Nephropathia EpidemicaHANTADIAGNCT02455375
Diagnostic of Puumala Virus Infection in France
An observational study of Nephropathia Epidemica and Hemorrhagic Fever With Renal Syndrome, run by Centre Hospitalier de Charleville-Mézières at 10 sites in France.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 75 years
- Conditions the study is for
- Nephropathia Epidemica, Hemorrhagic Fever With Renal Syndrome
- How many people
- 179 participants
- Where
- 10 sitesFrance
- Study dates
- Jul 2015to 30 Nov 2021
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 75 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Study population: Patients hospitalized for suspected PUUV infection
Who may be able to join
- Hospitalized patients, male or female, more than 18 years old and less than 76 years old1:
- having at admission or within 8 days preceding admission a pain , a documented febrile syndrome (body temperature ≥ 38°C) and a platelet count < 150 G/L,
- exposed to PUUV infection (for the last 6 weeks) or living in a French municipality where Hantavirus infection cases have been recorded during the 2003-2013 period or in a municipality bordering one of them ,
- giving their written consent after being informed of the research and the collection of data, and blood \& urine samples.
- NB: persons in emergency situation will be proposed to participate because their situation may affect the performances of laboratory diagnostics.
Who cannot join
- Hospitalized patients:
- who are known to have been previously diagnosed infected by an hantavirus (medical records and/or laboratory results),
- who are known to present stable thrombocytopenia,
- who, according to the medical staff, would not adhere to the protocol,
- for whom the health status, according to the medical staff, may interfere with the study or is not compatible with the sampling planned in the study.
- NB: Pregnant, parturient or breast-feeding women as well as patients under psychiatric care or patients subject to a legal protection order will be not proposed to participate.
Trial locations and contacts
10 sites in 1 country.
10 sites in 1 country
France10 sites
CH Belfort-Montbéliard
Belfort
CHU Besançon
Besançon
CH Charleville Mézières
Charleville-Mézières
CHP Sud de l'Oise
Creil
CHU Dijon
Dijon
CH de Laon
Laon
CHU Reims
Reims
CH de Saint Claude
Saint-Claude
CHU Nancy
Vandœuvre-lès-Nancy
CH de Verdun
Verdun
About this study
Official title: Puumala Hantavirus Infection in France: Evaluation of Commercial Assays for the Detection of Antibodies Against This Virus and the Use of Urine Samples for the Molecular Detection of This Infection
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.
Read the 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.
- Keywords
- Puumala virus, diagnostic, France
- Medical subject headings
- Hemorrhagic Fever with Renal Syndrome, Disease
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
| Study group | Role | What they receive |
|---|---|---|
| Cases | Case group = group of patients positive with reference tests including serological (ELISA, IF neutralization) and/or molecular assays: * detection of PUUV RNA in plasma collected at admission. * or/and detection of IgM and IgG against PUUV in serum collected at admission, * or/and detection of a seroconversion in IgG against PUUV from admission and late sera | |
| Controls | Control group = group of patients who do not have the criteria listed above |
What is being measured
The primary outcome is the main question the study is designed to answer.
Proportion of patients positive for the detection of IgG or IgM againt PUUV by commercial assays and by molecular/serological techniques
Proportion of patients tested positive for the detection of IgG or IgM against PUUV by the use of the commercial assays (index tests) and by the Hantavirus National Reference Center (NRC) molecular and serological techniques (reference tests) according to the information given in the notices of the commercial kits in use and in the version of the standard operating procedure of the Hantavirus NRC in use.
Measured: 33 months
Secondary outcomes (1)
Proportion of urine samples tested positive for the detection of PUUV
Proportion of urine samples tested positive for IgG or IgM against PUUV compare to plasma sample positive for IgG or IgM against PUUV
Measured: 33 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted27 May 2015 (estimated)
- Study startJul 2015
- Primary completion30 Nov 2021
- Study completion30 Nov 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (5)Papers the sponsor has linked to this study.
- Other trials for Nephropathia EpidemicaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Case-control
- Time perspective
- Prospective
- Enrolment
- 179 participants (actual)
Sponsor and investigators
- Lead sponsor
- Centre Hospitalier de Charleville-Mézières
- Sponsor type
- University, hospital or other
- Collaborators
- Institut Pasteur
- Responsible party
- Sponsor
- Investigators
- Jean Marc Galempoix, MD, Principal investigator, CH de Charleville-Mézières
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02455375
- Sponsor's protocol ID
- PHRC-14-0063
- Acronym
- HANTADIAG
- Status last verified
- Aug 2023
- First submitted
- 21 Apr 2015
- Last updated
- 25 Aug 2023
- Results posted
- No
- Data monitoring committee
- No
- Individual data sharing
- Undecided
Publications
Plyusnin A, Horling J, Kanerva M, Mustonen J, Cheng Y, Partanen J, Vapalahti O, Kukkonen SK, Niemimaa J, Henttonen H, Niklasson B, Lundkvist A, Vaheri A. Puumala hantavirus genome in patients with nephropathia epidemica: correlation of PCR positivity with HLA haplotype and link to viral sequences in local rodents. J Clin Microbiol. 1997 May;35(5):1090-6. doi: 10.1128/jcm.35.5.1090-1096.1997.
PubMed 9114386Prince HE, Lieberman JM. Impact of the Yosemite hantavirus outbreak on hantavirus antibody testing at a national reference laboratory. Clin Vaccine Immunol. 2013 Aug;20(8):1213-6. doi: 10.1128/CVI.00326-13. Epub 2013 Jun 5.
PubMed 23740929Lederer S, Lattwein E, Hanke M, Sonnenberg K, Stoecker W, Lundkvist A, Vaheri A, Vapalahti O, Chan PK, Feldmann H, Dick D, Schmidt-Chanasit J, Padula P, Vial PA, Panculescu-Gatej R, Ceianu C, Heyman P, Avsic-Zupanc T, Niedrig M. Indirect immunofluorescence assay for the simultaneous detection of antibodies against clinically important old and new world hantaviruses. PLoS Negl Trop Dis. 2013 Apr 4;7(4):e2157. doi: 10.1371/journal.pntd.0002157. Print 2013.
PubMed 23593524Hentzien M, Mestrallet S, Halin P, Pannet LA, Lebrun D, Drame M, Bani-Sadr F, Galempoix JM, Strady C, Reynes JM, Penalba C, Servettaz A. Bioclinical Test to Predict Nephropathia Epidemica Severity at Hospital Admission. Emerg Infect Dis. 2018 Jun;24(6):1045-1054. doi: 10.3201/eid2406.172160.
PubMed 29774835Reynes JM, Schaeffer L, Papadopoulos P, Ait-Ahmed M, Siby-Diakite D, Ripaux-Lefevre M, Buivan TP, Lechat S, Vray M, Galempoix JM; HANTADIAG Study Group. Molecular Detection of Orthohantavirus puumalaense in Plasma and Urine Samples from Hospitalized Patients Presenting with a Serologically Confirmed Acute Hantavirus Infection in France. J Clin Microbiol. 2023 Aug 23;61(8):e0037223. doi: 10.1128/jcm.00372-23. Epub 2023 Jul 24.
PubMed 37486218
Study at a glance
From the registry record, last updated by the sponsor on 25 Aug 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Puumala Hantavirus Infection in France: Evaluation of Commercial Assays for the Detection of Antibodies Against This Virus and the Use of Urine Samples for the Molecular Detection of This Infection
- ClinicalTrials.gov ID
- NCT02455375
- Acronym / sponsor ID
- HANTADIAG / PHRC-14-0063
- Keywords
- Puumala virus, diagnostic, France
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 179 participants (actual)
- Lead sponsor
- Centre Hospitalier de Charleville-MézièresUniversity, hospital or other
- Collaborators
- Institut Pasteur
- Study start
- Jul 2015 (actual)
- Primary completion
- 30 Nov 2021 (actual)
- Study completion
- 30 Nov 2021 (actual)
- First posted
- 27 May 2015 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Observational model
- Case-control
- Time perspective
- Prospective
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Cases | – | –Case group = group of patients positive with reference tests including serological (ELISA, IF neutralization) and/or molecular assays: * detection of PUUV RNA in plasma collected at admission. * or/and detection of IgM and IgG against PUUV in serum collected at admission, * or/and detection of a seroconversion in IgG against PUUV from admission and late sera |
| Controls | – | –Control group = group of patients who do not have the criteria listed above |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- Study population
- Patients hospitalized for suspected PUUV infection
Key inclusion criteria (5 listed)
- Hospitalized patients, male or female, more than 18 years old and less than 76 years old1:
- having at admission or within 8 days preceding admission a pain , a documented febrile syndrome (body temperature ≥ 38°C) and a platelet count < 150 G/L,
- exposed to PUUV infection (for the last 6 weeks) or living in a French municipality where Hantavirus infection cases have been recorded during the 2003-2013 period or in a municipality bordering one of them ,
- giving their written consent after being informed of the research and the collection of data, and blood \& urine samples.
- NB: persons in emergency situation will be proposed to participate because their situation may affect the performances of laboratory diagnostics.
Key exclusion criteria (6 listed)
- who are known to have been previously diagnosed infected by an hantavirus (medical records and/or laboratory results),
- who are known to present stable thrombocytopenia,
- who, according to the medical staff, would not adhere to the protocol,
- for whom the health status, according to the medical staff, may interfere with the study or is not compatible with the sampling planned in the study.
- NB: Pregnant, parturient or breast-feeding women as well as patients under psychiatric care or patients subject to a legal protection order will be not proposed to participate.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
Proportion of patients positive for the detection of IgG or IgM againt PUUV by commercial assays and by molecular/serological techniques
Time frame: 33 months
Proportion of patients tested positive for the detection of IgG or IgM against PUUV by the use of the commercial assays (index tests) and by the Hantavirus National Reference Center (NRC) molecular and serological techniques (reference tests) according to the information given in the notices of the commercial kits in use and in the version of the standard operating procedure of the Hantavirus NRC in use.
1 secondary outcome
Proportion of urine samples tested positive for the detection of PUUV
Time frame: 33 months
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 25 Aug 2023.
- Background: PubMed 9114386Plyusnin A, Horling J, Kanerva M, Mustonen J, Cheng Y, Partanen J, Vapalahti O, Kukkonen SK, Niemimaa J, Henttonen H, Niklasson B, Lundkvist A, Vaheri A. Puumala hantavirus genome in patients with nephropathia epidemica: correlation of PCR positivity with HLA haplotype and link to viral sequences in local rodents. J Clin Microbiol. 1997 May;35(5):1090-6. doi: 10.1128/jcm.35.5.1090-1096.1997.
- Background: PubMed 23740929Prince HE, Lieberman JM. Impact of the Yosemite hantavirus outbreak on hantavirus antibody testing at a national reference laboratory. Clin Vaccine Immunol. 2013 Aug;20(8):1213-6. doi: 10.1128/CVI.00326-13. Epub 2013 Jun 5.
- Background: PubMed 23593524Lederer S, Lattwein E, Hanke M, Sonnenberg K, Stoecker W, Lundkvist A, Vaheri A, Vapalahti O, Chan PK, Feldmann H, Dick D, Schmidt-Chanasit J, Padula P, Vial PA, Panculescu-Gatej R, Ceianu C, Heyman P, Avsic-Zupanc T, Niedrig M. Indirect immunofluorescence assay for the simultaneous detection of antibodies against clinically important old and new world hantaviruses. PLoS Negl Trop Dis. 2013 Apr 4;7(4):e2157. doi: 10.1371/journal.pntd.0002157. Print 2013.
- Background: PubMed 29774835Hentzien M, Mestrallet S, Halin P, Pannet LA, Lebrun D, Drame M, Bani-Sadr F, Galempoix JM, Strady C, Reynes JM, Penalba C, Servettaz A. Bioclinical Test to Predict Nephropathia Epidemica Severity at Hospital Admission. Emerg Infect Dis. 2018 Jun;24(6):1045-1054. doi: 10.3201/eid2406.172160.
- Results publication: PubMed 37486218Reynes JM, Schaeffer L, Papadopoulos P, Ait-Ahmed M, Siby-Diakite D, Ripaux-Lefevre M, Buivan TP, Lechat S, Vray M, Galempoix JM; HANTADIAG Study Group. Molecular Detection of Orthohantavirus puumalaense in Plasma and Urine Samples from Hospitalized Patients Presenting with a Serologically Confirmed Acute Hantavirus Infection in France. J Clin Microbiol. 2023 Aug 23;61(8):e0037223. doi: 10.1128/jcm.00372-23. Epub 2023 Jul 24.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Jean Marc Galempoix, MD principal investigator
CH de Charleville-Mézières
10 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Nephropathia Epidemica and Hemorrhagic Fever With Renal Syndrome, run by Centre Hospitalier de Charleville-Mézières at 10 sites in France.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 25 Aug 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 10 sites in France. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Proportion of patients positive for the detection of IgG or IgM againt PUUV by commercial assays and by molecular/serological techniques (time frame: 33 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02455375, which also lists 5 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 25 Aug 2023.