Multicentre Retrospective Study on the Clinical and Epidemiological Characteristics and Therapeutic Management of Non-cholera Vibrio Infections
Conditions: Vibrio Infections
Sponsor: Groupe Hospitalier de la Rochelle Ré Aunis

 
                         
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Epidemiological, retrospective, multicenter study on the clinical-
epidemiological characteristics and therapeutic management of 
non-cholera Vibrio infections. 
INFECTIVE 
2019/P02/358  
NCT04451707 
 
 
 
Version n°2.1 du 23/01/2019 
 
 
 
 
 
 
Sponsor 
Groupe Hospitalier de la Rochelle Ré Aunis 
Rue du Dr Schweizer 
17019 La Rochelle 
 
Study director : 
Dr Florence Hoefler 
Service de médecine interne et maladies infectieuses,  
Groupe Hospitalier de la Rochelle Ré Aunis 
rue du Dr Schweitzer 
17019 La Rochelle Cedex 
 
Statistical analysis : 
Caroline Allix-Béguec 
Unité de recherche clinique 
Groupe Hospitalier La Rochelle Ré Aunis 
Rue du Dr Schweitzer - 17019 La Rochelle 
recherche.clinique@ght-atlantique17.fr  
 
 
 
 
 

 
                         
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HISTORY OF PROTOCOL UPDATES 
 
VERSION 
DATE 
RAISON DE LA MISE A JOUR 
1 
09/12/2019 
 
2 
23/01/2020 
Amendments in accordance with the recommendations of the 
Comité d’expertise pour les recherches, les études et les évaluations 
dans le domaine de la santé 
2.1 
23/01/2020 
English version 
 
 
 
 

 
                         
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SOMMAIRE 
1. 
RESUME DE LA RECHERCHE 
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2. 
JUSTIFICATION SCIENTIFIQUE ET DESCRIPTION GENERALE 
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2.1. 
ETAT ACTUEL DES CONNAISSANCES 
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2.2. 
JUSTIFICATION DE LA DEMANDE DE DEROGATION A L’INFORMATION 
INDIVIDUELLE 5 
3. 
OBJECTIFS 
5 
3.1. 
OBJECTIF PRINCIPAL 
5 
3.2. 
OBJECTIFS SECONDAIRES 
5 
4. 
CONCEPTION DE LA RECHERCHE 
6 
5. 
CRITERES D’ÉLIGIBILITE 
6 
5.1. 
CRITERES D’INCLUSION 
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5.2. 
CRITERES DE NON INCLUSION 
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5.3. 
FAISABILITE ET MODALITES DE RECRUTEMENT 
6 
6. 
CRITERES D’EVALUATION 
7 
6.1. 
CRITERE D’EVALUATION PRINCIPAL 
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7. 
ASPECTS STATISTIQUES 
7 
7.1. 
CALCUL DE LA TAILLE D’ETUDE 
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7.2. 
METHODES STATISTIQUES EMPLOYEES 
8 
8. 
DROITS D’ACCES AUX DONNEES ET DOCUMENTS SOURCE 
8 
8.1. 
ACCES AUX DONNEES 
8 
8.2. 
DONNEES SOURCES 
8 
8.3. 
CONFIDENTIALITE DES DONNEES 
8 
9. 
CONTROLE ET ASSURANCE DE LA QUALITE 
ERREUR ! SIGNET NON DEFINI. 
9.1. 
CONSIGNES POUR LE RECUEIL DES DONNEES 
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9.2. 
SUIVI DE LA RECHERCHE 
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9.3. 
GESTION DES DONNEES 
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9.4. 
AUDIT ET INSPECTION 
9 
10. 
CONSIDERATIONS ETHIQUES ET REGLEMENTAIRES 
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10.1. 
CONFORMITE AUX TEXTES DE REFERENCE 
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11. 
CONSERVATION DES DOCUMENTS ET DES DONNEES RELATIVES A LA RECHERCHEERREUR ! SIGNET N
12. 
REGLES RELATIVES A LA PUBLICATION 
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12.1. 
COMMUNICATIONS SCIENTIFIQUES 
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12.2. 
COMMUNICATION DES RESULTATS AUX PATIENTS 
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12.3. 
CESSION DES DONNEES 
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13. 
REFERENCES BIBLIOGRAPHIQUES 
11 
14. 
ANNEXES 
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1. SUMMARY 
SPONSOR 
Groupe Hospitalier La Rochelle Ré Aunis 
Rue du Dr Schweitzer - 17019 La Rochelle 
STUDY DIRECTOR 
Dr Florence Hoefler 
TITLE 
Epidemiological, retrospective, multicenter study on the clinical-
epidemiological characteristics and therapeutic management of non-
cholera Vibrio infections (INFECTIVE). 
CONTEXT 
Vibrios are gram-negative, ubiquitous bacteria of the marine flora and 
are found particularly in warm waters. For example, the incidence is 
high in Florida and Vibrio infections are now reportable in the United 
States.  
Different species of Vibrio are described. We distinguish between 
choleric vibrios belonging to serogroups O1 and O139, responsible for 
cholera epidemics, and non-choleric vibrios. Our study will focus on 
non-epidemic vibrios. Vibrio infections develop by eating contaminated 
raw seafood or by exposure of a wound to the marine environment. They 
occur mainly during the hot summer months. This is explained on the 
one hand by a higher water temperature and on the other hand by an 
increased use of the beaches. With global warming, it is possible that 
Vibrio infections may increase in number and location. 
OBJECTIVES 
The purpose of this study is to identify the epidemiological and clinical 
characteristics of patients diagnosed with non-cholera Vibrio infection in 
Western France from 2000 to 2019. 
The different clinical forms will be described according to the different 
environmental and meteorological contexts. 
DESIGN 
Data-driven, retrospective, multi-center study 
INCLUSION CRITERIA 
- 
cases of non-epidemic vibriosis 
EXCLUSION CRITERIA 
- 
cases of infection with Vibrio cholerae O1 and O139 
OUTCOME MEASURES 
Socio-demographic, clinical and therapeutic criteria. 
SAMPLE SIZE 
Estimation entre 50 et 60 patients 
STATISTICAL ANALYSIS 
The data will be analyzed in a descriptive manner, and will be described 
by mean, standard deviation and median for continuous variables and by 
percentages for categorical variables. 

 
                         
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2.  SCIENTIFIC JUSTIFICATION AND GENERAL DESCRIPTION 
2.1. CURRENT STATE OF KNOWLEDGE 
Vibrios are gram-negative, ubiquitous bacteria of the marine flora and are found particularly in warm 
waters. For example, the incidence is high in Florida and Vibrio infections are now reportable in the 
United States. [1].  
Different species of Vibrio are described. We distinguish between choleric vibrios belonging to 
serogroups O1 and O139, responsible for cholera epidemics, and non-choleric vibrios. Our study will 
focus on non-epidemic vibrios. Among the non-epidemic vibrios, the predominant species are Vibrio 
vulnificus, Vibrio parahaemolyticus, Vibrio algolyticus and non-O1/O139 Vibrio cholerae. 
Vibrio infections develop by eating contaminated raw seafood - especially oysters - or by exposure of 
a wound to the marine environment. [2]. They occur mainly during the hot summer months. This can 
be explained on the one hand by a higher water temperature and on the other hand by an increased use 
of the beaches [3]. With global warming, it is possible that Vibrio infections may increase in number 
and location. 
 
Vibrio infections are rare but can be very severe or even fatal. They present themselves in the form of 
gastroenteritis, severe dermohypodermatitis or necrotizing fasciitis and can lead to septic shock. 
They are more common in patients with multiple co-morbidities including liver disease and heart 
failure [4]. 
 
Due to their rarity, Vibrio infections are very little known and therefore probably under-diagnosed. A 
delay in the therapeutic management with, in particular, targeted antibiotic therapy has been 
highlighted. [1]. Given the potential seriousness of these infections, it is important to sensitize 
healthcare professionals to take Vibrio into account in their therapeutic strategy when risk factors are 
identified (exposure to the marine environment, consumption of seafood). 
2.2. JUSTIFICATION OF THE REQUEST FOR DEROGATION FROM INDIVIDUAL 
INFORMATION 
The rarity of cases requires data collection from old records. It is planned to go back as far as 2000. A 
significant number of patients, who will no longer be followed up in the center where the diagnosis of 
vibriosis was made, is therefore to be expected. An authorization for a waiver of information is being 
sought as it will be difficult to locate the patients concerned. 
 
3. OBJECTIVES 
3.1. PRIMARY OBJECTIVE 
To describe the clinical and epidemiologic characteristics of patients diagnosed with non-cholera 
Vibrio infection. 
3.2. SECONDARY OBJECTIVES  
Describe the different clinical forms (gastroenteritis, moderate to severe skin disorders, bacteremia, 
ear infections) according to the different environmental contexts, particularly meteorological. 

 
                         
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4. DESIGN  
Data-driven, retrospective, multi-center study 
 
5. ELIGIBILITY CRITERIA 
5.1. INCLUSION CRITERIA 
Cases of vibriosis, other than Vibrio cholerae O1-O139, diagnosed between January 2000 and 
November 2019 will be included. 
 
A non-epidemic Vibrio infection is defined by a biological sample (blood culture, superficial sample, 
deep sample, ear sample) positive to a Vibrio species other than Vibrio cholerae O1-O139 taken from 
any patient. 
 
5.2. EXCLUSION CRITERIA 
Cases of Vibrio cholerae O1 and O139. 
 
5.3. FEASIBILITY AND RECRUITEMENT METHODS 
The data are collected in the hospital centers participating in the study, using a data collection form, 
directly by the person in charge of the study (Dr Florence Hoefler). 
The participating centers are the hospital centers of Poitiers, La Rochelle, Tours, La Roche-sur-Yon, 
Nantes, Angers and Rennes. 
A information letter will be sent to patients for whom the address is available. 
 
Identity 
Specialty 
Institution 
Professional 
registration 
number 
Centre 
N° 
Dr HOEFLER Florence 
Maladies infectieuses 
GH de la Rochelle Ré 
Aunis 
10101395555 
01 
Pr France ROBLOT 
 
Maladies infectieuses et 
tropicales 
CHU de Poitiers 
10002717147 
 
02 
Pr Louis BERNARD 
Médecine interne 
CHU de Tours 
10001058394 
03 
Dr Thomas GUIMARD 
Unité d'Infectiologie 
CH Départemental de 
la Vendée 
10100112449 
04 
Pr David  BOUTOILLE  Maladies infectieuses et 
tropicales 
CHU de Nantes 
10002582244 
05 
Dr Pierre 
ABGUEGUEN 
Maladies infectieuses 
CHU d’Angers 
10002575198 
06 
Pr Pierre TATTEVIN 
Service de Maladies 
Infectieuses et Réanimation 
Médicale 
CHU de Rennes 
10002669595 
07 
Pr Didier NEAU 
Maladies infectieuses et 
tropicales 
CHU de Bordeaux 
10002772936 
08 

 
                         
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Non-epidemic Vibrio infections are rare, and extending the research to eight centers over 20 years 
allows us to collect as many cases as possible. Data extraction will be done via the computer software 
in the microbiology laboratory of each center. Extraction may not be feasible until the year 2000 
depending on the different centers, which will be indicated within the limits of the study. The clinical 
records will then be consulted on the computer system of each center. 
6. EVALUATION CRITERIA 
6.1. PRIMARY OUTCOME 
Socio-demographic, clinical and therapeutic criteria. 
 
Details about the variables collected: 
 
Non-epidemic Vibrio infections can give four main clinical pictures: 
1) skin infections ranging from simple dermohypodermatitis to necrotizing fasciitis (skin damage with 
sores, blisters or necrosis will be sought) 
2) Digestive infections such as acute gastroenteritis (diarrhea, nausea, vomiting). 
3) bacteremia with a more or less severe sepsis pattern (fever, hemodynamic instability, dyspnea). The 
entry portal can be varied: digestive, cutaneous or pulmonary. 
4) ENT infections such as chronic otitis media (we will look for ear pain, discharge, deafness). 
 
Finally, Vibrio infections also give other clinical pictures but less common: pneumonia from inhaling 
contaminated water (typically from drowning), bone infections from an open fracture in contact with 
contaminated water. 
 
Vibrio infections are more common when the water temperature rises. More infections are expected 
during the summer months (June to September). It is therefore interesting to collect the month of 
exposure and infection in order to confirm this hypothesis.  
 
Therapeutic management is essentially based on antibiotic therapy. The literature shows that the initial 
antibiotic therapy is often not adapted because Vibrio is rarely taken into account in the first 
diagnoses. It is therefore voluntary to let the antibiotic therapy be specified rather than restricting the 
choice to a few molecules. Finally, in severe skin infections such as necrotizing fasciitis, surgical 
treatment such as debridement, lavage or amputation is necessary. Sometimes there is a need for 
several surgical revisions. 
 
7. STATISTICAL ANALYSIS 
Statistical analyses will be carried out by : 
Caroline Allix-Béguec, PhD 
Unité de recherche clinique 
Groupe Hospitalier de la Rochelle Ré Aunis 
17019 La Rochelle Cedex 
caroline.allix-beguec@ght-atlantique17.fr 
7.1. SAMPLE SIZE 
The study carried out by the National Reference Center for Vibriosis and Cholera between January 
1995 and December 1998 reported 29 cases of non-cholera vibriosis infections [5]. More than half 
(n=16) resided in a coastal department and 7 were from the Atlantic coast.  

 
                         
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Vibrios do not develop in waters with a high degree of salinity, which is why they are rarely isolated 
in France.   
Data collection in the hospital centers of Poitiers, La Rochelle, Tours, La Roche-sur-Yon, Nantes, 
Angers, Rennes and Bordeaux will make it possible to describe almost all Bay of Biscay and Celtic 
sea cases. Between 50 and 60 cases are thus expected over a period of 19 years in all participating 
centers. 
7.2. STATISTICAL ANALYSIS  
Between 50 and 60 cases are thus expected over a period of 19 years in all participating centers. 
 
8. RIGHTS OF ACCESS TO SOURCE DATA AND DOCUMENTS  
8.1. ACCES TO DATA 
Acceptance of participation in the protocol implies that the persons carrying out the research will 
make the documents and individual data strictly necessary for the monitoring, quality control and 
auditing of the research available to persons with access to these documents in accordance with the 
legislative and regulatory provisions in force. 
8.2. SOURCE DATA  
All information contained in original documents, or in authenticated copies of such documents, 
relating to clinical examinations, observations or other activities carried out in the course of research 
and necessary for the reconstruction and evaluation of the research. Documents in which source data 
are recorded are referred to as source documents. 
Source documents are patient medical records. 
8.3. CONFIDENTIALITY  
In accordance with the legislative provisions in force, persons with direct access to source data shall 
take all necessary precautions to ensure the confidentiality of information relating to the research, the 
persons involved, particularly with regard to their identity and the results obtained. These persons, in 
the same way as the persons directing and supervising the research, are subject to professional secrecy. 
During or at the conclusion of the research, data collected on individuals who are suitable for the 
research and provided to the sponsor by those conducting and monitoring the research (or other 
specialized stakeholders) will be coded. Under no circumstances should the names or addresses of the 
individuals concerned be made clear. 
The coding used will be as follows: 
ID : 
_ 
_ 
_ __ 
 
 
1st letter 
of patient 
surname 
 
1st letter 
of patient 
first name 
No 
centre 
 
No patient 

 
                         
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9. QUALITY CONTROL AND QUALITY ASSURANCE 
9.1. INSTRUCTIONS FOR DATA COLLECTION 
All information required by the protocol should be recorded on the paper case report forms and an 
explanation should be provided for each missing data item. Data should be collected as they are 
obtained, and recorded in these notebooks in a neat and legible manner. 
9.2. RESEARCH FOLLOW-UP 
Dr. Hoefler will follow up on the research. She will be in charge of : 
- 
the logistics and monitoring of the research, 
- 
reporting on its progress, 
- 
the verification of the update of the observation book (request for additional information, 
corrections, ...), 
She will work according to standard operating procedures. 
9.3. DATA MANAGEMENT 
The data will be entered on an Excel database stored on the developer's internal network protected 
from intrusions and with a daily backup system on disk. 
Consistency tests (data format, search for extremes) will be performed by the statistician who will 
provide feedback to Dr. Hoefler for verification of the data.  
The database will be frozen after the responses to all queries are received. 
9.4. AUDIT AND INSPECTION 
An audit may be carried out at any time by persons mandated by the sponsor and independent of the 
persons conducting the research. Its purpose is to verify the safety of participants and respect for their 
rights, compliance with applicable regulations and the reliability of data. 
The audit, as well as the inspection, may apply to all stages of the research, from the development of 
the protocol to the publication of the results and the classification of the data used or produced in the 
course of the research. 
 
Investigators agree to comply with the sponsor's requirements for an audit and with the competent 
authority for an inspection of the research. 
10. ETHICAL AND REGULATORY CONSIDERATIONS 
10.1. 
COMPLIANCE WITH REFERENCE TEXTS 
The data recorded during this research is subject to computerized processing at the Groupe Hospitalier 
de la Rochelle Ré Aunis in compliance with law n°78-17 of January 6, 1978 relating to data 
processing, files and liberties modified by law 2004-801 of August 6, 2004. 
 
The Groupe Hospitalier de la Rochelle Ré Aunis has declared the research to the Commission 
Nationale de l'Informatique et des Libertés (CNIL). 
 

 
                         
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11. ARCHIVE OF DOCUMENTS AND RESEARCH DATA 
The conservation of data from this study will be carried out in accordance with the institution's 
procedure for the conservation and archiving of research documents.  
The references of this procedure are the decree of August 11, 2008 modifying the decree of November 
8, 2006 setting the duration of storage by the sponsor and the investigator of documents and data 
relating to biomedical research involving medicinal products for human use and the decree of August 
11, 2008 setting the duration of storage by the sponsor and the investigator of documents and data 
relating to biomedical research other than that involving medicinal products for human use. 
The documents and data relating to the research constitute the essential documents that make up the 
permanent record of the research. These documents, individually and collectively, enable the 
evaluation of the conduct of biomedical research and the quality of the data produced. These 
documents serve to demonstrate that the investigator, the sponsor, and all those involved in the 
research comply with the laws and regulations in force. 
 
The following documents will be archived in the service until the end of the useful life. This indexed 
archiving includes:  
- 
Mail copies of the favorable opinion of the Committee of Expertise for Research, Studies and 
Evaluations in the field of Health (CEREES) and the authorization of the CNIL (French 
National Commission for Information Technology and Civil Liberties).  
- 
Successive versions of the protocol (identified by version number and version date),  
- 
The completed and validated observation notebook of each subject included, 
- 
All the specific appendices of the study,  
- 
The final study report from the statistical analysis and quality control of the study (duplicate 
sent to the sponsor).  
- 
Any audit certificates carried out during the course of the research  
 
The database having given rise to the statistical analysis must also be archived by the person in charge 
of the analysis.  
 
At the end of the period of practical usefulness, all documents to be archived, as defined in the 
procedure of "filing and archiving of documents related to biomedical research" of the Groupe 
Hospitalier de la Rochelle Ré Aunis will be transferred to the archiving site dedicated to clinical 
research and will be placed under the responsibility of the Sponsor for 15 years after the end of the 
study in accordance with institutional practices. 
12. RULES RELATING TO PUBLICATION 
12.1. 
SCIENTIFIC COMMUNICATIONS 
The analysis of the data provided by the centers is carried out by the Groupe Hospitalier de la Rochelle 
Ré Aunis. This analysis results in a written report that is submitted to the sponsor. This report allows 
the preparation of one or more publications. 
 
Any written or oral communication of the results of the research must receive the prior agreement of 
the person conducting and supervising the research and, where applicable, of any committee 
established for the research. 
 
The publication of the main results mentions the name of the sponsor, all persons who included or 
followed up patients in the research, and the methodologists, biostatisticians and data managers who 
participated in the research. The international rules for writing and publication will be taken into 
account (The Uniform Requirements for Manuscripts of the ICMJE, April 2010).  

 
                         
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12.2. 
COMMUNICATION OF RESULTS TO PATIENTS 
At their request, research participants are informed of the overall results of the research. 
12.3. 
TRANSFER OF DATA 
Data collection and management is provided by the Groupe Hospitalier de la Rochelle Ré Aunis. The 
conditions of transfer of all or part of the research database are decided by the research sponsor and 
are the subject of a written contract. 
13. REFERENCES  
 
[1] 
Weis KE, Hammond RM, Hutchinson R, Blackmore CGM. Vibrio illness in Florida, 1998-
2007. Epidemiol Infect 2011;139:591–598. doi:10.1017/S0950268810001354. 
[2] 
Morris JG, Acheson D. Cholera and Other Types of Vibriosis: A Story of Human Pandemics 
and Oysters on the Half Shell. Clin Infect Dis 2003;37:272–280. doi:10.1086/375600. 
[3] 
Givens CE, Bowers JC, Depaola A, Hollibaugh JT, Jones JL. Occurrence and distribution of 
Vibrio vulnificus and Vibrio parahaemolyticus - potential roles for fish, oyster, sediment and 
water. Lett Appl Microbiol 2014;58:503–510. doi:10.1111/lam.12226. 
[4] 
Jones MK, Oliver JD. Vibrio vulnificus: Disease and pathogenesis. Infect Immun 
2009;77:1723–1733. doi:10.1128/IAI.01046-08. 
[5] 
Geneste C, Dab W, Cabanes P, Vaillant V, Quilici M, Fournier J. Les vibrioses non cholériques 
en France : cas identifiés de 1995 à 1998 par le Centre National de Référence. Bull 
Epidémiologique Hebd 2000;9:38–40.