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. Author manuscript; available in PMC: 2023 Jul 21.
Published in final edited form as: Mycoses. 2019 Aug 1;62(10):920–927. doi: 10.1111/myc.12963

ECMM CandiReg—A ready to use platform for outbreaks and epidemiological studies

Philipp Koehler 1,2,✉, Maiken Cavling Arendrup 3,4,5, Sevtap Arikan-Akdagli 6, Matteo Bassetti 7, Stéphane Bretagne 8, Lena Klingspor 9, Katrien Lagrou 10,11, Jacques F Meis 12, Riina Rautemaa-Richardson 13,14, Silke Schelenz 15, Axel Hamprecht 16, Felix C Koehler 2,17, Oliver Kurzai 18,19, Jon Salmanton-García 1, Jörg-Janne Vehreschild 1,20,21, Alexandre Alanio 8, Ana Alastruey-Izquierdo 22, Valentina Arsic Arsenijevic 23, Jean-Pierre Gangneux 24, Neil A R Gow 25, Suzana Hadina 26, Petr Hamal 27,28, Elizabeth Johnson 29, Nikolay Klimko 30, Cornelia Lass-Flörl 31, Mihai Mares 32, Volkan Özenci 33,34, Tamas Papp 35, Emmanuel Roilides 36, Raquel Sabino 37, Esther Segal 38, Alida Fe Talento 39,40,41, Anna Maria Tortorano 42, Paul E Verweij 43, Martin Hoenigl 44,45, Oliver A Cornely 1,2,21,46, on behalf of the European Confederation of Medical Mycology (ECMM)
PMCID: PMC7614793  EMSID: EMS178619  PMID: 31271702

Summary

Background

Recent outbreaks of Candida auris further exemplify that invasive Candida infections are a substantial threat to patients and healthcare systems. Even short treatment delays are associated with higher mortality rates. Epidemiological shifts towards more resistant Candida spp. require careful surveillance.

Objectives

Triggered by the emergence of C auris and by increasing antifungal resistance rates the European Confederation of Medical Mycology developed an international Candida Registry (FungiScope™ CandiReg) to allow contemporary multinational surveillance.

Methods

CandiReg serves as platform for international cooperation to enhance research regarding invasive Candida infections. CandiReg uses the General Data Protection Regulation compliant data platform ClinicalSurveys.net that holds the electronic case report forms (eCRF). Data entry is supported via an interactive macro created by the software that can be accessed via any Internet browser.

Results

CandiReg provides an eCRF for invasive Candida infections that can be used for a variety of studies from cohort studies on attributable mortality to evaluations of guideline adherence, offering to the investigators of the 28 ECMM member countries the opportunity to document their cases of invasive Candida infection. CandiReg allows the monitoring of epidemiology of invasive Candida infections, including monitoring of multinational outbreaks. Here, we describe the structure and management of the CandiReg platform.

Conclusion

CandiReg supports the collection of clinical information and isolates to improve the knowledge on epidemiology and eventually to improve management of invasive Candida infections. CandiReg promotes international collaboration, improving the availability and quality of evidence on invasive Candida infection and contributes to improved patient management.

Keywords: Candidemia, epidemiology, invasive candidiasis, invasive fungal infection, outbreak

1. Introduction

Invasive Candida infections are among the most common blood-stream infections and are associated with high morbidity and mortality.1–3 Candida species are commensals of the human gastrointestinal microbiota and skin, but may translocate to the bloodstream and cause life-threatening infections. Invasive Candida infection (ICI) is an increasing threat to patients in the ICU, patients undergoing complicated or repeated gastrointestinal surgery and for immunocompromised patients, for example cancer patients or recipients of solid organ or stem cell transplants.4 In some cases, dissemination complicates acute bloodstream infection with deep tissue and organ involvement. Due to novel medical and immunological interventions and treatments, an increasing number of critically ill patients are at risk ICI. Common aetiological agents are Candida albicans, Candida glabrata, Candida tropicalis, Candida parapsilosis and Pichia kudriavzevii (formerly Candida krusei)—depending on geographical region and patients’ risk groups. The emergence of C auris, a novel, usually fluconazole resistant and often multidrug-resistant Candida species has caused outbreaks worldwide and led to clinical alerts to United States and European healthcare facilities.5–8 In an Indian hospital, C auris has become the second most common cause of candidemia after C tropicalis.9 The ECMM Candida Registry (CandiReg) was founded in January 2018, triggered by the recent C auris candidemia outbreaks in Spain and the United Kingdom.10–12

The main objective of CandiReg is to overcome the lack of knowledge on epidemiology, clinical course and molecular characteristics of invasive Candida infections and to function as a platform for international multicentre studies and surveillance of multinational C auris outbreaks. The specific objectives are to describe the incidence, to monitor trends globally and locally over time, to define patient risk groups, to assess antifungal resistance among Candida spp. causing invasive diseases worldwide, to assess attributable mortality and to assess to the cost augmentation associated with invasive Candida infection. A further goal of this platform is to set-up a multinational collection of resistant, and Candida isolates with characterisation at a molecular level, including the evaluation of resistance genes.

We herein describe how FungiScope™ CandiReg is set-up, maintained, and how it can be used to investigate the occurrence of ICI and potential outbreaks in future.

2. Methods

CandiReg is an international non-interventional multicentre registry project. Treating physicians and medical microbiologists alike are invited to participate in the collection of clinical data and fungal isolates from cases of candidemia and tissue-invasive candidiasis. The registry was founded in January 2018 and is ongoing without a defined endpoint. CandiReg uses an electronic case report form (eCRF) using the online electronic data capture platform www.clinicalsurveys. net (in cooperation with Questback GmbH, Cologne, Germany). The eCRF structure is modular, and the system is programmed to adapt the eCRF by displaying or hiding items according to the documented case (eg candidemia vs. control patient). Case registration is on a voluntary basis. Target groups are patients with invasive candidiasis or candidemia. Export will be performed in SPSS-labelled data files in SPSS binary format. Statistical analyses will be performed with IBM SPSS Statistics software v.25.0 (IBM Corp., Armonk, NY).

2.1. Ethical and general data protection regulation considerations

CandiReg is approved by the local Institutional Review Board and Ethics Committee of the University Hospital Cologne (UHC) (Identifier of the University of Cologne Ethics Committee: 17-485). If needed, further local Ethics Committee approvals will be included. The study is registered at clinicaltrials.gov, identifier NCT03450005. CandiReg uses the General Data Protection Regulation (GDPR) compliant platform ClinicalSurveys.net. Data entry is carried out via any Internet browser using encrypted communication. All documented data are automatically collected in a database. All Good Epidemiological Practice (GEP) requirements are met by the software.

3. Results

3.1. Case documentation and data collection

Patients with candidemia or invasive candidiasis confirmed by culture, histopathology or microscopy can be included. A second cohort is defined by patients with signs of disseminated Candida infection without culture, histological or microscopical evidence (eg CT-imaging of target-lesions in liver and spleen and positive Candida antigen or Beta-D-Glucan tests in a neutropenic patient), so that chronic disseminated, culture negative candidiasis can be documented in an adjusted eCRF separable from patients with candidemia. Patients without evidence of invasive disease or those with colonisation only are not eligible.

The following demographic data are collected: age group at the date of diagnosis, gender, year of infection, weight, ethnicity, details on primary underlying disease or conditions, immunosuppression, further risk factors, echocardiography and ophthalmology results, and mycological procedures allowing ICI diagnosis and sites of infection (Table 1). Details on management including antifungal treatment; recording drug, dose, duration, route of administration, therapeutic drug monitoring, reason for stopping, drug-related adverse events and surgical procedures, catheter management, clearance of bloodstream infection or infected sites are documented. Treatment indication is differentiated into prophylaxis, empiric, pre-emptive and targeted treatment for ambulatory and inpatient parenteral antifungal therapy.

Table 1. ECMM Candida Registry—Information categories captured.

Category Subcategory
Demographics Age group at diagnosis, gender, year of infection, weight, ethnicity
Host and risk factors Malignancy, SOT, HIV/AIDS, surgery trauma, burn, chronic diseases, autoimmune disease, alcoholism, iv drug use, ICU
stay, neutropenia, obesity, premature birth, central venous catheters, foreign bodies, low albumin levels, extracor-
poreal membrane oxygenation (ECMO)
Clinical presentation Signs and symptoms, site(s) of infection
Diagnostics Mycological procedures for diagnosis of ICI. Echocardiography and ophthalmoscopy
Treatment of IFD Prophylaxis, empiric and targeted therapy (antifungal drug, dose, duration, route of administration, reason for stopping, drug-related adverse events, ambulatory parenteral antifungal treatment) surgical procedures, catheter management, clearance of Candida spp. from bloodstream or infected sites.
Treatment response
and outcome		 Response to antifungal treatment, outcome of ICI and underlying disease, prolongation of hospital stay
Economics Hospital characteristics (normal ward/ ICU beds; admissions per year), consumption of antifungals in defined daily
doses (DDD)
Quality Guideline Implementation and Adherence (ECIL, ESCMID/ECMM, IDSA), EQUAL Candida Score, Infectious Diseases/
Microbiology consulting services; Fellow of the ECMM available, ECMM Excellence Center
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Abbreviations: AIDS, acquired immune deficiency syndrome; ECIL, European Conference on Infections in Leukaemia; ECMM, European Confederation of Medical Mycology; ESCMID, European Society of Clinical Microbiology and Infectious Diseases; HIV, human immunodeficiency virus; ICI, invasive Candida infection; ICU, intensive care unit; IDSA, Infectious Diseases Society of America; SOT, solid organ transplantation.

Response to antifungal therapy is evaluated after two and four weeks, three and six months and on the final day of observation. In addition, treatment response and outcome of the underlying disease as well as potential prolongation of hospital stay are also documented. Information on outcome includes overall mortality and attributable mortality. If available, autopsy results are recorded. Quality Management is covered once yearly from participating centres with regard to guideline implementation and adherence (ECIL, ESCMID,/ ECMM, IDSA); EQUAL Candida Score, Infectious Diseases/Microbiology consulting services; Fellow of the ECMM availability, treatment in an ECMM Excellence Centre).13–18 Furthermore, economic key figures and hospital characteristics with normal ward vs. ICU beds, candidemia per year, admissions per year, medical vs. surgical ward/ ICU, consumption of antifungals in defined daily doses (DDD) are gathered. To implement health economic analyses on the incremental costs and attributable mortality analysis, the study will in part use a matched case-control design. Controls will be included from the same hospitals that include cases (ie one control per case, both from the same hospital). Controls will be matched by demographics, underlying diseases and risk factors as well as duration of hospitalisation.19,20

3.2. Isolates collection

In addition to clinical data, partners can contribute Candida isolates considered as emergent (eg Candida auris) for formal species identification and susceptibility testing. Isolates will be stored and made available to all collaborating partners for developing research projects. The following laboratory-based research will be conducted: isolate identification, macro-morphology, in vitro susceptibility testing according to EUCAST, evaluation and analysis of resistance mechanisms. Isolates are processed de-centrally at National Reference Centers or ECMM Excellence Centers, which serve as the central mycology reference laboratories.21,22 Species identification and susceptibilities of all isolates are determined or confirmed using reference methods including mass spectrometry (MALDI-TOF MS/VITEK MS) and molecular methods (sequencing ITS, IGS or equivalent informative target). Mass-spectra and molecular data are analysed using the MALDI-TOF libraries as well as sequencing databases such as MycoBank (http://www.mycobank.org/) and CBS-KNAW GenBank (http://www.westerdijkinstitute.nl/collections/). In addition, all isolates are stored in triplicate at -80°C for research exchange among CandiReg collaborators. Any such exchange is preceded by the contributor’s approval. The only exception from this self-rule is, if a contributor cannot be reached despite all efforts. Results of these analyses are also included in CandiReg, while the isolate remains stored in that reference laboratory.

3.3. Case recruitment and data analyses and use

The main variables to be analysed are as follows: clinical course and features of ICI, diagnostic procedures performed to confirm the diagnosis, description of antifungal treatment regimens, guideline implementation and adherence and their efficacy and impact on patient survival. The aim is to analyse the efficacy of current recommendations for diagnosis and treatment, to inform future consensus guidelines and to develop clinical screening and diagnostic procedures.

4. Discussion And Outlook

CandiReg serves as platform for international cooperation and studies on attributable mortality, Candida-reactive T cells, evaluations of guideline adherence,23–25 and recently the third multicentre ECMM study26,27 on incremental costs associated with nosocomial invasive candidiasis in Europe, CANDIDA III was initiated taking advantage of this platform. The CANDIDA III study focuses on evaluating the attributable mortality and costs as well as diagnostic and therapeutic approaches (including prolonged hospital stay for completion of parenteral antifungal treatment) of nosocomial invasive candidiasis in Europe. As a secondary objective, it will evaluate the antifungal resistance among Candida spp. causing invasive disease across Europe. The study will use a matched case-control design, which will allow the implementation of health economic analysis on the incremental costs associated with invasive Candida infections. The ECMM will use the platform for future multinational surveillance studies on invasive candidemia in Europe. Moreover, investigators maintain familiarity with the platform, which may enable more rapid case entry in case of an outbreak. To date, 265 patients have been enroled in the register as part of five open or completed studies.23–25,28 The results derived from this platform will be promoted as poster or oral presentations at national and international infectious diseases, mycological and health economic conferences. Internationally visible publications obtained from the CandiReg registry have already been published in or will be submitted to peer-reviewed journals.

CandiReg will enhance knowledge about ICI and facilitate the analysis of epidemiological shifts and resistance trends. Currently, clinicians, microbiologists and researchers from 28 countries are involved (Figure 1). With this registry, we collect real-life data with long-term observations. The registry will provide controlled or uncontrolled level II evidence and is ready in case of an outbreak situation similar to other FungiScope™ Registries.29

Figure 1. ECMM Member countries contributing to CandiReg, as of May 2019.

Figure 1

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The current 28 member countries are coloured in blue

There are a number of limitations of registry-based studies. The retrospective acquisition of anonymised data of the individual patient reduces data quality, but is indispensable to protect privacy and comply with data protection guidelines. Also, the follow-up time of the cases may often be somewhat short. However, these registries offer the opportunity to contribute to progress in the understanding of epidemiology, pathophysiology, natural history and efficacy of treatments on a pan-European or even worldwide scale. As proven ICI is a relatively rare condition, pooling these cases and analysing them in large cohorts can significantly improve our knowledge of ICI in real-life settings and contribute to the design of clinical trials. Furthermore, they provide data unobtainable by controlled trials.

In conclusion, the CandiReg platform promotes international collaboration, increases the quality of available evidence on invasive Candida infection and can contribute to improvement of patient management.23

Acknowledgments

The authors thank Susann Blossfeld and Joyce van den Boogaard for their administrative and technical assistance.

Funding information

CandiReg is an academic project and funded by ECMM via the ECMM Candida III study (PI: Hoenigl, Co-PI Cornely; supported by Scynexis) and the University of Cologne.

Footnotes

Conflicts of interests

Philipp Koehler has received non-financial scientific grants from Miltenyi Biotec GmbH, Bergisch Gladbach, Germany, and the Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany, and received lecture honoraria from Akademie für Infektionsmedizin e.V., Astellas Pharma, Gilead Sciences, and MSD Sharp & Dohme GmbH outside the submitted work. Maiken Cavling Arendrup has received personal speaker’s honoraria from Astellas, Basilea, Gilead, MSD, Pfizer, T2Candida, and Novartis. She has received research grants and contract work paid to the Statens Serum Institute from Astellas, Basilea, Gilead, MSD, Novabiotics, Pfizer, T2Candida, F2G, Cidara, Scynexis and Amplyx outside the submitted work. Sevtap Arikan-Akdagli has received research grant from Pfizer, travel grants from Pfizer, and lecture honoraria from Gilead in the last three years outside the submitted work. Matteo Bassetti reports personal fees from Astellas Pharma GmbH, personal fees from Gilead Sciences, personal fees from MSD Sharp & Dohme GmbH, grants and personal fees from Pfizer, grants and personal fees from Cidara, personal fees from Biomerieux outside the submitted work. Stéphane Bretagne reports personal fees from Gilead Sciences, grants from MSD Sharp & Dohme GmbH, grants from Pfizer outside the submitted work. Lena Klingspor has received research grants from Gilead, and has received honoraria for educational lectures from Gilead, Merck, Sharpe & Dohme, and Vertex Pharmaceuticals outside the submitted work. Katrien Lagrou received consultancy fees from Pfizer, Abbott, MSD and SMB Laboratoires Brussels; travel support from Pfizer and MSD; speaker fees from Gilead, Roche and Abbott outside the submitted work. Jacques F. Meis received grants from F2G and Pulmozyme. He has been a consultant to Scynexis and Merck, and received speaker’s fees from United Medical, TEVA, and Gilead Sciences outside the submitted work. Riina Rautemaa-Richardson has received speaker honoraria from Astellas, Basilea, Gilead Sciences and Pfizer, and a research grant from Gilead Sciences outside the submitted work. Silke Schelenz reports personal fees from Pfizer outside the submitted work. Axel Hamprecht has received lecture honoraria from Bruker Daltonics, BD and Thermo Fisher outside the submitted work. Felix C. Koehler has received grants from the German Federal Ministry of Research and Education and non-financial support from Miltenyi Biotec GmbH, Bergisch Gladbach, Germany outside the submitted work. Oliver Kurzai has received honoraria from Basilea, BG Chemische Industrie, Heidelberg Engineering GmbH and research support from Astellas, Basilea, Gilead, MSD, Pfizer, Virotech and Fujifilm Wako outside the submitted work. Jon Salmanton-García has nothing to disclose. Jörg Janne Vehreschild has received personal fees from Merck/ MSD, Gilead, Pfizer, Astellas Pharma, Basilea, German Centre for Infection Research (DZIF), University Hospital Freiburg/ Congress and Communication, Academy for Infectious Medicine, University Manchester, German Society for Infectious Diseases (DGI), Ärztekammer Nordrhein, University Hospital Aachen, Back Bay Strategies, German Society for Internal Medicine (DGIM) and grants from Merck/ MSD, Gilead, Pfizer, Astellas Pharma, Basilea, German Centre for Infection Research (DZIF), German Federal Ministry of Education and Research (BMBF) outside the submitted work. Alexandre Alanio has received research grants from Astellas, Gilead, Merck/MSD and received lecture honoraria from Astellas, Gilead outside the submitted work. Ana Alastruey-Izquierdo has received research grants or honoraria as a speaker or advisor from Gilead Sciences, MSD, Astellas, Pfizer, F2G, Amplix and Scynexis in the last five years outside the submitted work. Valentina Arsic Arsenijevic has participated in advisory boards and/or received research grants and speaker honoraria from from Pfizer; Astellas, Schering-Plough, MSD, and Gilead in the past five years outside the submitted work. Jean-Pierre Gangneux reports personal fees from Astellas Pharma, Gilead Sciences and Pfizer outside the submitted work. Neil AR Gow has received honoria for presentations and lectures from Gilead Sciences and reports the following grants sources: Wellcome Trust and (101873, 086827, 075470, & 200208) and MRC Centre for Medical Mycology (N006364/1) outside the submitted work. Suzana Hadina has nothing to disclose. Petr Hamal has nothing to disclose. Elizabeth Johnson has nothing to disclose. Nikolay Klimko reports personal fees from Astellas, MSD and Pfizer outside the submitted work. Cornelia Lass-Flörl has received research grants from Astellas, Basilea, F2G, Gilead, is a consultant to Pfizer, Gilead and received lecture honoraria from Astellas, Basilea, Gilead, and Pfizer outside the submitted work. Mihai Mares has nothing to disclose. Volkan Özenci has nothing to disclose. Tamas Papp has nothing to disclose. Emmanuel Roilides has received research grants from Pfizer, Merck and Gilead to the Aristotle University of Thessaloniki outside the submitted work. Raquel Sabino has nothing to disclose. Esther Segal has nothing to disclose. Alida Fe Talento has received financial grants from Gilead Sciences Ltd., Pfizer Healthcare Ireland and MSD Ireland and received lecture honoraria from Gilead Sciences Ltd., and Pfizer Healthcare Ireland outside the submitted work. Anna Maria Tortorano received research funding from Gilead outside the submitted work. Paul E. Verweij has received research grants from F2G, Gilead Sciences, Merck/MSD, and Pfizer is a consultant to F2G and Scynexis, and received lecture honoraria from F2G, Gilead Sciences, Merck/MSD and Pfizer outside the submitted work. Martin Hoenigl received research funding by Gilead outside the submitted work. Oliver A. Cornely has received research grants from Actelion, Amplyx, Astellas, Basilea, Cidara, Da Volterra, F2G, Gilead, Janssen Pharmaceuticals, Medicines Company, MedPace, Melinta Therapeutics, Merck/MSD, Pfizer, Scynexis, is a consultant to Actelion, Allecra Therapeutics, Amplyx, Astellas, Basilea, Biosys UK Limited, Cidara, Da Volterra, Entasis, F2G, Gilead, IQVIA, Matinas, MedPace, Menarini Ricerche, Merck/MSD, Octapharma, Paratek Pharmaceuticals, Pfizer, PSI, Rempex, Scynexis, Seres Therapeutics, Tetraphase, Vical, and received lecture honoraria from Astellas, Basilea, Gilead, Merck/MSD and Pfizer outside the submitted work.

Author contributions

Philipp Koehler, Martin Hoenigl and Oliver A. Cornely conceived the project idea, drafted the manuscript, revised, discussed and approved the final manuscript. Maiken Cavling Arendrup, Sevtap Arikan-Akdagli, Matteo Bassetti, Stéphane Bretagne, Lena Klingspor, Katrien Lagrou, Jacques F. Meis, Riina Rautemaa-Richardson, Silke Schelenz, Axel Hamprecht, Felix C. Koehler, Oliver Kurzai, Jon Salmanton-Garcia, Jörg-Janne Vehreschild, Alexandre Alanio, Ana Alastruey-Izquierdo, Valentina Arsic Arsenijevic, Jean-Pierre Gangneux, Neil AR Gow, Suzana Hadina, Petr Hamal, Elizabeth Johnson, Nikolay Klimko, Cornelia Lass-Flörl, Mihai Mares, Volkan Özenci, Tamas Papp, Emmanuel Roilides, Raquel Sabino, Esther Segal, Alida Fe Talento, Anna Maria Tortorano and Paul E. Verweij revised, discussed and approved the final manuscript.

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