WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES Abhijit et al. World Journal of Pharmacy and Pharmaceutical Sciences SJIF Impact Factor 7.632 Volume 9, Issue 5, 658-668 Review Article ISSN 2278 – 4357

SEVERE HANTAVIRUS INFECTION NEW BEGINNING: A REVIEW

Hatagle Abhijit*1, Jadhav Manjula1, Nandkishor Bavage1, Shyamlila Bavage1, Vidyasagar Gali1

*Latur College of Pharmacy, Hasegaon, Tq. Ausa, Dist. Latur Maharashtra 413512 INDIA.

Article Received on ABSTRACT 06 March 2020, Hantavirus were primarily hosted by mammal species of Rodentia, Revised on 27 March 2020, Accepted on 17 April 2020 Eulipotyphl and Chiroptera. Despite its relevance for both intra & inter

DOI: 10.20959/wjpps20205-16094 species transmission of hantavirus in nature remains limited. It’s spread in humans is common, & to understand it’s working &

*Corresponding Author transmission in reservoir host population is important for efforts to Hatagle Abhijit reduce human diseases. Some experiments are done on laboratory Latur College of Pharmacy, rodents for deriving effect & it’s effect. It shows similar organ Hasegaon, Tq. Ausa, Dist. infection sites in non-rodent’s transmission routes as in rodents, but it Latur Maharashtra 413512 INDIA. requires direct assessment.

KEYWORDS: Hantavirus, Epidemiology, Treatment, Review.

Hantavirus

INTRODUCTION In past centuries there were two major outbreaks of disease led to the discovery of the Hantavirus in old & new world. First outbreak took place in Korean war where more than 3000 troops fell ill with hemorrhagic fever, which is referred to be Haemorrhagic Fever with

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Renal Syndrome (HFRS), however it’s causative agents where unknown until 1980’s when Lee et al reported it as Hantaan Virus.[1] The second outbreak of hantavirus infection was in the four corners region of USA in 1993 were it was known as Hantavirus Cardiopulmonary Syndrome (HCPS).[2] can cause serious diseases in humans & have reached death rate of 12 % (HFRS) & 60% (HCPS) in some outbreaks. The reservoir & causing agent the striped field rat was found by Lee et al in 1978.[3] This study helped in recognition of more HFRS-related viruses in Asia, Europe, United States (Table1).

Table 1: Geographic distribution of and disease associated with Old World and New World strains of hantavirus. Group & Virus isolate or Geographic Associated Abbreviation Rodent host subfamily strain Distribution diseases Old World China, South Murine Hantaan Virus HTNV Apodemus agrarius HFRS Korea, Russia Apodemus Dobrava-Belgrade DOBV Balkans HFRS Flavicollius Seoul Virus SEOV Worldwide Rattus HFRS SAAV Europe Apodemus agrarius HFRS Far East Apodemus Amur Virus AMRV HFRS Russia Peninsulae Apodemus - South Korea Unknown Peninsulae Europe, Asia, Clethrionomys Arvicolinae Puumala Virus PUUV HFRS/NE America glareolus Far East Khabarovsk Virus KHAV Microtus fortis Unknown Russia Muju Virus MUJV South Korea Myodes regulus Unknown Microtus Prospect Hill Virus PHV Maryland Unknown pennsylvanicus Russia, Tula Virus TULV Microtus arvalis Unknown Europe North Microtus ISLAV Unknown America californicus Topografov Virus TOPV Siberia Lemmus sibericus Unknown New World North Peromyscus Sigmodontinae Sin Nombre Virus SNV HCPS America maniculatus North Peromyscus MGLV HCPS America leucopus North Peromyscus New York Virus NYV HCPS America leucopus Black Creek Canal North BCCV Sigmodon hispidus HCPS Virus America Bayou Virus BAYV North Oryzomys palustris HCPS

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America Lime Stone Canyon North - Peromyscus boylii Unknown Virus America Jabora Virus - Brazil Akodon montensis HCPS Zygodontomys Calabazo Virus - Panama Unknown brevicauda

Research showed the presence of hantavirus A& other viruses in Apodemus agrarius & A. peninsulae rodents in far East Russia, China, & South Korea & a distinct virus, Dobrava virus, & Dobrava like viruses harbored by Apodemus flavicollis, A. agrarius, & A. ponticusin Europe.[4,5,6] Hantavirus is characterized by renal failure & haemorrhagic manifestation that vary from petechiae to severe internal bleeding, pneumonia & cardiovascular disfunction are characteristics of HCPS. The complex pathogenesis of hantavirus infection is suggested that it is not direct viral cytopathology, but immune mechanisms as an important role.[7] Hantavirus is carried out by specific rodents.

Lifecycle

Fig. Hantavirus Lifecycle. www.wjpps.com Vol 9, Issue 5, 2020. 660

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The genus of hantavirus resides in family Bunyaviridae, a large family consisting over 300 viruses that can infect animals, plants, humans, etc.[8,9,10] However the hantavirus is commonly referred to as Old & New World due to geographic distribution of their rodent carriers & type of disease that manifests upon transmission to humans.[11] The difference between the two world hantavirus as high homology in the origin of their nucleic sequence & exhibit similar aspects pf their life cycle.

In contrast to other Bunyaviruses, hantaviruses are not transmitted by an arthropod vector, but are carried & transmitted to humans by persistently infected rodent or insectivore hosts & even bats (Fig.2). Hence the ecology & geographical distribution of virus relate to distribution of their natural carriers (i). It is accepted that infection of the natural host is inapparent & does not cause disease. Some researches describe negative impact of hantavirus on the infected host.[12,13]

Fig 2: Hantavirus lifecycle & spillover infection to humans. In nature hantavirus are circulating via horizontal transmission bet chronically natural host. Most human infection occur when contaminated aerosolized rodent excreta are inhaled. www.wjpps.com Vol 9, Issue 5, 2020. 661

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Genome and Structure The first molecular analyses of HTNV showed that the genome comprises three negative- sense, single- stranded RNAs that share a terminal sequence of the three genome segments.[14] The three segments, S (small), M (medium), & L (large), encode the nucleoprotein (N), envelope glycoproteins (Gn, formerly G1, and Gc, formerly G2), & the L protein or viral RNA (v RNA)-dependent RNA polymerase (RdR p), respectively.[15] The total size of the RNA genomeranges from 11,845 nucleotides (nt) for HTNV to 12,317 nt for SNV. The treatment of HTNV with nonionic detergents re-leases three ribonucleoproteins (RNPs) that sediment to densities of 1.18 and 1.25 g/cm3in sucrose and CsCl, respectively, by using rate-zonal centrifugation methods.[16] The RNP structures within the virion each consist of one viral RNA segment complexed with the N protein.[17,18]

It is widely held for all of the viruses in the family Bunyaviridae that each genomic RNA forms a circular molecule that forms by base pairing between inverted complementary sequences at the 3 and 5 ends of linear viral RNA.[19] Hantavirus virions are generally spherical in nature, with an average diameter of approximately 80 to 120 nm.[20] Ultrastructural studies of HTNV suggest that the virion has a surface structure composed of a grid-like pattern distinct from that of other genera of the family Bunyaviridae.[21] The grid- like pattern of the outer surface reflects the glycoprotein projections, which extend 12 nm from the lipid bilayer. Biochemical studies confirmed that these projections are composed of heterodimers of Gn and Gc.[22]

Epidemiology The epidemiology of hantavirus infections in human populations is based largely on incidences of peridomestic exposure of humans to rodents in areas of endemicity. In the majority of these cases, humans acquire infection after direct contact with infected rodents or their excreta, which occurs mostly by inhaling virus-contaminated aerosol. In the Americas, person-to-person transmission has not been observed for the majority of hantaviruses[23] however, cases of person-to-person transmission of ANDV have been reported, although rarely, in Argentina & Chile.[24] Intriguingly, recent surveil-lance data showed PUUV RNA in saliva of patients; however, inhibitory substances in saliva may prevent the transmission of live virus[25] ANDV is less sensitive in vitro to the antiviral inhibitory substances in saliva than other hantaviruses.[26]

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Clinical Course & Pathology The incubation period of HFRS is 3 weeks, ranging from 10 days to 6 weeks.[27] The clinical pattern & disease potency varies from causative agent, individually from subclinical to lethal. In short, the HFRS caused by HTNV, Amur virus, & DOBV are more severe, while SEOV is more moderate & PUUV is mild. The clinical symptoms of the febrile stage are eventually augmented to the hypotensive stage, characterized by thirst, restlessness, nausea, and vomiting, each lasting hours or days (Table 2). Approximately one third of all patients during the hypotensive stage of HFRS develop shock and mental confusion.[28] Dialysis is required for approximately 40% of HTNV and 20% of SEOV patients. Death is usually due to complications from renal insufficiency, shock, or hemorrhage. These phases can be hard to distinguish, especially in less severe cases. Although the ―virus gradient‖ of severity of symptoms is, in general, as described above, an individual PUUV case may be severe, an individual HTNV infection may be mild, or cases may present with subclinical seroconversion.

Table 2: Occurrence of different signs, symptoms, & laboratory findings for patients with confirmed HFRS & HCPS. Findings HTNV SEOV PUUV SNV ARAV Fever 100 100 99-100 100 100 Dyspnea 87 Tachycardia 81 Shock 33 Headache 86-87 89 85-100 71 47 Abdominal Pain 85-92 68 64-67 24 NA Backache 91-95 85 82 29 NA Nausea 82-91 61 78-83 71 25 Dizziness 50 52 12-25 41 NA Minor bleeding 37 7-12 11 NA 9 Internal haemorrhages 34 13 NA NA NA ―Based on reports of HTNV, SEOV, PUUV, SNV, & ARAV infections.[29]‖

Death occurs in less than 0.1% in patients infected with PUUV, whereas fatality rates as high as 15% have been observed for HFRS patients infected with HTNV. SEOV is associated with a mortality rate of less than 1%. In contrast to PUUV in Europe, with approximately 0.1% mortality, the mortality rate for hospitalized DOBV (A. flavicollis-borne) cases has been reported to be 9 to 12% in the Balkans.[30] For PUUV cases, the disease usually starts abruptly with fever, followed by headache and abdominal pains, sometimes with vomiting or diarrhea.[31] Somnolence, dizziness, and other signs of central nervous system (CNS) www.wjpps.com Vol 9, Issue 5, 2020. 663

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involvement may occur. PUUV RNA has been found in cerebrospinal fluid, although encephalitis is rare.[32]

Symptoms Symptoms appear 1 to 6 weeks after being exposed to the virus. They can include:  Tiredness  Dizziness  Fever and chills  Muscle aches and headaches  Nausea and vomiting  Stomach pain  Coughing

More severe symptoms may include:  Shortness of breath  Severe difficulty breathing

TREATMENT & PREVENTION At present, we know of no antivirals, vaccines, or immune therapeutics approved by the U.S. Food and Drug Administration (FDA) for any of the hemorrhagic fever viruses, including HFRS and NE. Ribavirin has in vitro and in vivo antiviral activity against members of the Bunyaviridae and the Arenaviridae. Ribavirin reduces mortality and was proven effective for the treatment of lethal encephalitic suckling mice infected with HTNV.[33] Studies performed in China with HFRS patients suggest that the drug ribavirin provides an improved prognosis when given early in the course of disease. In that study, it was found that if ribavirin therapy was initiated before the end of the first week of illness, there was a 7-fold reduction in the risk of dying. Ribavirin has been examined for the treatment of HPS, but the results were inconclusive.[34] In those studies, intravenous ribavirin was well tolerated; 71% of recipients became anaemic, and 19% underwent transfusion. Based on these limited trials, ribavirin had no apparent clinical benefit for HPS patients. These results suggest that the efficacy of ribavirin as a treatment for hantavirus disease may depend on the phase of infection and the severity of disease at the time of first administration of the drug. A recent report by Rusnak et al. confirms that the early treatment of HFRS with intravenous ribavirin reduces the occurrence of oliguria and the severity of renal insufficiency.[35]

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The prevention of diseases caused by hantaviruses is based on principles of rodent control such as reducing rodent shelter and food sources in and around the home, eliminating rodents inside the home and preventing them from entering the home, using standard precautions for preventing hantavirus infection while rodent-contaminated areas are being cleaned up, prevention measures for persons who have occupational exposure to wild rodents, and precautions for campers and hikers. In addition to minimizing the risk of hantavirus exposure, the prevention of hantaviral disease could be augmented by effective vaccines and strategic vaccination of at-risk populations. Vaccination of individuals in areas of endemicity or those who could be exposed to the virus in military, clinical, and research settings may offer a strategy for reducing the risk and incidence of disease.

CONCLUSION Hantavirus infections belong to the increasing group of emerging zoonotic infectious diseases. Over the past few decades, the understanding and recognition of hantavirus infection has greatly improved worldwide. Both, the amplitude and the magnitude of hantavirus outbreaks have been increasing. This could be explained by better clinical awareness, development of sensitive diagnostic tests, intensive research on reservoir and changing climatic conditions. Although some are newly detected, hantaviruses are old viruses, but environmental changes may affect the geographic distribution, abundance and the dynamic of the carrier rodent species, and hence the epidemiology of hantavirus disease. Although, today we can only speculate how extensive environmental and climatic changes will be, hantavirus infections will remain a public health threat. Therefore, further research on hantavirus pathogenesis, diagnostics, antiviral and vaccine development are needed.

REFERENCES 1. Lee W, Lee PW, Johnson KM. Isolation of aetiology of Korean hemorrhagic fever. J Infect Dis., 1978; 137: 298. 2. Nichol ST, Spiropoulou CF, Morzunov S, Rollin PE, Ksiazek TG, Feldmann H. Genetic identification of hantavirus a associated with an outbreak of illness. Science, 1993; 262: 914. 3. Lee HW, Lee PW, Johnson KM. Isolation of aetiology of Korean hemorrhagic fever. J Infect Dis., 1978; 137: 308. 4. Avsic-Zupanc, T., K. Nemirov, M. Petrovec, T. Trilar, M. Poljak, A. Vaheri, and A. Plyusnin. Genetic analysis of wild-type Dobrava hantavirus in Slovenia: co-existence of

www.wjpps.com Vol 9, Issue 5, 2020. 665

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two distinct genetic lineages within the same natural focus. J. Gen. Virol., 2000; 81: 1747–1755. 5. Avsic-Zupanc, T., M. Petrovec, P. Furlan, R. Kaps, F. Elgh, and A. Lundkvist. Hemorrhagic fever with renal syndrome in the Dolenjska region of Slovenia—a 10-year survey. Clin. Infect. Dis., 1999; 28: 860–865. 6. Golovljova, I., V. Vasilenko, T. Prukk, K. B. Sjolander, A. Plyusnin, and A. Lundkvist. Puumala and Dobrava hantaviruses causing hemorrhagic fever with renal syndrome in Estonia. Eur. J. Clin. Microbial. Infect. Dis., 2000; 19: 968–969. 7. DJ Gubler, P Reiter, KL Ebi, W Yap, R Nasci, JA Patz Climate variability and change in the United States: potential impacts on vector- and rodent-borne diseases Environ Health Perspect, 2001; 109(2): 223-233 8. Bishop, D. H., C. H. Calisher, J. Casals, M. P. Chumakov, S. Y. Gaidamovich, C. Hannoun, D. K. Lvov, I. D. Marshall, N. Oker-Blom, R. F. Petters son, J. S. Porterfield, P. K. Russell, R. E. Shope, and E. G. Westaway. Bunyaviridae. Intervirology, 1980; 14: 125–143. 9. Fenner, F. The classification and nomenclature of viruses. Summary of results of meetings of the International Committee on Taxonomy of Viruses in Madrid, September 1975; Intervirology 6: 1–12. 10. Schmaljohn, C. S., and J. W. Hooper. Bunyaviridae: the viruses and their replication, 2001; 2: 1581–1602. In D. M. Knipe, P. M. Howley, D. E. Griffin, R. A. Lamb, M. A. Martin, B. Roizman, and S. E. Straus (ed.), Fields virology, 4th ed., Lippincott Williams & Wilkins, Philadelphia, PA. 11. James E. Childs, Gregory E. Glass, George W. Korch, and James W. LeDuc (1989) Effects Of Hantaviral Infection On Survival, Growth And Fertility In Wild Rat (Rattus Norvegicus) Populations Of Baltimore, Maryland. Journal of Wildlife Diseases., October, 1989; 25(4): 469-476. 12. Richard J. Douglass, Charles H. Calisher, Kent D. Wagoner, and James N. Mills (2007) Sin Nombre Virus Infection Of Deer Mice In Montana: Characteristics Of Newly Infected Mice, Incidence, And Temporal Pattern Of Infection. Journal of Wildlife Diseases., January, 2007; 43(1): 12-22. 13. Schmaljohn, C. S., and J. M. Dalrymple. Analysis of Hantaan virus RNA: evidence for a new genus of Bunyaviridae. Virology, 1983; 131: 482–491. 14. Schmaljohn, C. S., S. E. Hasty, J. M. Dalrymple, J. W. LeDuc, H. W. Lee, C. H. von Bonsdorff, M. Brummer-Korvenkontio, A. Vaheri, T. F. Tsai, H. L. Regnery, et al. www.wjpps.com Vol 9, Issue 5, 2020. 666

Abhijit et al. World Journal of Pharmacy and Pharmaceutical Sciences

Antigenic and genetic properties of viruses linked to hemorrhagic fever with renal syndrome. Science, 1985; 227: 1041–1044. 15. Schmaljohn, C. S., S. E. Hasty, S. A. Harrison, and J. M. Dalrymple. Characterization of Hantaan virions, the prototype virus of hemorrhagicfever with renal syndrome. J. Infect. Dis., 1983; 148: 1005–1012. 16. Dahlberg, J. E., J. F. Obijeski, and J. Korb. Electron microscopy of the segmented RNA genome of La Crosse virus: absence of circular molecules. J. Virol., 1977; 22: 203–209. 17. Obijeski, J. F., D. H. Bishop, E. L. Palmer, and F. A. Murphy. Segmented genome and nucleocapsid of La Crosse virus. J. Virol., 1976; 20: 664–675. 18. Hewlett, M. J., R. F. Pettersson, and D. Baltimore. Circular forms of Uukuniemi virion RNA: an electron microscopic study. J. Virol., 1977; 21: 1085–1093. 19. Schmaljohn, C. S., and S. T. Nichol. Bunyaviridae, 2007; 2: 1741–1789. In D. M. Knipe, P. M. Howley, D. E. Griffin, R. A. Lamb, M. A. Martin, B. Roizman, and S. E. Straus (ed.), Fields virology, 5th ed., Lippincott Williams & Wilkins, Philadelphia, PA. 20. Martin, M. L., H. Lindsey-Regnery, D. R. Sasso, J. B. McCormick, and E. Palmer. Distinction between Bunyaviridae genera by surface structure and comparison with Hantaan virus using negative stain electron mi- croscopy. Arch. Virol., 1985; 86: 17–28. 21. Antic, D., K. E. Wright, and C. Y. Kang. Maturation of Hantaan virus glycoproteins G1 and G2. Virology, 1992; 189: 324–328. 22. Wells, R. M., J. Young, R. J. Williams, L. R. Armstrong, K. Busico, A. S. Khan, T. G. Ksiazek, P. E. Rollin, S. R. Zaki, S. T. Nichol, and C. J. Peters. Hantavirus transmission in the United States. Emerg. Infect. Dis., 1997; 3: 361–365. 23. Padula, P. J., A. Edelstein, S. D. Miguel, N. M. Lopez, C. M. Rossi, and R. D. Rabinovich. Hantavirus pulmonary syndrome outbreak in Argentina: molecular evidence for person-to-person transmission of Andes virus. Virology, 1998; 241: 323–330. 24. Pettersson, L., J. Boman, P. Juto, M. Evander, and C. Ahlm. Outbreak of Puumala virus infection, Sweden. Emerg. Infect. Dis., 2008; 14: 808–810. 25. Hardestam, J., A. Lundkvist, and J. Klingstrom. Sensitivity of Andes hantavirus to antiviral effect of human saliva. Emerg. Infect. Dis., 2009; 15: 1140–1142. 26. Gajdusek, D. Virus hemorrhagic fevers. Special reference to hemorrhagic fever with renal syndrome J. Pediatr, 1961; 60: 841–857. 27. Lee, H. W. 1989. Clinical manifestations of HFRS, p. 19–38. In H. W. Lee and J. M. Dalrymple (ed.), Manual of hemorrhagic fever with renal syndrome. WHO, Seoul, South Korea? www.wjpps.com Vol 9, Issue 5, 2020. 667

Abhijit et al. World Journal of Pharmacy and Pharmaceutical Sciences

28. Kim, Y. S., C. Ahn, J. S. Han, S. Kim, J. S. Lee, and P. W. Lee. Hemorrhagic fever with renal syndrome caused by the Seoul virus. Nephron, 1995; 71: 419–427. 29. Huggins, J. W. Prospects for treatment of viral hemorrhagic fevers with ribavirin, a broad-spectrum antiviral drug. Rev. Infect. Dis., 1989; 11(4): S750–S761. 30. A. M. Johnson, P. C. Stockton, M. D. Bowen, C. F. Spiropoulou, S. Alexiou-Daniel, T. G. Ksiazek, S. T. Nichol, and A. Antoniadis. Retrospective serological and genetic study of the distribution of hantaviruses in Greece. J. Med. Virol, 1998; 55: 321–327. 31. Settergren, B., P. Juto, B. Trollfors, G. Wadell, and S. R. Norrby. Clinical characteristics of nephropathia epidemica in Sweden: prospective study of 74 cases. Rev. Infect. Dis., 1989; 11: 921–927. 32. S. M., T. Sironen, O. Vapalahti, E. Paakko, N. Hautala, J. Ilonen, V. Glumoff, O. Vainio, H. Kauma, A. Vaheri, A. Plyusnin, and T. Hautala. Puumala virus RNA in cerebrospinal fluid in a patient with uncomplicated nephropathia epidemica. J. Clin. Virol, 2007; 40: 248–251. 33. Schountz, T., J. Prescott, A. C. Cogswell, L. Oko, K. Mirowsky-Garcia, A. P. Galvez, and B. Hjelle. Regulatory T cell-like responses in deer mice persistently infected with Sin Nombre virus. Proc. Natl. Acad. Sci. U. S. A., 2007; 104: 15496–15501. 34. Chapman, L. E., G. J. Mertz, C. J. Peters, H. M. Jolson, A. S. Khan, T. G. Ksiazek, F. T. Koster, K. F. Baum, P. E. Rollin, A. T. Pavia, R. C. Holman, J. C. Christenson, P. J. Rubin, R. E. Behrman, L. J. Bell, G. L. Simpson, and R. F. Sadek. Intravenous ribavirin for hantavirus pulmonary syndrome: safety and tolerance during 1 year of open-label experience. Ribavirin Study Group. Antivir. Ther., 1999; 4: 211–219. 35. Rusnak, J. M., W. R. Byrne, K. N. Chung, P. H. Gibbs, T. T. Kim, E. F. Boudreau, T. Cosgriff, P. Pittman, K. Y. Kim, M. S. Erlichman, D. F. Rezvani, and J. W. Huggins. Experience with intravenous ribavirin in the treatment of hemorrhagic fever with renal syndrome in Korea. Antiviral Res., 2009; 81: 68–76.

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