Infokiri

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SoHO-Net Meeting: Organs group 18 – 19 June 2024, Stockholm

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Session 1 Introduction and presentations 18 June

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Session overview

1. Director’s welcome – Pamela Rendi-Wagner, ECDC 2. Introduction – Marieke van der Werf, ECDC 3. Key objectives for the meeting – Jenny Mohseni Skoglund,

ECDC 4. Presentations network members and invited experts – Tour

de table

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Welcome and introduction Pamela Rendi-Wagner, ECDC

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Welcome and introduction Marieke van der Werf, ECDC

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Vaccine-preventable diseases and Immunisation

Sexually transmitted infections, Blood-Borne Viruses

and Tuberculosis

Antimicrobial resistance and healthcare-associated

infections

Emerging, Food and vector- borne diseases

Disease Surveillance &

Epidemic intelligence

Response support & Risk assessments

Preparedness & capacity

strengthening

Scientific advice & guidance

EU and external stakeholders &

Country support

Public health training

Communication

ECDC mission & role

To identify, assess and communicate current and

emerging threats to human health posed by infectious

diseases.

ECDC SoHO team

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Sexually transmitted infections, blood-borne viruses and tuberculosis section

SDG-targeted diseases group • Hepatitis B and C • HIV • Sexually transmitted infections

• Chlamydia • Gonorrhoea • Syphilis

• Tuberculosis

SoHO team

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Juliana ReyesTeymur Noori

Csaba KödmönEls Driessens Erika Duffell Marijana Kukolj

Otilia Mårdh Lina Nerlander

Janelle Sandberg Marieke van der Werf

Charlotte Deogan

Ndeindo Ngangro Flavia Cunha Jenny Mosheni Skoglund

Senia Rosales-Klintz

Veronica Cristea

Anastasia Pharris

Francois-Xavier Lamy

Ana Finatto- Canabarro

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EU regulations relevant for SoHO

• Regulation (EC) No 851/2004 of the European Parliament and of the Council of 21 April 2004 establishing a European Centre for Disease Prevention and Control

• Regulation (EU) 2022/2370 of the European Parliament and the Council of 23 November 2022 amending Regulation (EC) No 851/2004 establishing a European Centre for Disease Prevention and Control

• Regulation (EU) 2022/2371 of the European Parliament and the Council of 23 November 2022 amending Regulation (EC) of 23 November 2022 on serious cross-border threats to health and repealing Decision No 1082/2013/EU

• Directive 2010/45/EU of the European Parliament and of the Council of 7 July 2010 on standards of quality and safety of human organs intended for transplantation

• Proposal for a Regulation on standards of quality and safety for substances of human origin intended for human application and repealing Directives 2002/98/EC and 2004/23/EC

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Framework for ECDC support to EU/EEA countries and the European Commission to reach microbial safety of substances of human origin

Source: https://www.ecdc.europa.eu/en/publications-data/ecdc-framework-relating-substances-human-origin-soho

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Coordinate SoHO network

Prevention of communicable disease transmission through application of substances of human origin

Provide guidance on microbial

safety

Threat detection, assessment, and

response

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Coordinate SoHO network

• Network of Member State services supporting the use of substances of human origin (SoHO-Net). Four sub-networks with National Focal Points and observers:

• Blood • Tissues and cells • Organs • Medically assisted reproduction

• SoHO Network Coordination Committee with elected members from the network

• Regular meetings of the SoHO Network Coordination Committee and of the four SoHO sub-networks

• EpiPulse platform for information exchange and collaboration between countries

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Provide guidance on microbial safety

• Develop and update guidelines as referred to in the SoHO Regulation

• Guideline development process according to ECDC procedures for developing guidelines

• Collaboration with the European Directorate for the Quality of Medicines & HealthCare (EDQM) to ensure that technical guidelines published by EDQM and ECDC are aligned

• Develop guidance and recommendations on topics relevant to the microbial safety of SoHO at the request of the SoHO network, the European Commission or on own initiative

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Threat detection, assessment, and response: Monitor threats and outbreaks

Detect, monitor, and report on serious cross-border threats to health related to SoHO.

• Results of daily screening of various information sources • Reports of cases of infectious diseases and pathogens that may

threaten microbial safety of SoHO in the EU/EEA in EpiPulse • Monitoring of serious adverse reactions*

→ Discussion of identified threats and an initial assessment of appropriate ECDC actions.

* Serious adverse reaction (SAR) is defined in the Proposal for a Regulation as an adverse reaction that results in death, a life-threatening, disabling or incapacitating condition, including transmission of a pathogen, hospitalisation or prolongation of hospitalisation, or the need for a major clinical intervention to prevent or reduce the effects. 13

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Threat detection, assessment, and response: Perform risk assessments and launch alerts

• Provide risk assessments including science-based recommendations and options for response in the case of a serious cross-border threat to health

• Launch an alert in the EU SoHO Platform when the risk assessment indicates a new risk to the safety of SoHOs

• Support response coordination in the Health Security Committee

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Threat detection, assessment, and response: Provide advice on serious adverse reactions*

SoHO National Authority will inform ECDC of serious adverse reactions concerning a transmission of a communicable disease that is rare, or unexpected for that SoHO type.

ECDC will support relevant follow-up actions including providing advice or information to SoHO National Authorities on options for response.

* Serious adverse reaction (SAR) is defined in the Proposal for a Regulation as an adverse reaction that results in death, a life-threatening, disabling or incapacitating condition, including transmission of a pathogen, hospitalisation or prolongation of hospitalisation, or the need for a major clinical intervention to prevent or reduce the effects. 15

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Empowering EU/EEA countries, the EC and other partners to drive public health policy and practice

Through the building blocks detailed in this framework, ECDC aims to achieve the following: • Robust SoHO network and mechanisms for the exchange of information. • Guidelines available and updated as needed for the prevention of donor-

derived communicable disease transmission through the application of SoHO.

• Well-functioning system for identification and information sharing of serious adverse reactions and communicable disease outbreaks relevant to the microbial safety of SoHO.

• High-quality risk assessments with science-based recommendations and options for response and timely alerts when a new risk to the safety of SoHOs is identified.

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Aim and key objectives for the meeting • To get to know each other and understand the network and the role of the NFPs

• To update the SoHO-Net Organs group and invited participants on ECDC scientific outputs and activities related to donor derived communicable diseases transmission

• To discuss current challenges in the fields related to donor derived communicable diseases transmission

• To exchange good practice of donor testing strategies

• To share experiences of reporting serios adverse reactions and events

• To identify and prioritize main topics for activities for the SoHO-Net Organs group.

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Session 2 SoHO-Net Organs group 18 June

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Session overview

1. The role of ECDC networks and the SoHO-Net Organs group – Jenny, Mohseni Skoglund, ECDC

2. Questions and answers – All 3. Breakout session: topics and expectations for the role of ECDC in the field of

SoHO safety for organs

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ECDC networks Jenny Mohsenis Skoglund, ECDC

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Dedicated Networks

“The Centre shall promote and coordinate the networking of bodies, organisations and experts operating in the Union in the fields relevant to the Centre’s mission, including networks arising from public health activities supported by the Commission, and operate dedicated networks on surveillance, while ensuring full compliance with rules on transparency and conflicts of interest.”

Dedicated network means any specific network on diseases, related special health issues or public health functions that is supported and coordinated by the Centre and is intended to ensure collaboration between the coordinating competent bodies of the Member States.

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Disease and Laboratory Networks and networks dedicated to health issues*

Antimicrobial resistance and healthcare-associated infections • European Antimicrobial Resistance Surveillance Network (EARS-Net) • European Surveillance of Antimicrobial Consumption Network (ESAC-

Net)* • Healthcare-associated Infections Surveillance Network (HAI-Net)* • European Antimicrobial Resistance Genes Surveillance Network

(EURGen-Net) Emerging and vector-borne diseases • Emerging and Vector-borne Diseases Network (EVD) • Emerging Viral Disease-Expert Laboratory Network (EVD LabNet) • European Network for sharing data on the geographic distribution of

arthropod vector, transmitting human and animal disease agents (Vector-Net)*

Food- and waterborne diseases, zoonoses • European Food- and Waterborne Diseases and Zoonoses Network

(FWD-Net) • European Legionnaires' disease Surveillance Network (ELDSNet) • European Creutzfeldt-Jakob Disease Surveillance Network (EuroCJD)

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Respiratory tract infections • European Tuberculosis Surveillance Network • European Reference Laboratory Network for TB (ERLTB-Net) • European Influenza Surveillance Network (EISN) • European Reference Laboratory Network for Human Influenza (ERLI-Net) • European COVID-19 Surveillance Network (ECOVID-Net) • European COVID-19 reference laboratory network (ECOVID-LabNet)

HIV, STI and blood-borne viruses • European Sexually Transmitted Infections Network • European Gonococcal Antimicrobial Surveillance Programme (Euro-GASP) • European Network for HIV/AIDS • European Network for hepatitis B and C surveillance

Vaccine-preventable diseases and invasive bacterial infections • European Invasive Bacterial Diseases Surveillance Network (EU-IBD) • EU laboratory Network for surveillance of Pertussis (EUPertNet) • European Diphtheria Surveillance Network (EDSN) • Network on measles, mumps, rubella surveillance (MMR)

Network for the Microbiological Safety of Substance of Human Origin (SoHO)*

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What?

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Provides information For monitoring the situation in your country and for identification of country needs.

Provides technical advice Review/comment technical documents .

Participates in ECDC activities Presentation on your subject area and/or your country.

Networking Interacting with other EU/EEA countries.

Coordinates Interactions with national stakeholders.

Provides input To ECDC strategic planning.

NFP

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How?

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E-mail exchange • Requesting information from your country. • Requesting information to ECDC.

Targeted request • Surveys or external consultations. • Country visits.

Bilateral interactions • With other EU/EEA countries. • Study visits/expert exchanges.

ECDC information systems • Discussion forums in EpiPulse.

Video conference • Ad hoc or regular virtual meetings.

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Regulation of the European parliament and of the Council amending Regulation (EC) No 851/2004 establishing a European Centre for disease prevention and control http://data.europa.eu/eli/reg/2022/2370/oj

brings a legal framework for ECDC’s recommendations to Member States regarding health threats preparedness, and also for hosting expert networks.

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The SoHO network

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ECDC SoHO network (SoHO-Net)

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Main objectives of the SoHO-Net

• Encourage cooperation between Member States

• Help to ensure that SoHO are microbially safe by monitoring, assessing and helping to address relevant disease outbreaks that can pose cross-border threats to health

• Support the detection, monitoring and reporting on serious cross-border threats to health related to SoHO

• Enhance preparedness and response planning activities in the Union

• Safeguard patients in need of SoHO

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Responsibilities of the SoHO NFPs

• Cooperate closely and communicate with National Competent Authorities

• Support and advise NCA in the establishment of the national communication channels

• Support ECDC in regular monitoring of microbial safety measures

• Contribute to the assessment of the impact of scientific advice produced by ECDC

• Report to the EpiPulse and analyse cases of infectious diseases and pathogens related to SoHO that may threaten public health in the EU/EEA

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Consists of 9 members of the SoHO-Net, nominated by SoHO-Net members • 2 members from each Blood, Organ and MAR group • 2 + 1 members from Tissues and Cells, respectively • Elected for a period of 3 years • Can be re-elected • Elected by the Network

Tasks: • Works closely with ECDC in between the network group meetings • Provides advice on urgent matters • Contributes to the agenda of the regular network meetings • Appoints a chair among its members

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The SoHO-Net Coordination Committee (NCC)

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The SoHO-Net Coordination Committee (NCC) Appointed by the ECDC Director

NCC members Number of members Elected member

NFP Blood 2 Anna Margrét Halldórsdóttir, Iceland Imad Sandid, France

NFP Human Organs 2 Sophie Lucas-Samuel, France Paolo Antonio Grossi, Italy

NFP MAR 2 Ioana Rugescu, Romania Sara Pimentel, Portugal

NFP Tissues and Cells 3 Vacant Gorazd Čebulc, Slovenia Vacant

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SoHO-Net Organs group – Expectations and topics Group discussion

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Breakout session: share expectations on ECDC activities in the field of Organs and describe topics for activities for the SoHO-Net Organs group

You will be divided into 5 groups with one facilitator per group to guide you. Each group you will:

1. Share and discuss your expectations on the role of ECDC and the SoHO-Net Organs group in the field of Organs safety. E.g.,: platform to share good practices in the prevention of communicable disease transmission.

2. Propose and discuss topics for activities for the SoHO-Net Organs group. E.g.,: Need for guidance on the screening of arboviruses.

Summarize your discussion and conclusions in bullet points and nominate one or two persons who will present the summary of the discussions, orally or with slides.

After the coffee break: each group will have 5 minutes for presentation, followed by a common discussion. The proposed topics will be discussed again at the end of the meeting.

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Session 3 ECDC activities and Organs safety in the context of the new SoHO regulation 18 June

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Session overview 1. Presentation of the SoHO regulation – Stefaan Van der Spiegel, DG

SANTE 2. Presentation of ECDC technical guidelines – Francois-Xavier Lamy, ECDC 3. ECDC guidelines for HIV and hepatitis B and C – Flavia Cunha, ECDC 4. Questions and answers – All 5. The impact of the SoHO regulation on Organs safety – horizon

scanning – Martina Brix-Zuleger, NFP Austria 6. Discussion on the overlap between tissue and organ donors testing

and considerations in the context of the new SoHO regulation - All

A new EU Regulation on standards of quality and safety for substances of human origin intended for human

application

SoHOnet meeting organs ECDC, Stockholm, 18 June 2024

(Slides for dissemination

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EU legislation since 2002 (4 Directives)

Current EU legislation on safety and quality of substances of human origin

BLOOD & PLASMA

Transfusion Medicines

TISSUES & CELLS

Bone marrow transplant

MAR Tissue transplantation

ORGANS

EU legislation since 2004 (4 Directives) EU legislation

since 2010 (2 Directives)

The EU legislative process

Member State governments in the European Council

European Commission

Evaluation of the problem (evidence and consultation)

Impact assessment – options to address the problems – cost, burden etc. (evidence and consultation)

Drafting of new legislation

Publication of a Proposal

Negotiation trilogues

Adoption of final text

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1. Patients are not fully protected from avoidable risks because some rules are out of date

Evaluation of the Blood, Tissue and Cell legislation - published in 2019

3. Member States have divergent approaches to oversight

2. Legislation does not mitigate risks for BTC donors and for children born from donated eggs, sperm or embryos

4. Full potential of innovative therapies is not reached for patients

5. Patients are vulnerable to interruptions in EU supply of some BTC

Overall – the legislation led to increased safety and quality of BTC but gaps and shortcomings were identified

CoVID confirmed problems

EU legislation since 2002 (4 Directives)

Current EU SoHO legislation on safety and quality

BLOOD & PLASMA

Transfusion Medicines

TISSUES & CELLS

Bone marrow transplant

MAR Tissue transplantation

ORGANS

EU legislation since 2004 (4 Directives) EU legislation

since 2010 (2 Directives)

Key improvements

https://health.ec.europa.eu/blood-tissues-cells-and- organs/overview/proposal-regulation-substances-human-origin_en

Check for updates – new link will be added

when the text is published in the OJ

• Scope and advice

• SoHO activities, entities and establishments

• SoHO Preparations and their authorisation

• Standards and hierarchy of technical guidelines

• Donor Protection and Voluntary Unpaid Donation

• Recipient and offspring protection

• Vigilance

• Supply continuity

• Digitalisation – the SoHO platform

Key new and changed concepts

This presentation explains the concepts in the Regulation, as proposed by the Commission and amended during negotiations.

Borderline criteria are not set in this Regulation.

They are set in the other legislative acts (medicinal

products, medical devices)

– FUTURE PROOFING

Scope: Regulation covers all steps for all SoHO (some limited provisions for autologous SoHO), unless processing or application steps fall under scope of other EU frameworks – then SoHO regulation is restricted to certain relevant activities

• Breast milk for own child

• Organs • Private

situations • Autologous

bedside (closed systems)

Publication obligations – national security or defence

+ Breast milk and

FMT

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The following activities are regulated by the SoHO Regulation:

• SoHO donor registration

• SoHO donor history review and medical examination

• Testing of SoHO donors or persons from whom SoHO are collected for autologous or within-relationship use

• Collection

• Release

When carried out before distribution to a manufacturer, the following are also regulated by the SoHO Regulation:

• Storage; Distribution; Import; Export.

In cases where SoHO move to another framework – which SoHO provisions apply? Article 2(6)

Art 2(7) – when the SoHO is used to manufacture an autologous

medicinal product – only testing and collection are covered by SoHO Reg

The SoHO Coordination Board (SCB) - supporting implementation in MS

Members: 2 per Member State

Observers: Union bodies/institutions/agencies

& other invitees

Co-chairing by Commission and MS

Secretariat: Commission

Advice on whether the SoHO

Regulation applies - Advisory bodies in

other legislative frameworks

Exchanges on good practices with Expert

bodies – ECDC, EDQM and with EMA

Compendium on regulatory status

Documentation of • best practices for

• supervisory functions

• compensation conditions;

• Indicative criteria for critical SoHO and critical SoHO entities

Record of: • National decisions

on regulatory status • Compendium of

advice given by SCB on regulatory status

Support for joint oversight activities - inspections - Preparation

assessments

SCB

Support for coordination during emergencies

Support to COMM on the specifications for the SoHO Platform

Own initiative – a list of

substances/ products where

an opinion is needed

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Building coherent Pharma/SoHO classification decisions and advice

1. National decisions

2. If needed, EU- level advice

3. If needed, COM decisions

SoHO Pharma

a. Consult other-sector NCA (12.2, 13.1-2)

b. Request SCB opinion (13.3)

c. Consult other-sector advisory bodies (69.1c)

d. Request/give COM decision (13.5)

b. Request scientific advice (R/58.1, 61.1)

d. Request/give COM decision (R/62)

c. Consult other-sector advisory bodies (R/58.2, 61.2)

a. consult other-sector Q

(D/201)

• Scope and advice

• SoHO activities, entities and establishments

• SoHO Preparations and their authorisation

• Standards and hierarchy of technical guidelines

• Donor Protection and Voluntary Unpaid Donation

• Recipient and offspring protection

• Supply continuity

• Digitalisation – the SoHO platform

Key new and changed concepts

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Any actor organising one or more SoHO activity/ies needs to

register as SoHO entity with the Competent Authority

Supervision of all SoHO Activities that directly impact safety, quality or effectiveness

Donor Registration

Donor History Review &

Medical examination Testing of donors or autologous recipients

DistributionExport Clinical

Outcome Registration

Import

Definitions provided for the SoHO activities and recitals explain them

….but risk-based authorisation, ensuring efficient use of authority resources

A SoHO entity carries out one or more SoHO activities

A SoHO establishment is a SoHO entity that carries out at least

• Both processing and storage, or

• Release, or

• Import, or

• Export

Note: CAs may regulate a SoHO entity as a SoHO establishment, even if it does not meet the criteria above, if it considers that the entity has a particularly important impact (e.g. a testing laboratory that tests donors for a whole region or country, a register that identifies and selects donors for one or more Member States).

A SoHO establishment may carry out many other

SoHO activities – all

will be included in

their authorisation

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The concept of SoHO entities and SoHO establishments: graded approach to oversight - high level of transparency

SoHO Entities

SoHO Establishments Must be registered, authorised,

and inspected regularly

SoHO entities must be registered

Importers Additional specific authorisation requirements

• Responsible person (+/- as today) • Releasing officer(s) • Nominated physician

• Responsible person (+/- as today)

Note – derogation for plasma for PDMP that is included in a PMF –

see Art 47(2)

Note – Risk-based scheduling – m x 4 years b tw en on-site inspections

• Scope and advice

• SoHO activities, entities and establishments

• SoHO Preparations and their authorisation

• Standards and hierarchy of technical guidelines

• Donor Protection and Voluntary Unpaid Donation

• Recipient and offspring protection

• Vigilance

• Supply continuity

• Digitalisation – the SoHO platform

Key new and changed concepts

SoHO

Blood

SoHO Preparations

Plasma

Red blood cells

Platelets

SoHO Preparation Authorisation – robust evidence of safety and effectiveness

What is a ‘SoHO Preparation’? A particular SoHO that has been subjected to processing, and where relevant other SoHO activities, has a specific clinical indication and is intended for immediate application to a recipient or for distribution.

Must be authorised

EXAMPLE

The concept of SoHO entities and SoHO establishments: graded approach to oversight - high level of transparency

SoHO Entities

SoHO establishments Must be registered, authorised,

and inspected regularly

SoHO preparations must be authorised – need for evidence of safety and effectiveness

Processing SoHO

SoHO entities must be registered

SoHO Preparation Authorisation

1 Systematic Benefit:Risk Assessment to determine the evidence available on safety, quality and effectiveness

2 Submission of an application, including laboratory validation and other safety, quality and effectiveness data and, where relevant, a clinical outcome monitoring plan proportionate to risk

OR Grant an

approval of the Clinical Outcome Monitoring plan or request an amended plan

3 Assessment of the application by the competent authority

Grant authorisation for

the SoHO preparation

Refuse authorisationOR

Based on preparatory work done by GAPP Joint Action (incl. stakeholders from 17 countries: 15 CAs & professional associations)

Taking into account any

relevant EDQM monograph

Assessment by the competent authority of evidence of safety, quality and effectiveness data gathered in clinical outcome monitoring

4

Grant authorisation

Refuse authorisation

OR

Clinical Outcome Monitoring Plans for gathering further evidence of safety and effectiveness in recipients

Negligible Risk

Low Risk

Moderate Risk

High Risk

No clinical outcome monitoring required Clinical follow-up of a defined number of patients is required

clinical investigation study with appropriate number of patients and pre-defined clinical endpoints

comparison to standard therapy

+

+

Positive expected benefit:risk

Sufficient evidence of positive benefit:risk

OR

Study summaries registered on SoHO Platform prior to

commencement

Evidence of ethics

committee approval

• Scope and advice

• SoHO activities, entities and establishments

• SoHO Preparations and their authorisation

• Standards and hierarchy of technical guidelines

• Donor Protection and Voluntary Unpaid Donation

• Recipient and offspring protection

• Vigilance

• Supply continuity

• Digitalisation – the SoHO platform

Key new and changed concepts

The challenge of setting technical rules

Clarity Agility

Detailed harmonised

rules

Rules that are

responsive to risk TECHNICAL GUIDELINES

The way to comply with the standards – defined outside

the Regulation Detailed and including SoHO

specific elements

STANDARDS

Defined in the Regulation Generic

Implementation of generic standards through technical guidelines – staying up-to-date with the science in an agile way

Commission Implementing Legislation

Technical Guidance on the EU SoHO Platform

“Equivalent” Guidance

Other guidelines or methods based on international standards

or scientific evidence

If none:

OR:

“where the Commission deems necessary”

Published & updated by ECDC/EDQM

Demonstrated by MS to achieve the standards in the Regulation

OR: Inspectors shall deem

the standards to be met

MS shall demonstrate compliance with standards – may do so by

demonstrating equivalence to ECDC and EDQM

Entities shall demonstrate equivalence to inspectors – may do so by demonstrating

equivalence to ECDC and EDQM

• Scope and advice

• SoHO activities, entities and establishments

• SoHO Preparations and their authorisation

• Standards and hierarchy of technical guidelines

• Donor Protection and Voluntary Unpaid Donation

• Recipient and offspring protection

• Vigilance

• Supply continuity

• Digitalisation – the SoHO platform

Key new and changed concepts

SoHO Donor Protection – significantly strengthened Protection of SoHO living donors before, during, and after the collection.

- Including for donations by relatives

- Information & consent

- Physical and mental integrity, non-discrimination, data protection & safeguarding of

anonymity (with some exceptions e.g. ID of MAR parents when allowed or obliged in

MS)

- Donor health evaluation

- Risk-proportionate approach to donor monitoring: registration of donors subjected to

- surgical procedures

- medicinal product treatment

- frequent or repeated donations implying risk to health.

- Required reporting of serious adverse reactions in donors

Protection of the dignity and integrity of SoHO deceased donors

- Information & consent by relatives, when applicable

• NO financial incentives or inducements to donate

• Compensation of living donors for losses can be allowed in accordance with the principle of VUD

• When a Member State allows compensation – upper limit to be set in national legislation – transparent criteria based on best practices established by the SCB

• Compensation conditions set in MS to be shared with the other MS via the SCB

• Donation promotion and publicity activities must not refer to compensation (without prejudice to national laws on information provision)

Voluntary & Unpaid Donation Principle maintained

Based on Recommendations of the Council of Europe Committee on Bioethics – aiming for financial

neutrality

Considerable elaboration of recitals (4) to explain provisions

• Scope and advice

• SoHO activities, entities and establishments

• SoHO Preparations and their authorisation

• Standards and hierarchy of technical guidelines

• Donor Protection and Voluntary Unpaid Donation

• Recipient and offspring protection

• Vigilance

• Supply continuity

• Digitalisation – the SoHO platform

Key new and changed concepts

• Identification and mitigation of risks from transmissible infectious, genetic, malignant diseases

• Identification and mitigation of risks from toxins, contaminants from the environment, other donations, the personnel, the equipment, reagents etc.

• Identification and mitigation of risks of detrimental effects on inherent properties of the SoHO concerned

• Identification and mitigation of risks of harmful immune reactions

• Application of national rules regarding the maximum numbers of offspring from one SoHO donor

• No application of SoHO unnecessarily or in cases where there is no proven benefit

• No promotion of SoHO application based on misleading information

• No human application of SoHO without therapeutic or assisted reproduction objective (i.e. no exclusively cosmetic or nutritional applications)

Recipient and offspring protection

• Scope and advice

• SoHO activities, entities and establishments

• SoHO Preparations and their authorisation

• Standards and hierarchy of technical guidelines

• Donor Protection and Voluntary Unpaid Donation

• Recipient and offspring protection

• Vigilance

• Supply continuity

• Digitalisation – the SoHO platform

Key new and changed concepts

Competent Authorities: working together for improved oversight

One or more SoHO competent authorities SoHO national authorities

of other Member States

SoHO Coordination Board

Other Non-SoHO Authorities

SoHO Establishments and entities

Designate

Member States

Note: Some SoHO supervisory activities can be delegated to delegated Bodies

SoHO national authority: Liaison & Cooperation

SoHO competent authorities: SoHO Supervisory Activities

Main Roles

Clearly defined principles on independence,

impartiality and transparency

If just 1 CA is designated → it is also considered as the

SoHO national authority

SNA

SoHO competent authoritiesIf more than 1 CA are designated → 1 among them to be designated

as the SoHO national authority

Send SAR/SAE notification & SAR/SAE investigation report to their CA

• Verify info of SAR/E notifications & investigation reports, assess the results of the investigation, inform the entity

• Send annual summary of SAR/E notifications & investigation reports received to their SoHO National Authority

• Launch SoHO rapid alerts

• Aggregate the summaries from the SoHO National Authorities

• publish annual SoHO vigilance report

Communication with CAs from other frameworks

• Submits annual summary to the EU SoHO Platform

• Publishes aggregated summary for their MS

SoHO Entities

Competent Authorities

Vigilance overview – largely unchanged

No change to SAR/SAE definitions!

• Inclusion of SAR reporting requirement for SAR in living SoHO donors

• Clarification that SAR/E detected during clinical outcome monitoring must be reported

• Obligation for reasonable efforts to encourage recipients of MAR donations to communicate information on genetic conditions in offspring – when serious these are reportable as SAR

• Role of ECDC for SAR concerning infectious disease transmissions

• Formalisation of communication requirements with CAs in other sectors, when appropriate

• Clarification that loss of critical SoHO constitutes an SAE in defined situations

• CAs to provide guidance and templates to professionals and to inform relevant SoHO entities of Rapid Alerts received

Vigilance enhancements Best practices agreed and

documented by SCB

• Scope and advice

• SoHO activities, entities and establishments

• SoHO Preparations and their authorisation

• Standards and hierarchy of technical guidelines

• Donor Protection and Voluntary Unpaid Donation

• Recipient and offspring protection

• Vigilance

• Supply continuity

• Digitalisation – the SoHO platform

Key new and changed concepts

Resilience of Supply Critical SoHO

‘Critical SoHO’ are SoHO that for which an

insufficient supply will result in serious harm or

risk of harm to patients or a serious interruption in

manufacture of critical products regulated by

other legislation.

A ‘critical SoHO entity’ is a SoHO entity

that carries out activities contributing to the

supply of critical SoHOs and the scale of

those activities is such that a failure to carry

them out cannot be compensated by

activities of other entities or alternative

substances or products for recipients.

- Obligations on Member States to

ensure a sufficient, adequate and

resilient supply

- Facilitate donation

- Communication and education

- Optimal use

- Activity data collection and

monitoring

- Supply alerts

- National SoHO emergency plans

- SoHO Entity emergency plans

- Derogations and additional measures

in emergency situations

Supply of critical SoHO is protected by:

New article!

• Scope and advice

• SoHO activities, entities and establishments

• SoHO Preparations and their authorisation

• Standards and hierarchy of technical guidelines

• Donor Protection and Voluntary Unpaid Donation

• Recipient and offspring protection

• Vigilance

• Supply continuity

• Digitalisation – the SoHO platform

Key new and changed concepts

Vigilance reporting

Rapid alerts

Member State National and

other competent authorities

Technical guidelines for

implementation of standards

More stringent national

measures

Supply flows and shortages

monitoring

Supply alerts

SoHo Coordination

Board Membership and compendium of

advice given

Registry of entities and

their authorisations

Digitalisation – efficiency, transparency, monitoring

The EU SoHO

Platform

Compendium of authorised

SoHO preparations

+ List of ongoing Clinical studies

ECDC NORMAL

SoHO Platform Roadmap

May 2024

2024

SOHO-X development and maintenance (internal team)

- Cloud architecture @ DIGIT

- Architecture & reuse - Automated testing - Releases 0.1 to 1.0

- Security Plan

Release 0.1 Release 0.2 Release 0.3 Release 1.0

- Home page + global search - Registration + preparation - Publication of technical guidelines

- Notifications and alerts - Reporting 1 - Publication 2

- Collaborative space - Indicators - Reporting 2 - Publication 3

- Interoperability - Testing phase with CA

Mapping and interoperability study

October 2024

2025

February 2025

September 2025

2026

February 2026

Q2 2026

Release 1.1

- Production phase

- Follow-up with CA and Entities

• Formal approval by the Council and publication in the Official Journal

• The Regulation will enter into force 20 days after its publication in the Official Journal of the European Union – during 2024 (~ before summer)

• 3 years before the provisions become applicable - 2027 (an additional year for some provisions)

Next steps Entry into Force and Date of Application

ECDC NORMAL

Project name (year) Scope 1. SUPPLY (2021) Shortages, supply continuity (plasma) 2. EGALITE (2021) Availability, accreditation (Tissues) 3. BRAVEST (2021) Crisis resilience (Organs) 4. EuroTRACTOR (2021) Outcome registry (HSC) 5. EUMAR (2021) Outcome registry (MAR) 6. SIGHTSoHO (2021) Training authorities (B, TC) 7. Cooperation Agreement EDQM (2021) Guidelines, vigilance, support professionals, supply (B, TC, O) 8. Readership (2022) New obligations entities in hospitals (B, TC) 9. GAPP-Pro (2022) New obligations process authorisation (B, TC) 10. New SoHO Breast Milk (2023) Implementation new requirements for Breast milk banks 11. New SoHO FMT (call will be relaunched in 2024)

Implementation new requirements for FMT

11. Paired kidney exchange (2023) Organs 12. Cooperation Agreement EDQM (2024) Guidelines, vigilance, support professionals, supply (B, TC, O) 13. SoHO-X ICT (2024) SoHO digital platform – new Regulation (B, TC) 14. Support for Organisational by SoHO Authorities (call to be launched in 2024)

Support the implementation of the supervisory functions in the new SoHO regulation

15. Regulatory Coherence (call to be launched in 2024)

Topics of concern across EU frameworks

Current & future EU4H actions SoHO Support implementation Focus on implementation

Thank you

ECDC NORMAL

Technical guidelines on the prevention of donor-derived transmission of communicable diseases through SoHOs SoHO-Net Organs Group meeting – 18 June 2024

76

ECDC NORMAL

Context

Article 59, paragraph 4 For those standards, or elements thereof, concerning protection of SoHO recipientsand offspring from medically assisted reproduction for which no implementing acthas been adopted, SoHO entities shall take into account: a) The most recent technical guidelines, as indicated on the EU SoHO Platform […] :

(i) published by the ECDC concerning the prevention of communicable disease transmission;

77Of note: organs are excluded from the definition of SoHO from the scope of this regulation and thus of this project

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Role of ECDC

78

• Develop and publish technical guidelines concerning the prevention of donor-derived communicable disease transmission through SoHO application

• Cover relevant pathogens for SoHO: those listed in the current directives and those with current acute relevance (e.g., Dengue virus)

• For SoHOs as defined in the Regulation (i.e., not including organs) • Supported by an ad hoc scientific expert panel(s)

The development of technical guidelines follows internal ECDC procedures approved by ECDC’s Advisory Forum

ECDC NORMAL

79

Overall project plan

SoHO-Net

(ToR: Cooperate closely and

communicate with relevant NCA on SoHO

microbial safety topics)

NCAs

Scientific expert panel provide expertise and

data/evidence; analyse;

deliver opinion

ECDC coordinate; organise; provide

data/evidence (literature searches, systematic reviews); deliver final recommendation

document

relevant decisions

Available on SoHO Sharepoint

ECDC NORMAL

Guideline content development process • The expert panel is ultimately expected to provide feedback on statements

regarding: • Testing strategies • Deferral strategies (including deferral periods) • Testing methods

• The feedback of the panel serves as a basis for ECDC to draft the guidelines

• The draft guidelines will be submitted for review to ECDC advisory forum, SoHO-Net, EDQM, EMA, WHO and to other relevant stakeholders (closed consultation)

80

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ECDC SoHO guidelines – update Overview

81

Expert panel meetings - HIV: Sept 23–Feb 24

- HBV/HCV: May 24–Sept 24 (next meeting: 03 July)

- T. pallidum: Dec 24–May 25

HIV Guideline draft and review - Drafting February to June 2024 - SoHO-Net review: June to August 2024  SoHO-Net should liaise with NCAs

- External stakeholder consultation: November-December

Publication Current plan: - HIV: March 2025 - HBV/HCV: End 2025 - T. pallidum: 2026

Note: timelines are according to current plan

ECDC NORMAL

ECON ECDC SoHO-Net Collaboration Centre

82

Guidelines: draft guidelines for SoHO-Net review

Meetings: “short minutes” of expert panel with decisions and agreements

Pathogen data sheets: Latest versions of the evidence base for the guidelines

ECDC NORMAL

Thank you

ECDC NORMAL

ECDC guidelines Recommendations for donor testing for HIV and HBV/HCV in SoHOs other than solid organs

Flávia Cunha, ECDC Stockholm, 18 June 2024

ECDC NORMAL

Context

• Which risks of exposure are relevant for SoHO safety?

• Which SoHO donors should be tested?

• When to test?

• Which laboratory screening tests should be used?

• What to do in case of reactive screening tests?

• What deferral period should be considered?

85

ECDC NORMAL

Context

86

Expert panel meetings - HIV: Sept 23–Feb 24

- HBV/HCV: May 24–Sept 24 (next meeting: 03 July)

- T. pallidum: Dec 24–May 25

HIV Guideline draft and review - Drafting February to June 2024 - SoHO-Net review: June to August 2024  SoHO-Net should liaise with NCAs

- External stakeholder consultation: November-December

Publication Current plan: - HIV: March 2025 - HBV/HCV: End 2025 - T. pallidum: 2026

ECDC NORMAL

Risks of exposure to HIV

87

Recent risks of exposure to HIV should be considered when assessing donor eligibility.

Deferral period in case of recent risk of exposure to HIV

• At least 8 weeks since the last event with a risk of exposure to HIV.

• Exceptions: oral PrEP or PEP - 12 weeks | injectable PrEP – 24 months.

• Deceased donors  not applicable; test results not reliable and risks of exposure to HIV should be considered.

ECDC NORMAL

Risks of exposure to HIV

88

It is advised to consider the following risks of exposure to HIV:

Active sexually transmitted infection (STI) Condomless anal sex with a new partner Condomless anal sex with more than one partner Condomless sex with a partner infected with HIV Condomless sex with a partner using injectable drugs Condomless sex with a partner using PrEP or PEP Condomless sex with a partner with an active STI Needle sharing and/or injecting drug use Transactional sex in a country with a higher HIV prevalence than in the EU/EEA Use of injectable PrEP Use of oral PrEP or PEP

ECDC NORMAL

Donor testing – HIV – Tissues/Deceased donors

REQUIRED

Testing of donors

• All donors, at donation, should be tested for HIV.

Screening tests

• NAT detecting HIV-1 RNA + anti-HIV-1/2.

• NAT should have two targets in the HIV genome.

• NAT 95% Limit of detection (LOD): ≤50 HIV RNA copies/ml.

* Reactive is defined as repeat reactive if the serological test is repeated. If the serological test is initially reactive and negative in retesting, the donation can be considered negative provided the NAT is also negative. 89

ECDC NORMAL

Donor testing – HIV – Tissues/Deceased donors

ADVISED Screening tests • Use of NAT detecting both HIV-1 and HIV-2 RNA.

Outcome of test results

• Retest initially reactive anti-HIV-1/2  retest with the same assay and in the same sample.

• No need to retest reactive NAT.

Practical consideration:

• Antigen-antibody (Ag-Ab) combination tests instead of Ab-only tests.

90

ECDC NORMAL

Donor testing – HIV – Tissues/Living donors

REQUIRED

Testing of donors

• All donors, at each donation, should be tested for HIV.

Screening tests

• NAT detecting HIV-1 RNA + anti-HIV-1/2.

• NAT should have two targets in the HIV genome.

91

ECDC NORMAL

Donor testing – HIV – Tissues/Living donors

ADVISED

Screening tests

• Use of NAT detecting both HIV-1 and HIV-2 RNA.

• NAT 95% LOD ≤ 50 HIV RNA copies/mL

Outcome of test results

• Retest initially reactive anti-HIV-1/2  retest with the same assay and in the same sample.

• No need to retest reactive NAT.

• If first confirmatory test positive or indeterminate  second confirmatory test on a separate sample.

Practical consideration:

• Ag-Ab combination tests can be used instead of Ab-only tests.

92

ECDC NORMAL

Donor testing - HBV

• First panel meeting on 07 May 2024. • List of risks of exposure to HBV assessed, but still open for further discussion.

TESTING STRATEGY

93

For all SoHOs:

All donors should be tested for HBV at each donation.

ECDC NORMAL

Donor testing - HCV

• First panel meeting on 07 May 2024. • List of risks of exposure to HCV assessed, but still open for further discussion.

TESTING STRATEGY

95

For all SoHOs:

All donors should be tested for HBV at each donation.

ECDC NORMAL

Thank you!

97

sozialministerium.at

The impact of the SoHO-regulation on organs safety – horizon scanning

Martina Brix-Zuleger Federal Ministry of Social Affairs, Health, Care and Consumer Protection Stockholm, 18th June 2024

ECDC – NFP Organ meeting 18., 19.6.2024

sozialministerium.at ECDC NORMAL

General conditions in Austria

• Federal state with 9 federal countries

• Eurotransplant-Member

• 4 TX-centres

Bild von Freepik 99

sozialministerium.at ECDC NORMAL

Interface SoHO-regulation and organs

• Physiological:

− Vessels

− Stemcells

− Subsidiary tissues- and/or cell collection, e.g. valvular, bones, skin

− Blood transfusions

• Effectings:

− Vigilance: SAR, SAE

− Communication

− Supply

100

sozialministerium.at ECDC NORMAL

Horizon scanning

101

Notification Allocation Explantation Transplantation Follow-up

care

Testing

Standards EDQM/ECDC

SAR/SAE, Vigilance

Communication Supply

sozialministerium.at ECDC NORMAL

Conclusion

Possible effects of the SoHO-regulation on the organ area:

• optimizing the treatment of patients and

• increasing the safety for transplantpatients

we have to work together

102

but

sozialministerium.at ECDC NORMAL

Coming together is a beginning; keeping together is progress; working together is success.

Martina Brix-Zuleger Federal Ministry of Social Affairs, Health, Care and Consumer Protection [email protected]

Edward Everett Hale

ECDC NORMAL

Session 4 Hepatitis 18 June

104

ECDC NORMAL

Session overview 1. Epidemiological overview of Hepatitis (B and) C in EU/EEA – Ndeindo

Ndeikoundam Ngangro, ECDC 2. Questions and answers – All

Sharing of experience with hepatitis C positive donors in Member States

3. France – Corinne Antoine, Agence de la biomédecine, France 4. Italy – Paolo Antonio Grossi, NFP Italy 5. Discussion – All

Epidemiological overview of Hepatitis B and C in EU/EEA

Ndeindo Ndeikoundam Ngangro, Ana Paula Finatto-Canabaro and Erika Duffell, ECDC

ECDC SoHO-Net meeting for Organs 18-19th June 2024

Global epidemiological situation of hepatitis B and C in 2022

254 million with chronic hepatitis B

50 million with chronic

hepatitis C

1.2 million new hepatitis B

infections/year

1 million new hepatitis C

infections/year

1.1 million deaths from hepatitis B

0.2 million deaths from hepatitis C

Hepatitis B Hepatitis C

Source: Global hepatitis report 2024: action for access in low- and middle-income countries. Geneva: World Health Organization; 2024. Licence: CC BY-NC-SA 3.0 IGO. https://www.who.int/publications/i/item/9789240091672

3.6 million people living with chronic HBV (2016 estimate)

1.8 million people living with chronic HCV (2022 estimate)

Variation in disease burden across countries and between different population groups

The burden of viral hepatitis B and C in the EU/EEA

Source: Bivegete S et al. Estimates of hepatitis B virus prevalence among general population and key risk groups in EU/EEA/UK countries: a systematic review. Eurosurveillance, 28, 2200738 (2023), https://doi.org/10.2807/1560-7917.ES.2023.28.30.2200738 . Thomadakis C, Gountas I, Duffell E, Gountas K, Bluemel B, Seyler T, et al. Prevalence of chronic HCV infection in EU/EEA countries in 2019 using multiparameter evidence synthesis. Lancet Reg Health Eur. 2023 Dec 13;36:100792. doi: 10.1016/j.lanepe.2023.100792.

Hepatitis B (HBsAg) prevalence (%) in the adult general population in the EU/EEA, 2021

Source: Bivegete S et al. Estimates of hepatitis B virus prevalence among general population and key risk groups in EU/EEA/UK countries: a systematic review. Eurosurveillance, 28, 2200738 (2023), https://doi.org/10.2807/1560-7917.ES.2023.28.30.2200738

Hepatitis C (RNA) prevalence (%) in the overall population in EU/EEA countries, 2022

v

Source: Thomadakis C, Gountas I, Duffell E, Gountas K, Bluemel B, Seyler T, et al. Prevalence of chronic HCV infection in EU/EEA countries in 2019 using multiparameter evidence synthesis. Lancet Reg Health Eur. 2023 Dec 13;36:100792. doi: 10.1016/j.lanepe.2023.100792..

Prevalence of hepatitis B and C in key population groups

Source: Bivegete S et al. Estimates of hepatitis B virus prevalence among general population and key risk groups in EU/EEA/UK countries: a systematic review. Eurosurveillance, 28, 2200738 (2023), https://doi.org/10.2807/1560-7917.ES.2023.28.30.2200738. Christos T et al. National estimates of the prevalence of chronic HCV infection in EU/EEA countries in 2019 using multiparameter evidence synthesis. Awaiting publication in Lancet. EMCDDA Viral Hepatitis Elimination Barometer https://www.emcdda.europa.eu/publications/html/viral-hepatitis-elimination-barometer_en; ECDC hepatitis C prevalence data base https://www.ecdc.europa.eu/en/infectious-disease-topics/z-disease-list/hepatitis-c/tools/hepatitis-c-prevalence-database; Nakitanda et al. Hepatitis C virus infection in EU/EEA and United Kingdom prison: opportunities and challenges for action https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7650151/pdf/12889_2020_Article_9515.pdf.

Hepatitis B (HBsAg prevalence) Hepatitis C (anti-HCV)

Migrant populations 0.9 - 31.7% People who inject drugs 15.4 – 96.8% (RNA prevalence 15.0 – 64.2%)

People who inject drugs 0 - 16.9% People in prison 2.3 – 82.6%

People in prison 0.3 - 8.3% Migrant populations 0 – 16.8%

Men who have sex with men 2.3 - 4.3% Men who have sex with men 0.6 – 4.8%

32%

68%

Key populations affected by hepatitis B and C across EU/EEA countries

36%

64% Other groups

Hepatitis B Hepatitis C

People who inject drugs

Migrant populations

Other groups

Source: HBV estimate – Canabarro APF et al Chronic hepatitis B infections in the European Union: estimates of prevalence using the workbook methodology (awaiting publication). HCV estimate - Thomadakis C et al. Prevalence of chronic HCV infection in EU/EEA countries in 2019 using multiparameter evidence synthesis. Lancet Reg Health Eur. 2023 Dec 13;36:100792.

Proportion of total cases %

Notification rates of acute hepatitis B per 100 000 population in EU/EEA countries, 2022

Source: ECDC (2024). Acute cases: Country reports from Austria, Cyprus, Czechia, Denmark, Estonia, Finland, France*, Germany, Greece, Hungary, Iceland, Ireland, Latvia, Lithuania, Malta, the Netherlands, Norway, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden. Chronic cases: Country reports from Austria, Cyprus, Denmark, Estonia, Finland, Ireland, Latvia, Luxembourg, Malta, the Netherlands, Norway, Portugal, Romania, Slovakia, Slovenia and Sweden

0

1

10

2013 2014 2015 2016 2017 2018 2019 2020 2021 2022

Ra te

p er

1 00

0 00

p op

ul at

io n

Year

Logarithmic scale

Chronic Acute

Acute hepatitis B notifications – by age and gender, EU/EEA, 2022 1 971 notified acute cases from 24 MS

ECDC, The European Surveillance System 2023 (unpublished).

GENDER (n=1 971) AGE GROUPS (n=1 919) Differences between acute and chronic cases:

 More chronic cases reported than acute cases

 Chronic cases mostly older

0.4% 0.5% 2.1%

5.5%

15.6%

21.5% 21.1%

16.6% 16.7%

0.0%

5.0%

10.0%

15.0%

20.0%

25.0%

<5 5–14 15–19 20–24 25–34 35–44 45–54 55–64 ≥65

acute (%)

Notification rates of hepatitis C per 100 000 population in EU/EEA countries, 2022

115

Source: Country reports from Austria, Bulgaria, Croatia, Cyprus, Czechia, Denmark, Estonia, Finland, Germany, Greece, Iceland, Ireland, Italy, Latvia, Luxembourg, Malta, Norway, Poland, Portugal, Slovakia, Slovenia, and Sweden.

0.0

1.0

2.0

3.0

4.0

5.0

6.0

7.0

8.0

9.0

2013 2014 2015 2016 2017 2018 2019 2020 2021 2022

Ra te

p er

1 00

0 00

p op

ul at

io n

Acute hepatitis C notifications – by age and gender, EU/EEA, 2022 1 308 notified acute cases from 19 MS

Source: ECDC, The European Surveillance System 2023 (unpublished).

GENDER (n=1 213) AGE GROUPS (n=224) Differences between acute and chronic cases:

 More chronic cases reported than acute cases

 Chronic cases mostly older

Male 65%

Female 35%

Other 0%

0.9% 2.2% 1.8%

5.4%

23.7% 22.8%

19.2%

14.3%

9.8%

0.0%

5.0%

10.0%

15.0%

20.0%

25.0%

<5 5–14 15–19 20–24 25–34 35–44 45–54 55–64 ≥65

Transmission category of acute hepatitis B and C cases in EU/EEA countries, 2022

Source: ECDC, The European Surveillance System 2023 (unpublished). Reports for acute hepatitis B from Austria, Croatia, Czechia, Denmark, Estonia, Finland, Francei , Germany, Hungary, Iceland, Ireland, Italy, Latvia, Malta, the Netherlands, Norway, Poland, Portugal, Romania, Slovakia, Spain and Sweden. Reports for acute hepatitis C from Austria, Croatia, Cyprus, Denmark, Estonia, Germany, Greece, Hungary, Ireland, Italy, Latvia, the Netherlands, Poland, Portugal, Romania, Slovakia, Spain, and Sweden. *: Nosocomial transmission includes hospitals, nursing homes, psychiatric institutions, and dental services. This category refers mainly to patients exposed through healthcare settings, distinct from ’needle-stick and other occupational exposure’, which refers to staff. **: ‘Non-occupational injuries’ include needle sticks that occur outside a healthcare setting, bites, tattoos, piercings.

Hepatitis B Hepatitis C

Sex work Organ and tissues

Haemodialysis Needle-stick, occupational exposure***

Mother-to-child transmission Blood and blood products

Other Household

Sexual transmission (not specified) Non-occupational injuries**

Injecting drug use Nosocomial*

Sex between men Heterosexual transmission

Proportion of cases (%)

Tr an

sm is

si on

c at

eg or

y

0 20 40 60 80

Sex work Transplant

Mother-to-child transmission Haemodialysis

Sexual transmission (not specified) Other

Needle-stick and other occupational exposure*** Household

Blood and blood products Non-occupational injuries**

Heterosexual transmission Sex between men

Nosocomial* Injecting drug use

Proportion of cases (%)

Mortality due to viral hepatitis B and C in the EU/EEA over time

Source: Eurostat, 2022.

No significant decrease in total mortality from liver cancer and chronic liver diseases at EU/EEA level

Mortality from hepatocellular carcinoma continues to increase

Nu m

be r o

f d ea

th s

Deaths from hepatocellular carcinoma across EU/EEA countries, 2011 - 2019

Hepatitis specific mortality estimated to be 64,000 in 2015 for EU/EEA countries and the UK

Global health sector strategies on HIV, viral hepatitis and STIs for 2022-2030; WHO Europe Regional action plan 2022-2030

• “End viral hepatitis as a major public health threat by 2030”

Source: https://apps.who.int/iris/rest/bitstreams/1451670/retrieve; https://apps.who.int/iris/bitstream/handle/10665/361524/72wd09e-AIDS-Hepatitis-220605.pdf?sequence=1&isAllowed=y 119

Estimated proportion of undiagnosed people living with viral hepatitis B and C

Source: The Polaris Observatory Collaborators. https://doi.org/10.1016/ S2468-1253(23)00233-9

Progress towards the WHO elimination targets for prevention across the EU/EEA countries, 2022

Source: European Centre for Disease Prevention and Control. Evidence brief: Prevention of Hepatitis B and C in the EU/EEA. Stockholm: ECDC; 2024.

HBV vaccination

Antenatal screening HBV

Blood safety

Harm reduction

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

90% COVERAGE WITH HBV B IRTH DOSE ( FOR COUNTR IES WITH UN IVERSAL PROGRAMME)

95% COVERAGE OF THREE DOSES OF HBV VACC INE

90% COVERAGE OF ANTENATAL SCREEN ING FOR HBV

90% COVERAGE OF POST -EXPOSURE PROPHYLAX IS FOR INFANTS BORN TO HBV INFECTED MOTHERS

100% BLOOD UN ITS SCREENED FOR HBV AND HCV

>200 CLEAN NEEDLES AND SYR INGES PER PERSON WHO IN JECTS DRUGS PER YEAR

40% OF OP IOID DEPENDANT PEOPLE WHO IN JECT DRUGS ACCESS ING OP IOID AGONIST TREATMENT

PROPORTION OF COUNTRIES ACHIEVING TARGET OF THOSE WITH DATA (%)

Reached target Did not reach target

Conclusion

 No data source provides a complete overview of the situation in the EU/EEA: • Epidemiological data to be understood considering monitoring data and vice-versa • Triangulation of several data sources

 High disease burden for hepatitis B and C in EU/EEA despite a declining incidence :

• Large estimates of prevalences and proportions of undiagnosed infections • Large geographic variation • Key populations (migrants, IDU…) disproportionately affected • Increasing mortality

 Many progress towards 2030 elimination goals but: • Many countries are far from the elimination targets • Need to upscale the prevention and control interventions targeting

vulnerable populations and areas

Acknowledgements Austria: Ziad El-Khatib; Irene Kászoni-Rückerl; Sigrid Kiermayr; Anna Nagel; Maria Paulke-Korinek; Elise Schabus; Irrene Schmuttere; Margit, Winterleitner. Belgium: Benoit Kabamba; Sofieke Klamer; Els Plettinckx; Vanessa Suin; Dominique van Beckhoven; Thomas Vanwolleghem. Bulgaria: Mariya Tyufekchieva; Tonka Varleva. Croatia: Maja Ilic; Tatjana Nemeth- Blažić, Adriana Vince. Cyprus: Fani Theophanous. Czechia: Jitka Cástková; Vratislav,Nemecek. Denmark: Peer Brehm Christensen; Susan Cowan; Martine Grosos Aabye; Anne Øvrehus. Estonia: Jevgenia Epštein; Kristi Rüütel. Finland: Henrikki Brummer; Kirsi Liitsola; Henna Rautiainen; Päivi Viitanen. France: Cécile Brouard; Mathias Bruyand; Florcence Lot; Joisane Pillonel. Germany: Sandra Dudavera; Gyde Steffen; Ruth Zimmermann. Greece: Stergios Georgoulas; Georgia Nikolopoulou; George Papatheodoridis; Ioanna Samiou; Panagiota Touloumi ; Sois Zoutsos. Hungary: Agnes Danielisz; Maria Dudas; Emese Kozma; Zsuzsanna Molnár. Iceland: Guðrún Aspelund; Már Kristjánsson. Ireland: Jeff Connell; Suzanne Cotter; Cillian De Gascun; Joanne Moran; Aiden McCormick; Niamh Murphy; Aisling O'Leary; Mary O'Riordan. Italy: Loreta Kondili; Francesco Maraglino; Barbara Suligoi; Maria Elena Tosti; Sabrina Valle. Latvia: Inga Ažiņa; Raina Nikiforova; Serges Nikisins. Liechtenstein: Silvia Dehler; Esther Walser-Domjan. Lithuania: Brigita Kairiene. Luxembourg: Carole Devaux. Malta: Jackie Melillo; Tanya Melillo. Netherlands: Silke David; Jaap Maas; Annemarie Meiberg; Eline Op de Coul; Marleen van Dijk; Irene Veldhuijzen. Norway: Hilde Kløvstad. Poland: Robert Flisiak; Małgorzata Stępień; Karolina Zakrzewska. Portugal: Joana Bettencourt; Rui Tato Marinho; Sofia Ribeiro. Romania: Odette Popovici; Corina Silvia Pop. Slovakia: Mária Avdicová. Slovenia: Marta Grgič-Vitek; Jože Hren; Irena Klavs; Janja Križman Miklavčič; Eva Leban; Mojca Matičič; Mario Poljak; Urška Rahne Potokar. Spain: Agustín Albillos; Maria Buti; Javier Crespo; Julia del Amo; Asunción Diaz; José Luis Calleja; Javier García-Samaniego; Victoria Hernando; Oriana Ramírez-Rubio; Pablo Ryan. Sweden: Soo Aleman; Maria Axelsson; Hanna Edberg; Josefine Lundberg Ederth; Martin Kåberg. European Liver Patients’ Association: Marko Korenjak. European Monitoring Centre for Drugs and Drug Addiction: Thomas Seyler. WHO Regional Office for Europe: Marcelo Naveira, Giorgi Kuchukhidze. EMIS: Axel J Schmidt. Correlation Network: Rafaela Rigoni, Tammi Tuukka. Viral Hepatitis Prevention Board: Greet Hendrickx. European Association for the Study of the Liver: Maria Buti. National AIDS Trust: Katherine Turpie. World Hepatitis Alliance: Rachel Halford, Cary James.

Thank you!

w w w . a g e n c e - b i o m e d e c i n e . f r

Sharing of French experience with hepatitis C positive donors and with early and large access to DAAs treatment

—Dr C. Antoine, Dr Camille Legeai, Dr Sophie Lucas Samuel, Pr F. Kerbaul, Pr Michel Tsimaratos—

French context about HCV infection 1. Scandal over tainted blood in France “national traumatism” ● Distribution of contaminated blood stocks until 1985 to patients,

leading to an outbreak of HIV/AIDS and hepatitis C

2. Donor serologic and nucleic acid amplification testing (NAT) : mandatory by law ● Triplex assay allowing NAT results for HIV, HBV, and HCV on organ donors are mandatory since 2010 ● In an exhaustive manner available before organ allocation since 2021 ● Procurement and organ transplantation have been authorized, as an exception, according to a national

protocol specified by law since 2006

3. In 2013, France was one of the first countries to market the new direct antiviral agents to treat chronic hepatitis C ● Covered by the French Health Insurance System ● Multidisciplinary committee had to validate the best timing and treatment option to allow drugs delivery

SOHO-NET ORGANS MEETING – June 2024

HCV liver disease in France Before 2013 : 24-26% of patients were listed for LT due to HCV liver disease

● 55-60 % of them have decompensated cirrhosis, 10-12% for retransplant The 2th-generation of DAAs = progress in the therapeutic management of patients with HCV

● Sustained virological response. ● Extent use of DAAs for both liver transplant candidates and recipients

• To eradicate HCV • To avoid liver decompensation

Belli et al, Journal of hepatology, 2016

• To prevent and to treat HCV-reinfection of the graft • To improve transplant results

Study objectives Impact of the 2th-generation of DAAs on registration and outcome on the WL for LT Impact of the 2th-generation of DAAs on transplant results

2023

SOHO-NET ORGANS MEETING – June 2024

A. Candidates on the waiting list B. Liver transplant recipients

All adult patients with HCV induced liver diseases Comparison of the 2 periods before and after DAA introduction: 2010–2012 (n = 766) versus 2013–2018 (N = 1406) Post transplant mortality analysis Kaplan-Meier method and the log-rank test

Newly adult registered candidates from 2010 to 2018 in France Comparison of the 2 periods before and after DAA introduction: 2010–2013 (n = 1600) versus 2014–2018 (N = 1573). Trends over time of 1. Registration on WL 2. Liver TR indications

3. Cumulative incidence of death and delisting for worsening conditions (Competing risk analysis)

Patients with positive HCV antibodies +/-

positive HCV viral load

National database : CRISTAL SOHO-NET ORGANS MEETING – June 2024

Changes in the waiting list

1. Candidates listed for HCV-induced liver diseases : - 33 % from 2013 to 2018

2. Listing for retransplantation decreased of 43% since 2013.

3. HCV-HCC : predominant indication : 21% (2003) →63% (2018)

Prevalents : candidates with HCV-induced liver diseases

Incidents : new registrations for HCV-induced liver diseases

-90%

+30% -33%

SOHO-NET ORGANS MEETING – June 2024

4. Significant decrease of WL mortality (-65%) 5. Decrease of 42% of delisting for worsening

condition from 2014 to 2018 6. Significant increase of 113% of delisting for

improving condition 7. Increase in the rate of inactive patients on WL :

from 26% in 2013 to 51% in 2018

1 5

7 1 9

6

1 7

5

1 7

5 2 2

2

1 7

8

1 9

5

1 8

1

1 6

5 2 1

8

1 7

9

1 6

7 1 9

1 2 1

1

1 5

3

1 1

6

1 0

8

7 4 7 8

3 3

4 4

4 0 5 5

5 1

6 2

9 8

1 1

3

1 2

5

1 2

6

1 4

6

1 4

3

1 9

8 1 7

5

1 9

3

1 6

4

1 6

8

1 6

7 1 8

6

3 8

2 9

2 6 2

8

2 4

3 2

2 8 3 5 4 5

3 7

4 6

4 0

3 1 4

4

3 2

2 4

3 0

2 2

2 5

14%

16%

17% 30%

33% 47% 50%

54%

63%

0%

10%

20%

30%

40%

50%

60%

70%

0

100

200

300

400

500

600

2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018

% o

f H

C C

/ a

ll H

C V

+ a

d u

lt r

eg is

tr at

io n

s

N u

m b

e r

o f

p at

ie n

ts r

e gi

st e

re d

Retransplant HCC

Other Acute hepatitis

Cirrhosis % of HCC

The waiting list patient survival increased Comparison of 2 periods (2010-2013 versus 2014-2018)

Cumulative incidence of death or delisting for worsening condition on

the LT waiting list taking into account the competive risk of

transplantation in % [95% CI]

Period N

at 3

months

At 6

months

at 12

months

At 24

months

at 36

months

2010-

2013

159

8 8 [7-9] 12 [10-14] 16 [15-18] 22 [20-24] 24 [22-26]

2014-

2018

157

2 5 [4-6] 8 [7-10] 13 [11-15] 17 [15-20] NCC

u m

u la

ti ve

In ci

d en

ce

SOHO-NET ORGANS MEETING – June 2024

Factors independently associated with death or delisting for worsening condition : ➢ MELD score at registration ➢ Period (2010- 2013) compared to (2014-2018) No difference in 1-y waiting list survival in non-HCV patients

Post transplant outcome HCV-induced liver diseases

➢ 26% of liver transplant in 2010 ➢ 16 % of liver transplant in 2018

(overall LT activity : + 21,3% from 2010 to 2018)

The 1y-graft survival rate was significantly improved after the extent use of DAAs ( (2010-2012) versus (2013-2018)

1 y graft survival 76,9 % → 84,9% Remained significantly lower in 2013-2018 in a multivariate survival (cox model) adjusted on MELD at LTR, recipient and donor age and donor’s etiology of death (HR=0,5 [0,4-0,6

60% 62,4%

70,1% 76,9%

85,6%

90,7%

84,9% 80,2%

72,1% 70,1%

SOHO-NET ORGANS MEETING – June 2024

Great impact of the early and large access to DAAs treatment in France (1)

From HCV candidates and recipients perspectives They have been benefiting from access to DAAs.

SOHO-NET ORGANS MEETING – June 2024

● Decrease of WL mortality and delisting for worsening condition

● Increase of delisting for improving condition

● Increase of inactive patients rate on waiting list

● With improving graft and patient survival, including less relisting for retransplantation

.

Great impact of the early and large access to DAAs treatment in France (2) From non HCV candidates perspectives The decrease of transplant needs for HCV liver disease ● May contribute to the decrease of overall waiting list mortality and removal for worsening conditions

observed in France ● Grafts could be redistributed towards HCV negative severe liver transplant candidates ● Despite overall increase of new registrations (Total candidates + 15,8%)

Significant decrease of overall waiting list mortality and removal for worsening

conditions from 2013 to 2019

SOHO-NET ORGANS MEETING – June 2024

National Prevention Plan to eradicate hepatitis C

Great impact of the early and large access to DAAs treatment in France (3)

From French Health Insurance System perspectives ● Cost effective strategy : very high annual direct medical cost associated with HCV hepatic and

extrahepatic manifestations → DAA treatment was projected to result in cost savings of €316 million per year. (Cacoub et Al, J Viral Hepat 2018)

● A reduced risk for mortality and incidence of hepatocellular carcinoma (French ANRS CO22 cohort Carra Lancet 2019)

● Leading to a secondary decline in HCC transplantation indications ( - 20% in 5 years)

→ Decreasing number of HCV positive donors

Over time: Decrease of positive-HCV donors Exhaustivity of Viral load assessment before organ allocation

2023 : deceased donors with positive HCV serology ● Systematic screening by NAT before organ allocation ● 78% of potential donors have a negative HCV viremia ● 100% of actual donors have a negative HVC viremia

2023 16 kidney transplants (80% of utilized donors) 6 liver transplants (60% of utilized donors)

SOHO-NET ORGANS MEETING – June 2024

29%

78%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

0

10

20

30

40

50

60

P o

te n

ti al

H C

V p

o si

ti ve

D D

B D

d o

n o

rs

NAT not available Negative HCV viremia

HCV viremic donors % of non HCV viremic donors

1

3

1 6

5 4 6 3

6 5 6 7 7 11 11 11 13

10

25,0%

42,9%

75,0%

44,4%

66,7%

50,0%

75,0%

91,7% 91,7% 100,0%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

0

5

10

15

20

25

30

35

40

45

50

A ct

u al

H C

V p

o si

ti ve

D B

D d

o n

o rs

NAT not available HCV non viremaic donors

HCV viremic donors % of non viremic donors

Legal framework for HCV positive donors : derogatory exception

Donor risk assessment Recipient profile

HCV Antibodies

Viral load (nucleic acid amplification test positive) ● Positive or not available ● Negative

Only if the Fibrosis scoring is less than F2 ● Liver biopsy ● Non invasive methods for assessing liver fibrosis

Traced in CRISTAL Donor Registry

HCV antibodies

Viral load (nucleic acid amplification test positive) ● If not available, considered as negative ● Date of the last viral load assessment

Informed and consent

Traced in CRISTAL Recipient Registry

If patient's prognosis is life-threatening and the therapeutic alternatives become inappropriate,

● «so that waiting for a graft other than the one proposed in this derogation exception is detrimental to the recipient's survival».

VHC

SOHO-NET ORGANS MEETING – June 2024

13

Derogatory exception according to viral profile Deceased donors

Positive HCV Antibodies Liver: fibrosis score < F2

Positive HCV viral load

HCV‐viremic donor At the time of graft offer For recipients with : • Positive HCV Antibodies • Positive HCV viral load • Informed and consent

Negative HCV viral load

Non HCV‐viremic donor At the time of graft offer For recipients with : • Positive HCV Antibodies • Positive or negative HCV viral

load • Informed and consent

Living donors Positive HCV Antibodies Negative HCV viral load

Negative viral load > 3 months after complete treatment or

documented spontaneous viral eradication

Non HCV‐viremic living donor For recipients with : • Positive or negative HCV Antibodies • Whatever HCV viral load • Informed and consent

Negative viral load known to be negative < 3 months

Recent non HCV‐viremic living donor For recipients with : • Positive HCV Antibodies • Whatever HCV viral load • Informed and consent

Experts assessment Metavir Scoring < F2 (Non invasive Methods for Assessing Liver Fibrosis)

consent to the disclosure to the recipient of medical information concerning his/her immune status with regard to viral infection

SOHO-NET ORGANS MEETING – June 2024

Graft survival according to donor HCV serology and viremia in HCV positive recipients

Donor HCV status

and viremia N 1-year survival 3-years survival 5-years survival 10-years survival

Median

(months)

Negative HCV donor 3507 80,5%

[79,2% - 81,8%]

70,6%

[69,0% - 72,1%]

63,8%

[62,2% - 65,4%]

51,0%

[49,1% - 52,9%]

124,6

[114,4 -

135,6] Positive HCV non-

viremic donor 56 89,2%

[77,6% - 95,0%]

78,4%

[64,1% - 87,5%]

78,4%

[64,1% - 87,5%] NO NO

HCV‐viremic donor 18 83,3%

[56,8% - 94,3%]

77,8%

[51,1% - 91,0%]

64,8%

[37,5% - 82,5%]

48,6%

[22,0% - 70,9%]

114,3

[38,4 - .]

Times (months)Times (months)

SOHO-NET ORGANS MEETING – June 2024

Donor HCV status

and viremia N 1-year survival 3-years survival 5-years survival 10-years survival

Median

(months)

Negative HCV

donor 2020 90,6%

[89,3% - 91,8%] 83,0%

[81,3% - 84,6%] 73,7%

[71,6% - 75,7%] 51,6%

[49,0% - 54,2%]

123,9 [116,5 - 130,8]

Positive HCV non-

viremic donor 78 93,6% [85,3% - 97,3%]

83,9% [72,6% - 90,8%]

62,6% [46,2% - 75,2%] NO NO

HCV‐viremic donor 33 84,8% [67,4% - 93,4%]

63,6% [44,9% - 77,5%]

50,7% [32,6% - 66,3%] NO 65,9

[29,3 - 98,8]

01/012006-30/06/2021 01/012006-30/06/2021

Viremic recipients++ Older D & R More time on dialysis Previous KTR

2006-2012 LTR tended to reduce the risk of death, more specifically LTR from an HCV+ donor

Lower graft survival in viremic recipents before DAA introduction

15

Regulatory developments expected Deceased donors

Positive HCV Antibodies Liver: fibrosis score < F2

positive HCV viral load

Negative HCV viral load

Living donors Positive HCV Antibodies

Negative viral load >3 months after complete treatment or

documented spontaneous viral eradication

For recipients with : • Positive or negative HCV Antibodies • Whatever HCV viral load • Informed and consent

Negative viral load known to be negative < 3 months

For recipients with : • Positive HCV Antibodies • Whatever HCV viral load • Informed and consent

Experts assessment Metavir Scoring < F2 (Noninvasive Methods for Assessing Liver Fibrosis)

consent to the disclosure to the recipient of medical information concerning his/her immune status with regard to viral infection

SOHO-NET ORGANS MEETING – June 2024

HCV‐viremic donor At the time of graft offer For recipients with : • Positive HCV Antibodies • Positive HCV viral load • Informed and consent

Non HCV‐viremic donor At the time of graft offer For recipients with : • Positive or negative HCV

Antibodies • Positive or negative HCV viral

load • Informed and consent

Any cases of HCV transmission from seropositive, nonviremic donors in 15 years

if I bite you, you get chikunguya

if you bite me, you'll get chicken flu

It's all a question of benefit/risk balance…

SOHO-NET ORGANS MEETING – June 2024

ECDC NORMAL

Session 5 Screening of donors for HTLV-1 18 June

126

ECDC NORMAL

Session overview

1. Epidemiological overview of HTLV-1 – Antoine Gessain, Institut Pasteur, France

2. Testing of organ donors for HTLV-1 in Spain – Beatriz Mahillo Durán, NFP Spain

3. Strategies for testing organ donors for HTLV-1 in Romania – Guenadiy Roumenov Vatachki, National Transplant Agency, Romania

4. Discussion on strategies for testing of organ donors for HTLV-1 in EU/EEA – All

127

ECDC NORMAL

But first… a couple of questions

ECDC NORMAL

But first… a couple of questions

Epidémiologie et Physiopathologie des Virus Oncogènes

Global Epidemiological Aspects of HTLV-1 in the World

Antoine Gessain/Olivier Cassar

Unité d’Epidémiologie et Physiopathologie des Virus Oncogènes

Institut Pasteur, CNRS UMR 3659

Epidémiologie et Physiopathologie des Virus Oncogènes

Primate T Lymphotropic Viruses: Four Types

HTLV-1/STLV-1

HTLV-2/STLV-2

HTLV-3/STLV-3

HTLV-4/STLV-4

1980

1982

1994

2005

Epidémiologie et Physiopathologie des Virus Oncogènes

Prototype: The Human Onco-Retrovirus HTLV-I • Discovery: 1980 NIH USA, 1981 Japan.

• Several associated diseases (hematological ATL, neurological TSP/HAM, dermatological ID, muscular Myositis,…)

• Peculiar epidemiology (foci, high endemic areas, > 5/10 millions of infected persons, increase with age and > in women).

• In vivo tropism: CD4+ and CD8 + lymphocytes

• Clonal way of life = Great genetic stability ++

Extracellular Type C Retroviral particles produced by a T lymphoid cell line established from the culture of the PBMCs of a patient with a TSP/HAM. Gessain et al., 1989.

Human T Lymphotropic Viruses (1- 4)

Isolation of HTLV-1 1980, USA

Description of ATL

1973-1977, Japan

Epidémiologie et Physiopathologie des Virus Oncogènes

ATL cells TSP/HAM patients

Infective dermatitis patients

Biopsy of a sIBM

Diseases associated with HTLV-1infection

Gessain et al., lancet1985

Epidémiologie et Physiopathologie des Virus Oncogènes

In Japan, 1 000 000 HTLV-1 carriers.

1000 cases of ATL each year.

1000 patients die of ATL each year.

The Life Time Risk of ATL among HTLV-1 Carriers

is around 6-7% for men and 2-3% for Women in Japan

The annual incidence of ATL among adut HTLV-1 carriers

is around 1.3-0.5 / 1000 (higher in men > women)

Epidémiologie et Physiopathologie des Virus Oncogènes

Discovery of the association between HTLV-1 infection and a chronic neuro-myelopathy frequent in tropical areas, especially the Caribbean

region, named Tropical Spastic Paraparesis.

Ici photo du papier

Epidémiologie et Physiopathologie des Virus Oncogènes

Blood transfusion is a major risk factor for TSP/HAM development Strong Epidemiological Data Several Case Reports with Molecular

Evidence Linking Donor and Recipient

A) In a case-control study in Japan, more patients with TSP/HAM reported

a history of blood transfusion (20%) than did controls (healthy general

population (3%), hospitalized neurological patients (5%)).

B) In the first two years of screening blood donors for

HTLV-1 in Japan, the number of reported cases of

TSP/HAM has decreased of 16%.

Epidémiologie et Physiopathologie des Virus Oncogènes

Mother - Child Prolonged breast feeding

Neurological risk TSP/HAM

Short incubation 3 months - 3 years

Sexual contacts Male Female

Infected blood cells Male Female

- Transfusion (cellular products) - IVDU

Long incubation 20 - 50 years

ATL Hematological risk ?

++

++

?

In most of the high endemic areas, HTLV-1 is mainly disseminated and maintained in the human population through intra-familial transmission

(mother-to-child and by sexual intercourses). More rarely, transmission may also occur by transfusion or Intra-venous drug use.

?

Epidémiologie et Physiopathologie des Virus Oncogènes

What are the different modes of transmission of HTLV-1 and what is their relative importance in the populations of infected persons?

1) Sexual transmission mainly from male to women. Most probably responsible for the great majority of infected persons in endemic regions and for the increase in seroprevalence with age among women.

2) Mother-to-child transmission mainly linked to prolonged breastfeeding >6 months. Responsible for a small proportion of HTLV-1 infected persons.

3) Transmission via contaminated blood products (cell-associated virus) during transfusion, in IDUs, when using infected syringes or non-sterile ustensils. Rare, but present in endemic regions and disappearing in regions where blood donors are screened (Japan, USA, Brazil, Europe,..)

4) Transmission during organ transplantation. Rare

5) Transmission in a religious/ritual context as self flagellation/scarification. Rare

6) Zoonotic transmission mainly through severe bites by a STLV-1 infected monkeys or apes among hunters in Central Africa. Rare

Epidémiologie et Physiopathologie des Virus Oncogènes

What is the current real geographical distribution of HTLV-1 and

how many individuals are infected worldwide ? This is difficult to estimate due to the following factors:

1) Several large and highly populated regions/areas have not been investigated for HTLV-1as India/China and North and East Africa.

2) Results of HTLV-1 screening serology should be tested by a specific confirmatory test as WB, Innolia and/or PCR.

3) Most of the studies concern blood donors and pregnant women. Very few large population-based study.

4) HTLV-1 distribution is not homogenous. Mainly present as small foci or clusters of high or very prevalence with nearby quite low endemic area.

Epidémiologie et Physiopathologie des Virus Oncogènes

The origin of this puzzling geographical or often ethnic distribution, associated with

high prevalence is not well explained, but is most likely linked to a founder

effect in certain groups, with the persistence of a high viral

transmission rate

The major modes of transmission coud be different among the

populations with the highest prevalences : Central African

Pygmies, Indigenous Australians, Inhabitants of South Japan,

Mashhad (Iran), Haut-Ogoué (Gabon) and villages in DRC,....

Epidémiologie et Physiopathologie des Virus Oncogènes

Indigenous Australians have one of the

highest HTLV-1prevalence in the world

Such high prevalences have been already

reported in some very high endemic areas

Villagers

from South Japan

Noir-Marron

(population of African Origin)

in French Guyana,

South America

Epidémiologie et Physiopathologie des Virus Oncogènes

Minimum estimate of 5-10 million HTLV-1 infected carriers based on available data for 1.5 billion people from known endemic areas

The actual number is probably much higher

Gessain and Cassar: Frontiers in Microbiology, 2012

World distribution

major HTLV-1 endemic

foci

Prevalence can reach >>20/30% in adults > 50 years

Epidémiologie et Physiopathologie des Virus Oncogènes

Map of geographical distribution of HTLV-1 (a–g) genotypes and main modes of viral dissemination through movements of infected populations

Afonso, Cassar, Gessain. Retrovirology, 2019

Low genetic

variability

with 7 different

HTLV-1 main

genotypes

(a-g) with

specific

geographical

distribution.

Epidémiologie et Physiopathologie des Virus Oncogènes

2) STLV-1 infection is widespread in

Old World monkey and ape species

(chimpanzee, gorilla, mandrill, AGM,

macaques, Orang-utan,….).

1) Some of the infected monkeys

develop a typical ATL with clonal

integration of STLV-1 provirus in the

tumor cells.

PTLV = Primate T-lymphotropic viruses If found in Human = HTLV

If found in NHP = STLV

HTLVs originate from STLVs found in Apes and Monkeys through interspecies

transmission especially by severe bites in central Africa

3) The simian origin for

most HTLV-1 genotypes is

known except for the most

frequent one HTLV1a

cosmopolitan genotype.

Epidémiologie et Physiopathologie des Virus Oncogènes

In 2012, the EU Commission requested ECDC to construct a map indicating all the HTLV-1 high prevalence areas in the world. EPVO unit, thanks to its expertise, was asked to respond to a request for offer entitled : “ Systematic Review of Scientific Evidence on the Prevalence of HTLV-1 Infection” By analysing more than 1000 papers and hundreds of abstracts,

we provided the first complete epidemiological data (maps and tables) for the 203 world’s countries.

Epidémiologie et Physiopathologie des Virus Oncogènes

Europe (UK, France, Spain,..) Individuals originating from high HTLV-1 endemic

areas (Caribbean area, South America and Africa,..), except Romania.

Epidémiologie et Physiopathologie des Virus Oncogènes

 In Europe, HTLV-1 is rare, except in people who have immigrated from

countries where HTLV-1 is highly endemic, such as The UK, France and Spain,

mainly from The West Indies, sub-Saharan Africa and South America. The only

“true” endemic region for HTLV-1 in Europe is Romania even if the exact risk

factors associated with this high seroprevalence are unknown

 Indeed, the Seroprevalence in FTBD is around 10 times

higher than in France and The UK (Laperche S. et al.,

Vox sang, 2009) and around 20 times Higher than in

Spain (Piron M. et al., Viruses, 2022)

HTLV-1 Technical report, ECDC, 2012

Epidémiologie et Physiopathologie des Virus Oncogènes

HTLV-1 Epidemiological and Clinical studies in Romania Indeed, “ancient” seroepidemiological studies have reported the presence of HTLV-1 in Romanian

individuals

Several sporadic case report and ATL case-series have also been described

1994

1996 1997

2005 2019 2020

Epidémiologie et Physiopathologie des Virus Oncogènes

HTLV-1 Genetic studies in Romania Characterization of partial genomic sequences derived from Romanian HTLV-1 isolates

Limited number of sequences and genetic information

19971991

Study of 8 Romanian patients with ATL : Clinico-epidemiological data

Collaborative study mainly with the hematology department of the Necker Hospital in Paris (O. Hermine, A. Marçais and E-M. Deruelle) and hematological colleagues in Romania

Epidémiologie et Physiopathologie des Virus Oncogènes

HTLV-1 Genetic study: Material and Methods DNA extraction from PBBCs and PCR amplification of 4 genomic

fragments (F1-F4) with 4 different primers sets

High fidelity Hot start Phire DNA polymerase

F1

F2

F3

F4

The complete proviral sequence was obtained by direct

sequencing using 16 pairs of overlapping primers

Epidémiologie et Physiopathologie des Virus Oncogènes

HTLV-1 Genetic study: Phylogenetic analyses (full genome)

• Comparison of an 8,160-bp fragment of the complete HTLV-1 genome, obtained from the 8 Romanian individuals and 47 reference strains, shows that the

proviral Romanian strains are very close to each other with nucleotide identity ranges from 99.8% to 100% (0-18 different bases)

• Phylogenetic analysis clearly indicates that the 8 new

Romanian HTLV-1 strains belong to the Cosmopolitan HTLV-1-a genotype and the Transcontinental subgroup (a-TC)

• If we considered the clades defined and named according to LTR analyses (Vicente AC. et al., PLOS NTD, 2011 and Afonso

PV. et al., Retrovirology, 2029), these strains are included in a

specific « Romania » clade, strongly phylogenetically

supported, and within the TC-Southern Africa subgroup

HTLV-1c Australo- Melanesia (outgroup)

ML 8,160-bp

Bootstrap, 1000

Epidémiologie et Physiopathologie des Virus Oncogènes

•LTR sequences analysis, including 70 reference strains (without South American ones), confirm that the new HTLV-1 Romanian strains belong to the HTLV-1-a TC subgroup and are different from strains found Japan and Middle-

East. They are close to the only strain already characterized in a Romanian individual (RKI2) and close to strains from Southern Africa and especially Mozambique and South Africa

Epidémiologie et Physiopathologie des Virus Oncogènes

Deciphering the origin of HTLV-1 in Romania requires a

multidisciplinary approach involving in depth epidemiological study, associated with genetic

and historical research.

Difficult because retrospective study, on facts that are already

old, asssociated with public health decisions taken at least more

than 40 years ago (ATL).

It is esential to pursue surveillance and research efforts to limit

the spread of this oncogenic retrovirus in Romania.

Epidémiologie et Physiopathologie des Virus Oncogènes

HTLV-1 in Spain

Epidémiologie et Physiopathologie des Virus Oncogènes

>106 >5.105 >105

>5.105 >104 >103

Asia & Australo-Melanesia

For nearly 3 billion persons (China, India,…), no

reliable epidemiological data, despite the

presence of small series or sporadic cases of

ATLL and TSP/HAM and studies in blood donors

(China +)

Epidémiologie et Physiopathologie des Virus Oncogènes

Solid organ transplantation and HTLV-1

Epidémiologie et Physiopathologie des Virus Oncogènes

What is the situation of HTLV-1 in Africa?

‘high prevalence’ – a prevalence over 1% in the general adult population or prevalence of over 1/10 000 among first-time blood donors;

‘low prevalence’ – a prevalence below 1% in the general adult population or prevalence of below 1/10 000 among first-time blood donors.

Report commissioned in 2014 by the ECDC, coordinated by Dragoslav Domanović and produced by Antoine Gessain and Olivier

Cassar ( EPVO Unit, Institut Pasteur)

Remains poorly known

- WHO HTLV-1 Technical Report, 2020

- Legrand et al. Clin. Microbio. Review, 2022

Epidémiologie et Physiopathologie des Virus Oncogènes

HTLV-1 prevalence in pregnant women

HTLV-1 prevalence in blood donors HTLV-1 prevalence in adult population

Epidémiologie et Physiopathologie des Virus Oncogènes

Very probably the largest HTLV-1 endemic area in the world (>2.5-5.5 millions)

No reliable estimation for the highly populated areas of North and East Africa.

Need large epidemiological surveys in Nigeria, DRC,

East and North Africa (> half of African population)

>106 >5.105 >105

>5.105 >104 >103

Epidémiologie et Physiopathologie des Virus Oncogènes

General distribution of ATL and HAM/TSP cases reported on the African continent and in certain Indian Ocean islands

360 cases of HAM/TSP/40 years

160 cases of ATL/40 years

Huge under-reporting (factor >100)

Very few studies have been carried out in

situ, by local MDs and ATLL has been

described only very rarely in

Africa (< 80 cases). Estimates range from at least 500 to 2,500

cases/year

Local situation on the clinico-

/epidemiological aspects of ATL and ID

and, to a lesser extent, HAM/TSP remains

virtually unknown in most parts of Africa.

Epidémiologie et Physiopathologie des Virus Oncogènes

Distribution of the HTLV-1 Genotypes across the African Continent

Afonso, Cassar, Gessain. Retrovirology, 2019

HLTV-1-a Cosmopolitan genotype with five clades a-WA, a-Sen, a-Na, a-TC and a G-Rec

In central Africa different genotypes (b, d, e, f, g) with b predominant

Epidémiologie et Physiopathologie des Virus Oncogènes

What are the predominant modes of HTLV-1 acquisition in Central Africa?

The relative contribution of each of the different HTLV-1/STLV-1

transmission routes (between the different inter-humans modes and inter-humans vs

inter-species/NHP-Humans) remains unknown

In Central Africa, there are at least six different modes of acquisition/transmission:

Mother-to-child Sexual Transfusion Scarification Contact with fluids from NHPs

These data are crucial for public health actions

aimed to reduce the incidence of HTLV-1 infection

Use of unsterile syringes,…

Epidémiologie et Physiopathologie des Virus Oncogènes

First study in Cameroon on the origin and interspecies transmission of

different retroviruses from NHPs living in the wild

More than 5000 plasmas and buffy-coats of adults (mean age 50 years) were tested in a

retrospective study in general rural population including Pygmees or Bantus living close to

NHPs habitats and in a prospective study focused on more than 300 individuals who

reported direct contacts (bites, wounds,..) with animals, especially NHPs, mainly

during hunting activities.

Epidémiologie et Physiopathologie des Virus Oncogènes

Simian Foamy VirusesSTLV-4/HTLV-4STLV-3/HTLV-3

STLV-1/HTLV-1

HTLV-1 infection was associated to the severity of the bite

Epidémiologie et Physiopathologie des Virus Oncogènes

Blood Donors Survey in Libreville, Gabon

Overall prevalence of 0,74

% (23/3123),1% in FTBD

and 0,5 % in repeat

donors

Age and sex-adjusted

prevalence was five

fold lower in FTBD

that in the general

adult population of

rural areas

Epidémiologie et Physiopathologie des Virus Oncogènes

Screening tests +/- confirmation assays ? Depends on the country

The more there are, the less we test the fewer there are, the more we test

Epidémiologie et Physiopathologie des Virus Oncogènes

Large Rural Population-based Survey In South Cameroon

Overall prevalence of 1.1 % in

adult rural population (36/3400) with a distribution

heterogenous in the area.

Factors independently

associated with HTLV-1 were

Pygmy ethnicity, history of

surgery and a NHP bite.

All detected strains belong to

HTLV-1 b genotype but were

highly diverse

A new large ongoing study is ongoing in blood

donnors from Cameroon

Epidémiologie et Physiopathologie des Virus Oncogènes

Take-Home Messages 1) The actual geographical distribution of HTLV-1 and the number of HTLV-1 infected individuals remain largely unknown: large-scale epidemiological surveys are needed in North and East Africa, as well as in Asia (India, China, etc.).

2) Modes of transmission are well known: Sexual transmission mainly from male to women (IST WHO), Mother-to-child transmission mainly linked to prolonged breastfeeding, Contaminated blood products (cell-associated virus), during organ transplantation, in a religious/ritual context, Zoonotic transmission.

3) In Africa, the largest HTLV-1 endemic area, there is a diversity of transmission routes that vary from region to region, but their relative contribution remains unknown and there are no public health measures implemented to reduce the transmission and dissemination of this oncogenic retrovirus.

Epidémiologie et Physiopathologie des Virus Oncogènes

Acknowledgments

Institut Pasteur

Buseyne F

Filippone C

Afonso P V

Tortevoye P

Cassar O

Gessain A

IRD/MNHN, Orléans/Paris Alain Froment

Université Médicale

du Cameroun Yaoundé

Edouard Betsem

Field mission, South Cameroon, Pygmy Settlement Epidémiologie des maladies émergentes Arnaud Fontanet

CIRMF, Franceville,Gabon Augustin Mouinga Ondeme

CPC yaoundé, Richard Njouom

Djuicy D Ramassamy JL

Screening of donors for HTLV-1 Sharing of experience- testing of donors in Spain

Beatriz Mahillo [email protected]

SOHO-NET ORGANS MEETING

Stockholm 18-19 June 2024

RISKS ATTRIBUTABLE TO INCIDENTS DURING THE DONATION AND TRANSPLANTATION PROCESS

RISKS INHERENT TO TRANSFER OF BIOLOGICAL MATERIAL BETWEEN INDIVIDUALS

(never risk 0)

RISKS ARE OFTEN SHARED BY DIFFERENT TEAMS PHYSICALLY LOCATED DISTANT FROM

EACH OTHER

RISKS FREQUENTLY ASSUMED

IDENTIFICATION EVALUATION/

SELECTION PROCUREMENT

PRESERVATION/ TRANSPORT

TRANSPLANT

Organ Transplantation risks

Coordination

LIMITATIONS OF DONOR HISTORY (MEDICAL, SOCIAL AND BEHAVIOURAL DATA)

DONOR HISTORY FROM RELATIVES

Preventable Errors in Organ Transplantation: An Emerging Patient Safety Issue Ison et al. Am J Transplant. 2012

The risk of disease transmission from donors is known since the early days of clinical transplantation

Cancer Infections

Disease transmission through organ transplantation

 RecipientImpact

 Transplant / Health system

 Transplant / Medical team

Survival and Quality of life

Second victims

Credibility, trust, safety

Learning opportunity

Transmission: GETTING THE RIGHT BALANCE

MINIMIZE THE RISK OF DONOR-

TRANSMITTED DISEASES

AVOID THE UNNECESARY

LOSS OF ORGANS SUITABLE FOR

TRANSPLANTATION

DONOR CHARACTERIZATION AND EVALUATION: A MULTIDISCIPLINARY PROCESS

PREVENTION AND

PROACTIVE STRATEGIES QUALITY AND SAFETY

Recommendations for HTLV screening in organ donors:

Screening indicated in: a) donors from or who have lived in endemic areas of HTLV 1 infection; b) donors who are children of mothers born or residing in endemic area; c) Donors whose partners have resided in endemic areas.

Consensus Document on the Selection Criteria of Donors of Solid Organs in relation to Infectious Diseases . First Edition 2004

2004-2019

In this period 3 cases of organ donors with HTLV-I transmission to patients transplanted

First case of HTLV-I transmission from organ donor in Spain

2003

Donor: young man born in Spain, Road accident. Donor after brain death.

Mother born in Venezuela. Retrospectively, it was found that, although she remained asymptomatic, she was seropositive for HTLV-I.

Once the first case was detected, a serological determination for HTLV-I (ELISA and western blot) was performed on stored blood from the donor. Those determinations resulted positive.

The liver, both kidneys, the heart, and both corneas were used for transplantation. Liver and kidney recipients: myelopathy and paraplegia (18-24 months postx).

Heart transplantation, no information reported. Patients who received the cornea: HTLV-I negative.

Second case of HTLV-I transmission from organ donor in Spain

Donor: Woman born in Bolivia. Donor after uncontrolled circulatory death.

Bolivia was not in the list of countries with HTLV test at that moment.

Only one kidney was transplanted, patient developed spastic paraparesis 24 months after transplant

2005

Third case of HTLV-I transmission from organ donor in Spain

2015

Donor: 38 year old man, born in Spain. Donation after controlled circulatory death.

Corneas were also retrieved – HTLV screening at tissue bank 24 h after organs procurement (positive).

Epidemiological risk factors: Sexual partner from endemic country (non detected during the organ donation process).

Both kidneys transplanted

- First patient: TSP/HAM within 1 year in one recipient, despite antiretroviral prophylaxis attempted within the first weeks.

- Second patient: seroconverted for HTLV-1 but the kidney had to be removed soon due to rejection. Immunosuppression was stopped and the patient remains in dialysis but otherwise asymptomatic.

• Global spread of HTLV

• Asymptomatic carriers

• No vaccine or antivirals

• Limitations of donor history (medical, social and behavioural data), donor history from relatives. short period of time to evaluate deceased donors.

• Poor prognosis in patients transplanted (Immunosupression)

• Available tests for screening (Enzime immunoassay .EIA-, indirect imunofluorencence –IIF-, others, Western blot for confirmatory tests)

Considering…

- National Transplant Committee approval 17 Regions (competent authorities) 185 hospital authorized for organ procurement 45 hospitals authorized for organ tx

- Period (6 months) to implement the HTLV test in hospitals

Number of false positive tests???

2302

1777 1905

2196 2346

49

37.4 40.2

46.3 48.9

0 5 10 15 20 25 30 35 40 45 50

0

500

1000

1500

2000

2500

2019 2020 2021 2022 2023

N Rate (PMP)N pmp

2019 (July) 2020 2021 2022 2023 HTLV I-II + 3 (1/1000) 1 (0.6/1000) 8 (4/1000) 3 (1/1000) 6 (2.5/1000)

Number of potential organ donors contraindicated due to HTLV I-II

Conclusion

EXPERIENCE OF HTLV-1 IN ROMANIA AND THE STRATEGIES FOR TESTING DONORS FOR HTLV-1.

Dr. Guenady Roumenov Vatachki

Executive Director

National Transplant Agency

Stockholm at the ECDC SoHO-Net Organs meeting.

The threat of viral disease in transplantation

 Opportunistic infections cause considerable morbidity and mortality in transplant recipients

 Common viral threats  CMV  HHV-6, HHV-7, HSV-1, HSV-2, EBV, and VZV  These viruses may have direct or indirect effects, or may interact with each

other or other viruses

 Emerging viral threats  SARS and West Nile Virus  Community acquired respiratory viruses

 Respiratory Syncytial Virus (RSV), Influenza virus, Avian influenza (H5N1),  Rhinovirus, Enterovirus, Adenovirus, Coronavirus,

Legislation – mandatory testing

┌────────────────────┬─────────────── │ HIV 1 şi 2 │ antibodies anti-HIV-1,2 │ ├────────────────────┼─────────────── │ Hepatita B │ antigen Hbs │ │ │ antibodies Anti HBc │ ├────────────────────┼─────────────── │ Hepatita C │ antibodies anti-HCV │ └────────────────────┴───────────────

Legislation

 HTLV-I antibody testing should be performed in the case of donors who live or come from areas with high prevalence or who have sexual partners from those areas or when the parents of the donors come from those areas.

 Additional testing may be required in certain circumstances, depending on the donor's travel and the characteristics of the donated organ, tissues or cells (eg: malaria, CMV, T. cruzi)

 For donations, blood samples must be obtained at the time of each donation.

Prevalence

 In Romania, the HTLV-1 prevalence has been reported to be 5.3/10,000 among first-time blood donors, and 3-25% in poly-transfused patients.

 In non-endemic areas, due to the migration of people and the sexual transmission of the virus, HTLV-1 and 2 have also been detected.

In practice- solid organs donor testing Hystocompatibility

 HLA A low-resolution

 HLA B low-resolution

 HLA C low-resolution

 HLA DRB1 low-resolution

 HLA DQA1 low-resolution

 HLA DQB1 low-resolution

 HLA DPA1 low-resolution

 HLA DPB1 low-resolution

Immunological risk assessment: Crossmatch Luminex

In practice- solid organ donor testing viral screening

 AgHBs

 AgHBe

 Anti-HBe

 Anti-HBc

 Anti-HBs

 Anti-HCV

 CMV IgG

 CMV IgM

 EBV IgG

 EBV IgM

 HAV IgG

 HAV IgM

 HIV

 HTLV 1/2

 Syphilis

 Toxoplasma IgG

 Toxoplasma IgM

 Screening SARS-CoV-2 RT- PCR (GeneXpert)

In practice- solid organ donor testing tumoral screening

 AFP

 CEA

 CA 19-9

 CA 125

 CA 15-3

 PSA Total

 PSA Free

Renal recipient testing histocompatibility/ ambiguity solving

 HLA A low-resolution

 HLA B low-resolution

 HLA C low-resolution

 HLA DRB1 low-resolution

 HLA DQA1 low-resolution

 HLA DQB1 low-resolution

 HLA DPA1 low-resolution

 HLA DPB1 low-resolution

• HLA A high-resolution • HLA B high-resolution • HLA C high-resolution • HLA DRB1 high-resolution • HLA DQA1 high-resolution • HLA DQB1 high-resolution • HLA DPA1 high-resolution • HLA DPB1 high-resolution

 Anticorpi anti HLA clasa I si clasa II

 Single antigen clasa I (identificare clasa 1)

 Single antigen clasa II (identificare clasa 2)

 C1q clasa I

 C1q clasa II

 Crossmatch Luminex

 Autocrossmatch

Renal recipient testing Immunological risk assessment

 AgHBs

 AgHBe

 Anti-HBe

 Anti-HBc

 Anti-HBs

 Anti-HCV

 CMV IgG

 CMV IgM

 EBV IgG

 EBV IgM

 HAV IgG

 HAV IgM

 HIV

 HTLV 1/2

 Sifilis

 Toxoplasma IgG

 Toxoplasma IgM

 Screening SARS-CoV-2 prin RT-PCR (GeneXpert)

Renal recipient testing viral screening

Renal recipient testing tumoral screening

 AFP

 CEA

 CA 19-9

 CA 125

 CA 15-3

 PSA Total

 PSA Free

Post transplant testing renal transplant

 Antibodies anti HLA clasa I si clasa II

 Single antigen clasa I (identification clasa 1)

 Single antigen clasa II (identification clasa 2)

 ADN CMV - Real Time PCR

 ADN EBV - Real Time PCR

 ADN VHB - Real Time PCR

 ARN HDV - Real Time PCR

 ARN VHC - Real Time PCR

 ADN BKV - Real Time PCR

 ADN Parvovirus B19 - Real Time PCR

 *** if receptors cu AgHBs present- ADN VHB - Real Time PCR

 *** If receptors HCV present ARN VHC - Real Time PCR

Monitoring the immunosuppression post renal transplant

 Ciclosporina C0 si C2

 Tacrolimus

 Sirolimus

Tumoral Screening

 AFP

 CEA

 CA 19-9

 CA 125

 CA 15-3

 PSA Total

 PSA Free

Summary

 Viral infections cause considerable morbidity and mortality in transplant recipients

 Viral threats exist  HHV-6, HHV-7, HSV, VZV, EBV, polyomaviruses, RSV, influenza, WNV

 viral threat still the most significant pathogen in SOT recipients  Direct and indirect effects  Subclinical viral replication  Interaction with other viruses

 HTLV testing is common in SOT in Romania because we are endemic area.

Conclusions policies regarding HTLV

 all Blood donor screening ;

 Preventing the mother-to-child transmission of HTLV-1 by screening pregnant women from endemic areas,

 all SOD screening

 for assisted reproduction technologies HTLV-I antibody testing should be performed in the case of donors who live or come from areas with high prevalence or with sexual partners from those areas or when the parents of the donors come from those areas

 There are no other HTLV-1-related health policies in Romania

 No consistent screening for children born from positive mothers.

THANKS FOR YOUR ATTENTION

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And to finish…

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Session 6 Conclusion of day 1 18 June

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Session 7 Biovigilance and reporting of serious adverse reactions and events 19 June

164

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Session overview

1. Issues in reporting serious adverse reactions and events for Organs – Paul Hendrick, Organ Donation Transplant Ireland, HSE, Ireland

2. Biovigilance guideline repository – Francois-Xavier Lamy, ECDC 3. SARE reporting – communicable diseases transmission cases – Ana

Paula Barreiros, NFP, Germany 4. Discussion – All 5. Strongyloides stercoralis transmission through organs – case report –

Sophie Lucas Samuel, NFP, France and Morten Hagness, Oslo University Hospital, Norway

6. Questions and answers – All

165

166

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Biovigilance Implementation The Irish Experience

166

Paul Hendrick, Director of Quality ODTI

167

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Regulatory Landscape

EU Directive • Commission Directive 2010/53/EC

Irish Law • S.I. No: 325 of 2012

ODTI Policy • Quality & Safety Framework (2014)

168

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Regulatory Landscape National Competent Authority - Joint

Delegated from the SI by the Department of Health

 Non Clinical – Health Products Regulatory Authority (HPRA) (Regulator for Medical Devices, Medicines, Blood and Tissue – including vigilance on all)

 Clinical – Organ Donation Transplant Ireland

169

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Operational Landscape – Transplantation in Ireland

Pre Procurement

• 6 CLOD Regional

• 6 ODNM Regional

• Covering 26 x ICU

• Regulatory Gap

Procurement

• NOPS • Centralised • 10 Donor

Coordinators • Licensed to SI

/ EU Directive

Transplantation

• Heart / Lung Tx Centre

• Liver / Pancreas Tx Centre

• Kidney Tx Centre

• Licensed to SI / EU Directive

170

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Organisation Development

Year Milestone Event Biovigilance System in Place

2012 Established ODTI - Clinic Lead Appointed / Function

Established in Health System with clerical support / NODTAG

Manual SARE Reports reviewed with relevant

NODTAG– all manual 2012 - 2014

Establish & Licensed Transplant Centre QMS – mandated

SARE reporting

2014 Quality & Safety Framework Policy Developed and Adapted

2015 Establish & Licensed NOPS QMS - SARE reporting Manual SARE Reports reviewed with relevant

NODTAG– all manual – basic Excel Sheet with basic

reports / email communication etc. 2015 - 2022 Development of NOPS / Transplant QMS & Services / Covid

2022 – To Date Established dedicated ODTI Quality Biovigilance Function Biovigilance Road Map Next

171

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Reporting to Date

 169 Reports (2012 – now – 07 June 2024 latest report)

 163 Clinical (>96%) / 6 Non Clinical

 SAE – 147 / SAR – 20 / Incorrect reports 2

 Reporting level is satisfactory

 Reporting of Issues which are technically outside the definition

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Bio Vigilance Roadmap

Process

• Biovigilance Process (aligned to EDQM – Quality & Safety)

• Associated Continuous Improvement Process

Organisation

• ODTI person with responsibility for Biovigilance

• Clinical Governance – Independent Sub Committee

• Continuous Improvement Implementation Group

• ODTI membership on VES Group / Liaison with NCA

Systems

• Electronic Reporting System & Database

• Rapid Alert utilising NOPS Donor System

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Agreed SARE Process

 Reviewed and Agreed with HPRA – Joint Competent Authority

 Endorsed and Agreed with NODTAG

 Process Proceduralised within ODTI

ODTI SARE Management Process

SARE Report Recieved

SARE Logged in paper and electronic file

Receipt of SARE Acknowledged and Communicated

SARE RCA Review with the relevant Stakeholders

Identification of Relevant Stakeholders

Review of identified / proposed continuous improvement action plan

SARE Case File reviewed by NODTAG / NODTAG Delegate Group

Assessment for remit for ODTI/HPRA Responsibil ity

Action Plan revised if required

Action Plan and timeline Communicated and Agreed with the relevant stakeholders

Action Plan Implemented by Stakeholder Group and progress report to ODTI

NODTAG / NODTAG Delegate Group review

progress report at standing meetings

SARE Close Out Report Complete

SARE Close Out Report Approved and SARE Log Updated

Annual SARE Review and generation of Annual Report

Process End

Communication of close out to Stakeholders / HPRA

ODTI

Reporter

Cross Functional Group

Identified Action Plan Delivery Group

NODTAG / NODTAG Delegate Group

Responsibility Legend

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SAR/E Working Group

ODTI SARE Working Group

(Chair ODTI Quality)

ODTI Quality / Biovigilance

Intensive Care

Immunological Representative

Virology Representative

Microbiological Representative

Transplant Centre

Representative Mr. Ian Robertson (BMT)

Prof. Mary Keoghan

Dr. Daniel Hare

Dr. Sinead McDermott

Dr. Audrey Dillion (SVUH)

Dr. Michelle Murray (MMUH)

Claire Dalton

Dr. Catherine Motherway

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SARE Working Group

 To provide the clinical oversight and direction for the :  Review Report Classification

 Review of investigation report

 Management of the SARE

 Continuous improvement actions

 Recommendations for further corrective actions / learning

 Contribute BV Section to ODTI Annual Report

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 To provide the clinical oversight and support for ODTI participation in VES and others/relevant groups:

 Report Review for Irish Annual Submission *on behalf of ODTI or in conjunction with HPRA

 Review of European wide report(s)/working groups to identify continuous improvement initiatives for Ireland

SARE Working Group

177

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Operational Landscape Electronic Systems Introduction

iTransplant Donor System (Live 2023)

iTransplant Recipient System (Live Q4 2024)

178

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Biovigilance Systems Challenge # 1 Rapid Alert Notification / Tracking

 Predominantly Retrospective Information

 No Quarantine

 No Recall

 Normally Transplanted

 Immediate Patient Action Required by the Transplant Physicians

 Current Process Phone Call / Email from Procurement Service

179

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Continuous Improvement Initiative

Rapid Alert Notification

• Trigger Retrospective Information Event on Procurement Service – Donor System (EOS)

• Automatic simultaneous update to all relevant Transplant Centres immediate attention (on Recipient System)

• eMail • Text • Call

180

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Biovigilance Systems Challenge # 2 Reporting System

 Paper Form – Scanned and eMail

 Basic Excel Log

 No Case Management System

181

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Continuous Improvement Initiative # 2

Case Reporting

• Accessible • User Friendly

Case Management

• Report Management • Investigation

Management • Communication • Root Cause Analysis • Risk Determination

Continuous Improvement Plan

• Define • Measure • Analyse • Improve • Control

182

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Continuous Improvement Initiative # 2

Case Reporting

• Accessible • User Friendly

Case Management

• Report Management • Investigation

Management • Communication • Root Cause Analysis • Risk Determination

Continuous Improvement Plan

• Define • Measure • Analyse • Improve • Control

183

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Thank You

184

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Questions ?

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SARE reporting – communicable diseases transmission cases Ass. Prof. Ana Paula Barreiros, MD

Deutsche Stiftung Organtransplantation (DSO), OPO Germany

Stockholm/Sweden, 19.06.2024

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1. Definition of SAE /SAR and legal principles of SAE / SAR reporting

2. Donor-Derived infections (DDI) in Germany 2016-2023

3. Results of the survey and pilot data collection EU Organ SAE/R reporting

4. Case report

5. Conclusion

186

Agenda Reporting of SAE / SAR in Germany

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1. Definition of SAE /SAR and legal principles of SAE / SAR reporting

2. Donor-Derived infections (DDI) in Germany 2016-2023

3. Results of the survey and pilot data collection EU Organ SAE/R reporting

4. Case report

5. Conclusion

187

Agenda Reporting of SAE / SAR in Germany

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Reporting of SAE / SAR in Germany

2010/53/EU 2012/25/EU

188

EU Directives 2010/53/EU and 2012/25/EU

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189

Serious Adverse Event (SAE) „… any undesired and unexpected occurrence associated with any stage of the chain from donation to transplantation that might lead to the transmission of communicable disease, to death or life-threatening, disabling or incapacitating conditions.”

Reporting of SAE / SAR in Germany Definition of SAE and SAR according to EU Directive 2010/53/EU/Efretos project

SAR = serious adverse reaction (SAR) „ … an unintended response, including a communicable disease, … in the recipient that might be associated with any stage of the chain from donation to transplantation that is fatal, life-threatening, disabling, incapacitating, or which results in, or prolongs, hospitalization or morbidity.”

Possible harm Actual harm

Donor Recipient

Böhler K, Barreiros AP, Rahmel A |

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Reporting of SAE / SAR in Germany

§ 11 Zusammenarbeit bei der Entnahme von Organen und Geweben, Koordinierungsstelle … (1a) Die Koordinierungsstelle hat die Zusammenarbeit zur Organentnahme bei verstorbenen Spendern und die Durchführung aller bis zur Übertragung erforderlichen Maßnahmen mit Ausnahme der Vermittlung von Organen durch die Vermittlungsstelle nach § 12 unter Beachtung der Richtlinien nach § 16 zu organisieren. … Hierzu erstellt die Koordinierungsstelle geeignete Verfahrensanweisungen unter Beachtung der Richtlinien nach §16, insbesondere … 9. zur Sicherstellung der unverzüglichen Meldung schwerwiegender Zwischenfälle und schwerwiegender unerwünschter Reaktionen und der in diesem Zusammenhang getroffenen Maßnahmen auf der Grundlage der Rechtsverordnung nach § 13 Absatz 4.

Important: The German organ procurement organisation (DSO) is the delegated body assigned by the national authority ( Federal ministry of health )

Responsible for tisssue donation – Paul-Ehrlich-Institut (PEI) Responsible for living donation – Transplantation center

190

Legal foundation: German Transplantation Law (TPG)

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191

Reporting of SAE / SAR in Germany Procedural Instructions and Notification Form

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192

Reporting of SAE / SAR in Germany 7 regions, each with 1-2 medical colleagues working in the SAE / SAR team 24/7

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Reporting of SAE / SAR in Germany Team and Contact SAE / SAR 2024

SAE/SAR – Contact us 24/7

Telefon 0800 – 376 7273 0800 – DSO SARE

Email [email protected]

Fax 069 – 677 328 - 89998

Ressortleitung PD Dr. Ana Paula Barreiros Stabsstelle SAE/SAR Dr. Klaus Böhler Regionale Koordinatoren

Karsten Tiede (Nord) Dr. Thorsten Doede (Nord-Ost) Dr. Monika Scholle (Ost) N.N.(NRW) Sören Melsa, Ruth Lindner (Mitte) Dr. Carl-Ludwig Fischer-Fröhlich, Kevin Otero (Ba-Wü) Susanne Schmidt (Bayern)

193

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1. Definition of SAE /SAR and legal principles of SAE / SAR reporting

2. Donor-Derived infections (DDI) in Germany 2016-2023

3. Results of the survey and pilot data collection EU Organ SAE/R reporting

4. Case report

5. Conclusion

194

Agenda Reporting of SAE / SAR in Germany

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195

Reporting of SAE / SAR in Germany 2023 Publication of six years German SAE / SAR data

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• The reports from 01/2016 to 12/2022 were analysed by the SAE / SAR team

of the DSO

• 21.060 organs were transplanted from 8.519 donors

• 543 SAE/ SAR reports have been received by the DSO

• 53 SAE / SAR report with probable / proven transmission of a disease from

the donor to one (or more) recipients

196Böhler K, Barreiros AP, Rahmel A

Reporting of SAE / SAR in Germany Six year German SAE / SAR data 2016-2022

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197

Reporting 2016-22: Categorization of cases with p/p transmission

12, 23%

10, 19%

7, 13%1, 2%

7, 13%

16, 30%

N=53

Bacteria Fungi Virus Parasite Other diseases Malignancy

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198

Reports with suspected Donor-derived infections (DDI) in Germany 2016-2023

All SAE SAR reports N=612

Reports suspicion/risk of donor- derived infection

n=377

Other Reports (Malignancy, Genetic, Other diseases)

N=235

SAE N=295

SAR N=82

Total donors realized N= 9771

AP Barreiros, K Böhler, Rahmel A, submitted for publication

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199

SAR reports – imputability analysis DDI in Germany 2016-2023

AP Barreiros, K Böhler, Rahmel A, submitted for publication

8, 10%

33, 40%

10, 12%

23, 28%

5, 6% 3, 4%

N=82

Proven

Probable

Possible

Unlikely

Excluded

Not assessable

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200

Categories of DDI in Germany 2016-2023 All pathogens – Type of pathogenes

• P/P: proven/probable Barreiros AP, Böhler K, Rahmel A, submitted for publication

All Reports P/P*

donors

Recipients

from P/P

donors

Recipients with

P/P

transmission

Death from P/P

Transmission

Bacteria 182 18 65 27 (42%) 0 (0 %)

Fungus 135 14 52 16 (31%) 3 (19%)

Virus 55 8 29 14 (48%) 3 (21%)

Parasites 5 1 4 1 (25%) 1 (100%)

Total 377 41 150 58 (39%) 7 (12%)

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201

Categories of DDI in Germany 2016-2023 Bacterial pathogens

• * In 79 cases more than one pathogen ** MDR – multi drug resistant *** includes 6 organ loss (kidneys) , two due to Klebsiella , three due to Enterococcus and one due to Streptococcus. Barreiros AP, Böhler K, Rahmel A, submitted for publication

All

Cases

MDR** P/P

donors

Recipients from

P/P donors

Recipients with

P/P transmission

Death from P/P

Transmission

Staph. spp 64 20 1 3 1 0

Klebsiella spp 28 10 3 10 6 0

E.coli 25 5 4 11 5 0

Enterococcus 22 8 5 22 10 0

Pseudomonas 17 5 1 4 1 0

Mycobacteria 9 0 3 12 3 0

Other 102 27 1 3 1 0

Total 267* 75 18 65 27 0***

ECDC NORMAL

202

Categories of DDI in Germany 2016-2023 Fungal pathogenes

• *In 13 cases more than one pathogen ** 4 kidneys and one kidney/pancreas, three of the recipients died • Barreiros AP, Böhler K, Rahmel A, submitted for publication

All

Cases

P/P

donors

Recipients

from P/P

donors

Recipients

with P/P

transmission

Graft loss Death from

P/P

Transmission

Candida spp. 125 10 38 11 (29%) 6** 3

Aspergillus spp. 16 2 6 3 (50%) 0 0

Cryptococcus 2 2 8 2 (25%) 0 0

Other 5 0 0 0 0 0

Total 148* 14 52 16 (31%) 6 3 (19%)

ECDC NORMAL

203

Categories of DDI in Germany 2016-2023 Viral pathogenes

* Includes one CMV transmission (incorrectly reported CMV status of the donor) and one HHV -6 transmission to a child Barreiros AP, Böhler K, Rahmel, submitted for publication

All

Cases

P/P

donors

Recipients

from P/P

donors

Recipients with

P/P

transmission

Death from P/P

Transmission

HBV 9 1 3 1 0

HCV 7 1 5 5 0

HEV 5 2 6 2 0

BoDV-1 1 1 3 3 2

HHV-8 1 1 1 1 1

Other* 32 2 11 2 0

Total 55 8 29 14 3 (21%)

ECDC NORMAL

Total Donors recovered 9771 N(%) with risk/suspicious for DDI

295 (3,0%)

N(%) with Proven/Probable transmission

41 (0,42%)

Total recipients transplanted 27919 N(%) with Proven/Probable DDI transmission

58 (0,21%)

N(%) with deaths due to Proven/Probable transmission

7 (0,025%) 204

DDI in Germany 2016-2023: Cumulative Incidence

Barreiros AP, Böhler K, Rahmel A, submitted for publication

3 viral 3 fungal 1 parasite (Toxoplas.)

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1. Definition of SAE /SAR and legal principles of SAE / SAR reporting

2. Donor-Derived infections (DDI) in Germany 2016-2023

3. Results of the survey and pilot data collection EU Organ SAE/R reporting

4. Case report

5. Conclusion

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Agenda Reporting of SAE / SAR in Germany

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1. Definition of SAE /SAR and legal principles of SAE / SAR reporting

2. Donor-Derived infections (DDI) in Germany 2016-2023

3. Results of the survey and pilot data collection EU Organ SAE/R reporting

4. Case report

5. Conclusion

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Agenda Reporting of SAE / SAR in Germany

ECDC NORMAL

• Kidney recipient in transplant center in the South of Germany (A):

• Neurological symptoms 3.5 months post transplant

• Initially force reduction both legs, increasing until tetraplegia

• In addition progredient dysarthria, vigilance reduction, loss of cranial nerves reflexes, coma

• Nephrectomy 6 months post Tx (Histology: marginal interstitially nephritis, no hint for pathogens)

• Contact to transplant center of contralat. donor kidney (B): recipient passed away shortly before, with same symptoms and comparable course of disease

• SAR-report 6.5 months pos Tx, information all involved transplant centers immediately

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Case report

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208

Case report

• Donor, 70 years, male

• Origin: rural region in the south of Germany, married, two sons, decision pro donation lifetime

• Medical history: coronary heart disease, COPD, gout, thyreoidektomia, appendectomia

• Admission with abdominal pain unclear reason, no neurological symptoms

• Two days after admission resuscitation due to arrhythmia

• cCT: pansinusitis and signs for massive hypoxia: diagnosis of brain death

• Organ procurement with

• Transplantation of liver, both kidneys, no tissue

ECDC NORMAL

• Extensive analysis of clinical course and medical history, also social and familial history

• No further information

• Information: kidney recipient (A) passed away 7 months post Tx,

• No autopsy (denied by family)

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Case report

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• Biopsies of brains of both kidney recipients, also liquor and serum of kidney recipient A (Friedrich-Löffler-Institut, German Federal Institut for Veterinary medicine):

- Diagnostics for rabies plus Next-Generation-Sequencing NGS (metagenomdiagnostics, gensequenzing , search for foreign DNA/RNA)

• Detection of Bornavirus-Genom (Mammalian 1 Bornavirus) in high concentration in brain biopsy kidney recipient (A), confimation via realtime - PCR (Pan-Bornavirus-PCR).NGS: Genomsequencing of the whole genom. Minimaler detection in Liquor dieses of the patient. Detection Bornavirus-RNA in explanted kidney graft patienten (A) via realtime-PCR.

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Case report

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• Results confirmed via material of transplant center B: Pan-Bornavirus-PCR positiv.

• Parallel: immunhistological investigations on brain biopsies of patient B showed also Bornavirus-Antigen .

• First liquor samples, throat swap, urin and stool samples of the liver recipient initially Pan-Bornavirus-RT-PCR negativ, but then getting positive with developement of increasingly neurological symptoms (dysarthria, tremor, insecure walk )

• Exclusion of other transmission sources (ATG therapy e.g.)

• Cave: Bornavirus was not known as human pathogenic !! (only squirells, horses e.g.)

211

Case report

ECDC NORMAL

212

Publikation: New England Journal 10/2018

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1. Definition of SAE /SAR and legal principles of SAE / SAR reporting

2. Donor-Derived infections (DDI) in Germany 2016-2023

3. Results of the survey and pilot data collection EU Organ SAE/R reporting

4. Case report

5. Conclusion

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Agenda Reporting of SAE / SAR in Germany

ECDC NORMAL

• Transmission of infections, infectious diseases or infectious pathogens important and obvious risk for organ recipients.

• DDI rate in our cohort low (0,21%), comparable with other countries.

• But: Significant mortality with 12 % in recipients with transmitted infections (p/p).

• Detailed and careful analysis of SAE and SAR cases may help to develop strategies to reduce the risk of transmitting donor disease to transplant recipients.

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Reporting of SAE / SAR in Germany Conclusion

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• European pilot study:

- established vigilance system in almost all participating countries (15/27)

- low rate of serious adverse reactions

- variability in definition of serious adverse events and serious adverse reactions

- uniforme use of definition would be helpful

- stay in contact and learn from each other, especially in very rare cases

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Reporting of SAE / SAR in Germany Conclusion

ECDC NORMAL

216

www.fotolia.com/18540827/©Styf

Thank you for your attention!

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Repository of policy and practice resources – bio-vigilance SoHO-Net Organs Group meeting – 19 June 2024

217

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Aim

ECDC aims to set up a repository of policy and practice resources to facilitate and improve the sharing of such resources and expertise

This repository will cover different areas of relevance for ECDC.

218

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Methods

219

Last update: January 2023

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Repository

220

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SoHO page on the ECDC website

221 https://www.ecdc.europa.eu/en/substances-human-origin

ECDC NORMAL

Repository

222https://qap.ecdc.europa.eu/public/extensions/repository-ppr/repository-ppr.html

ECDC NORMAL

Thank you

ECDC NORMAL

Strongyloides stercoralis transmission through organs

– case reports –

Sophie Lucas Samuel, NFP, France

Morten Hagness, Oslo University Hospital, Norway

ECDC NORMAL

REMINDER ON THE STRONGYLOIDES STERCORALIS LIFE CYCLE

WHO / Strongyloides stercoralis threadworm in stool, analyze by microscope.

Duodenal nematode

Fleitas and all 2022

WHO more than 600 million people are infected worldwide

Earth contaminated

ECDC NORMAL

Anguillulosis in immunocompetent patients : Acute anguillulosis may evolve toward chronic anguillulosis if not treated

 20-50% of cases are asymptomatic;  Dissemination phase: 4 to 6 days;  Clinical signs depend on severity and degree of infestation;

 Rash at point of penetration (fleeting), transient allergic reaction;  Diarrhea associated with cutaneous manifestations (larva currens)  Blood hypereosinophilia : not systematically found (in 75% of the

chronic cases)

REMINDER ON THE STRONGYLOIDES STERCORALIS INFECTION

ECDC NORMAL

REMINDER ON THE STRONGYLOIDES STERCORALIS INFECTION Chronic anguillulosis in the immunocompromised patients: 2 forms associated with corticoids treatment, immunological disorder (notably HTLV infection) or immunosuppression

 Hyperinfectious anguillulosis :  Immune reconstitution syndrome (IRS)  Exacerbation of intestinal syndrome, absence of dissemination to other organs

 Disseminated anguillulosis : multivisceral syndrome that may evolve to maligne

anguillulosis  Multivisceral larval dissemination  Digestive involvement (intestinal malabsorption, pseudo-occlusive syndrome),  Pulmonary involvement (cough, dyspnea, wheezing and/or hemotypsis, pulmonary

infiltrate, ARDS),  Cardiac involvement possible  Secondary infection due digestive bacteria transported by larvae that migrate to tissue

level  Death 60 to 80 % if not treated

ECDC NORMAL

REMINDER ON THE STRONGYLOIDES STERCORALIS INFECTION Diagnosis

•History of living or travelling in endemic area •Clinical: diarrhea associated with cutaneous manifestations (larva currens) •Biology : hypereosinophilia (that may fluctuating in the chronic phase) •Parasitology : direct diagnosis, stool examination = Coproculture • Indirect diagnosis : serodiagnosis = ELISA, immunofluorescence

Treatment •Common and hyperinfectious anguillulosis : Ivermectin: 2 courses at 3-week intervals depending on efficacy

•Disseminated anguillulosis : usually combines antiparasitic (Ivermectin+/-albendazole) and antibiotic therapy

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Origins of the infection to the recipient: donor-derived or reactivation of an unknown infection or de novo Frequency of post-transplant occurrence by organ: kidney > liver > heart > pancreas > lung /

intestinal transplant Mortality> 50% due to increased risk of serious infection

Mortality appears to be higher when infection occurs early after transplantation (within 3 months) than when it occurs later (in endemic areas)

Reactivation and donor-derived infection generally occur during the first three to four months post-transplant, when immunosuppression is the most intense

REMINDER ON THE STRONGYLOIDES STERCORALIS INFECTION Infection reported to organ recipients

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DESCRIPTION OF THE BIOVIGILANCE NOTIFICATION Recipient of the right lung

21/09/21 : Graft of the right lung 19/10/21 : Good outcome, return home 26/10/21 : Cellular rejection treated with corticoids 12/12/21 : VRS pneumopathy 21/01/22 : Hospitalization for abdominal pain, vomiting, coughing and hemoptoic sputum Additional examens: ⚬Bronchial fibroscopy: no visible bleeding ⚬Chest CT scan: ground glass on the right and pleural effusion ⚬NFS: hypereosinophilia 1100 /mm3 29/01/22: Deterioration of clinical condition leading to transfer to intensive care unit BAL: haemorrhagic fluid containing numerous nematodes, suggesting pulmonary

anguillulosis 31/01/22: Death of the lung recipient 19/04/22 : biovigilance notification

ECDC NORMAL

DESCRIPTION OF THE BIOVIGILANCE NOTIFICATION Donor history

Travel to Réunion island in 2020

Recipient of the liver

4 months after the graft the recipient presented an acute respiratory failure and septic shock due to a disseminated anguillulosis leading to death

Recipients of the heart and recipient of the left kidney

Both treated with Ivermectin 4 months after the graft when the deaths of the liver and lung recipients were known. Heart recipient : no sign of anguillulosis, Left kidney recipient: increase of eosinophils just before Ivermectin treatment

Recipient of the right kidney

Detransplantation just after the graft for another reason

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SEROLOGICAL RESULTS REGARDING THE STRONGYLOIDES STERCORALIS

Imputability to the graft was proved

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SURVEILLANCE

French Public Health Agency

ECDC alert

ABM (Biovigilance)

Recommandations disseminate to professionals in charge of donors selection and their biological qualification

FRENCH SYSTEM ORGANIZATION

French High Council of Public Health (HCPH)

ECDC NORMAL

No transmission has been reported from SoHo collected from living donors (organs, tissues, cells and blood)

For deceased donors:  it is now mandatory to test all the donors, not only the ones who are coming, living or travelling from an endemic area.  result of the serological test could be sent to clinical team in charge of the recipient within 10 days post graft;  It is not mandatory to have them before the transplant

Rational:  due to regular and frequent international travelling of the population, it may be difficult to trace historical data from deceased donors

regarding this risk  serological test is easy to performed, good sensitivity, reasonable price  treatment is well tolerated with reasonable price

Results: Positive (donor): the recipient is treated (after the graft) : Ivermectine : 200mg/kg at J1 and J4 : if the recipient is positive to HTLV 1: the duration of the treatment is increased : if the recipient is coming from Africa (central or west) the search of a loasis with microfilaremia (sup to 2000/ml) is needed and if positive, the recipient is treated with Albendazole (400mg/kg during 3 consecutive days) (avoid encephalopathy linked to the intensity of filarial infection and massive release of parasitic antigens)  A follow-up serology test should be carried out 1 month after the second course of treatment to verify the absence of infection.

Negative (donor): nothing to do

PROPOSED MEASURES

ECDC NORMAL

For all living organ donors :  it is now mandatory to do a serological tests to all the donors, not only the ones who are coming,

living or travelling from an endemic area.  Positive result (donor): the donor is treated before donation : Ivermectine : 200mg/kg at J1 and J4

: if the donor is coming from Africa (central or west) the search a loasis with microfilaremia (sup to 2000/ml) is needed : the donor is treated with

Albendazole (400mg/kg during 3 consecutive days) (avoid encephalopathy linked to the intensity of filarial infection and massive release of parasitic antigens)

 A follow-up serology test should be carried out 1 month after the second course of treatment to verify the absence of infection.

For all potential organ recipient :  Before the graft, it is now mandatory to do a serological tests to all the potential recipient of an

organ graft, not only the ones who are coming, living or travelling from an endemic area.  Positive result: the patient is treated before the graft or re-treated if the donor is also positive

PROPOSED MEASURES

ECDC NORMAL

Donor-derived strongyloidiasis after organ transplantation in Norway

ECDC NORMAL

Donor:

• Young, previously healthy. • Born in Thailand • Living in west coast Norway for years, without any symptoms of

Strongyloides infection. • Pronounced dead ( DBD) sept 2015 • Organs utilized: Kidney, simultaneous kidney and pancreas (SPK) and

heart.

ECDC NORMAL

Recipient 1 54 Years old caucasian male Kidney Tx 2015 CMV +/- Induction: Basiliximab, methylprednisolon. Maintenance: Tx, MMF, Prednisone. Postop: No rejections or infections. S-Creatinin 100 µmol/L

Day 65: Readmission: Nausea, vomiting, diarrhea. Coloscopy: Inflammation CMV Colitis suspected. (antiviral treatment) Septicemia, headache, no eosinophilia. Poynuclear cells in CBS.

Day 84: Gastric retention, larvae of Strongyloides in gastro-jeunal aspirate.

No travel history. Ivermectin 200 µg/kg/day, subsequently albendazole. Immunosuppression altered from tac to CyA

No sequela and well-preserved graft function.

ECDC NORMAL

SPK 2015 CMV+/+

Induction ATG, Metylprednisolone. Maintainance: tac, MMF and prenisone.

No complications, excellent graftunction

Day 90: hospitalized with septicemia. CMV reactivation. Gastric retention and eosinophilia.

- Donor-duodenal biopsies revealed Strongyloides larvae

- Pre donation serum analysis donor showed Strongyloides IgG

Day 102: Albendazole 400 mg x2, ivermectin 200µg/kg. Immunosuppresion from tac to CyA

From day 112: Life – threatening GI –bleeding. 4 endoscopic procedures.

Day 116: Surgical resection of the duodenal segment.

Albendazole discontinued after 3 weeks, Ivermectin continued daily for 5 weeks, then once a month for 6 months.

Persisting IgG1/IgG4 positive. PCR in stool negative(2016/19/20/21/23)

PCR neg biopsies duodenum.

Good graftfunction. Never really recovered after infection/ transplant/reoperations

Recipient 2 36 year old old caucasian male

ECDC NORMAL

Recipient 3 50 Years old caucasian female Heart transplant 2015 No eosinophilia, no severe infections After donor testing: negative Strongyloides IgG 3 days of ivermectin 200 µg/kg Remains asymptomatic

ECDC NORMAL

All donors serologically tested: Test Result: Clinical interpretation: Negative Negative Grey-zone Negative, unless from endemic area Slightly positive Positive Positive: Positive

Asymptomatic Patients: - Stool Strongyloides PCR - Serological testing - After testing: Ivermectin 200µg/kg/day for 3 days, repeat after 2 weeks.

Symptomatic Patients: Individualized treatment.

Oslo policy :

ECDC NORMAL

Results: ca 800 donors tested Treated patients:

Year ID Organer Comment

2015 D186/15 Hear, Kidney, SPK Thailand,

Lved in norway for years

Recipients treated

Disease in SPK, and kidney recipient

2017 D226/17 Liver, Kidney Norwegian male 70 Recpients treated

2019 D93/19 Lungs, liver, kidney x2 Norwegian female 18 Recpients treated

2019 D207/19 Liver, kidneys x 2 Vietnamese male 62 Recpients treated

2021 D20/21 Lungs, liver, kidneys x2 Norwegian female 66 Recpients treated

2021 D129/21 Liver, kidneys x2 Polish male 53 Recpients treated

2021 D141/21 Liver, kidney x2 Grey-zone, Vietnam Recpients treated

2021 D210/21 Liver, kidneysx2 Etnic Norwegian 74 Recpients treated

2021 D240/21 Kidneys x 2 Grey-zone, Bulgaria Recpients treated

2022 D57/22 Liver, kidneys,

Heart thomograft

Norwegian Recpients treated

2022 D114/22 Llver Norwegian female 61 Recpients treated

ECDC NORMAL

Patients not treated

Year ID Organer Nationality, test treatment 2023 D70/23 Norwegian Grey-zone Not treated 2023 D80/23 Unknown origin, Grey-zone Not treated 2023 D213/23 Liver, kidneys x2 Norwegian 75, Grey-zone Not treated 2023 D201/23 Liver, kidneys x2 Norwegian male 52, Grey-zone Not treated 2024 D42/24 Liver Norwegian male 69, Grey-zone Not treated 2024 D72/24 Kidneysx 2 Norwegian male 43, Grey-zone Not treated 2024 D98/24 Hear, lungs, kidneys x2 Polish male 42, Grey-zone Not treated

ECDC NORMAL

Thank you!

ECDC NORMAL

Sharing of information in EpiPulse 19 June

245

ECDC NORMAL

Session overview

Serious adverse reactions - reporting and sharing of experience 1. EpiPulse and the role for the SoHO-Net Organs group – Agoritsa Baka

and Stefania De Angelis, ECDC 2. Breakout session: What events are of interest to share in EpiPulse for the

SoHO-Net Organs group 3. Discussion and reporting back from group discussions

246

EpiPulse Event-Based Surveillance

Substances of human origin (SoHO)

Agoritsa Baka and Stefania De Angelis, ECDC 19 June 2024

European Centre for Disease Prevention and Control

Agenda

1. EpiPulse platform, its purpose and functionalities

2. Roles and responsibilities

3. Sensitive information

4. The platform

5. Next steps

248

The EpiPulse platform

What is EpiPulse? The European surveillance portal for infectious diseases

• Online portal for EU/EEA public health authorities, public health stakeholders and international partners o forum for information exchange and collaboration between countries​ o up-to-date-overview on potential cross-border threats to health

• Collect, analyse, share, and discuss data for threat detection, monitoring, risk assessment and outbreak response.

249

Integrates indicator-based and event-based surveillance, including molecular typing.

The regulation

Regulation (EU) 2022/2371 of the European Parliament and of the Council of 23 November 2022 on serious cross- border threats to health (SCBTH) and repealing Decision No 1082/2013/EU

Complies with the General Data Protection Regulation (GDPR)

250

Events, Forum and News sections launched in 2021

Epidemiologic surveillance is the systematic collection, analysis and interpretation of data on communicable diseases to inform action EU Dec 2018/945 ~60 diseases

EpiPulse for the SoHO-Net

Information to be shared by the SoHO-Net in EpiPulse  Events related to donor-derived communicable

disease transmission through SoHO  Events related to a communicable disease

relevant to SoHO safety  Sharing of experience and good practice related

to SoHO donor selection

(To be discussed further with each SoHO-Net group)

251

Receive information reported by ECDC and by other ECDC networks  Up-to-date-overview on potential cross-border

threats to health relevant for the SoHO networks

• Surveillance data on infectious diseases relevant to the SoHO networks

Access to EpiPulse

• Public health stakeholders

o EU/EEA countries

o EU candidate and potential candidate countries

o European Neighbourhood Policy countries

o selected countries outside the EU/EEA that have agreed cooperation frameworks with ECDC [for specific domains]

• European Commission (DG-SANTE, DG-ECHO, DG HERA)

• Early warning and response system (EWRS) users

• EU Agencies (EFSA, EMA, EEA, ECHA, EU-OSHA)

• WHO-Regional Office for Europe

252

ECDC infectious disease networks

Each ECDC network has a domain in EpiPulse

• As ECDC National Focal Points for SoHO, you have access to the SoHO domain

• Different sub-networks in the SoHO domain:

o Blood o Tissues and cells o Human organs o Medically assisted reproduction

Other users can be invited to specific events (when applicable):

WHO Euro DG SANTE

You will receive only notifications related to events relevant to SoHO and your sub-network(s). o upon creation of an event o Only if you want, for new comments and other

updates

253

EpiPulse items

There are different Item types to facilitate different activities within the platform:

• Signals

• Events

• Threats

• [events under] Long-term monitoring

• Forum

• News

254

Event-based surveillance

Event

• case(s)/cluster(s)/outbreak(s)/epidemiological situation(s)/incident(s)/public health risk situation(s) • detected in/reported by one or several countries • that according to your assessment pose (or may pose) a public health risk for the EU/EEA

Examples:

• a case of yellow fever imported from a country where the virus is not known to circulate

• an autochthonous case of a disease in the EU/EEA, where it has not been detected previously

• detection of a novel virus/disease

• first human case for the season of locally acquired West Nile Virus in the EU/EEA

• a human case of avian influenza infection

• an increase in the number of imported malaria cases in one EU/EEA country

• an increase of hepatitis E cases in one EU/EEA country

Role of ECDC assessment and Round Table

* Access to daily/weekly restricted CDTR is limited to nominated Epidemic Intelligence and Preparedness domains 256

New EpiPulse Event

ECDC assessment

ECDC Round Table review Follow-up actions

• Review Event and classification e.g. Event  Threat SCBTH criteria

• Open to relevant stakeholders e.g. WHO EURO, EFSA

• Review Event post and responses from other countries

• Follow-up with countries • Situation Awareness

Summary - restricted version - public version

• Follow-up with countries • Situation Awareness Summary

included in CDTR - Daily restricted - Weekly restricted - Weekly public

EpiPulse *

ECDC website

What information can be shared further

 Only personal account to access EpiPulse – no generic email

 Info cannot be shared further, unless ECDC agrees following request

Terms of Service - Purpose and legal basis of EpiPulse

The purpose of EpiPulse is to support infectious disease surveillance, early threat detection and risk assessment in the European Union/European Economic Area (EU/EEA). The web-based platform is designed for collecting, retrieving, exploring, exchanging and discussing data and information on cases of infectious diseases, pathogens and signals and events posing potential threats to public health in Europe and beyond. EpiPulse brings together nominated national experts from EU/EEA and non-EU/EEA countries, ECDC staff and representatives of other European authorities and international organisations.

The legal basis for this activity is Regulation (EC) No 851/2004 (ECDC’s Founding Regulation), in particular articles 3, 4, 8, 10 and 11, and Decision 1082/2013/EU on serious cross-border threats to health.

Confidentiality As a User, I hereby declare that: 1. I will use EpiPulse only for the purposes and within the legal framework described in art. 1 above.

257

Please treat the data in the platform as sensitive non-classified unless specifically indicated as public

The platform

258

Homepage, instructional videos, help and support docs

Main menu

259

Events list

Event details

260

Notifications

261

Next steps

September • EpiPulse hands on training and workshop, more information will follow. • You will be able to communicate and report events in EpiPulse after the hands-on training.

262

Thank you!

263

Questions?

• General EpiPulse feedback and technical issues - [email protected] • Access support or login questions - [email protected] • For SoHO specific content in EpiPulse - [email protected]

ECDC NORMAL

EpiPulse for the SoHO-Net

Information to be shared by the SoHO-Net in EpiPulse  Events related to donor-derived communicable

disease transmission through SoHO  Events related to communicable disease

relevant to SoHO safety  Sharing of experience and good practice related

to SoHO donor selection.

264

Receive information reported by ECDC and by other ECDC networks  Up-to-date-overview on potential cross-border

threats to health relevant for SoHO  Surveillance data on infectious diseases relevant

to SoHO

ECDC NORMAL

Breakout session: what events are of interest to share in EpiPulse for the SoHO-Net Organs group

You will be divided into 5 groups with one facilitator per group to guide you. Each group you will:

1. Discuss which event that you find would be relevant to share in EpiPulse related to I. donor-derived communicable disease transmission through SoHO II. communicable disease relevant to SoHO safety

2. Discuss what kind of experience and good practice related to SoHO donor selection that you find would be relevant to share in EpiPulse.

Try to be as specific as possible, you are welcome to give examples. Summarize your discussion and conclusions in bullet points and nominate one or two persons who will present the summary of the discussions, orally or with slides.

Each group will have 5 minutes for their presentation, followed by a common discussion. The proposed topics will be discussed again at the EpiPulse hands-on training for network members in September.

265

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Session 8 Emerging diseases 19 June

266

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Session overview

Emerging diseases – overview and trends 1. Emerging vector-borne diseases in EU/EEA – Overview and trends

and available surveillance tools – Celine Gossner, ECDC 2. Questions and answers – All 3. Proposal for a repository for guidance on emerging diseases and

organ transplantation – Francois-Xavier Lamy, ECDC 4. Discussion – All

267

European Centre for Disease Prevention and Control

Vector-borne diseases in EU/EEA – Overview, trends and available surveillance tools Céline Gossner, Principal Expert Emerging and Vector-Borne Diseases / Group Leader Emerging, Food and Vector -Borne Diseases, [email protected] SoHO-Net Organs meeting, 18-19 June 2024

Data sources, not exhaustive

269

ECDC

EVD-network National public health institutes in

EU/EEA countries and pre- accession countries

EVD-LabNet 65 laboratories in EU/EEA

and neighbouring countries

VectorNet Entomologists in EU/EEA and

neighbouring countries

Disease case data

(Weekly to annual data

collection) and outbreak data

Early warning and specific data

collections on viruses and viral

diseases Vector distribution (i.e.

ticks, mosquitoes and sandflies)

Media and other public health organisations

(e.g. WHO)

Other competent authorities in EU/EEA countries e.g. veterinary authorities, blood safety

authorities

TESSy/ EpiPulse

Dengue

• Transmitted among humans by Aedes aegypti (yellow fever mosquito) and Aedes albopictus (Asian tiger mosquito)

• ¼ people infected with dengue virus will get sick

• On average 2,300 cases per year in Europe; >99 % are imported

• While autochthonous outbreaks are occurring within continental Europe, the disease is NOT considered endemic.

270

Overview of the dengue situation in the EU

271

Number of locally-acquired cases of dengue per region, 2010-2023

0

2

4

6

8

10

12

14

16

0

20

40

60

80

100

120

140

2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023

Nu m

be r o

f o ut

br ea

ks

Nu m

be r o

f d en

gu e

ca se

s

Number of locally-acquired dengue cases and outbreaks in the European Union, 2010-2023 (n=275)

Croatia France Italy Spain Outbreaks

272

Spread of Aedes albopictus

May 2014 May 2024

Imported cases of dengue reported in the EU/EEA, 2015-2023*

273

0

1,000

2,000

3,000

4,000

5,000

6,000

2015 2016 2017 2018 2019 2020 2021 2022 2023

*preliminary data for 2023

Place of infection of imported cases of the dengue to the EU/EEA, 2022

274

275

Place of infection of imported cases of the dengue to the EU/EEA, 2018-2022

https://www.ecdc.europa.eu/en/dengue-monthly 276

Notification rate of dengue, per 100 000 population, Feb- Apr 2024 (as reported by countries)

0

500000

1000000

1500000

2000000

2500000

20 15

-0 1

20 15

-0 5

20 15

-0 9

20 16

-0 1

20 16

-0 5

20 16

-0 9

20 17

-0 1

20 17

-0 5

20 17

-0 9

20 18

-0 1

20 18

-0 5

20 18

-0 9

20 19

-0 1

20 19

-0 5

20 19

-0 9

20 20

-0 1

20 20

-0 5

20 20

-0 9

20 21

-0 1

20 21

-0 5

20 21

-0 9

20 22

-0 1

20 22

-0 5

20 22

-0 9

20 23

-0 1

20 23

-0 5

20 23

-0 9

20 24

-0 1

0

1000000

2000000

3000000

4000000

5000000

6000000

7000000

8000000

9000000

2015 2016 2017 2018 2019 2020 2021 2022 2023 2024

Western Pacific Region South-East Asia Region Region of the Americas European Region

Risk of dengue importation into Europe, 2024

Source: International Air Travel Association and World Health Organisation 277

Flight passengers arriving to the EU/EEA from selected dengue endemic countries*, 2015-2024 (As of March)

*20 countries of infection from where the most travel-related cases were reported in TESSy for the period 2018-2023

Dengue cases reported to WHO, by region, 2010-2024 (As of April)

West Nile virus infections

• Endemic to Europe • Primarily transmitted by the mosquito

Culex pipiens (common house mosquito) • Virus circulate in the bird population;

humans and equids are dead-end hosts • 1/5 people infected with West Nile virus

will get sick

• On average, 460 cases per year in Europe; 98% are locally-acquired

278

0

200

400

600

800

1000

1200

1400

1600

1800

2012 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023

Number of locally acquired cases of human West Nile virus infection per reporting EU/EEA country,

2012-2023 (n=5,476)

Greece Italy Romania Other

Surveillance of West Nile virus infections

Enhanced surveillance from June to November, with weekly reports and monthly enhanced analysis

https://www.ecdc.europa.eu/en/west-nile-fever/surveillance-and-disease-data/disease-data-ecdc

Weekly updates on ECDC website, with a focus on distribution of human cases

Timely inform SoHO authorities for implementation of Commission Directive 2014/110/EU, requesting that prospective blood donors are deferred for 28 days after leaving a risk area for locally acquired WNV infection, unless the result of an individual nucleic acid test is negative.

Weekly data collection on human cases, through TESSy

Surveillance of West Nile virus infections

Monthly enhanced analysis on ECDC website

Inform public health and veterinary authorities and provide a risk assessment of the situation

Weekly data collection on human cases, through TESSy

Collection of animal cases (equids and birds), through ADIS

Situation in 2024, as of 12 June

283

Malaria

• Transmitted among humans by Anopheles mosquito

• The vast majority of people infected will develop symptoms

• On average, 5400 cases per year in Europe; >99% are imported.

• While autochthonous outbreaks are occurring within continental Europe, the disease is NOT considered endemic.

284

Travel-related cases of malaria reported in the EU/EEA, 2015-2023

285

0

1,000

2,000

3,000

4,000

5,000

6,000

7,000

2015 2016 2017 2018 2019 2020 2021 2022 2023

*preliminary data for 2023

286

Distribution of travel-associated malaria cases reported to ECDC, by place of infection, 2018–2022

Distribution of travel-associated malaria cases reported to ECDC, by place of infection, 2022

Locally-acquired cases of malaria

287

• 65 cases reported from 2015 to 2023, primarily by Greece (n=33).

• Among these, 43% are due to Plasmodium vivax and 52% are due to P. falciparum

• Cases are classified as introduced, health-care associated, airport/luggage malaria, laboratory acquired or cryptic.

Actions against mosquito-borne diseases

1 Individual protection

against mosquito bites 2

3

Vector control measures

Early detection of cases

AWARENESS

4 Timely

surveillance

5 Research

Thank you

Useful links Autochthonous vectorial transmission of dengue virus in mainland EU/EEA, 2010-present: https://www.ecdc.europa.eu/en/all-topics-z/dengue/surveillance-and-disease-data/autochthonous- transmission-dengue-virus-eueea Dengue worldwide overview: https://www.ecdc.europa.eu/en/dengue-monthly Dengue imported cases: https://www.ecdc.europa.eu/en/dengue/surveillance/dengue-virus-infections- travellers West Nile virus updates: https://www.ecdc.europa.eu/en/west-nile-fever/surveillance-and-disease- data/disease-data-ecdc Annual Epidemiological Reports (AERs): https://www.ecdc.europa.eu/en/publications-data/monitoring/all- annual-epidemiological-reports Mosquito surveillance maps: https://www.ecdc.europa.eu/en/disease-vectors/surveillance-and-disease- data/mosquito-maps Surveillance_prevention_and_control_of_WNV_and_Usutu_virus_infections_in_the_EU- EEA: https://www.ecdc.europa.eu/sites/default/files/documents/Surveillance_prevention_and_control_of_WNV _and_Usutu_virus_infections_in_the_EU-EEA.pdf

290

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A repository for guidance on emerging diseases and organ transplantation: proposal SoHO-Net Organs Group meeting – 19 June 2024

291

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Aim

Within the repository of policy and practice resources: Sharing of guidance documents published by Member States (MS) on the prevention of transmission of emerging and vector borne diseases (EVD) in organ transplantation

Rationale: Some affected MS are already addressing donor selection issues related to EVD while others are preparing for future cases in their country. All countries could benefit from the sharing of practices.

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Methods and scope: for discussion

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ECDC sends a call for published guidance documents on EVD and organ transplantation

(should include donor selection topics)

MS provide links to published documents in scope of the call

ECDC confirms the documents are in scope (possible clarifications with MS) and updates

the repository

ECDC repeats the call annually

MS provide updates/new

documents as available

Scope: • Published documents by national competent

authorities or scientific societies (in EU/EEA)

• On emerging and vector-borne diseases: WNV infection, TBE, Dengue, Chikungunya, Zika…

• Includes (but not necessarily restricted to) guidance related to organ donor selection

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Repository

294

Guidance on EVD

Organs

TBE

Dengue

Classification to be discussed • A single group (“EVD”) as one

guidance may cover several disease?

• Or disease related? “EVD guidance: WNV”

• Some guidance may cover several SoHO (tissues), these can be selected: a similar call will be discussed with other groups

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Timelines

• Initial call for guidance: September – October 2024 • Confirmation of documents and update of the repository:

November-December 2024 • Publication and annual call: January 2025+

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Thank you

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Session 9 Rapid risk assessments 19 June

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Session overview

ECDC Rapid Risk Assessment (RRA) and technical reports 1. BRAVEST Project status update – Devy Mey and Luciano Potena, ESOT

2. Presentation on ECDC rapid risk assessment (RRA) process and updates – Orlando Cenciarelli, ECDC

3. Discussion on the content of RRA for Organs – All

4. Request for NPFs as expert reviewers on ECDC RRA – All

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Luciano Potena Devi Mey ESOT

SOHO-NET ORGANS MEETING 18-19 JUNE 2024

EU4Health (2021-2027) – a vision for a healthier European Union

EU4Health is EU’s response to COVID-19 to:

• boost EU’s preparedness for major cross border health threats by creating • strengthen health systems so that they can face epidemics as well as long-term challenges • make medicines and medical devices available and affordable, advocate the prudent and

efficient use of antimicrobials as well as promote medical and pharmaceutical innovation and greener manufacturing

Action grants on substances of human origin (SoHO) - increase resilience, ensure continuity of supply and access to safe and high quality therapies, in particular in times of crisis

This action aims to enable the medical/professional organisations and Member State authorities in SoHO subsectors to develop and exchange good practices for professionals and authorities to optimise supply and increase access to quality and safe use of critical therapies based on substances of human origin donated by fellow citizens.

Bravest project

Building Resilience Against crisis: a systematic and global approach to adVancE organ Safety and supply in Transplantation

9 Partners 7 Countries

Aims

Analysing organizational and management procedures in organ donation and transplantation based on real world evidence and cutting-edge analysis methodologies.

• Identify the most effective clinical practice and procedures during a crisis

• Propose sustainable innovative actions directed at improving the resilience of the donation and transplant networks

• Ensure the continuity of supply of organs while maintaining the safety of donation and transplant

• Increase the accessibility to transplantation for all patients with end-stage organ disease

BRAVEST project: three steps approach

1) Collect evidences and perform multiparametric analysis of the efficiency in pandemic management by the project partners

2) Development of specific recommendations in form of evidence-based guidelines 3) Analysis of the sustainability of the proposed measures

Data analysis approach: study endpoints Primary outcome measures

1. Change in rate per million inhabitants of deceased organ donors signalled and procured before, during and after the pandemic period

2. Change in number and kind of organs allocated and successfully transplanted before, during and after the pandemic period

3. Change in one year of patient and graft survival before, during, and after the pandemic period.

Secondary outcome measures, we will consider:

- Number of potential donors declined and the reason,

- Number of potential donors with a positive test for SARS-Cov2 and their outcome,

- Outcome of recipients receiving organs from SARS-Cov2 positive donors,

- Change in transplants from living donors (this outcome will be analysed only by aggregated data)

Impact

Short term • Improve the knowledge on the effect of COVID-19 pandemic on donor procurement and transplant activities • Develop evidence-based guidelines to improve resilience of donation and transplant systems (war, local crisis,

migration, environmental etc.)

Long term • Transferability of developed models to European Countries not included in the consortium, based on

sustainability and cost-effectiveness analysis

Step 1 – collection of country recommendations

Survey consisting of 36 questions and its subquestions (132 items), based on the recommendations of the working group. We applied mixed method with opened and multiple choice questions.

Information on restrictions on SOT, protective measures, (non)governmental information policies, and individual opinion on how to deal with SOT during COVID-19 was designed.

Sections of the survey:

1. COVID-19 first outbreak in the country 2. First measures 3. Ongoing measures 4. Measures regarding organization of international organ exchanges 5. Measures regarding donors 6. Measures regarding recipients

Descriptive analysis – Conclusions COVID-19 first outbreak in the country

Were organ donation programs active during the first outbreak?

The donation programs during the first outbreak of COVID-19 experienced varying degrees of restrictions across different countries: options: open, closed, moderate, severe

Open Availability: Croatia, Slovenia, France, Belgium Reasons: These countries maintained open availability for organ donation programs during the COVID-19 pandemic, indicating a proactive approach to ensuring continued access to transplantation services without significant restrictions.

Moderate Limitations: Italy, The Netherlands, Hungary, Germany Reasons: These countries implemented moderate restrictions on organ donation programs, which included temporary suspensions of specific programs (e.g., Living Transplantation program in Italy, lung donation program in Hungary), restrictions due to resource constraints (e.g., lack of intensive care beds in The Netherlands), and enhanced donor evaluation procedures (e.g., PCR testing, careful assessment of infection signs in Germany).

Severe Limitations: Spain Reasons: Spain experienced severe limitations on organ donation programs during the most critical weeks of the first wave of the pandemic. The collapse of the healthcare system and overwhelmed ICU capacity necessitated prioritization of resources, leading to substantial decreases in donation activity. Organ donation was limited to optimal donors, and uncontrolled DCD programs were closed. Additionally, donors who tested positive for COVID-19 or exhibited symptoms suspicious of COVID-19 were rejected.

Descriptive analysis – Conclusions COVID-19 first outbreak in the country Were transplantation programs active during the first outbreak?

The transplantation programs during the first outbreak of COVID-19 experienced varying degrees of restrictions across different countries: options: open, closed, moderate, severe

Severe Limitations in Spain, Hungary Reasons: Collapse of the healthcare system, overwhelmed ICU capacity, priority given to urgent cases and critically ill individuals, substantial decrease in transplantation activity, live donor transplant programs were closed.

Moderate Restrictions in Italy, The Netherlands, Germany, France, Belgium Reasons: Temporary suspension of living donor transplantation program, closure of some transplantation programs, prioritization of resources, variations in transplantation decisions among centers based on individual risk- benefit evaluations, suspension of specific types of transplants (e.g., renal transplantation in France temporarly suspended).

Limited Restrictions/Open Programs in Slovenia Reasons: Transplantation programs remained open and active without significant restrictions during the first outbreak, indicating a proactive approach to maintaining transplantation services during the pandemic.

Q5. Adoption of 1st measure regarding organ donation at national level

Q6. Adoption of 1st measure regarding transplantation activity

Q7. Adoption of 1st measure regarding transplant waiting list

Q9. 1st COVID-19 specific OD&T recommendation or guideline issued

Q18.3. First wave’s peak of the COVID- 19 pandemic

Q25. Initiation of SARS-CoV-2 PCR (NAT) screening of deceased donors

Q29. Initiation of the SARS-CoV-2 PCR/NAT screening of recipients

Next steps and challenges

Full completion of survey analysis for publication

Completion of GDPR implementation to comply with the different interpretations across countries which currently represent a barrier to clinical data collection

 Development of project specific DPIA and DSA with partners

Collection of clinical data from data controllers and processor(s)

B R AV E S T: Building Resilience Against crisis: a systematic and global approach to adVancE organ Safety and supply in Transplantation

Disclaimer: Funded by the European Union. Views and opinions expressed are however those of the author(s) only and do not necessarily reflect those of the European Union or European Health and Digital Executive Agency (HADEA). Neither the European Union nor the granting authority can be held responsible for them. REF: 101056986 — BRAVEST — EU4H-2021-PJ

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Orlando Cenciarelli, Emergency Preparedness and Response, ECDC SoHO-Net meeting, Stockholm, 19 June 2024

ECDC rapid risk assessment (RRA) process and updates

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ECDC threat detection: the epidemic intelligence process

314

Review of large number of items

Contextualize information for assessment

Rapid sharing of information. Reporting at Round Table. Rapid Risk Assessment.

Use official sources to validate information

Selection of relevant items

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Restricted platforms: • EpiPulse Events • EWRS • WHO Event Information site • RASFF

Official public sources: • National public health institute

websites​ • WHO websites​ • CDC websites​

Threat detection – sources and validation

315

TESSy (EpiPulse cases)

Web scraping

Event-based surveillanceIndicator-based surveillance

Epidemic Intelligence from Open Sources (EIOS)

Social media platforms

Other web aggregators as backup

Media monitoring (including social media)

Global coverage

• In EU/EEA: • ECDC disease specific networks • Epidemic Intelligence activities

• Outside EU/EEA: • Public Health Institutes/Ministries of health where direct links (e.g. existing MoU, personal contacts) • Other CDCs – e.g. Africa CDC • World Health Organization (mainly WHO/Europe)

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Outputs

316

Rapid Risk Assessment

Threat Assessment Brief

Communicable disease threat reports

Restricted and Public versions Daily and weekly editions

Epidemiological Updates

Risk assessment outputs

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What is an ECDC risk assessment?

Assessment in EU: relative quantification of the risk to human health of an event (potential threat) represents in one or more EU/EEA countries or for EU/EEA citizens living in affected areas outside of the EU.

• Support the EU/EEA countries public health authorities and the EC in their preparedness and response to the threat by:

• Alerting about the event • Providing timely information on the estimated risk related to the public health threat • Addressing uncertainty by using a systematic appraisal of the best scientific evidence

available • Determining whether a response is needed • Providing [non-binding] recommendations for mitigating the risks

• Inform health professionals and the public at large (e.g. clinicians, media, travellers…)

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Triggering criteria for ECDC rapid risk assessments

• Outbreak extending to more than one EU/EEA country • Risk of introduction to and/or propagation within the EU/EEA • Event for which cross border contact tracing is needed • Unusual or unexpected event • Outbreak of unknown origin • Emerging disease(s) affecting touristic areas • Contaminated food product(s) with EU dimension

• Event triggering high media attention

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ECDC process for conducting a RRA

319

Decision to develop an

RRA

Multidisciplinary internal

response team

Notification to ECDC external stakeholders - Advisory Forum members - National Coordinators (Coordinating Competent Body) - NFP for Preparedness and Response; for Threat Detection, EWRS and IHR; for specific area/disease - European Commission

Independent external rapid

review

External distribution under embargo: - Advisory Forum members - National Coordinators (Coordinating Competent Body) - NFP for Preparedness and Response; for Threat Detection, EWRS and IHR; for specific area/disease - European Commission

Publication ECDC

EC posts on EWRS

MS can post on national websites

Ensuring traceability and transparency: - Rapid risk assessments are registered and followed in the ECDC

Scientific Advice Repository and Management System. - Declarations of interest are collected and assessed for all external

reviewers prior to review and publication. - Actions taken (or not taken) on external reviewers’ and AF

comments and edits are stored.

Internal procedure for Response operations: Internal procedure 98 – SRS – Risk assessment workflow, first revision October 2018

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ECDC operational tool on rapid risk assessment methodology

Aim • Support for consistency, reproducibility and transparency

using a systematic approach • Provide an analytical framework • Helps to manage time constraints limited evidence

available expert opinions

Ongoing, 2024 • Review and update of methodology. Maintain the basis, with further

improvement of the existing algorithm. ECDC’s amended mandate, Article 8a: - “Risk assessments…shall include general and targeted (non-binding)

science-based recommendations and options for response as a basis for coordination in the HSC”.

https://www.ecdc.europa.eu/sites/default/files/documents/operational-tool-rapid-risk-assessment-methodolgy-ecdc-2019.pdf​

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Assessing the risk /1

https://www.ecdc.europa.eu/sites/default/files/documents/operational-tool-rapid-risk-assessment-methodolgy-ecdc-2019.pdf

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Assessing the risk /2

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Key steps for the development of a RRA

1. Signal verification and event information systematically collected 2. RRA decision: at the ECDC RT meeting 3. Internal Response Team: formulate the risk question(s) and develop text 4. Conduct a rapid but structured literature review 5. Appraise the evidence and acknowledge confidence, unknowns & limitations 6. Estimate and assess the risk using the operational algorithms 7. Integrate uncertainties and limitations 8. Provide recommendations for member state public health authorities 9. Prepare RRA communication material 10.Re-assess new information and decide on need to update RRA

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ECDC Rapid Risk Assessment - structure

• Title ​ • Summary​ • Epidemiological situation (brief description of the current event)​ • Risk question(s) • Risk assessment for the EU/EEA​ • ECDC recommendations​ for mitigating the assessed risks • Limitations ​ • References​ • Technical Annex (can include event background and/or disease

background and other in-depth information related to the RRA)​

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SoHO aspects in the ECDC rapid risk assessment

Consideration/non-binding recommendation for public health and SoHO authorities

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The new regulation CBTH Regulation (EU) 2022/2371 on serious cross-border threats to health – Art. 20

Where an alert is notified […] the Commission shall, where necessary for the coordination of the response at Union level […], make promptly available to the national competent […] a risk assessment of the potential severity of the threat to public health, including possible public health measures. That risk assessment shall be carried out by one or more of the following Union agencies or bodies:

a) the ECDC […] in the case of a serious cross-border threat to health […], including where it relates to substances of human origin that can potentially be impacted by communicable diseases […];

b) the European Medicines Agency (EMA) […] where the serious cross-border threat to health is linked to medicinal products and medical devices;

c) the European Food Safety Authority (EFSA) […] in the case of a serious cross-border threat to health […] falls under the mandate of EFSA;

d) the European Chemicals Agency (ECHA) […] in the case of a serious cross-border threat to health […] falls under the mandate of the ECHA;

e) the European Environment Agency (EEA) […] in the case of a serious cross-border threat to health […] falls under the mandate of the EEA;

f) the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA), […] in the case of a serious cross-border threat to health […] falls under the mandate of the EMCDDA.

The risk assessment shall be carried out […] in cooperation with the European Union Agency for Law Enforcement Cooperation (Europol) where the serious cross-border threat to health emanates from terrorist or criminal activity […]

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Thank you

327

What content in RRA for SoHO – organs?

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Session 10 Topics and ECDC activities identified by the SoHO-Net Organs group 19 June

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Session overview

Reflection on topics for the SoHO-Net Organs group and the role of ECDC

1. Reflection and prioritisation of topics for the SoHO-Net Organs group

2. Role of ECDC in ensuring the safety of organs

3. Future meetings

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Expectations for SoHO-Net and ECDC in Organs

• Sharing of experience with nonstandard donors in emerging diseases • Sharing of recommendations and good practices on emerging diseases • Recommendations on harmonised minimum standards • Collaboration with other ECDC networks • Clarify roles of different stakeholders: Notify, VES… • Leave room for country decisions

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Topics for SoHO-Net listed in day 1

• Use and handling of donors with MDR/XDR pathogens • Guidance on arboviruses • COVID-19 update • Position paper on the use of HCV+ donors and post-transplantation treatment (ECDC led) • Registry of outcomes in recipients receiving organs from non-standard donors (infectious disease) • Sharing of measures and good practices for donor selection (infectious disease) • Information on infectious disease risks based on country of origin • Methodology for a risk assessment for organ donors • Collaboration in creating trainings on issues related to infectious diseases in donor selection • Establish collaboration with EU Reference Laboratories (EURL) and SoHO-Net • Sharing of transmission events and outcomes • Creation of an expert repository for real-time advice • Situation overview of measures to prevent HTLV-1 transmission

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One final question!

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Future network meetings

Meeting Date

Workshop: Information to be shared in EpiPulse - Virtual September 2024

EpiPulse hands-on training – Virtual September 2024

SoHO-Net blood group meeting – Stockholm 4-5 December 2024

SoHO-Net plenary meeting – Virtual 15 April 2025 (not confirmed)

SoHO-Net tissues and cells and MAR groups meeting – Stockholm 30 September – 01 October 2025

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Session 11 Closing remarks 19 June

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Thank you! To the NCC, chairs, presenters, and all participants

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SoHO-Net Meeting: Organs group 18 – 19 June 2024, Stockholm

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Session 1 Introduction and presentations 18 June

2

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Session overview

1. Director’s welcome – Pamela Rendi-Wagner, ECDC 2. Introduction – Marieke van der Werf, ECDC 3. Key objectives for the meeting – Jenny Mohseni Skoglund,

ECDC 4. Presentations network members and invited experts – Tour

de table

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Welcome and introduction Pamela Rendi-Wagner, ECDC

4

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Welcome and introduction Marieke van der Werf, ECDC

5

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6

Vaccine-preventable diseases and Immunisation

Sexually transmitted infections, Blood-Borne Viruses

and Tuberculosis

Antimicrobial resistance and healthcare-associated

infections

Emerging, Food and vector- borne diseases

Disease Surveillance &

Epidemic intelligence

Response support & Risk assessments

Preparedness & capacity

strengthening

Scientific advice & guidance

EU and external stakeholders &

Country support

Public health training

Communication

ECDC mission & role

To identify, assess and communicate current and

emerging threats to human health posed by infectious

diseases.

ECDC SoHO team

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Sexually transmitted infections, blood-borne viruses and tuberculosis section

SDG-targeted diseases group • Hepatitis B and C • HIV • Sexually transmitted infections

• Chlamydia • Gonorrhoea • Syphilis

• Tuberculosis

SoHO team

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Juliana ReyesTeymur Noori

Csaba KödmönEls Driessens Erika Duffell Marijana Kukolj

Otilia Mårdh Lina Nerlander

Janelle Sandberg Marieke van der Werf

Charlotte Deogan

Ndeindo Ngangro Flavia Cunha Jenny Mosheni Skoglund

Senia Rosales-Klintz

Veronica Cristea

Anastasia Pharris

Francois-Xavier Lamy

Ana Finatto- Canabarro

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EU regulations relevant for SoHO

• Regulation (EC) No 851/2004 of the European Parliament and of the Council of 21 April 2004 establishing a European Centre for Disease Prevention and Control

• Regulation (EU) 2022/2370 of the European Parliament and the Council of 23 November 2022 amending Regulation (EC) No 851/2004 establishing a European Centre for Disease Prevention and Control

• Regulation (EU) 2022/2371 of the European Parliament and the Council of 23 November 2022 amending Regulation (EC) of 23 November 2022 on serious cross-border threats to health and repealing Decision No 1082/2013/EU

• Directive 2010/45/EU of the European Parliament and of the Council of 7 July 2010 on standards of quality and safety of human organs intended for transplantation

• Proposal for a Regulation on standards of quality and safety for substances of human origin intended for human application and repealing Directives 2002/98/EC and 2004/23/EC

9

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Framework for ECDC support to EU/EEA countries and the European Commission to reach microbial safety of substances of human origin

Source: https://www.ecdc.europa.eu/en/publications-data/ecdc-framework-relating-substances-human-origin-soho

10

Coordinate SoHO network

Prevention of communicable disease transmission through application of substances of human origin

Provide guidance on microbial

safety

Threat detection, assessment, and

response

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Coordinate SoHO network

• Network of Member State services supporting the use of substances of human origin (SoHO-Net). Four sub-networks with National Focal Points and observers:

• Blood • Tissues and cells • Organs • Medically assisted reproduction

• SoHO Network Coordination Committee with elected members from the network

• Regular meetings of the SoHO Network Coordination Committee and of the four SoHO sub-networks

• EpiPulse platform for information exchange and collaboration between countries

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Provide guidance on microbial safety

• Develop and update guidelines as referred to in the SoHO Regulation

• Guideline development process according to ECDC procedures for developing guidelines

• Collaboration with the European Directorate for the Quality of Medicines & HealthCare (EDQM) to ensure that technical guidelines published by EDQM and ECDC are aligned

• Develop guidance and recommendations on topics relevant to the microbial safety of SoHO at the request of the SoHO network, the European Commission or on own initiative

12

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Threat detection, assessment, and response: Monitor threats and outbreaks

Detect, monitor, and report on serious cross-border threats to health related to SoHO.

• Results of daily screening of various information sources • Reports of cases of infectious diseases and pathogens that may

threaten microbial safety of SoHO in the EU/EEA in EpiPulse • Monitoring of serious adverse reactions*

→ Discussion of identified threats and an initial assessment of appropriate ECDC actions.

* Serious adverse reaction (SAR) is defined in the Proposal for a Regulation as an adverse reaction that results in death, a life-threatening, disabling or incapacitating condition, including transmission of a pathogen, hospitalisation or prolongation of hospitalisation, or the need for a major clinical intervention to prevent or reduce the effects. 13

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Threat detection, assessment, and response: Perform risk assessments and launch alerts

• Provide risk assessments including science-based recommendations and options for response in the case of a serious cross-border threat to health

• Launch an alert in the EU SoHO Platform when the risk assessment indicates a new risk to the safety of SoHOs

• Support response coordination in the Health Security Committee

14

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Threat detection, assessment, and response: Provide advice on serious adverse reactions*

SoHO National Authority will inform ECDC of serious adverse reactions concerning a transmission of a communicable disease that is rare, or unexpected for that SoHO type.

ECDC will support relevant follow-up actions including providing advice or information to SoHO National Authorities on options for response.

* Serious adverse reaction (SAR) is defined in the Proposal for a Regulation as an adverse reaction that results in death, a life-threatening, disabling or incapacitating condition, including transmission of a pathogen, hospitalisation or prolongation of hospitalisation, or the need for a major clinical intervention to prevent or reduce the effects. 15

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Empowering EU/EEA countries, the EC and other partners to drive public health policy and practice

Through the building blocks detailed in this framework, ECDC aims to achieve the following: • Robust SoHO network and mechanisms for the exchange of information. • Guidelines available and updated as needed for the prevention of donor-

derived communicable disease transmission through the application of SoHO.

• Well-functioning system for identification and information sharing of serious adverse reactions and communicable disease outbreaks relevant to the microbial safety of SoHO.

• High-quality risk assessments with science-based recommendations and options for response and timely alerts when a new risk to the safety of SoHOs is identified.

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Aim and key objectives for the meeting • To get to know each other and understand the network and the role of the NFPs

• To update the SoHO-Net Organs group and invited participants on ECDC scientific outputs and activities related to donor derived communicable diseases transmission

• To discuss current challenges in the fields related to donor derived communicable diseases transmission

• To exchange good practice of donor testing strategies

• To share experiences of reporting serios adverse reactions and events

• To identify and prioritize main topics for activities for the SoHO-Net Organs group.

17

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Session 2 SoHO-Net Organs group 18 June

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Session overview

1. The role of ECDC networks and the SoHO-Net Organs group – Jenny, Mohseni Skoglund, ECDC

2. Questions and answers – All 3. Breakout session: topics and expectations for the role of ECDC in the field of

SoHO safety for organs

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ECDC networks Jenny Mohsenis Skoglund, ECDC

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Dedicated Networks

“The Centre shall promote and coordinate the networking of bodies, organisations and experts operating in the Union in the fields relevant to the Centre’s mission, including networks arising from public health activities supported by the Commission, and operate dedicated networks on surveillance, while ensuring full compliance with rules on transparency and conflicts of interest.”

Dedicated network means any specific network on diseases, related special health issues or public health functions that is supported and coordinated by the Centre and is intended to ensure collaboration between the coordinating competent bodies of the Member States.

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Disease and Laboratory Networks and networks dedicated to health issues*

Antimicrobial resistance and healthcare-associated infections • European Antimicrobial Resistance Surveillance Network (EARS-Net) • European Surveillance of Antimicrobial Consumption Network (ESAC-

Net)* • Healthcare-associated Infections Surveillance Network (HAI-Net)* • European Antimicrobial Resistance Genes Surveillance Network

(EURGen-Net) Emerging and vector-borne diseases • Emerging and Vector-borne Diseases Network (EVD) • Emerging Viral Disease-Expert Laboratory Network (EVD LabNet) • European Network for sharing data on the geographic distribution of

arthropod vector, transmitting human and animal disease agents (Vector-Net)*

Food- and waterborne diseases, zoonoses • European Food- and Waterborne Diseases and Zoonoses Network

(FWD-Net) • European Legionnaires' disease Surveillance Network (ELDSNet) • European Creutzfeldt-Jakob Disease Surveillance Network (EuroCJD)

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Respiratory tract infections • European Tuberculosis Surveillance Network • European Reference Laboratory Network for TB (ERLTB-Net) • European Influenza Surveillance Network (EISN) • European Reference Laboratory Network for Human Influenza (ERLI-Net) • European COVID-19 Surveillance Network (ECOVID-Net) • European COVID-19 reference laboratory network (ECOVID-LabNet)

HIV, STI and blood-borne viruses • European Sexually Transmitted Infections Network • European Gonococcal Antimicrobial Surveillance Programme (Euro-GASP) • European Network for HIV/AIDS • European Network for hepatitis B and C surveillance

Vaccine-preventable diseases and invasive bacterial infections • European Invasive Bacterial Diseases Surveillance Network (EU-IBD) • EU laboratory Network for surveillance of Pertussis (EUPertNet) • European Diphtheria Surveillance Network (EDSN) • Network on measles, mumps, rubella surveillance (MMR)

Network for the Microbiological Safety of Substance of Human Origin (SoHO)*

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What?

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Provides information For monitoring the situation in your country and for identification of country needs.

Provides technical advice Review/comment technical documents .

Participates in ECDC activities Presentation on your subject area and/or your country.

Networking Interacting with other EU/EEA countries.

Coordinates Interactions with national stakeholders.

Provides input To ECDC strategic planning.

NFP

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How?

24

E-mail exchange • Requesting information from your country. • Requesting information to ECDC.

Targeted request • Surveys or external consultations. • Country visits.

Bilateral interactions • With other EU/EEA countries. • Study visits/expert exchanges.

ECDC information systems • Discussion forums in EpiPulse.

Video conference • Ad hoc or regular virtual meetings.

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Regulation of the European parliament and of the Council amending Regulation (EC) No 851/2004 establishing a European Centre for disease prevention and control http://data.europa.eu/eli/reg/2022/2370/oj

brings a legal framework for ECDC’s recommendations to Member States regarding health threats preparedness, and also for hosting expert networks.

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The SoHO network

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ECDC SoHO network (SoHO-Net)

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Main objectives of the SoHO-Net

• Encourage cooperation between Member States

• Help to ensure that SoHO are microbially safe by monitoring, assessing and helping to address relevant disease outbreaks that can pose cross-border threats to health

• Support the detection, monitoring and reporting on serious cross-border threats to health related to SoHO

• Enhance preparedness and response planning activities in the Union

• Safeguard patients in need of SoHO

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Responsibilities of the SoHO NFPs

• Cooperate closely and communicate with National Competent Authorities

• Support and advise NCA in the establishment of the national communication channels

• Support ECDC in regular monitoring of microbial safety measures

• Contribute to the assessment of the impact of scientific advice produced by ECDC

• Report to the EpiPulse and analyse cases of infectious diseases and pathogens related to SoHO that may threaten public health in the EU/EEA

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Consists of 9 members of the SoHO-Net, nominated by SoHO-Net members • 2 members from each Blood, Organ and MAR group • 2 + 1 members from Tissues and Cells, respectively • Elected for a period of 3 years • Can be re-elected • Elected by the Network

Tasks: • Works closely with ECDC in between the network group meetings • Provides advice on urgent matters • Contributes to the agenda of the regular network meetings • Appoints a chair among its members

29

The SoHO-Net Coordination Committee (NCC)

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The SoHO-Net Coordination Committee (NCC) Appointed by the ECDC Director

NCC members Number of members Elected member

NFP Blood 2 Anna Margrét Halldórsdóttir, Iceland Imad Sandid, France

NFP Human Organs 2 Sophie Lucas-Samuel, France Paolo Antonio Grossi, Italy

NFP MAR 2 Ioana Rugescu, Romania Sara Pimentel, Portugal

NFP Tissues and Cells 3 Vacant Gorazd Čebulc, Slovenia Vacant

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SoHO-Net Organs group – Expectations and topics Group discussion

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Breakout session: share expectations on ECDC activities in the field of Organs and describe topics for activities for the SoHO-Net Organs group

You will be divided into 5 groups with one facilitator per group to guide you. Each group you will:

1. Share and discuss your expectations on the role of ECDC and the SoHO-Net Organs group in the field of Organs safety. E.g.,: platform to share good practices in the prevention of communicable disease transmission.

2. Propose and discuss topics for activities for the SoHO-Net Organs group. E.g.,: Need for guidance on the screening of arboviruses.

Summarize your discussion and conclusions in bullet points and nominate one or two persons who will present the summary of the discussions, orally or with slides.

After the coffee break: each group will have 5 minutes for presentation, followed by a common discussion. The proposed topics will be discussed again at the end of the meeting.

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Session 3 ECDC activities and Organs safety in the context of the new SoHO regulation 18 June

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Session overview 1. Presentation of the SoHO regulation – Stefaan Van der Spiegel, DG

SANTE 2. Presentation of ECDC technical guidelines – Francois-Xavier Lamy, ECDC 3. ECDC guidelines for HIV and hepatitis B and C – Flavia Cunha, ECDC 4. Questions and answers – All 5. The impact of the SoHO regulation on Organs safety – horizon

scanning – Martina Brix-Zuleger, NFP Austria 6. Discussion on the overlap between tissue and organ donors testing

and considerations in the context of the new SoHO regulation - All

A new EU Regulation on standards of quality and safety for substances of human origin intended for human

application

SoHOnet meeting organs ECDC, Stockholm, 18 June 2024

(Slides for dissemination

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EU legislation since 2002 (4 Directives)

Current EU legislation on safety and quality of substances of human origin

BLOOD & PLASMA

Transfusion Medicines

TISSUES & CELLS

Bone marrow transplant

MAR Tissue transplantation

ORGANS

EU legislation since 2004 (4 Directives) EU legislation

since 2010 (2 Directives)

The EU legislative process

Member State governments in the European Council

European Commission

Evaluation of the problem (evidence and consultation)

Impact assessment – options to address the problems – cost, burden etc. (evidence and consultation)

Drafting of new legislation

Publication of a Proposal

Negotiation trilogues

Adoption of final text

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1. Patients are not fully protected from avoidable risks because some rules are out of date

Evaluation of the Blood, Tissue and Cell legislation - published in 2019

3. Member States have divergent approaches to oversight

2. Legislation does not mitigate risks for BTC donors and for children born from donated eggs, sperm or embryos

4. Full potential of innovative therapies is not reached for patients

5. Patients are vulnerable to interruptions in EU supply of some BTC

Overall – the legislation led to increased safety and quality of BTC but gaps and shortcomings were identified

CoVID confirmed problems

EU legislation since 2002 (4 Directives)

Current EU SoHO legislation on safety and quality

BLOOD & PLASMA

Transfusion Medicines

TISSUES & CELLS

Bone marrow transplant

MAR Tissue transplantation

ORGANS

EU legislation since 2004 (4 Directives) EU legislation

since 2010 (2 Directives)

Key improvements

https://health.ec.europa.eu/blood-tissues-cells-and- organs/overview/proposal-regulation-substances-human-origin_en

Check for updates – new link will be added

when the text is published in the OJ

• Scope and advice

• SoHO activities, entities and establishments

• SoHO Preparations and their authorisation

• Standards and hierarchy of technical guidelines

• Donor Protection and Voluntary Unpaid Donation

• Recipient and offspring protection

• Vigilance

• Supply continuity

• Digitalisation – the SoHO platform

Key new and changed concepts

This presentation explains the concepts in the Regulation, as proposed by the Commission and amended during negotiations.

Borderline criteria are not set in this Regulation.

They are set in the other legislative acts (medicinal

products, medical devices)

– FUTURE PROOFING

Scope: Regulation covers all steps for all SoHO (some limited provisions for autologous SoHO), unless processing or application steps fall under scope of other EU frameworks – then SoHO regulation is restricted to certain relevant activities

• Breast milk for own child

• Organs • Private

situations • Autologous

bedside (closed systems)

Publication obligations – national security or defence

+ Breast milk and

FMT

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The following activities are regulated by the SoHO Regulation:

• SoHO donor registration

• SoHO donor history review and medical examination

• Testing of SoHO donors or persons from whom SoHO are collected for autologous or within-relationship use

• Collection

• Release

When carried out before distribution to a manufacturer, the following are also regulated by the SoHO Regulation:

• Storage; Distribution; Import; Export.

In cases where SoHO move to another framework – which SoHO provisions apply? Article 2(6)

Art 2(7) – when the SoHO is used to manufacture an autologous

medicinal product – only testing and collection are covered by SoHO Reg

The SoHO Coordination Board (SCB) - supporting implementation in MS

Members: 2 per Member State

Observers: Union bodies/institutions/agencies

& other invitees

Co-chairing by Commission and MS

Secretariat: Commission

Advice on whether the SoHO

Regulation applies - Advisory bodies in

other legislative frameworks

Exchanges on good practices with Expert

bodies – ECDC, EDQM and with EMA

Compendium on regulatory status

Documentation of • best practices for

• supervisory functions

• compensation conditions;

• Indicative criteria for critical SoHO and critical SoHO entities

Record of: • National decisions

on regulatory status • Compendium of

advice given by SCB on regulatory status

Support for joint oversight activities - inspections - Preparation

assessments

SCB

Support for coordination during emergencies

Support to COMM on the specifications for the SoHO Platform

Own initiative – a list of

substances/ products where

an opinion is needed

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Building coherent Pharma/SoHO classification decisions and advice

1. National decisions

2. If needed, EU- level advice

3. If needed, COM decisions

SoHO Pharma

a. Consult other-sector NCA (12.2, 13.1-2)

b. Request SCB opinion (13.3)

c. Consult other-sector advisory bodies (69.1c)

d. Request/give COM decision (13.5)

b. Request scientific advice (R/58.1, 61.1)

d. Request/give COM decision (R/62)

c. Consult other-sector advisory bodies (R/58.2, 61.2)

a. consult other-sector Q

(D/201)

• Scope and advice

• SoHO activities, entities and establishments

• SoHO Preparations and their authorisation

• Standards and hierarchy of technical guidelines

• Donor Protection and Voluntary Unpaid Donation

• Recipient and offspring protection

• Supply continuity

• Digitalisation – the SoHO platform

Key new and changed concepts

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Any actor organising one or more SoHO activity/ies needs to

register as SoHO entity with the Competent Authority

Supervision of all SoHO Activities that directly impact safety, quality or effectiveness

Donor Registration

Donor History Review &

Medical examination Testing of donors or autologous recipients

DistributionExport Clinical

Outcome Registration

Import

Definitions provided for the SoHO activities and recitals explain them

….but risk-based authorisation, ensuring efficient use of authority resources

A SoHO entity carries out one or more SoHO activities

A SoHO establishment is a SoHO entity that carries out at least

• Both processing and storage, or

• Release, or

• Import, or

• Export

Note: CAs may regulate a SoHO entity as a SoHO establishment, even if it does not meet the criteria above, if it considers that the entity has a particularly important impact (e.g. a testing laboratory that tests donors for a whole region or country, a register that identifies and selects donors for one or more Member States).

A SoHO establishment may carry out many other

SoHO activities – all

will be included in

their authorisation

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The concept of SoHO entities and SoHO establishments: graded approach to oversight - high level of transparency

SoHO Entities

SoHO Establishments Must be registered, authorised,

and inspected regularly

SoHO entities must be registered

Importers Additional specific authorisation requirements

• Responsible person (+/- as today) • Releasing officer(s) • Nominated physician

• Responsible person (+/- as today)

Note – derogation for plasma for PDMP that is included in a PMF –

see Art 47(2)

Note – Risk-based scheduling – m x 4 years b tw en on-site inspections

• Scope and advice

• SoHO activities, entities and establishments

• SoHO Preparations and their authorisation

• Standards and hierarchy of technical guidelines

• Donor Protection and Voluntary Unpaid Donation

• Recipient and offspring protection

• Vigilance

• Supply continuity

• Digitalisation – the SoHO platform

Key new and changed concepts

SoHO

Blood

SoHO Preparations

Plasma

Red blood cells

Platelets

SoHO Preparation Authorisation – robust evidence of safety and effectiveness

What is a ‘SoHO Preparation’? A particular SoHO that has been subjected to processing, and where relevant other SoHO activities, has a specific clinical indication and is intended for immediate application to a recipient or for distribution.

Must be authorised

EXAMPLE

The concept of SoHO entities and SoHO establishments: graded approach to oversight - high level of transparency

SoHO Entities

SoHO establishments Must be registered, authorised,

and inspected regularly

SoHO preparations must be authorised – need for evidence of safety and effectiveness

Processing SoHO

SoHO entities must be registered

SoHO Preparation Authorisation

1 Systematic Benefit:Risk Assessment to determine the evidence available on safety, quality and effectiveness

2 Submission of an application, including laboratory validation and other safety, quality and effectiveness data and, where relevant, a clinical outcome monitoring plan proportionate to risk

OR Grant an

approval of the Clinical Outcome Monitoring plan or request an amended plan

3 Assessment of the application by the competent authority

Grant authorisation for

the SoHO preparation

Refuse authorisationOR

Based on preparatory work done by GAPP Joint Action (incl. stakeholders from 17 countries: 15 CAs & professional associations)

Taking into account any

relevant EDQM monograph

Assessment by the competent authority of evidence of safety, quality and effectiveness data gathered in clinical outcome monitoring

4

Grant authorisation

Refuse authorisation

OR

Clinical Outcome Monitoring Plans for gathering further evidence of safety and effectiveness in recipients

Negligible Risk

Low Risk

Moderate Risk

High Risk

No clinical outcome monitoring required Clinical follow-up of a defined number of patients is required

clinical investigation study with appropriate number of patients and pre-defined clinical endpoints

comparison to standard therapy

+

+

Positive expected benefit:risk

Sufficient evidence of positive benefit:risk

OR

Study summaries registered on SoHO Platform prior to

commencement

Evidence of ethics

committee approval

• Scope and advice

• SoHO activities, entities and establishments

• SoHO Preparations and their authorisation

• Standards and hierarchy of technical guidelines

• Donor Protection and Voluntary Unpaid Donation

• Recipient and offspring protection

• Vigilance

• Supply continuity

• Digitalisation – the SoHO platform

Key new and changed concepts

The challenge of setting technical rules

Clarity Agility

Detailed harmonised

rules

Rules that are

responsive to risk TECHNICAL GUIDELINES

The way to comply with the standards – defined outside

the Regulation Detailed and including SoHO

specific elements

STANDARDS

Defined in the Regulation Generic

Implementation of generic standards through technical guidelines – staying up-to-date with the science in an agile way

Commission Implementing Legislation

Technical Guidance on the EU SoHO Platform

“Equivalent” Guidance

Other guidelines or methods based on international standards

or scientific evidence

If none:

OR:

“where the Commission deems necessary”

Published & updated by ECDC/EDQM

Demonstrated by MS to achieve the standards in the Regulation

OR: Inspectors shall deem

the standards to be met

MS shall demonstrate compliance with standards – may do so by

demonstrating equivalence to ECDC and EDQM

Entities shall demonstrate equivalence to inspectors – may do so by demonstrating

equivalence to ECDC and EDQM

• Scope and advice

• SoHO activities, entities and establishments

• SoHO Preparations and their authorisation

• Standards and hierarchy of technical guidelines

• Donor Protection and Voluntary Unpaid Donation

• Recipient and offspring protection

• Vigilance

• Supply continuity

• Digitalisation – the SoHO platform

Key new and changed concepts

SoHO Donor Protection – significantly strengthened Protection of SoHO living donors before, during, and after the collection.

- Including for donations by relatives

- Information & consent

- Physical and mental integrity, non-discrimination, data protection & safeguarding of

anonymity (with some exceptions e.g. ID of MAR parents when allowed or obliged in

MS)

- Donor health evaluation

- Risk-proportionate approach to donor monitoring: registration of donors subjected to

- surgical procedures

- medicinal product treatment

- frequent or repeated donations implying risk to health.

- Required reporting of serious adverse reactions in donors

Protection of the dignity and integrity of SoHO deceased donors

- Information & consent by relatives, when applicable

• NO financial incentives or inducements to donate

• Compensation of living donors for losses can be allowed in accordance with the principle of VUD

• When a Member State allows compensation – upper limit to be set in national legislation – transparent criteria based on best practices established by the SCB

• Compensation conditions set in MS to be shared with the other MS via the SCB

• Donation promotion and publicity activities must not refer to compensation (without prejudice to national laws on information provision)

Voluntary & Unpaid Donation Principle maintained

Based on Recommendations of the Council of Europe Committee on Bioethics – aiming for financial

neutrality

Considerable elaboration of recitals (4) to explain provisions

• Scope and advice

• SoHO activities, entities and establishments

• SoHO Preparations and their authorisation

• Standards and hierarchy of technical guidelines

• Donor Protection and Voluntary Unpaid Donation

• Recipient and offspring protection

• Vigilance

• Supply continuity

• Digitalisation – the SoHO platform

Key new and changed concepts

• Identification and mitigation of risks from transmissible infectious, genetic, malignant diseases

• Identification and mitigation of risks from toxins, contaminants from the environment, other donations, the personnel, the equipment, reagents etc.

• Identification and mitigation of risks of detrimental effects on inherent properties of the SoHO concerned

• Identification and mitigation of risks of harmful immune reactions

• Application of national rules regarding the maximum numbers of offspring from one SoHO donor

• No application of SoHO unnecessarily or in cases where there is no proven benefit

• No promotion of SoHO application based on misleading information

• No human application of SoHO without therapeutic or assisted reproduction objective (i.e. no exclusively cosmetic or nutritional applications)

Recipient and offspring protection

• Scope and advice

• SoHO activities, entities and establishments

• SoHO Preparations and their authorisation

• Standards and hierarchy of technical guidelines

• Donor Protection and Voluntary Unpaid Donation

• Recipient and offspring protection

• Vigilance

• Supply continuity

• Digitalisation – the SoHO platform

Key new and changed concepts

Competent Authorities: working together for improved oversight

One or more SoHO competent authorities SoHO national authorities

of other Member States

SoHO Coordination Board

Other Non-SoHO Authorities

SoHO Establishments and entities

Designate

Member States

Note: Some SoHO supervisory activities can be delegated to delegated Bodies

SoHO national authority: Liaison & Cooperation

SoHO competent authorities: SoHO Supervisory Activities

Main Roles

Clearly defined principles on independence,

impartiality and transparency

If just 1 CA is designated → it is also considered as the

SoHO national authority

SNA

SoHO competent authoritiesIf more than 1 CA are designated → 1 among them to be designated

as the SoHO national authority

Send SAR/SAE notification & SAR/SAE investigation report to their CA

• Verify info of SAR/E notifications & investigation reports, assess the results of the investigation, inform the entity

• Send annual summary of SAR/E notifications & investigation reports received to their SoHO National Authority

• Launch SoHO rapid alerts

• Aggregate the summaries from the SoHO National Authorities

• publish annual SoHO vigilance report

Communication with CAs from other frameworks

• Submits annual summary to the EU SoHO Platform

• Publishes aggregated summary for their MS

SoHO Entities

Competent Authorities

Vigilance overview – largely unchanged

No change to SAR/SAE definitions!

• Inclusion of SAR reporting requirement for SAR in living SoHO donors

• Clarification that SAR/E detected during clinical outcome monitoring must be reported

• Obligation for reasonable efforts to encourage recipients of MAR donations to communicate information on genetic conditions in offspring – when serious these are reportable as SAR

• Role of ECDC for SAR concerning infectious disease transmissions

• Formalisation of communication requirements with CAs in other sectors, when appropriate

• Clarification that loss of critical SoHO constitutes an SAE in defined situations

• CAs to provide guidance and templates to professionals and to inform relevant SoHO entities of Rapid Alerts received

Vigilance enhancements Best practices agreed and

documented by SCB

• Scope and advice

• SoHO activities, entities and establishments

• SoHO Preparations and their authorisation

• Standards and hierarchy of technical guidelines

• Donor Protection and Voluntary Unpaid Donation

• Recipient and offspring protection

• Vigilance

• Supply continuity

• Digitalisation – the SoHO platform

Key new and changed concepts

Resilience of Supply Critical SoHO

‘Critical SoHO’ are SoHO that for which an

insufficient supply will result in serious harm or

risk of harm to patients or a serious interruption in

manufacture of critical products regulated by

other legislation.

A ‘critical SoHO entity’ is a SoHO entity

that carries out activities contributing to the

supply of critical SoHOs and the scale of

those activities is such that a failure to carry

them out cannot be compensated by

activities of other entities or alternative

substances or products for recipients.

- Obligations on Member States to

ensure a sufficient, adequate and

resilient supply

- Facilitate donation

- Communication and education

- Optimal use

- Activity data collection and

monitoring

- Supply alerts

- National SoHO emergency plans

- SoHO Entity emergency plans

- Derogations and additional measures

in emergency situations

Supply of critical SoHO is protected by:

New article!

• Scope and advice

• SoHO activities, entities and establishments

• SoHO Preparations and their authorisation

• Standards and hierarchy of technical guidelines

• Donor Protection and Voluntary Unpaid Donation

• Recipient and offspring protection

• Vigilance

• Supply continuity

• Digitalisation – the SoHO platform

Key new and changed concepts

Vigilance reporting

Rapid alerts

Member State National and

other competent authorities

Technical guidelines for

implementation of standards

More stringent national

measures

Supply flows and shortages

monitoring

Supply alerts

SoHo Coordination

Board Membership and compendium of

advice given

Registry of entities and

their authorisations

Digitalisation – efficiency, transparency, monitoring

The EU SoHO

Platform

Compendium of authorised

SoHO preparations

+ List of ongoing Clinical studies

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SoHO Platform Roadmap

May 2024

2024

SOHO-X development and maintenance (internal team)

- Cloud architecture @ DIGIT

- Architecture & reuse - Automated testing - Releases 0.1 to 1.0

- Security Plan

Release 0.1 Release 0.2 Release 0.3 Release 1.0

- Home page + global search - Registration + preparation - Publication of technical guidelines

- Notifications and alerts - Reporting 1 - Publication 2

- Collaborative space - Indicators - Reporting 2 - Publication 3

- Interoperability - Testing phase with CA

Mapping and interoperability study

October 2024

2025

February 2025

September 2025

2026

February 2026

Q2 2026

Release 1.1

- Production phase

- Follow-up with CA and Entities

• Formal approval by the Council and publication in the Official Journal

• The Regulation will enter into force 20 days after its publication in the Official Journal of the European Union – during 2024 (~ before summer)

• 3 years before the provisions become applicable - 2027 (an additional year for some provisions)

Next steps Entry into Force and Date of Application

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Project name (year) Scope 1. SUPPLY (2021) Shortages, supply continuity (plasma) 2. EGALITE (2021) Availability, accreditation (Tissues) 3. BRAVEST (2021) Crisis resilience (Organs) 4. EuroTRACTOR (2021) Outcome registry (HSC) 5. EUMAR (2021) Outcome registry (MAR) 6. SIGHTSoHO (2021) Training authorities (B, TC) 7. Cooperation Agreement EDQM (2021) Guidelines, vigilance, support professionals, supply (B, TC, O) 8. Readership (2022) New obligations entities in hospitals (B, TC) 9. GAPP-Pro (2022) New obligations process authorisation (B, TC) 10. New SoHO Breast Milk (2023) Implementation new requirements for Breast milk banks 11. New SoHO FMT (call will be relaunched in 2024)

Implementation new requirements for FMT

11. Paired kidney exchange (2023) Organs 12. Cooperation Agreement EDQM (2024) Guidelines, vigilance, support professionals, supply (B, TC, O) 13. SoHO-X ICT (2024) SoHO digital platform – new Regulation (B, TC) 14. Support for Organisational by SoHO Authorities (call to be launched in 2024)

Support the implementation of the supervisory functions in the new SoHO regulation

15. Regulatory Coherence (call to be launched in 2024)

Topics of concern across EU frameworks

Current & future EU4H actions SoHO Support implementation Focus on implementation

Thank you

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Technical guidelines on the prevention of donor-derived transmission of communicable diseases through SoHOs SoHO-Net Organs Group meeting – 18 June 2024

76

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Context

Article 59, paragraph 4 For those standards, or elements thereof, concerning protection of SoHO recipientsand offspring from medically assisted reproduction for which no implementing acthas been adopted, SoHO entities shall take into account: a) The most recent technical guidelines, as indicated on the EU SoHO Platform […] :

(i) published by the ECDC concerning the prevention of communicable disease transmission;

77Of note: organs are excluded from the definition of SoHO from the scope of this regulation and thus of this project

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Role of ECDC

78

• Develop and publish technical guidelines concerning the prevention of donor-derived communicable disease transmission through SoHO application

• Cover relevant pathogens for SoHO: those listed in the current directives and those with current acute relevance (e.g., Dengue virus)

• For SoHOs as defined in the Regulation (i.e., not including organs) • Supported by an ad hoc scientific expert panel(s)

The development of technical guidelines follows internal ECDC procedures approved by ECDC’s Advisory Forum

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79

Overall project plan

SoHO-Net

(ToR: Cooperate closely and

communicate with relevant NCA on SoHO

microbial safety topics)

NCAs

Scientific expert panel provide expertise and

data/evidence; analyse;

deliver opinion

ECDC coordinate; organise; provide

data/evidence (literature searches, systematic reviews); deliver final recommendation

document

relevant decisions

Available on SoHO Sharepoint

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Guideline content development process • The expert panel is ultimately expected to provide feedback on statements

regarding: • Testing strategies • Deferral strategies (including deferral periods) • Testing methods

• The feedback of the panel serves as a basis for ECDC to draft the guidelines

• The draft guidelines will be submitted for review to ECDC advisory forum, SoHO-Net, EDQM, EMA, WHO and to other relevant stakeholders (closed consultation)

80

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ECDC SoHO guidelines – update Overview

81

Expert panel meetings - HIV: Sept 23–Feb 24

- HBV/HCV: May 24–Sept 24 (next meeting: 03 July)

- T. pallidum: Dec 24–May 25

HIV Guideline draft and review - Drafting February to June 2024 - SoHO-Net review: June to August 2024  SoHO-Net should liaise with NCAs

- External stakeholder consultation: November-December

Publication Current plan: - HIV: March 2025 - HBV/HCV: End 2025 - T. pallidum: 2026

Note: timelines are according to current plan

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ECON ECDC SoHO-Net Collaboration Centre

82

Guidelines: draft guidelines for SoHO-Net review

Meetings: “short minutes” of expert panel with decisions and agreements

Pathogen data sheets: Latest versions of the evidence base for the guidelines

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Thank you

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ECDC guidelines Recommendations for donor testing for HIV and HBV/HCV in SoHOs other than solid organs

Flávia Cunha, ECDC Stockholm, 18 June 2024

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Context

• Which risks of exposure are relevant for SoHO safety?

• Which SoHO donors should be tested?

• When to test?

• Which laboratory screening tests should be used?

• What to do in case of reactive screening tests?

• What deferral period should be considered?

85

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Context

86

Expert panel meetings - HIV: Sept 23–Feb 24

- HBV/HCV: May 24–Sept 24 (next meeting: 03 July)

- T. pallidum: Dec 24–May 25

HIV Guideline draft and review - Drafting February to June 2024 - SoHO-Net review: June to August 2024  SoHO-Net should liaise with NCAs

- External stakeholder consultation: November-December

Publication Current plan: - HIV: March 2025 - HBV/HCV: End 2025 - T. pallidum: 2026

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Risks of exposure to HIV

87

Recent risks of exposure to HIV should be considered when assessing donor eligibility.

Deferral period in case of recent risk of exposure to HIV

• At least 8 weeks since the last event with a risk of exposure to HIV.

• Exceptions: oral PrEP or PEP - 12 weeks | injectable PrEP – 24 months.

• Deceased donors  not applicable; test results not reliable and risks of exposure to HIV should be considered.

ECDC NORMAL

Risks of exposure to HIV

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It is advised to consider the following risks of exposure to HIV:

Active sexually transmitted infection (STI) Condomless anal sex with a new partner Condomless anal sex with more than one partner Condomless sex with a partner infected with HIV Condomless sex with a partner using injectable drugs Condomless sex with a partner using PrEP or PEP Condomless sex with a partner with an active STI Needle sharing and/or injecting drug use Transactional sex in a country with a higher HIV prevalence than in the EU/EEA Use of injectable PrEP Use of oral PrEP or PEP

ECDC NORMAL

Donor testing – HIV – Tissues/Deceased donors

REQUIRED

Testing of donors

• All donors, at donation, should be tested for HIV.

Screening tests

• NAT detecting HIV-1 RNA + anti-HIV-1/2.

• NAT should have two targets in the HIV genome.

• NAT 95% Limit of detection (LOD): ≤50 HIV RNA copies/ml.

* Reactive is defined as repeat reactive if the serological test is repeated. If the serological test is initially reactive and negative in retesting, the donation can be considered negative provided the NAT is also negative. 89

ECDC NORMAL

Donor testing – HIV – Tissues/Deceased donors

ADVISED Screening tests • Use of NAT detecting both HIV-1 and HIV-2 RNA.

Outcome of test results

• Retest initially reactive anti-HIV-1/2  retest with the same assay and in the same sample.

• No need to retest reactive NAT.

Practical consideration:

• Antigen-antibody (Ag-Ab) combination tests instead of Ab-only tests.

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ECDC NORMAL

Donor testing – HIV – Tissues/Living donors

REQUIRED

Testing of donors

• All donors, at each donation, should be tested for HIV.

Screening tests

• NAT detecting HIV-1 RNA + anti-HIV-1/2.

• NAT should have two targets in the HIV genome.

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ECDC NORMAL

Donor testing – HIV – Tissues/Living donors

ADVISED

Screening tests

• Use of NAT detecting both HIV-1 and HIV-2 RNA.

• NAT 95% LOD ≤ 50 HIV RNA copies/mL

Outcome of test results

• Retest initially reactive anti-HIV-1/2  retest with the same assay and in the same sample.

• No need to retest reactive NAT.

• If first confirmatory test positive or indeterminate  second confirmatory test on a separate sample.

Practical consideration:

• Ag-Ab combination tests can be used instead of Ab-only tests.

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ECDC NORMAL

Donor testing - HBV

• First panel meeting on 07 May 2024. • List of risks of exposure to HBV assessed, but still open for further discussion.

TESTING STRATEGY

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For all SoHOs: