Hantavirus disease: A review of global epidemiology, immunopathogenesis, clinical management, and future research priorities

Abstract

Hantaviruses are rodent-borne zoonotic pathogens responsible for two major clinical syndromes: Hemorrhagic fever with renal syndrome and hantavirus pulmonary syndrome/cardiopulmonary syndrome. Although significant progress has been achieved in hantavirus research over recent decades, major challenges remain in surveillance, diagnostics, therapeutics, and vaccine development. This review comprehensively synthesizes current evidence on hantavirus virology, taxonomy, reservoir ecology, transmission dynamics, global epidemiology, pathogenesis, clinical manifestations, diagnosis, treatment, prevention, and One Health surveillance strategies. Particular emphasis is placed on the immunopathological mechanisms underlying endothelial dysfunction and vascular hyperpermeability, the hallmark features of severe disease. The review further explores how climate variability, land-use change, biodiversity loss, and rodent population dynamics shape spillover risk and geographic expansion. Current diagnostic approaches, including serology, RT-PCR, and next-generation sequencing, are critically evaluated alongside emerging point-of-care technologies. Therapeutic limitations are highlighted, particularly the absence of universally effective antivirals and globally approved vaccines. Key research gaps identified include inadequate surveillance in South Asia and Africa, insufficient understanding of Andes virus human-to-human transmission, limited validation of rapid diagnostics, and unresolved mechanisms of immune-mediated pathology. Adopting a One Health perspective, this review proposes priority research and public health directions to strengthen global preparedness, improve outbreak prediction, and accelerate development of effective diagnostics, therapeutics, and vaccines against hantavirus disease.

Keywords

Hantavirus / Hemorrhagic fever with renal syndrome / Hantavirus pulmonary syndrome / Zoonotic diseases / One Health / Rodent-borne disease

References

[1] Balami AD, Munro S, Ball S, Sullivan A, Epstein JH. Viral zoonoses at the human-animal interface in southern Africa: A systematic review. One Health Bull 2026; 6(2): 49-58. doi: 10.4103/ohbl. ohbl_52_25.

[2] Jonsson CB, Figueiredo LTM, Vapalahti O. A global perspective on hantavirus ecology, epidemiology, and disease. Clin Microbiol Rev 2010; 23(2): 412-441.

[3] Vaheri A, Henttonen H, Voutilainen L, Mustonen J, Sironen T, Vapalahti O. Hantavirus infections in Europe and their impact on public health. Rev Med Virol 2013; 23(1): 35-49.

[4] Bi Z, Formenty PB, Roth CE. Hantavirus infection: A review and global update. J Infect Dev Ctries 2008; 2(1): 3-23.

[5] Vial PA, Ferrés M, Vial C, Klingström J, Ahlm C, López R, et al. Hantavirus in humans: A review of clinical aspects and management. Lancet Infect Dis 2023; 23(9): e371-e382.

[6] Hjelle B, Torres-Pérez F. Hantaviruses in the Americas and their role as emerging pathogens. Viruses 2010; 2(12): 2559-2586.

[7] Forbes KM, Sironen T, Plyusnin A. Hantavirus maintenance and transmission in reservoir host populations. Curr Opin Virol 2018; 28: 1-6.

[8] Singh S, Numan A, Sharma D, Shukla R, Alexander A, Jain GK, et al. Epidemiology, virology and clinical aspects of hantavirus infections: An overview. Int J Environ Health Res 2022; 32(8): 1815-1826.

[9] Iheukwumere IH, Iheukwumere CM, Unaeze BC, Ike VE, Nnadozie HC, Onyema SO. Hantaviruses, transmission dynamics, clinical outcomes, and preventive approaches: A review. IPS J Basic Clin Med 2025; 2(4): 115-121.

[10] Watson DC, Sargianou M, Papa A, Chra P, Starakis I, Panos G. Epidemiology of hantavirus infections in humans: A comprehensive, global overview. Crit Rev Microbiol 2014; 40(3): 261-272.

[11] Tortosa F, Perre F, Tognetti C, Lossetti L, Carrasco G, Guaresti G, et al. Seroprevalence of hantavirus infection in non-epidemic settings over four decades: A systematic review and meta-analysis. BMC Public Health 2024; 24(1): 2553.

[12] Tian H, Stenseth NC. The ecological dynamics of hantavirus diseases: From environmental variability to disease prevention largely based on data from China. PLoS Negl Trop Dis 2019; 13(2): e0006901.

[13] Dearing MD, Dizney L. Ecology of hantavirus in a changing world. Ann N Y Acad Sci 2010; 1195(1): 99-112.

[14] Muyaert RL, Sabino-Santos G Jr, Prist PR, Oshima JE, Niebuhr BB, Sobral-Souza T, et al. Spatiotemporal dynamics of hantavirus cardiopulmonary syndrome transmission risk in Brazil. Viruses 2019; 11(11): 1008.

[15] Gorris ME, Whitesell A, Telford C, Shoemaker T, Bartlow AW. Hantavirus is associated with open developed areas and arid climates, highlighting increased risk in the western United States. Transbound Emerg Dis 2025; 2025: 7126411.

[16] Wei X, Li X, Song S, Wen X, Jin T, Zhao C, et al. Trends and focuses of hantavirus researches: A global bibliometric analysis and visualization from 1980 to 2020. Arch Public Health 2022; 80(1): 218.

[17] Guterres A, de Lemos ERS. Hantaviruses and a neglected environmental determinant. One Health 2018; 5: 27-33.

[18] Chen RX, Gong HY, Wang X, Sun MH, Ji YF, Tan SM, et al. Zoonotic Hantaviridae with global public health significance. Viruses 2023; 15(8): 1705.

[19] Sulleiro E, Aznar ML, Serre-Delcor N, Salvador F, Sanchez-Montalvá A, Espasa M, et al. Hantavirus pulmonary syndrome in traveler returning from Nepal to Spain. Emerg Infect Dis 2020; 26(1): 150-153.

[20] Muthugala R, Dheerasekara K, Harischandra N, Wickramasinghe D, Abeykoon M, Dasanayake D, et al. Hantavirus infection with pulmonary symptoms in north central part of Sri Lanka. J Clin Virol Plus 2021; 1(4): 100052.

[21] Bradfute SB, Calisher CH, Klempa B, Klingström J, Kuhn JH, Laenen L, et al. ICTV virus taxonomy profile: Hantaviridae 2024. J Gen Virol 2024; 105(4): 001975.

[22] Jacob AT, Ziegler BM, Farha SM, Vivian LR, Zilinski CA, Armstrong AR, et al. Sin Nombre virus and the emergence of other hantaviruses: A review of the biology, ecology, and disease of a zoonotic pathogen. Biology (Basel) 2023; 12(11): 1413.

[23] Koehler FC, Di Cristanziano V, Späth MR, Hoyer-Allo KJR, Wanken M, Müller RU, et al. The kidney in hantavirus infection-epidemiology, virology, pathophysiology, clinical presentation, diagnosis and management. Clin Kidney J 2022; 15(7): 1231-1252.

[24] Milholland MT, Castro-Arellano I, Suzán G, Garcia-Peña GE, Lee TE Jr, Rohde RE, et al. Global diversity and distribution of hantaviruses and their hosts. EcoHealth 2018; 15(1): 163-208.

[25] Milholland MT, Castro-Arellano I, Garcia-Peña GE, Mills JN. The ecology and phylogeny of hosts drive the enzootic infection cycles of hantaviruses. Viruses 2019; 11(7): 671.

[26] Schmaljohn C, Hjelle B. Hantaviruses: A global disease problem. Emerg Infect Dis 1997; 3(2): 95-104.

[27] Mackow ER, Gavrilovskaya IN. Hantavirus regulation of endothelial cell functions. Thromb Haemost 2009; 102(12): 1030-1041.

[28] Spiropoulou CF, Srikiatkhachorn A. The role of endothelial activation in dengue hemorrhagic fever and hantavirus pulmonary syndrome. Virulence 2013; 4(6): 525-536.

[29] Khalil H, Hörnfeldt B, Evander M, Magnusson M, Olsson G, Ecke F. Dynamics and drivers of hantavirus prevalence in rodent populations. Vector Borne Zoonotic Dis 2014; 14(8): 537-551.

[30] Kallio ER, Henttonen H, Koskela E, Lundkvist Å, Mappes T, Vapalahti O. Maternal antibodies contribute to sex-based difference in hantavirus transmission dynamics. Biol Lett 2013; 9(6): 20130887.

[31] Tersago K, Verhagen R, Leirs H. Temporal variation in individual factors associated with hantavirus infection in bank voles during an epizootic: Implications for Puumala virus transmission dynamics. Vector Borne Zoonotic Dis 2011; 11(6): 715-721.

[32] Khalil H, Ecke F, Evander M, Bucht G, Hörnfeldt B. Population dynamics of bank voles predicts human puumala hantavirus risk. EcoHealth 2019; 16(3): 545-557.

[33] Kallio ER, Begon M, Henttonen H, Koskela E, Mappes T, Vaheri A, et al. Cyclic hantavirus epidemics in humans-predicted by rodent host dynamics. Epidemics 2009; 1(2): 101-107.

[34] Laenen L, Vergote V, Vanmechelen B, Tersago K, Baele G, Lemey P, et al. Identifying the patterns and drivers of Puumala hantavirus enzootic dynamics using reservoir sampling. Virus Evol 2019; 5(1): vez009.

[35] Glass GE. Forecasting outbreaks of hantaviral disease: Future directions in geospatial modeling. Viruses 2023; 15(7): 1461.

[36] Sauvage F, Langlais M, Pontier D. Predicting the emergence of human hantavirus disease using a combination of viral dynamics and rodent demographic patterns. Epidemiol Infect 2007; 135(1): 46-56.

[37] Gutiérrez-Jara JP, Muñoz-Quezada MT, Cordova-Lepe F, Silva-Guzmán A. Mathematical model of the spread of hantavirus infection. Pathogens 2023; 12(9): 1147.

[38] Riaz A, Lail NU, Laiba, Sufyan M, Raza MQ, Zaib-un-Nisa, et al. Hantavirus conducted route from mice to human: Potential dangers and outcomes of zoonosis. In: Abbas RZ, Akhtar T, Jamil M (eds). Pathways of infection: Zoonoses and environmental disease transmission. Faisalabad, Pakistan: Unique Scientific Publishers; 2025, p. 89-94.

[39] Toledo J, Haby MM, Reveiz L, Sosa Leon L, Angerami R, Aldighieri S. Evidence for human-to-human transmission of hantavirus: A systematic review. J Infect Dis 2022; 226(8): 1362-1371.

[40] Akhtar N, Hayee S, Idnan M, Nawaz F, Bibi S. Rodents human zoonotic pathogens transmission: Historical background and future prospects. In: Shah MM (ed). Rodents and their role in ecology, medicine and agriculture. London: IntechOpen; 2023.

[41] Shehata AA, Parvin R, Tasnim S, Duarte PM, Rodriguez-Morales AJ, Basiouni S. The hidden threat: Rodent-borne viruses and their impact on public health. Viruses 2025; 17(6): 809.

[42] Douglas KO, Payne K, Sabino-Santos G Jr, Agard J. Influence of climatic factors on human hantavirus infections in Latin America and the Caribbean: A systematic review. Pathogens 2021; 11(1): 15.

[43] Prist PR, Uriarte M, Tambosi LR, Prado A, Pardini R, D’Andrea PS, et al. Landscape, environmental and social predictors of Hantavirus risk in São Paulo, Brazil. PLoS One 2016; 11(10): e0163459.

[44] Moirano G, Botta A, Yang M, Mangeruga M, Murray K, Vineis P. Land-cover, land-use and human hantavirus infection risk: A systematic review. Pathog Glob Health 2024; 118(5): 361-375.

[45] Suzán G, Marcé E, Giermakowski JT, Mills JN, Ceballos G, Ostfeld RS, et al. Experimental evidence for reduced rodent diversity causing increased hantavirus prevalence. PLoS One 2009; 4(5): e5461.

[46] Peixoto ID, Abramson G. The effect of biodiversity on the hantavirus epizootic. Ecology 2006; 87(4): 873-879.

[47] Prist PR, D’Andrea PS, Metzger JP. Landscape, climate and hantavirus cardiopulmonary syndrome outbreaks. EcoHealth 2017; 14(3): 614-629.

[48] Tian H, Hu S, Cazelles B, Chowell G, Gao L, Laine M, et al. Urbanization prolongs hantavirus epidemics in cities. Proc Natl Acad Sci U S A 2018; 115(18): 4707-4712.

[49] Heyman P, Thoma BR, Marié JL, Cochez C, Essbauer SS. In search for factors that drive hantavirus epidemics. Front Physiol 2012; 3: 237.

[50] Min KD, Schneider MC, Cho SI. Association between predator species richness and human hantavirus infection emergence in Brazil. One Health 2020; 11: 100196.

[51] Ivanova AV, Popov NV, Karnaukhov IG, Chumachkova EA. Hantavirus diseases: A review of epidemiological situation and epidemiological risks in the regions of the world. Probl Part Danger Infect 2021; 1: 23-31.

[52] Li Y, Cazelles B, Yang G, Laine M, Huang ZX, Cai J, et al. Intrinsic and extrinsic drivers of transmission dynamics of hemorrhagic fever with renal syndrome caused by Seoul hantavirus. PLoS Negl Trop Dis 2019; 13(9): e0007757.

[53] Kim WK, Cho S, Lee SH, No JS, Lee GY, Park K, et al. Genomic epidemiology and active surveillance to investigate outbreaks of hantaviruses. Front Cell Infect Microbiol 2021; 10: 532388.

[54] Hayat MU, Rehman MH, Alaban AG, Hussain S, Mehmood M, Hanif M, et al. Hanta virus: An emerging threat for public health. In: Aguilar-Marcelino L, Zafar MA, Abbas RZ, Khan A (eds). Zoonosis. Vol. 3. Faisalabad, Pakistan: Unique Scientific Publishers; 2023, p. 157-164.

[55] Sunil-Chandra NP, Clement J, Maes P, De Silva HJ, Van Esbroeck M, Van Ranst M. Concomitant leptospirosis-hantavirus co-infection in acute patients hospitalized in Sri Lanka: Implications for a potentially worldwide underestimated problem. Epidemiol Infect 2015; 143(10): 2081-2093.

[56] Olsson GE, Leirs H, Henttonen H. Hantaviruses and their hosts in Europe: Reservoirs here and there, but not everywhere? Vector Borne Zoonotic Dis 2010; 10(6): 549-561.

[57] Krüger DH, Ulrich RG, Hofmann J. Hantaviruses as zoonotic pathogens in Germany. Dtsch Arztebl Int 2013; 110(27-28): 461-467.

[58] Faber M, Krüger DH, Auste B, Stark K, Hofmann J, Weiss S. Molecular and epidemiological characteristics of human Puumala and Dobrava-Belgrade hantavirus infections, Germany, 2001 to 2017. Euro Surveill 2019; 24(32): 1800675.

[59] Koroknai A, Nagy A, Nagy O, Csonka N, Zsichla L, Szomor K, et al. Human hantavirus infections in Hungary (2018-2025): Epidemiology, molecular detection across clinical sample types, and phylogenetic analysis. Viruses 2026; 18(3): 366.

[60] Burrell DN. Hantavirus pulmonary syndrome (HPS), native communities and public health epidemic surveillance in the United States. Arab Gulf J Sci Res 2024; 42(4): 1271-1286.

[61] Mello JHF, Muylaert RL, Grelle CEV. Hantavirus expansion trends in natural host populations in Brazil. Viruses 2024; 16(7): 1154.

[62] Muylaert RL, Bovendorp RS, Sabino-Santos G Jr, Prist PR, Melo GL, Priante CDF, et al. Hantavirus host assemblages and human disease in the Atlantic Forest. PLoS Negl Trop Dis 2019; 13(8): e0007655.

[63] Astorga F, Escobar LE, Poo-Muñoz D, Escobar-Dodero J, Rojas-Hucks S, Alvarado-Rybak M, et al. Distributional ecology of Andes hantavirus: A macroecological approach. Int J Health Geogr 2018; 17(1): 22.

[64] Júnior DPL, De Oliveira EC, Vasconcelos KR, Pedroso C, Arruda MLDSM, De Paula CC. Zoonotic spillover: Global diversity of mammals and distribution of hantaviral strains in synanthropic animals and the perspective for public health. Int J Health Res 2024; 3(2). doi: 10.58806/ijhmr.2024.v3i2n04.

[65] Simons D, Rivero R, Guiote AMC, Gordon H, Milne GC, Rickard G, et al. Protocol for the production of an Arenavirus and Hantavirus host-pathogen database: Project ArHa. bioRxiv 2025. doi: 10.1101/2025.01.17.633514.

[66] Enria DA, Pinheiro F. Rodent-borne emerging viral zoonosis: Hemorrhagic fevers and hantavirus infections in South America. Infect Dis Clin North Am 2000; 14(1): 167-184.

[67] Vaheri A, Strandin T, Hepojoki J, Sironen T, Henttonen H, Mäkelä S, et al. Uncovering the mysteries of hantavirus infections. Nat Rev Microbiol 2013; 11(8): 539-550.

[68] Kuhn JH, Adkins S, Agwanda BR, Al Kubrusli R, Alkhovsky SV, Amarasinghe GK, et al. 2021 taxonomic update of phylum Negarnaviricota (Riboviria: Orthornavirae), including the large orders Bunyavirales and Mononegavirales. Arch Virol 2021; 166(12): 3513-3566.

[69] Hepojoki J, Strandin T, Lankinen H, Vaheri A. Hantavirus structure-molecular interactions behind the scene. J Gen Virol 2012; 93(8): 1631-1644.

[70] Ekanayake E, Govinna M, Wakkumbura S, Samarajeewa Y, Arachchige N, Weerathunga A, et al. Detection of probable hantavirus infections in clinically suspected dengue patients in a tertiary care hospital in Sri Lanka. BMC Infect Dis 2025; 25(1): 1193.

[71] Lederer S, Lattwein E, Hanke M, Sonnenberg K, Stoecker W, Lundkvist Å, et al. Indirect immunofluorescence assay for the simultaneous detection of antibodies against clinically important Old and New World hantaviruses. PLoS Negl Trop Dis 2013; 7(4): e2157.

[72] Klempa B, Fichet-Calvet E, Lecompte E, Auste B, Aniskin V, Meisel H, et al. Hantavirus in African wood mouse, Guinea. Emerg Infect Dis 2006; 12(5): 838-840.

[73] Khan A, Khan M, Ullah S, Wei DQ. Hantavirus: The next pandemic we are waiting for? Interdiscip Sci 2021; 13(1): 147-152.

[74] Zeimes CB, Olsson GE, Ahlm C, Vanwambeke SO. Modelling zoonotic diseases in humans: Comparison of methods for hantavirus in Sweden. Int J Health Geogr 2012; 11(1): 39.