.0 6.1 6.2 Ulloa-Morrison R, Pavez N, Parra E, Medel JN, Cornejo R, Díaz R, Tomicic V, Fajardo C, Cerda J, Vial PA (2024). "Critical care management of hantavirus cardiopulmonary syndrome. A narrative review". J Crit Care. 84: 154867. doi:10.1016/j.jcrc.2024.154867. PMID 39024823 Check
|pmid=value (help). - ↑ 7.0 7.1 7.2 Levy H, Simpson SQ (1994). "Hantavirus pulmonary syndrome". Am J Respir Crit Care Med. 149 (6): 1710–3. doi:10.1164/ajrccm.149.6.8004332. PMID 8004332.
- ↑ Dietl CA, Wernly JA, Pett SB, Yassin SF, Sterling JP, Dragan R, Milligan K, Crowley MR (2008). "Extracorporeal membrane oxygenation support improves survival of patients with severe Hantavirus cardiopulmonary syndrome". J Thorac Cardiovasc Surg. 135 (3): 579–84. doi:10.1016/j.jtcvs.2007.11.020. PMID 18329474.
- ↑ Mertz GJ, Hjelle B, Crowley M, Iwamoto G, Tomicic V, Vial PA (2006). "Diagnosis and treatment of new world hantavirus infections". Curr Opin Infect Dis. 19 (5): 437–42. doi:10.1097/01.qco.0000244048.38758.1f. PMID 16940866.
- ↑ Crowley MR, Katz RW, Kessler R, Simpson SQ, Levy H, Hallin GW, Cappon J, Krahling JB, Wernly J (1998). "Successful treatment of adults with severe Hantavirus pulmonary syndrome with extracorporeal membrane oxygenation". Crit Care Med. 26 (2): 409–14. PMID 9468181.
- ↑ 11.0 11.1 Huggins JW, Hsiang CM, Cosgriff TM, Guang MY, Smith JI, Wu ZO, LeDuc JW, Zheng ZM, Meegan JM, Wang QN (1991). "Prospective, double-blind, concurrent, placebo-controlled clinical trial of intravenous ribavirin therapy of hemorrhagic fever with renal syndrome". J Infect Dis. 164 (6): 1119–27. doi:10.1093/infdis/164.6.1119. PMID 1683355.
- ↑ Saavedra F, Díaz FE, Retamal-Díaz A, Covián C, González PA, Kalergis AM (2021). "Immune response during hantavirus diseases: implications for immunotherapies and vaccine design". Immunology. 163 (3): 262–277. doi:10.1111/imm.13322. PMID 33462643 Check
|pmid=value (help). - ↑ Safronetz D, Falzarano D, Scott DP, Furuta Y, Feldmann H, Gowen BB (2013). "Antiviral efficacy of favipiravir against two prominent etiological agents of hantavirus pulmonary syndrome". Antimicrob Agents Chemother. 57 (10): 4673–80. doi:10.1128/AAC.00886-13. PMID 23856782.
- ↑ Mayor J, Engler O, Rothenberger S (2021). "Antiviral efficacy of ribavirin and favipiravir against Hantaan virus". Microorganisms. 9 (6): 1306. doi:10.3390/microorganisms9061306. PMID 34203936 Check
|pmid=value (help). - ↑ Brocato RL, Wu H, Kwilas SA, Principe LM, Josleyn MD, Jangra RK, Chandran K, Hooper JW (2024). "Preclinical evaluation of a fully human, quadrivalent-hantavirus polyclonal antibody derived from a non-human source". mBio: e0160024. doi:10.1128/mbio.01600-24. PMID 39258903 Check
|pmid=value (help). - ↑ Mittler E, Wec AZ, Tynell J, Guardado-Calvo P, Wiber SC, Engdahl TB, Keeffe JR, Bornholdt ZA, Bakken RR, Brocato RL, Hooper JW, Crowe JE Jr, Rey FA, Chandran K, Stass R (2022). "Human antibody recognizing a quaternary epitope in the Puumala virus glycoprotein provides broad protection against orthohantaviruses". Sci Transl Med. 14 (636): eabl5399. doi:10.1126/scitranslmed.abl5399. PMID 35294259 Check
|pmid=value (help). - ↑ Mittler E, Serris A, Esterman ES, Tynell J, Guardado-Calvo P, Stass R, Bakken RR, Brocato RL, Hooper JW, Keeffe JR, Crowe JE Jr, Rey FA, Chandran K (2023). "Structural and mechanistic basis of neutralization by a pan-hantavirus protective antibody". Sci Transl Med. 15 (700): eadg1855. doi:10.1126/scitranslmed.adg1855. PMID 37315110 Check
|pmid=value (help). - ↑ Garrido JL, Prescott J, Calvo M, Bravo F, Alvarez R, Vial C, Riquelme R, Rioseco ML, Williamson BN, Haddock E, Feldmann H, Vial PA (2018). "Two recombinant human monoclonal antibodies that protect against lethal Andes hantavirus infection in vivo". Sci Transl Med. 10 (468): eaat6420. doi:10.1126/scitranslmed.aat6420. PMID 30463919.
- ↑ Engdahl TB, Binshtein E, Brocato RL, Kuzmina NA, Principe LM, Kwilas SA, Kim RK, Chapman NS, Porter MS, Guardado-Calvo P, Rey FA, Bukreyev A, Hooper JW, Crowe JE Jr (2023). "Antigenic mapping and functional characterization of human New World hantavirus neutralizing antibodies". eLife. 12: e81743. doi:10.7554/eLife.81743. PMID 36971354 Check
|pmid=value (help). - ↑ 20.0 20.1 Chai S, Wang L, Du H, Jiang H (2025). "Achievement and challenges in orthohantavirus vaccines". Vaccines. 13 (2): 198. doi:10.3390/vaccines13020198. PMID 40006744 Check
|pmid=value (help). - ↑ Tscherne A, Guardado-Calvo P, Clark JJ, Krause R, Krammer F (2025). "Puumala orthohantavirus: prevalence, biology, disease, animal models and recent advances in therapeutics development and structural biology". Front Immunol. 16: 1575112. doi:10.3389/fimmu.2025.1575112. PMID 40406115 Check
|pmid=value (help).