Hemorrhagic Fever with Renal Syndrome (History, problems and Research Perspectives)

The work is devoted to clarify the etiological aspects of the hemorrhagic fever with renal syndrome (HFRS), clinical and epidemiological features that are closely linked to the etiology, as well as to development of methods and products for specific diagnosis and vaccine prevention of hantavirus infection. That regard to hantaviruses a set of virological, immunological and molecular-genetics methods were developed significantly enhance the effectiveness of the specific diagnostics of HFRS. The features of humoral immunity in HFRS were identified and atypical clinical forms of HFRS was istablished; indicators of natural immunity to hantavirus in the population living in different regions of Russia and the former Soviet republics have been identified that allowed us to refine nosological area of HFRS; new, previously unknown natural foci of HFRS, including hantavirus RNA, in the central regions of Russia and in the subtropical zone of Krasnodar region have been identified and studied; 76 strains and 70 isolates of 9 rodent species and one species of birds, as well as from the blood of patients with HFRS and sectional materials from HFRS dead patients have been isolated and identified; new hantavirus species - Khabarovsk, Taimyr-Topografov, Adler, as well as two new genotypes Dobrava/Belgrad virus - Kurkino and Sochi have been identified; species composition of small mammals - the natural reservoir of hantaviruses was the refined; etiological role and epidemiological importance of different hantaviruse types in HFRS incidence structure was established; the existence of new etiologically distinct hantavirus infections with significant epidemiological differences has been proven; manufacturing techniques and methods of control of the culture inactivated vaccine against HFRS has been developed.

ГЛПС, хантавирусы, генотип, штамм, HFRS, hantaviruses, genotype, strain

1. Myhrman G. En njursjukdom med egenartad symptombild (Renal disease with peculiar symptomatology). Nord Med. Tidskr. 1934; l.7: 793 – 794.

2. Zetterholm S.G. Akuta nefriter simulerande akuta bukfall (Acute nephritis simulating acute abdoment). Svenska Lakartidningen. 1934; 31 (16): 425 – 429.

3. Targanskaya V.A. (1935) Clinical course of acute nephritis Proceedings of Far Eastern Medical Institute (Khabarovsk) 1935; 2 (1): 156 – 161 (in Russian).

4. Mayer C.F. Epidemic hemorrhagic fever of the Far East, or endemic hemorrhagic nephrosonephritis. Mil. Surgeon. 1952; 110: 276 – 284.

5. Terskikh V.I. Dmitrov's leptospirosis. PhD of med. sci. diss. 1936 (in Russian).

6. Kitano M., Shiro K. Epidemic hemorrhagic fever Nippon byorigakki Kaisi. 1943; 33: 476 – 477.

7. Chumakov M.P., Lesthinskay E.V. HFRS in Volga region. Vopr Virusol. 1956; 4: 26 – 30 (in Russian).

8. Chumakov M.P. Gemorrhagic fevers. Proceedings of Ac. Med. Sci. of USSR. 1954; Tashkent: 28 – 31 (in Russian).

9. World Health Organization: Hemorrhagic fever with renal syndrome. Memorandum from a WHO meeting. Bull. WHO. 1983; 61: 26.

10. Smorodintsev A.A. Etiology and clinic of nephrozo-nephrit. VIEM. Меdgiz. 1944: 250 (in Russian).

11. Chumakov M.P., Lesthinskay E.V., Belyaeva A.P. Reproduction experimental fever in psychiatric patients with the aim of pyrogenic therapy after inoculation blood serum of HFRS patients. Endemic viral infections. 1965; 7: 12 – 22 (in Russian).

12. Lee H.W., Lee P.W., Johnson K.M. Isolation of the etiologic agent of Korean hemorrhagic fever. J .Infect. Dis. 1978; 137: 298 – 308.

13. Schmaljohn C., Dalrymple J. Analysis of Hantaan virus RNA: evidence for a new genus of Bunyaviridae. Virology. 1983: 131: 482 – 491.

14. Dzagurova T.K., Lesthinskay E.V., Tkachenko E.A. Serological examination HFRS patients in European part of Russia. Vopr Virusol. 1983; 6: 676 – 680 (in Russian).

15. Dzagurova T.K., Solopova O.N., Sveshnikov P.G., Korotina N.A., Balovneva M.V., Leonovich O.A., Varlamov N.E. et al. The development of ELISA on the basis of monoclonal antibodies for detecting of specific activity of the vaccine against hemorrhagic fever with renal syndrome. Vopr. Virusol. 2013; 1: 40 – 44 (in Russian).

16. Dzagurova T.K, Tkachenko E.A., Petrov V.A. Efficacy of culture antigens for serodiagnosis of HFRS using immunofluorescence method. Vopr Virusol. 1988; 1: 71 – 75 (in Russian).

17. Ivanov A.P., Dekonenko A.E., Dzagurova T.K, Tkachenko E.A. Polyclonal immunoassay system for determining hantavirus antigens: assessment of specificity by using monoclonal antibodies and polymerase chain reaction. Vopr. Virusol. 1996; 3: 110 – 112 (in Russian).

18. Tkachenko E.A., Donets M.A., Dzagurova T.K. Improvement of laboratory diagnostics of HFRS. Vopr Virusol. 1981; 5: 618 – 621 (in Russian).

19. Tkachenko E.A. Specific laboratory diagnosis, etiology and distribution of HFRS. PhD of med. sci. diss. Мoscow; 1988 (in Russian).

20. Tkachenko E.A., Ivanov A.P., Dzagurova T.K., Donets M.A., Rezapkin G.V. Immunosorbent assay for diagnosis of HFRS. The Lancet. 1982; 2 (8240): 257 – 258.

21. Dzagurova T.K., Tkachenko E.A., Bashkirtsev V.N., Okulova N.M., Apekina N.S., Bernstein A.D. et al. Isolation and typing of hantavirus strains in European Russia. Medical Virology. 2008; XXV: 142 – 150 (in Russian).

22. Slonova, R.A., E.A. Tkachenko, E.L. Kushnarev, T.K. Dzagurova, T.I. Astakova. Hantavirus isolation from birds. Acta Virol. 1992; 36 (5): 493.

23. Tkachenko E., Dzagurova T., Dekonenko A., Ivanov A., Yampolskiy A., Brudniy R., Schmaljohn С. First identified acute severe HFRS case in Russia caused by Dobrava hantavirus type and associated with Apodemus sylvaticus. Abstr. of 5th Intern. Conference on HFRS, HPS, and hantaviruses. France, Veyrier-du-Lac. 2001: 167.

24. Ivanov L.I., Zdanovskay N.I., Dzagurova T.K, Tkachenko E.A. Hantavirus adaptability in isolation in cell culture of Vero-E6, depending on the host species ecological. Medical Parasitology and Parasitic Diseases. 2000; 4: 22 – 25 (in Russian).

25. Tkachenko E.A, Dzagurova T.K., Bryuhanov A.F., Morozov V.G.,Yunicheva Y.V., Morozov V.G., Bashkircev V.N. et al. Discovery, clinical and etiological characteristic of hemorrhagic fever with renal syndrome in the subtropical zone of Krasnodar region. J. Microbiol. Epidemiol. Immunol. 2008; 1: 12 – 16 (in Russian).

26. Ivanov A.P., Dekonenko A.E., Tkachenko E.A., Lipskaya G.Yu., Dzagurova T.K., Ivanov L.I. et al. Genetic differentiation of hantaviruses using polymerase chain reaction and sequencing. Vopr. Virusol. 1996; 1: 24 – 27 (in Russian).

27. Horling J., Chizhikov V., Ivanov L., Dekonenko A., Dzagurova T., Tkachenko E. et al. Khabarovsk virus: a phylogenetically and serologically distinct Hantavirus isolated from Microtus fortis trapped in far-east Russia. J. Gen. Virol. 1996; 77: 687 – 694.

28. Tkachenko E.A., Witkowski P.T., Radosa L., Dzagurova T.K., Okulova N.M., Yunicheva Y.V. et al. Adler hantavirus, a new genetic variant of Tula virus identified in Major’s pine voles (Microtus majori) sampled in southern European Russia. Infect. Genet. Evol. 2015; 29: 159 – 163.

29. Tkachenko E., Bernshteyn A., Dzagurova T., Bashkirtsev V., Sedova N,, Маlkin А. Comparative analysis of epidemic HFRS outbreaks caused by Puumala and Dobrava viruses. Epidemiology & Vaccinal Prevention. 2005; 4: 28 – 34 (in Russian).

30. Klempa B., Tkachenko E., Dzagurova T. Hemorrhagic fever with renal syndrome caused by two distinct lineages of Dobrava hantavirus emerging in Russia. Emerg. Infect. Dis. 2008: 14 (4): 617 – 625.

31. Klempa B., Avsic-Zupanc T., Clement J., Dzagurova T.K., Henttonen H., Jakab F. et al. Complex evolution and epidemiology of Dobrava-Belgrade hantavirus: definition of genotypes and their characteristics. Arch. Virol. 2013; 158: 521 – 529.

32. Avsic-Zupanc T., Xiao S.Y., Stojanovic R., Gligic A., G. van der Groen, LeDuc J.W. Characterization of Dobrava virus: a Hantavirus from Slovenia, Yugoslavia. J. Med. Virol. 1992; 38 (2): 132 – 137.

33. Gligic A., Dimkovic N., Xiao S.Y., Buckle G.J., Jovanovic D., Velimirovic D., Stojanovic R., Obradovic M., Diglisic G., Micic J. Belgrade virus: a new hantavirus causing severe hemorrhagic fever with renal syndrome in Yugoslavia. J. Infect. Dis. 1992; 166 (1): 113 – 120.

34. Klempa B., Schmidt H., Ulrich R. Genetic interaction between distinct Dobrava hantavirus subtypes in Apodemus agrarius and A.flavicollis in nature. J. Virol. 2003; 77: 804 – 809.

35. Dekonenko Е.А., Dzagurova T.K., Drozdov S.G., Khaibulina S.Ph., Okulova N.M., Tkachenko E.A. et al. The epizootological and virological characteristics of a natural hantavirus infection focus in the subtropic zone of the Krasnodar territory. Vopr. Virusol. 2005; 3: 14 – 19 (in Russian).

36. Lesthinskay E.V. About the clinic of hemorrhagic fever with renal syndrome in the Tula region. J. Microbiol Epidemiol Immunol. 1960; 9: 134 – 138 (in Russian).

37. Ivanov A.P., Tkachenko E.A., Petrov V.A., Pashkov A.J., Dzagurova T.K., Vladimirova T.P. et al. Enzyme immuno assay for the detection of virus specific IgG and IgM antibody in patients with haemorrhagic fever with renal syndrome. Arch. Virol. 1988; 100 (1 – 2): 1 – 7.

38. Ivanov A.P., Tkachenko E.A., Dzagurova T.K., Roschyupkin V.I., Morozov V.G., Morzunov S.P. et al. Genetic identification of hantavirus in the blood of HFRS patients Epidemiol. and Infect. diseases. 2004; 2: 43 – 47 (in Russian).

39. Dzagurova T.K., Klempa B., Tkachenko E.A. Molecular diagnostics of hemorrhagic fever with renal syndrome during a Dobrava virus outbreak in the European part of Russia. J. Clin. Microbiol. 2009; 47: 12: 4029 – 4036.

40. Horling J., Lundkvist A., Persson K., Mullart M., Dzagurova T., Dekonenko A. et al. Tkachenko E., Niklasson B. Detection and subsequent sequencing of Puumala virus from human specimens by PCR. J. Clin. Microbiol. 1995; 33 (2): 277 – 282.

41. Bernshteyn A.D. HFRS: the ecological background activation of European forest foci. Climate change and health of the Russian population in the 21st century. 2004: 105 – 113 (in Russian).

42. Bernshteyn A.D. Features of natural foci of hantavirus zoonozis. Epidemiology & Vaccinal Prevention. 2010; 2: 5 – 13 (in Russian).

43. Lee H.W., Ahn C.N. Development of a vaccine against hemorrhagic fever with renal syndrome. J. Korean. Soc. Virol. 1988; 18: 143 – 148.

44. Lee H.W., Ahn C.N., Song J.W., Baek L.J., Seo T.J., Park S.C. Field trial of an inactivated vaccine against hemorrhagic fever with renal syndrome in humans. Arch. Virol. (Suppl. l). 1990: 35 – 47.

45. Zhu Z.Y., Zeng R.F., Yu X.Y. Efficacy of inactivated EHF vaccine in clinical trial. Virol Sin. 1991; 6: 315 – 319.

46. Lee H.W., Chu Y.K., Woo Y.D., An C.N., Kim H., Tkachenko E. et al. Vaccines against HFRS. Emergence and Control of Rodent-Borne Viral Diseases. France. Elsevier. 1999: 147 – 156.

47. Filatov F., Tkachenko E., Schmaljohn C., Hooper J. Immune response to aerosol delivery of the cloned hantavirus genes. Abstract VII Intern. Conf. on HFRS, HPS and Hantaviruses. Buenos Aires, Argentina. 2007: 187.

48. Tkachenko E.A., Dzagurova T.K., Mikhailov M.I.. Hantavirus strains for manufacturing of vaccine against HFRS. Patent 2,423,520, 10 July 2011 (in Russian).

49. Nur Hardy Abu Daud, Kariva H., Tkachenko E., Dzagurova T. Genetic and antigenic analyses of a Puumala virus isolate as a potential vaccine strain. Japanese Journal of Veterinary Research. 2008; 56 (3): 151 – 165.

50. Tkachenko E.A., Dzagurova T.K., Mikhailov M.I. Method of manufacturing of the inactivated VERO cell-derived PUUV-DOBV combined vaccine against HFRS Patent 2,445, 117, 20 March 2012 (in Russian).

51. Nabatnikov P.A., Dzagurova T.K., Tkachenko E.A. Device for obtaining virions from virus-containing suspension of hantaviruses. Patent No 97729 from 20.09.10 (in Russian).

52. Tkachenko E.A., Dzagurova T.K., Mikhailov M.I. Development of experimental vaccine against HFRS Medical virology. 2009; 26: 194 – 196 (in Russian).

53. Barkhaleva О.А., Vorobyova M.S., Ladyginskaya I.P., Tkachenko E.A., Dzagurova T.K. The vaccine against HFRS. Biopreparats. 2011; 1: 27 – 30 (in Russian).