Diagnostic of Puumala Virus Infection in France
Condition: Nephropathia Epidemica; Hemorrhagic Fever With Renal Syndrome
MeSH terms: Hemorrhagic Fevers, Viral; Hemorrhagic Fever with Renal Syndrome; Balkan Nephropathy
Study type: Observational

Summary: 
      Routine Puumala virus (PUUV) infection diagnosis is performed using serological commercial
      kits of which performances have not been established in real life, which use recombinant
      protein from strains from Central or North Europe. Molecular diagnostic of these infection is
      not the rule. Consequently the objectives of the project are to evaluate the performances of
      the serological commercial assays in real life in France and to assess the use of urine
      versus plasma for the molecular diagnostic of this infection.
    

Detailed description: 
      Hantaviruses constitute one of the 5 genera in the family Bunyaviridae and are associated
      with several natural host species including rodents, insectivores and bats. Infection of
      these species remains unapparent. Transmission of the virus between individuals occurs
      through direct contact or through inhalation of saliva, feces, or urine. Using these routes,
      some rodent-borne hantaviruses can be transmitted to humans and cause hemorrhagic fever with
      renal syndrome or cardiopulmonary syndrome. Human-to-human transmission is rare. There is no
      specific treatment. Inactivated vaccines against Hantaan and Seoul (SEOV) viruses are only
      available and licensed in China and South Korea.

      Puumala (PUUV), SEOV, Tula and Nova hantaviruses are reported in metropolitan France but only
      the 2 first are of medical importance. One single human SEOV infection has been confirmed and
      very few cases have been suspected. In contrast, about 100 PUUV human cases are detected
      yearly and occurred in the North East quarter of France.

      Routine PUUV infection diagnosis is performed using serological commercial kits, allowing
      detection of IgM or IgG against PUUV or other hantaviruses. The performances (sensitivity and
      specificity) of these tests as reported by the manufacturers are very good. However, 1/ they
      have been established with panels of reference sera and not in real life for all assays but
      one; 2/ these assays are based on N recombinant protein but it has been reported that using
      whole virus antigens, instead of the single N protein, detection of IgG against hantavirus
      would be earlier; 3/ PUUV strains used to produce the recombinant N proteins are
      phylogenetically far from the strains detected in France, and the use of a Belgian strain
      close to the French strains (instead of a Scandinavian strain) since 1990 has improved the
      performances of the Institut Pasteur, Hantavirus National Reference Center, home-made assays.

      Molecular diagnosis is not performed routinely and only 3 very recent studies reported data
      on PUUV viremia, using blood, plasma or sera. Urine samples previously showed to be a good
      alternative for PUUV detection but the use if this type of sample has not been evaluated in
      real life and the viruria not studied.

      The performances of most of the commercial immunoassays for the detection of antibodies
      against hantaviruses, especially PUUV, has not yet been reported when used in real life.

      The investigators propose to perform this evaluation for 9 assays, some of them now being
      used for the last few years by 13 French clinical laboratories:

        -  Euroimmun AG : Hantavirus Pool 1 " Eurasia " IgM and IgG ELISA

        -  Focus Diagnostics Hantavirus DxSelect IgM and IgG ELISA

        -  Progen Hantavirus (Puumala) IgM and IgG ELISA

        -  Reagena Puumala IgM and IgG EIA

        -  Reagena Reascan Puumala IgM (rapid test)

      Furthermore, they will explore the use of urine as a sample type for molecular diagnostics.
      Hantaviruses are excreted in the urine of rodents and have been detected in a few studies in
      the urine of patients, as well as IgG and IgM against hantaviruses. The shedding of the virus
      may be higher and/or longer in the urine than in plasma. Viruria compared to viremia has
      never been reported.

      The results of the study will allow the recommendation of some commercial assays to be used
      at admission of patients for the serological diagnosis of PUUV infection.

      Furthermore, the results of the study, assessing the use of the urine versus blood for the
      molecular detection of PUUV, may recommend the use of the molecular techniques for the
      diagnostic of this infection.
    

Observational model: Case-Control
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Patients hospitalized for suspected PUUV infection
      
Biospecimen description: 
      Urine Plasma Serum
    
Keywords: Puumala virus; diagnostic; France