Risk factors for symptoms of infection and microbial carriage among French medical students abroad
Authors: Tran Duc Anh Ly
Laetitia Ninove
Naomie Canard
Philippe Gautret
Tassadit Drali
Florence Fenollar
Philippe Parola
Didier Raoult
Pierre Marty
Van Thuan Hoang
Thi Loi Dao
Journal: International Journal of Infectious Diseases (2020)
Discipline: IMMUNOLOGY
Keywords: E. coli; Medical students; Respiratory symptoms; Risk factor; Streptococcus pneumonia
Affiliations: Aix Marseille University, IRD, AP-HM, SSA, VITROME, Marseille, France; IHU-Méditerranée Infection, Marseille, France; Thai Binh University of Medicine and Pharmacy, Thai Binh, Viet Nam., Aix Marseille University, IRD, AP-HM, SSA, VITROME, Marseille, France; IHU-Méditerranée Infection, Marseille, France., IHU-Méditerranée Infection, Marseille, France; Unité des Virus Émergents (UVE: Aix-Marseille University - IRD 190 - Inserm 1207), Marseille, France., Aix Marseille University, IRD, AP-HM, SSA, VITROME, Marseille, France; Aix Marseille University, IRD, AP-HM, MEPHI, Marseille, France., Université Côte d'Azur, Inserm, C3M, Nice Cedex 3, France; Parasitologie-Mycologie, Centre Hospitalier Universitaire l'Archet, Nice Cedex 3, France., Aix Marseille University, IRD, AP-HM, SSA, VITROME, Marseille, France; IHU-Méditerranée Infection, Marseille, France. Electronic address: .

Abstract:  Objectives: To investigate symptoms of infections and their risk factors among French medical students undertaking an internship abroad. Methods: Clinical follow up, and qPCR-based respiratory, gastrointestinal, and vaginal pathogen carriages were prospectively assessed pre-travel and post-travel, in a cohort of medical students departing from Marseille, France. Results: 293 students were included. 63.5%, 35.8%, and 3.6% of students reported gastrointestinal, respiratory, and vaginal symptoms, respectively. The acquisition rate of Enteroaggregative Escherichia coli and Enteropathogenic E. coli was 40.9% and 18.6%, respectively. A significant increase was observed for rhinovirus and Streptococcus pneumoniae by comparing the prevalence of pathogens in pre-travel and post-travel samples. Gardnerella vaginalis and Atopobium vaginae acquisition rates were 12.9% and 13.9%, respectively. Being female, primarily traveling to Vietnam, and living in basic accommodation conditions were independent risk factors for reporting respiratory symptoms. Students reporting respiratory symptoms were three times more likely to acquire S. pneumoniae. Traveling primarily to north India and Senegal were independent risk factors for diarrhea. Conclusion: This study makes it possible to identify the leading infectious diseases linked to travel in a group of French medical students undertaking an internship abroad and the risk factors on which to base targeting students for reinforced pre-travel advice. 

Retracted: No

PubPeer comments:
 This paper is part of a set of 3 papers from the Aix-Marseille Universitu00e9 Institut Hospitalo-Universitaire Mu00e9diterranu00e9e-Infection (IHU) in Marseille, France, that all describe a study in French Medical students but without mentioning ethical approval from a Comitu00e9 de Protection des Personnes (IRB). **The 3 papers use the same ethics approval number 2019-006. ** Considering the same ethics approval number, the 3 papers are related to the same study with the same protocol. In the video provided by the instiution, the IHU team describes human research in medical students. [] **Prospective study, prospective recruitment** This study recruits medical students from the Aix-Marseille Universitu00e9. The recruitment is done before their vacation abroad. The study assessed several criteria (search for resistant bacteria, carriage of bacteria). In the video, the authors described this study as prospective. ![file] (source : video at 1min38) This is in line with the title and the content of the paper  Infectious disease symptoms and microbial carriage among French medical students travelling abroad: A prospective study . The protocol approved under number 2019-006 is a prospective study. **Recruitment of healthy volunteers** The study recruits medical students at a travel vaccination center. They take self-samples before and after the trip and send the samples to the IHU laboratory. This is therefore a prospective study on healthy volunteers with interventions not included in routine care. ![file] (source : video at 2min22) This is in line with the content of the 3 papers mentioned at the end of this comment. **Nose, pharynx, rectum, vagina and armpit swabs** The IHU requested to participants to self-samples nasal, pharyngeal, vaginal, rectal and armpit swabs. ![file] (source : video at 3min12) This is in line with the content of the 3 papers mentioned at the end of this comment. **Children were recruited** The video mentions that at least one 17 years-old participant were recruited. At this age, the participant is a child under the French law. Children are considered as a vulnerable population. The French Regulation and the Helsinki Declaration provide strict ethical consideration when a child is included in a study involving a human. ![file] (Source: video at 4min02) Nevertheless, none of the 3 papers mentioned the inclusion of children in the study. There is no mention of the consent of the parents in the paper (or in the video). The papers only mention adults from 18 years but the video mentions that children have been included in the results. There is here a serious concern related to ethics and a discrepancy in the presentation of the results between the video and the articles. **The IHU Ethics committee is not a  Comitu00e9 de Protection des Personnes ** In France, only the Comitu00e9 de Protection des Personnes can deliver an IRB approval for a prospective research in human. IHU Ethics Committee do not have the power to validate a prospective research in human. In France, a prospective study in human collecting nose, pharynx, rectum, vagina and armpit swabs is a research involving humans of level 2. The official body called GIRCIs has been created to organize the clinical research in France. The GIRCI Ile de France provides on its website, an application to verify the nature of a study and the authorization needed before to start the recruitment. Based on this assessment and the details of the recruitment mentioned in this paper, this study meets the criteria of an RIPH2 (research involving human Level 2). According to this assessment, an investigator of the study must obtain an approval of a Comitu00e9 de Protection des Personnes (certified IRB in France) before to start the recruitment of participant in a RIPH2. ![file] Source : https: girci-idf.fr Home EssaiQuestionnaire?Questionnaire=SMARTREG However, none of the articles mentioned an approval of a Comitu00e9 de Protection des Personnes. IHU Ethics Committee can not validate this type of study in France. **Retrospective ethics approval is a cause for rejection** According to point 23 of the Helsinki declaration, an approval from an ethics committee should have been obtained before undertaking the research. Retrospective ethics approval is usually a cause for rejection according to Editors Policies. It can be assumed that the ethics approval number 2019-006 has been requested or obtained in 2019. But, as mentioned in the video or in the 3 papers, the recruitment started before 2019. As a consequence, the ethics approval is retrospective. According to the Editor Policy and the Helsinki Declaration, these papers should have been rejected by the Editor before to be peer-reviewed. It would be interesting to know why it was not the case. **Conclusion:** Can the authors clarify - if this prospective study was approved by a Comitu00e9 de Protection des Personnes before to start the recruitment. Disclosing the ethics approval number from a Comitu00e9 de Protection des Personnes, obtained before the beginning of the recruitment would answer to all the concerns detailed here. - if the consent of parents have been obtained for the minors participating to the study - why the results of minors are not mentioned in the 3 papers but are included in the results displayed in the video? Considering the retrospective ethics approval, can the Editor explain why a study which not comply with the Helsinki Declaration was peer-reviewed ? **LIST OF THE PAPERS** - [Travel Medicine and Infectious Disease - Infectious disease symptoms and microbial carriage among French medical students travelling abroad: A prospective study] - [Travel Medicine and Infectious Disease - Acquisition of multidrug-resistant bacteria and colistin resistance genes in French medical students on internships abroad] - [International Journal of Infectious Diseases - Risk factors for symptoms of infection and microbial carriage among French medical students abroad] , 
 According to this [Mediapart s article] , the French Medicines Agency (ANSM) performed a GCP inspection in November 2021 (GCP = Good Clinical Practices). This inspection covers the 3 articles mentioned by #1 (including this article). In the preliminary report, the French Medicines Agency mentioned that: - this study in students (including one minor) is a research in humans. - this study was not approved by a Comitu00e9 de Protection des Personnes (CPP), which is mandatory in France for the research in humans. Approval must be obtained before the first recruitment. Based on this article comment from #1 seems to be accurate. These 3 articles (including this article) mentioned an ethics approval from an internal ethics committee. However, this point needs to be carefully considered. Indeed, according to the newspaper, the inspection report would mention that one of the author provides a false ethics approval document to the ANSM. Author of the ethics document contest to have signed this approval and provides to ANSM the original ethics opinion which recommends to request a CPP approval. The newspaper also mentions that the French Medicines forwards the false document, the original one and testimonies to the French Prosecutor. This article from Mediapart raises serious ethical issues and an expression of concern should be issued with no delay to alert the readers about the on-going investigations of French authorities on this study. , 
 Following the ANSM inspection and the preliminary report, the institution (IHU Marseille) and one of the authors (Didier Raoult) provided an answer to the French Health Agency. This answer confirms major violations to: - The Helsinki Declaration - The French Health Law - The Editorial Policy of the Journal. As a reminder, as stated in comments above, this study included minors who are a vulnerable populations. **Answer from the IHU Marseille** The IHU Marseille provided to ANSM the following [statement] signed by one of the author: **Quote page 13, translated from french** *Point R6: During the submission of the articles (in 2019), we have requested from the IHU Ethics Committee a retrospective ethics approval, only to answer to the possible requests from the medical journals. The ethics approval was favorable under the condition we get a CPP approval first. But this answer from IHU Ethics after approval the last patient included of the medical students in 2019. At this point, the CPP request was pointless as the study was already completed.* **Quote page 14, translated from french** *In this situation, the approval from the IHU ethics committee is a retrospective ethics approval before the submission for publication* **Comments:** The author recognizes 2 points : - They did not get a CPP approval for this prospective research in human - They did not get an ethics approval before to start the study. The ethics approval was delivered after the completion of the study. This a major violations to the Good Clinical Practices. **Violation of the Helsinki Declaration** Starting a prospective study in humans without an ethics approval is a serious violation of the article 23 of the [Declaration of Helsinki] . Here, the author recognized this fact and mentioned that they obtained a retrospective ethics approval for the only objective to publish in medical journals. As a reminder, article 23 provides that: * The research protocol must be submitted for consideration, comment, guidance and approval to the concerned research ethics committee before the study begins. This committee must be transparent in its functioning, must be independent of the researcher, the sponsor and any other undue influence and must be duly qualified. It must take into consideration the laws and regulations of the country or countries in which the research is to be performed as well as applicable international norms and standards but these must not be allowed to reduce or eliminate any of the protections for research subjects set forth in this Declaration. * Article 36 reminds that: * Reports of research not in accordance with the principles of this Declaration should not be accepted for publication. * Based on the Declaration of Helsinki and the official statement from the author, the article must be retracted with no delay for serious ethical concern. **Violation of the French Health Law** The IHU ethics committee, in 2019, confirmed that this study must obtain an approval from a Comitu00e9 de Protection des Personnes (CPP). CPP is the only institution that can approve a prospective research in humans in France. The IHU ethics committee acknowledged that the study is a prospective research in humans and this study must obtain a CPP approval before to start. And the author confirms by his own statement that this study was completed before to get a CPP approval. this is a serious violation to the French Health Law. This is a cause for an immediate retraction of the article. **Violation of the Editorial policy** Per [Editorial policy] , * If the work involves the use of human subjects, the author should ensure that the work described has been carried out in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki) for experiments involving humans. * As described above, this study is not compliant with the article 23 of the Declaration of Helsinki. As a consequence, the article is not compliant with the Editorial policy. , 
 ANSM has suspended this study and confirmed this is an unauthorized study. * The authority accuses the IHU of having freed itself for years from multiple rules to conduct research on patients. On many occasions, trials have thus been undertaken without obtaining the mandatory opinion of an independent committee or, sometimes, the consent of all the patients examined. The ANSM will therefore suspend one of these trials, which was still in progress and involved taking samples from themselves from medical students of different nationalities. * Source: https: aw-journal.com the-health-authorities-formalize-their-measures-against-the-ihu-of-didier-raoult ANSM has also mentioned they will inform the Journal about their decision to suspend this unauthorized study. Before these serious ethical breaches, it is utterly surprising that the Journal and the Editor did not retract the article yet. ,