sábado, 20 de diciembre de 2014

Clinical Course and Long-Term Outcome of Hantavirus-Associated Nephropathia Epidemica, Germany - Volume 21, Number 1—January 2015 - Emerging Infectious Disease journal - CDC

full-text ►

Clinical Course and Long-Term Outcome of Hantavirus-Associated Nephropathia Epidemica, Germany - Volume 21, Number 1—January 2015 - Emerging Infectious Disease journal - CDC

Volume 21, Number 1—January 2015


Clinical Course and Long-Term Outcome of Hantavirus-Associated Nephropathia Epidemica, Germany

Joerg Latus, Matthias Schwab, Evelina Tacconelli, Friedrich-Michael Pieper, Daniel Wegener, Juergen Dippon, Simon Müller, David Zakim, Stephan Segerer, Daniel Kitterer, Martin Priwitzer, Barbara Mezger, Birgit Walter-Frank, Angela Corea, Albrecht Wiedenmann, Stefan Brockmann, Christoph Pöhlmann, M. Dominik Alscher, and Niko BraunComments to Author 
Author affiliations: Robert-Bosch-Hospital, Stuttgart, Germany (J. Latus, F.-M. Pieper, D. Wegener, D. Zakim, D. Kitterer, C. Pöhlmann, M.D. Alscher, N. Braun)Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart (M. Schwab)University Hospital Tübingen, Germany (M. Schwab, E. Tacconelli)University of Stuttgart, Stuttgart (J. Dippon, S. Müller)University Hospital Zurich, Zurich, Switzerland (S. Segerer)Local Health Authority, Stuttgart (M. Priwitzer, B. Mezger)Local Health Authority, Böblingen, Germany (B. Walter-Frank)Local Health Authority, Esslingen, Germany (A. Corea, A. Wiedenmann)Local Health Authority, Reutlingen, Germany (S. Brockmann)


Human infection with Puumala virus (PUUV), the most common hantavirus in Central Europe, causes nephropathia epidemica (NE), a disease characterized by acute kidney injury and thrombocytopenia. To determine the clinical phenotype of hantavirus-infected patients and their long-term outcome and humoral immunity to PUUV, we conducted a cross-sectional prospective survey of 456 patients in Germany with clinically and serologically confirmed hantavirus-associated NE during 2001–2012. Prominent clinical findings during acute NE were fever and back/limb pain, and 88% of the patients had acute kidney injury. At follow-up (7–35 mo), all patients had detectable hantavirus-specific IgG; 8.5% had persistent IgM; 25% had hematuria; 23% had hypertension (new diagnosis for 67%); and 7% had proteinuria. NE-associated hypertension and proteinuria do not appear to have long-term consequences, but NE-associated hematuria may. All patients in this study had hantavirus-specific IgG up to years after the infection.
Hantaviruses, enveloped RNA viruses of the family Bunyaviridae, are transmitted to humans by rodents, the natural reservoir of these viruses (1). In North America, hantavirus infection can lead to hantavirus cardiopulmonary syndrome and to case–fatality rates of up to 35% (2,3), and in Asia and Europe, infection can lead to hemorrhagic fever with renal syndrome (HFRS) (4).
In Germany, the incidence of HFRS increased from 0.09 cases/100,000 persons in 2001 to 2.47 cases/100,000 persons in 2010 (5). During October 2011–April 2012, a total of 852 HFRS cases were reported in Germany, of which 580 (68%) originated in the southern federal state of Baden-Wurttemberg (6). Puumala virus (PUUV), by far the most frequent cause of hantavirus disease in Germany (7), causes a milder form of HFRS (8) called nephropathia epidemica (NE). Hantavirus infections are one of the 5 most common notifiable viral diseases in Germany, along with norovirus infections, hepatitis C, influenza, and rotavirus infections (7).
NE is characterized by acute kidney injury associated with thrombocytopenia and, frequently, with proteinuria (9). Severe and often prolonged gastrointestinal symptoms and severe back and abdominal pain also occur (10). The severity of infection with PUUV varies from subclinical disease to severe acute kidney injury, including a fatal outcome (11,12). Renal replacement therapy is required in ≈5% of hospitalized patients with acute NE (8,10,13,14), although some studies report rates of up to 25% (15,16).
Despite the high and increasing incidence of hantavirus infection, long-term follow-up data have not been reported for a large, representative cohort of patients. Moreover, it remains unclear whether NE has long-term consequences, such as hypertension, proteinuria (17), and alteration of kidney function (18,19). Two previous studies that followed up 36 Finnish patients 5 and 10 years after they experienced PUUV-associated NE, reported that the patients had increased urinary protein excretion, glomerular hyperfiltration, and elevated blood pressure at a 5-year but not a 10-year follow-up (18,19). Other reports support an association between previous hantavirus infection and subsequent hypertension (2023).
Data on humoral immunity years after PUUV infection are not available for a representative cohort of German patients. Thus, we conducted this study in such a cohort to describe the detailed clinical phenotype of patients with clinical manifestations of PUUV infection and their long-term outcomes and humoral immunity to PUUV.

Dr. Latus is a resident in the Nephrology department at the Robert-Bosch-Hospital, Stuttgart, Germany. His primary research interests are zoonoses, especially the clinical course of hantavirus infections.


This study was supported by the Robert-Bosch Foundation.


  1. Schmaljohn CSDalrymple JMAnalysis of Hantaan virus RNA: evidence for a new genus of Bunyaviridae. Virology1983;131:48291 .DOIPubMed
  2. Krüger DHUlrich RLundkvist AAHantavirus infections and their prevention. Microbes Infect2001;3:112944DOIPubMed
  3. Peters CJSimpson GLLevy HSpectrum of hantavirus infection: hemorrhagic fever with renal syndrome and hantavirus pulmonary syndrome.Annu Rev Med1999;50:53145DOIPubMed
  4. Watson DCSargianou MPapa AChra PStarakis IPanos GEpidemiology of hantavirus infections in humans: a comprehensive, global overview.Crit Rev Microbiol2014;40:26172DOIPubMed
  5. Ettinger JHofmann JEnders MTewald FOehme RMRosenfeld UMMultiple synchronous outbreaks of Puumala virus, Germany, 2010. Emerg Infect Dis2012;18:14614 . DOIPubMed
  6. Boone IWagner-Wiening CReil DJacob JRosenfeld UMUlrich RGRise in the number of notified human hantavirus infections since October 2011 in Baden-Wurttemberg, Germany. Euro Surveill2012;17:20180 .PubMed
  7. Krüger DHUlrich RGHofmann JHantaviruses as zoonotic pathogens in Germany. Dtsch Arztebl Int2013;110:4617 .PubMed
  8. Vapalahti OMustonen JLundkvist AHenttonen HPlyusnin AVaheri AHantavirus infections in Europe. Lancet Infect Dis2003;3:65361.DOIPubMed
  9. Krautkrämer EZeier MPlyusnin AHantavirus infection: an emerging infectious disease causing acute renal failure. Kidney Int2013;83:237.DOIPubMed
  10. Braun NHaap MOverkamp DKimmel MAlscher MDLehnert HCharacterization and outcome following Puumala virus infection: a retrospective analysis of 75 cases. Nephrol Dial Transplant2010;25:29973003DOIPubMed
  11. Hjertqvist MKlein SLAhlm CKlingstrom JMortality rate patterns for hemorrhagic fever with renal syndrome caused by Puumala virus. Emerg Infect Dis2010;16:15846DOIPubMed
  12. Makary PKanerva MOllgren JVirtanen MJVapalahti OLyytikainen ODisease burden of Puumala virus infections, 1995–2008. Epidemiol Infect.2010;138:148492DOIPubMed
  13. Mustonen JBrummer-Korvenkontio MHedman KPasternack APietila KVaheri ANephropathia epidemica in Finland: a retrospective study of 126 cases. Scand J Infect Dis1994;26:713DOIPubMed
  14. Settergren BJuto PTrollfors BWadell GNorrby SRHemorrhagic complications and other clinical findings in nephropathia epidemica in Sweden: a study of 355 serologically verified cases. J Infect Dis1988;157:3802DOIPubMed
  15. Rasche FMUhel BKruger DHKarges WCzock DHampl WThrombocytopenia and acute renal failure in Puumala hantavirus infections. Emerg Infect Dis2004;10:14205 . DOIPubMed
  16. Ala-Houhala IKoskinen MAhola THarmoinen AKouri TLaurila KIncreased glomerular permeability in patients with nephropathia epidemica caused by Puumala hantavirus. Nephrol Dial Transplant2002;17:24652DOIPubMed
  17. Niklasson BHellsten GLeDuc JHemorrhagic fever with renal syndrome: a study of sequelae following nephropathia epidemica. Arch Virol.1994;137:2417DOIPubMed
  18. Mäkelä SAla-Houhala IMustonen JKoivisto AMKouri TTurjanmaa VRenal function and blood pressure five years after Puumala virus–induced nephropathy. Kidney Int2000;58:17118DOIPubMed
  19. Miettinen MHMäkelä SMAla-Houhala IOHuhtala HSKoobi TVaheri AITen-year prognosis of Puumala hantavirus–induced acute interstitial nephritis. Kidney Int2006;69:20438DOIPubMed
  20. Lähdevirta JNephropathia epidemica in Finland. A clinical histological and epidemiological study. Ann Clin Res1971;3:154 .PubMed
  21. Lähdevirta JCollan YJokinen EJHiltunen RRenal sequelae to nephropathia epidemica. Acta Pathol Microbiol Scand [A]1978;86:26571.PubMed
  22. Rubini MEJablon SMc DMRenal residuals of acute epidemic hemorrhagic fever. Arch Intern Med1960;106:37887DOIPubMed
  23. Kleinknecht DRollin PEHypertension after hemorrhagic fever with renal syndrome. Nephron1992;61:121DOIPubMed
  24. Krautkrämer EGrouls SUrban ESchnitzler PZeier MNo gender-related differences in the severity of nephropathia epidemica, Germany. BMC Infect Dis2013;13:457DOIPubMed
  25. Pickering TGHall JEAppel LJFalkner BEGraves JHill MNRecommendations for blood pressure measurement in humans and experimental animals: part 1: blood pressure measurement in humans: a statement for professionals from the Subcommittee of Professional and Public Education of the American Heart Association Council on High Blood Pressure Research. Hypertension2005;45:14261DOIPubMed
  26. Chobanian AVBakris GLBlack HRCushman WCGreen LAIzzo JL JrThe seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA2003;289:256072 . DOIPubMed
  27. Bellomo RRonco CKellum JAMehta RLPalevsky PAcute renal failure—definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care.2004;8:R20412DOIPubMed
  28. Outinen TKTervo LMäkelä SHuttunen RMäenpää NHuhtala HPlasma levels of soluble urokinase-type plasminogen activator receptor associate with the clinical severity of acute Puumala hantavirus infection. PLoS ONE2013;8:e71335DOIPubMed
  29. Outinen TKMäkelä SMAla-Houhala IOHuhtala HSHurme MPaakkala ASThe severity of Puumala hantavirus induced nephropathia epidemica can be better evaluated using plasma interleukin-6 than C-reactive protein determinations. BMC Infect Dis2010;10:132DOIPubMed
  30. Krautkrämer EGrouls SStein NReiser JZeier MPathogenic old world hantaviruses infect renal glomerular and tubular cells and induce disassembling of cell-to-cell contacts. J Virol2011;85:981123DOIPubMed
  31. Vaheri AStrandin THepojoki JSironen THenttonen HMäkelä SUncovering the mysteries of hantavirus infections. Nat Rev Microbiol.2013;11:53950DOIPubMed
  32. Turčinov DPuljiz IMarkotić AKuzman IBegovac JClinical and laboratory findings in patients with oliguric and non-oliguric hantavirus haemorrhagic fever with renal syndrome: an analysis of 128 patients. Clin Microbiol Infect2013;19:6749DOIPubMed
  33. Heyman PVaheri ALundkvist AAvsic-Zupanc THantavirus infections in Europe: from virus carriers to a major public-health problem. Expert Rev Anti Infect Ther2009;7:20517DOIPubMed
  34. Hautala NKauma HVapalahti OMahonen SMVainio OVaheri AProspective study on ocular findings in acute Puumala hantavirus infection in hospitalised patients. Br J Ophthalmol2011;95:55962DOIPubMed
  35. Wolf-Maier KCooper RSBanegas JRGiampaoli SHense HWJoffres MHypertension prevalence and blood pressure levels in 6 European countries, Canada, and the United States. JAMA2003;289:23639DOIPubMed
  36. Elgh FLinderholm MWadell GTarnvik AJuto PDevelopment of humoral cross-reactivity to the nucleocapsid protein of heterologous hantaviruses in nephropathia epidemica. FEMS Immunol Med Microbiol1998;22:30915DOIPubMed
  37. Elgh FLundkvist AAlexeyev OAStenlund HAvsic-Zupanc THjelle BSerological diagnosis of hantavirus infections by an enzyme-linked immunosorbent assay based on detection of immunoglobulin G and M responses to recombinant nucleocapsid proteins of five viral serotypes. J Clin Microbiol1997;35:112230 .PubMed
  38. Maes PClement JGavrilovskaya IVan Ranst MHantaviruses: immunology, treatment, and prevention. Viral Immunol2004;17:48197.DOIPubMed
  39. Klempa BMeisel HRath SBartel JUlrich RKruger DHOccurrence of renal and pulmonary syndrome in a region of northeast Germany where Tula hantavirus circulates. J Clin Microbiol2003;41:48947DOIPubMed
  40. Klempa BSchutt MAuste BLabuda MUlrich RMeisel HFirst molecular identification of human Dobrava virus infection in central. J Clin Microbiol2004;42:13225DOIPubMed


Technical Appendix

Suggested citation for this article: Latus J, Schwab M, Tacconelli E, Pieper F-M, Wegener D, Dippon J, et al. Clinical course and long-term outcome of hantavirus-associated nephropathia epidemica, Germany. Emerg Infect Dis. 2015 Jan [date cited]. http://dx.doi.org/10.3201/eid2101.140861
DOI: 10.3201/eid2101.140861

No hay comentarios:

Publicar un comentario