Updates from UKPIN and conferences

Update from ESID and IPOPI Conference 2018

Summary of the main research findings and the challenges ahead:

Diagnosis and screening

  • There is increased understanding of the complications (clinical profile) of PID and the concept of immune dysregulation resulting in autoimmunity and inflammation.  
  • There is an expanding list of EU countries screening for PID using KREC (B-cell) and TREC (T cell) analysis. 
  • In the USA, the National Institute of Health has plans to use genome sequencing for screening newborns. The project called NSIGHT (Newborn Sequencing in Genomic Medicine and Public Health) has ethical, legal, and social implications.
  • To help poorer countries that have limited access to advances in genomic medicine, a gene panel array covering a limited of genes affected in PID has been developed in collaboration with IPOPI. The cost per screening will be approximately 25 Euros.  
  • ‘Multiomics’ analysis, a combination of technological approaches looking at genome (DNA), proteome (proteins), transcriptome (RNA), and microbiome (microbes that live in a person), is being used increasingly to achieve a correct diagnosis. 

Identification of new PID conditions

  • Several new PID conditions have been molecularly characterised e.g. ZNF341 regulates STAT3 activity and there were comprehensive reviews of major signalling pathways where genetic defects lead to PID.
  • Over thirty different genes have now been identified in patient populations grouped under the CVID umbrella.
  • Identifying and managing the ongoing challenge of secondary immunodeficiency was discussed.

Advances in treatment

  • New data was presented on biologics e.g. Abatacept, Vedolizumab for the treatment of inflammation in PID were discussed. Small molecule inhibitors are being increasingly used e.g. Ruxolitinib in HLH, Tofacitinib, Baricitinib in early presenting autoinflammatory disorders.
  • Low dose oral azithromycin may be effective in treating bronchiectasis and may have an additional immunomodulatory effect building on knowledge from chronic obstructive pulmonary disease (COPD) and applying it to PID.
  • The effectiveness of the antiviral drug pocapavir to treat chronic enteroviral infection in PID was described, as was topical Cidofovir under occlusion for advanced warts in EVER 1/2. 
  • Over eighty different PID conditions have now been treated by haematopoietic stem cell transplant (HSCT), also referred to as BMT.  With advances in HSCT chemotherapy/conditioning regimes that significantly reduce the chance of graft versus host disease, donor availability may no longer be a problem. HSCT can also be appropriate now for patients with inflammatory complications. 
  • The age range of who can be successfully treated by HSCT is now increasing and over 150 adult patients worldwide have been treated with HSCT (see article in our newsletter issue 8 on recent UK results).  
  • The number of PIDs that can be treated by gene therapy (GT) is increasing through international collaboration and commercial interest in the development of these therapies.  These include types of SCID, Wiskott Aldrich Syndrome, HLH, IPEX, CGD and Leucocyte Adhesion Deficiency (LAD). 
  • Preclinical data was presented on the use of gene editing in treating X-SCID.

Challenges ahead

  • Overwhelming knowledge about the fundamental immunology and clinical presentation of PID was presented but how this translates into real patient information to guide care is not straightforward.  Linking clinical history and laboratory results to genetic diagnosis will be key and this is best done in specialised centres.
  • The welfare gap between PID patients in the Western world and other geographical areas is not closing.
  • Overall Improvements in patient care (specialist care and access to medicines) is lagging behind advances in basic and translational science.  Access to immunoglobulin therapy, new medicines and very high cost curative therapies such as HSCT and GT is challenging in many countries, and even in more well-off areas of the world access, is becoming increasingly constrained due to pressure on health budgets.

July 2015 - RCP to host Quality in Primary Immunodeficiency Services accreditation scheme

The Royal College of Physicians’ (RCP) accreditation unit is pleased to announce the publication of the Quality in Primary Immunodeficiency Services (QPIDS) clinical service accreditation standards and evidence requirements. The standards are being made available ahead of the official launch of the QPIDS accreditation scheme in the autumn.

The RCP is adopting the existing UK Primary Immunodeficiency Network (UKPIN) accreditation scheme and the revised standards will underpin the renamed QPIDS accreditation scheme. Publishing the standards ahead of the launch will allow hospitals and healthcare professions to familiarise themselves with the new standards before they register their services in order to be accredited.

The RCP accreditation schemes have a strong track record in improving the quality and safety of patient healthcare. It hosts several accreditation schemes, including the Joint Advisory Group (JAG) on gastrointestinal endoscopy, Safe Effective Quality Occupational Health Service (SEQOHS), Improving Quality in Physiological diagnostic Services (IQIPS) and Improving Quality in Allergy Services (IQAS).

Dr Claire Bethune, QPIDS clinical lead and consultant immunologist, said:

‘The new QPIDS scheme hosted by the RCP accreditation unit will build on the success of the UKPIN accreditation scheme for primary immunodeficiency services. It will have effective processes and a supportive accreditation pathway for services working towards accreditation, and a more robust governance structure. The revised standards document published today will provide services with clear recommendations for the evidence required to demonstrate compliance with the standards.’

Full details of the new QPIDS clinical service accreditation and evidence requirements can be found here.

There are currently 11 fully accredited immunology centres in England. 

UK Primary Immunodeficiency Network (UKPIN) update - May 2015

The UK PID registry

The UK Primary Immunodeficiency Registry (UKPID Registry) is the first on-line registry of primary immune deficiency in the UK and currently contains data on over 3146 patients.  The registry is now in its sixth year and is starting to give important information on numbers of patients affected by a particular PID conditions, their geographical spread across the UK, details of diagnostics delay and the effectiveness of different treatments for patients. 

Validating the data

A major piece of work has been revalidation of the data within the registry and has involved ensuring that patients entered on the registry fit specific diagnostic criteria.  In some cases this has led to patients being identified that have had a miss diagnosis. Data from patients who have been lost to follow up have also had their data removed from the registry. These checks ensure that the registry data is robust and reliable so that it can be used for research purposes.

Historical data from people who have passed away will be stored in the inactive component of the registry, so that this key variable in patient outcome can still be analysed.  In the future patients presenting in extremis as a new diagnosis who subsequently die can be registered, so that we can continue to learn from these thankfully rare but distressing events.

One major achievement has been the publication of the paper The United Kingdom Primary Immune Deficiency (UKPID) Registry: report of the first 4 years’ activity 2008 - 2012 that appeared in the journal of Clinical and Experimental Immunology in 2013.  

The data is now at a stage where it can be used for research purposes, for example comparing different treatments and their outcomes. It is envisaged that the registry will be linked with other projects involving PID patients for example the BRIDGE project and 100, 000 genome project so that clinicians and scientists can start to study any correlations between clinical problems and underlying genetic causes.

Linking the UK PID registry with larger sets of data

The UK is a central partner of the European Society of Immunodeficiencies (ESID) registry steering committee and shares anonymised data with the ESID registry, which captures PID patient data from European countries where appropriate patient consent has been given.  

Dr Matthew Buckland, who is the UK representative on the ESID Registry Steering Committee said the re-designed registry, harmonised in the UK with the rest of Europe provides us with the tools to analyse data at 3 distinct levels:

Level 1 – basic epidemiology
Level 2 – disease specific data
Level 3 – bespoke, usually prospective research questions.

If you are not on the Registry and you want to help then please take a look at our frequently asked questions about this project.

Accreditation of immunology centres

UK Primary Immunodeficiency Network’s (UKPIN) officially recognised accreditation process helps ensure a high quality of service by immunology teams involved in the care of patients affected by PIDs.

The accreditation process covers six key areas: staffing levels, facilities required, organisation and administration of the service, quality of clinical care including home therapy training and support for patients and audit, education and management of the service. The process currently involves perspectives from two patients.

Increase in number of accredited centres

Over the last couple of years there has been an increase in the number of centres going through the accreditation process. This has been due to the requirement within the service specification of NHS England Clinical Reference Group for Allergy and Immunology that centres should be working towards full UK PIN accreditation. At present there are 11 fully accredited centres in England:

  • Royal Victoria Infirmary, Newcastle (the adult service)
  • St James University Hospital, Leeds
  • Salford Royal Hospital
  • Northern General Hospital, Sheffield
  • Heartlands Hospital, Birmingham
  • John Radcliffe, Oxford
  • Derriford Hospital, Plymouth
  • Royal Hospitals, Belfast
  • University Hospital of Wales, Cardiff
  • Barts and The London
  • Royal Free Hospital, London

The involvement of the Royal College of Physicians

Recently the Royal College of Physicians (RCP) accepted the UK PIN accreditation process under its auspices and going forward the RCP will be hosting a new quality in PID services (QPIDs) platform. It will have an associated web tool for centres to enter the necessary information to gain and maintain their accreditation standard. This will eventually lead to a virtual assessment of centres on an annual basis. New standards and guidance for the accreditation process are being developed and will be published later this year. It is unclear, at present, whether there will be an aligned inspection process for immunology and allergy services. 

November 2014

IPOPI 16th Biennial Meeting, Prague, 29th October – 1st November 2014

Presentations from this meeting are available here.  Educational topics on how the immune system functions, PIDs and autoimmunity and an update on newborn screening for SCID are covered.

April 2014

Report from the International Primary Immunodeficiency Congress, November 2013 published

Key highlights from The International Primary Immunodediciencies Congress on clinical care and diagnosis of PIDs have been published. The report gives an update on advances in the understanding of the disease processes in PID, details of new technologies to improve diagnosis and where clinicians are in the treatment of PIDs by replacement therapy, bone marrow transplant and gene therapy.

December 2013

Update from UK PIN 2013 – UK Primary Immunodeficiency Network Forum, Liverpool.

Next Generation Sequencing and its application to PIDs

Next Generation Sequencing is a new and powerful method that can give a read out of a person’s DNA code very quickly and accurately.  This means that finding ‘errors’ (mutations) in DNA, for example those genetic changes that cause PIDs, is much easier to do.  Already it is being used to help the diagnosis of PIDs and helping further research, however it will be some time before this technique is used routinely in clinic.  When it does many ethical and societal considerations will need to be taken into account. These include the potential of finding DNA mutations unrelated to the condition being looked for and how these findings would be handled and how insurance companies could use the data generated.

Newborn screening: TRECs and KRECs

Screening for X-SCID in newborns uses a method that looks for the absence or low numbers of T-cells using what is known TREC (T-cell receptor excision circles) analysis. Dr Hammarstrom, from the Karolinska Institute, Sweden described his research to pick up PID conditions where few or no B cells are made. This uses a similar technique to TREC but is called KREC (B-cell kappa chain excision circles) analysis. The number of KRECs in the newborn blood sample being directly related to the number of B cells present.  This would lead to the widening of newborn screening programmes, in some countries in Europe, to include combining both TRECs and KRECs analysis into one screening programme.  This means that many different PIDs could be detected at the same time in the screening test, without the need for additional sampling. 

Dr Hammerstrom showed evidence that this combined approach could be used to detect not only SCID but XLA, Nijmegen Breakage Syndrome and Ataxia telangiectasia, conditions where B cells are absent or reduced. The method is not perfect and does not detect all these conditions so awareness in combination with other diagnostic methods remains important.  In the future it may be possible to start to screen for complement deficiencies and disorders that affect how phagocytes work, such Chronic Granulomatous Disease (CGD).

The UKPID Registry

Dr Buckland updated the conference on the progress of the UK Primary Immunodeficiency Registry (UKPID Registry). It is the first on-line registry of primary immune deficiency in the UK and contains data on over 2890 patients.  The registry is in its fifth year and is starting to give valuable information on how many patients are affected by particular PID conditions, the geographical spread of PID patients across the UK, their diagnoses, how old they when they are diagnosed, details of diagnostics delay and the effectiveness of different treatments for patients. 

November 2013

Update from the International Primary Immunodeficiency Congress (IPIC 2013).

‘Half-way house’ for the implementation of a UK national screening programme for X-SCID

Professor Bobby Gaspar, Professor of Paediatrics and Immunology at Great Ormond Street Hospital, updated the conference on the current position of the UK national screening programme for X-SCID.

SCID can be a fatal condition for children who are not diagnosed within the first 2-3 years of life. However, if detected early the condition can be managed effectively so as to avoid life-threatening infections and treatments such as stem cell transplants and gene therapy are available with good success rates.  In 2012 proposals were put forward to UK National Screening Committee (UKNSC) to put in place a national screening programme to test newborns for SCID using blood spots taken from Guthrie cards. This would help ensure children do not die needlessly from this condition.

Review and consultation

Professor Gaspar explained ‘For the national screening to be implemented it had to meet 19 strict criteria set by the UKNSC and this was assessed by an independent review, followed by a public consultation. We involved a professional lobbying company to help and organise awareness and coordinate a response to the consultation process. We also had some political support with meetings between families affected by SCID and MPs. The committee received around 200 letters of support for the programme.’

However, in March 2013 the committee decided that they were not yet ready to implement national screening. This decision was based on the need for further evidence covering four key areas: knowledge of how many people in the UK are likely to be affected by SCID, known as epidemiology; the performance of the test for SCID, for example taking into consideration if the test picks up babies with other related conditions and how these children might be managed and the likelihood of good clinical outcomes, and finally the clinical cost effectiveness of having a test in place.

‘A very big step forward’

‘Although disappointing, the recommendations of the committee were actually a very big step forward.’ said Professor Gaspar.  ‘We have been asked to do an evaluation study to address the committee’s areas of concern. These studies will lead ultimately to screening 350,000 newborn babies per year, representing about half the number of babies born each year in the UK. There will be a full policy review after 3 years. It’s been a long and tortuous process so far but we are making progress. However, even when an effective screening programme is in place some immunodeficiency conditions will not be picked up so awareness of these conditions remains still extremely important.’

The aim is to implement screening at a European level and this is a key objective for the International Patient Organisation for Primary Immunodeficiencies (IPOPI). ‘This will need an economic cost benefit analysis at a European level’, said Johan Prevot, IPOPI’s Chief Executive.

You can access the presentations from other speakers at this conference at www.ipic2013.com/speakers-presentations.php

October 2013

Report from Cross Party Group on Rare Diseases held at Scottish Parliament, 1st October 2013

Rae McNairney, one of our patient representatives from Scotland, reports on her attendance at this important meeting on Rare Diseases held on the 1st October 2013.

‘The issues the Cross Party Group want to tackle are important to people affected by any rare diseases and that of-course means people who have a primary immune deficiency’, says Rae. ‘The group acts as a channel of communication between the Scottish Parliament and families affected by rare diseases in Scotland and people and organisations working in rare disease research, raising awareness treatment, care and prevention. The Group want to identify areas where inequalities exist in provision of care and campaign for their improvement and also examine areas of policy or service provision relating to rare diseases in Scotland.’

Current members of this group are patient organisations representing the needs and interests of patients and families, with PID UK being represented by Rae. There are also a number of clinicians, academics and health professionals who are members. Malcolm Chisholm, MSP, chaired the meeting and speakers included Alastair Kent, OBE Chair of Rare Disease UK and Elizabeth Porterfield, Scottish Government Health & Social Care. 

‘In Scotland about 300,000 people will be affected by a rare disease and just 30% of rare disease patients are diagnosed in under 3 months one in five have to wait longer than 5 years to obtain a correct diagnosis. So there’s much work to be done. As part of this, a key issue for the Cross Party Group on rare diseases would be the work currently being undertaken to develop a strategy for rare diseases in the UK and the subsequent implementation plan that will be developed for Scotland’, comments Rae.

‘In February 2013 Earl Howe established a stakeholders forum to pull together a UK strategy for rare disease and it is planned for this report to be published by mid to late November 2013. Folllowing publication of the UK Strategy for Rare Diseases, there will be work to develop a Scottish specific implemention plan which they plan to publish in time for Rare Disease Day (28 February 2014)’.

Many thanks to Rae for bringing our Scottish members up to date on these important plans.

April 2013

Update from the European Group for Blood and Marrow Transplantation, 7th - 10th April 2013

Dr Bobby Gaspar of Great Ormond Street Hospital gives us his update on the European Group for Blood and Marrow Transplantation (EBMT) meeting that took place this year in London at the ExCel centre. Dr Bobby Gaspar of Great Ormond Street Hospital sits on the working group for Inborn Errors covering PIDs.

'Over 4000 delegates attended and this is now one of the most important and well-attended transplant meetings worldwide. Within EBMT there is a working party on transplantation for inborn errors, which has a specific focus on transplantation for primary immunodeficiencies.

‘This year the Inborn Errors group discussed the use of extra corporeal photopheresis for the management of graft versus host disease, the use of specific antibodies in the conditioning of patients, the outcome of transplants for NEMO deficiency and the implementation of newborn screening for SCID in Europe. In the bulk of the meeting were other oral presentations and posters. The general move is now look at each individual type of PID, its underlying genetic diagnosis and determine which is the best way to transplant these conditions rather that looking at all PIDs as one entity. We are making good progress with this and the EBMT working party has been very active in this field. As we gather more disease specific information, we will be able to counsel families more accurately and hopefully further improve transplant outcomes.’

December 2012

IPOPI report on abstracts from the 15th Biennial Meeting of the European Society for Immunodeficiencies

This meeting took place in Florence in October 2012. The IPOPI medical advisory panel has written a short report highlighting specific work on bone marrow transplant for chronic granulomatous disease (CGD), diagnosis of autoinflammatory disease and Combined Variable Immune Deficiency (CVID).

Download the report here.