Prion Infection in Antibody Deficient Patients Surveillance for Asymptomatic Prion Infection in Primary Immunodeficiency Patients Exposed to UK Sourced Immunoglobulin National CJD Research & Surveillance Unit Western General Hospital, Edinburgh, EH4 2XU National Creutzfeldt-Jakob Disease Research & Surveillance Unit (Edinburgh) Prion Infection in Antibody Deficient Patients Principle Investigator: Dr Anna Molesworth, PhD Research Nurse: Ms Emma Hughes BACKGROUND Prion diseases are associated with a naturally occurring protein (the prion protein) that has changed into an abnormal form. Most cases have no known cause, but one type of prion disease called variant Creutzfeldt-Jakob Disease (vCJD), usually linked to eating beef, may more rarely be transmitted by blood transfusion from someone who themselves later developed vCJD. Variant CJD may also be spread by treatment with certain blood products, which were made from mixing plasma from several thousand donors. A total of 177 cases of vCJD have been reported in the UK to date, the last occurring in 2012, although research has shown that as many as 1 in 2000 people in the UK may be infected without signs of disease. There have been 4 instances of transmission of vCJD through blood transfusion and one asymptomatic infection detected in a haemophilia patient who died of other causes. It is possible that this latter patient, identified by the UK Haemophilia Centre Doctor’s Organisation through their enhanced prion surveillance study amongst patients with bleeding disorders, may have been infected as a consequence of past exposure to multiple batches of Factor VIII. At the time of writing, there is no blood test for prion infection that can reliably tell us if someone is infected with vCJD before they develop symptoms of disease, although scientists are working on this. The purpose of this study is to see if we can find any evidence of prion infection in antibody deficient patients who received certain UK sourced immunoglobulin products between December 1996 and December 2000. We do this by following participants over several years and testing any available tissue (for example, the tissue left over from routine biopsies) and blood (when a suitable blood test becomes available) for the abnormal prion protein that causes prion disease. This will inform policy makers in managing the risk to patients and protecting public health. STUDY TRANSFER This study began in July 2006 under sponsorship of Central Manchester & Manchester Children’s University Hospitals NHS Trust, lead by Dr Matthew Helbert, Consultant Immunologist and Research Nurse Cathy Bangs. In April 2015, management of study transferred to the UK National CJD Research & Surveillance Unit (NCJDRSU) in Edinburgh, under the co-sponsorship of the University of Edinburgh and NHS Lothian, and funded by the Department of Health (UK) Policy Research Programme. The NCJDRSU has been involved with the study since the first participants joined in 2006; the project continues now under NCJDRSU management with continued support of the previous research team, with PIDUK & UKPIN. THE EDINBURGH RESEARCH TEAM The research team at the NATIONAL CJD RESEARCH & SURVEILLANCE UNIT (NCJDRSU), which is part of the University of Edinburgh, brings together doctors, scientists and nurses with a special interest in prion disease surveillance, epidemiology and clinical & laboratory research. We provide doctors with information about prion disease, and advice on how to look after their patients. We also do research into the causes of prion disease. In this research project we are working with immunology teams and patients throughout the UK to help us understand more about the causes of prion disease, particularly about the risks that may be associated with previous blood product treatment in patients with primary immunodeficiencies. Dr Anna Molesworth, PhD is an epidemiologist by training and has been with the University of Edinburgh since 2010. She contributes to the clinical surveillance of CJD in the UK and related public health activities, including enhanced surveillance of patients exposed to CJD in the medical setting, and also works closely with the UK national public health agencies as part of her current work. Anna takes overall responsibility for the conduct of the study and its coordination at different sites. Ms Emma Hughes is the newly appointed Research Nurse, and has clinical experience around the UK, Australia & New Zealand. Emma will coordinate field operations, liaising with immunology teams and facilitating multi-site participation in the study. When not working on the study, Emma is currently studying for a PhD through Edinburgh University. In addition, Anna and Emma are supported by colleagues working in clinical neurology and neuropathology laboratories, including Suzanne Lowrie (Senior Biomedical Scientist), Dr Diane Ritchie and Dr Alexander Peden (Postdoctoral Research Fellows), Nick Attwood (Database Manager), Dr Mark Head (Reader, Prion Protein Biochemistry), Professor James Ironside (Professor of Clinical Neuropathology), and Professor Richard Knight, Consultant Neurologist and NCJDRSU Director. RESULTS SO FAR By the end of March 2015, 77 of approximately 175 potentially eligible patients had joined the study, of whom ten had died and two were lost to follow up. The study findings, published recently, report no evidence of asymptomatic vCJD infection in immunodeficiency patients treated with UK sourced immunoglobulin (Helbert, MR et al. Vox Sanguinis 2015; DOI: 10.1111/vox.12358). There was no clinical evidence of vCJD observed in any of the 75 participants. There was no evidence of prion infection in the tissues of 15 patients, spanning 3-18 years after their last exposure. This was based on 23 tissue samples of sufficient quality to inform analysis, including samples from 4 autopsies. FUTURE PLANS With transfer of the study to the NCJDRSU in Edinburgh, some changes have been made to protocol, with the intention of simplifying the research process. These changes require ethical and R&D approval. They include: A questionnaire to record immunoglobulin treatment, as well as past medical history of blood/products transfusion and surgery. We would also like to ask participants where they have lived, their type of work and any family history of dementia. This information helps to identify the most likely cause of prion infection, if ever we have a positive finding. Restriction of tissue analysis to those samples most informative for laboratory investigations, including lymph node, tonsil, spleen, gut (includes appendix), brain and bone marrow trephine; identifying tissue samples retrospectively. Continued collection of blood for storage for future testing, but doing this once every 2-years instead of annually, collecting 1x10ml and 1x 5ml blood sample. Blood samples will now be sent to the CJD Resource Centre at the National Institute of Biological Standards and Control (NIBSC) in Hertfordshire for storage and future testing, instead of Manchester where they have previously been stored. We will continue to seek consent in life from all participants for post-mortem examination and tissue investigation for evidence of CJD. The study aims to include all specialist immunology centres providing treatment and/or care for PID patients throughout the UK. CONTACT US Research Nurse Emma Hughes will be undertaking site visits at the start of 2016. Emma will be in touch over the next few weeks to arrange these visits. In the meantime, don’t hesitate to contact us if you have any questions: Ms Emma Hughes (Research Nurse) Dr Anna Molesworth (PhD, Principal Investigator) National CJD Research & Surveillance Unit, University of Edinburgh Western General Hospital Crewe Road, Edinburgh EH4 2XU Telephone: 0131 537 2128 Email: emma.hughes19@nhs.net We would like to thank participants, their families and their care teams for their continued support of the study. We are looking forward to working with you. 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