SPECIAL REPORT
Screening for Primary Immunodeficiency Disorders in Infants
Enhanced Screening for Immunodeficiency Diseases Treating Immunodeficiency Disease Why Newborn Screening for SCID is Vital Choosing Neonatal Screening for SCID The Evolution of Neonatal Tests
Sponsored by
Published by Global Business Media
SPECIAL REPORT
Screening for Primary Immunodeficiency Disorders in Infants
Enhanced Screening for Immunodeficiency Diseases Treating Immunodeficiency Disease
SPECIAL REPORT: SCREENING FOR PRIMARY IMMUNODEFICIENCY DISORDERS IN INFANTS
Contents
Why Newborn Screening for SCID is Vital Choosing Neonatal Screening for SCID The Evolution of Neonatal Tests
Foreword
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Tom Cropper, Editor
Enhanced Screening for Immunodeficiency Diseases 3 James White, DO, Vice President, Medical Affairs, Lumendi LLC
The Burden of Delay Sponsored by
Developing Newborn Screening Published by Global Business Media
The SPOT-itTM TREC & KREC Screening Platform
Published by Global Business Media
Clinical and Financial Benefits
Global Business Media Limited 62 The Street Ashtead Surrey KT21 1AT United Kingdom
Treating Immunodeficiency Disease
Switchboard: +44 (0)1737 850 939 Fax: +44 (0)1737 851 952 Email: info@globalbusinessmedia.org Website: www.globalbusinessmedia.org
Treating Immunity Deficiencies
Publisher Kevin Bell
Tom Cropper, Editor
Developments of Gene Therapy The Need for Better Screening
Why Newborn Screening for SCID is Vital
Business Development Director Marie-Anne Brooks
Jo Roth, Staff Writer
Editor Tom Cropper
Campaigning for Change
Senior Project Manager Steve Banks Advertising Executives Michael McCarthy Abigail Coombes Production Manager Paul Davies For further information visit: www.globalbusinessmedia.org The opinions and views expressed in the editorial content in this publication are those of the authors alone and do not necessarily represent the views of any organisation with which they may be associated. Material in advertisements and promotional features may be considered to represent the views of the advertisers and promoters. The views and opinions expressed in this publication do not necessarily express the views of the Publishers or the Editor. While every care has been taken in the preparation of this publication, neither the Publishers nor the Editor are responsible for such opinions and views or for any inaccuracies in the articles.
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More Evidence Needed Effectiveness of Neonatal Screening
Choosing Neonatal Screening for SCID
10
Tom Cropper, Editor
Counting the Cost Choosing the Best Screening Tests
The Evolution of Neonatal Tests
12
James Butler, Staff Writer
Universal Newborn Screening The Search for Combined T-cell and B-cell Tests Faster More Accurate Tests
References 14
Š 2019. The entire contents of this publication are protected by copyright. Full details are available from the Publishers. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means, electronic, mechanical photocopying, recording or otherwise, without the prior permission of the copyright owner.
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SPECIAL REPORT: SCREENING FOR PRIMARY IMMUNODEFICIENCY DISORDERS IN INFANTS
Foreword
T
HERE WAS a time when the outlook for
and assesses the growing body of evidence which
babies with severe immunodeficiencies was
suggests that they should pick up the pace of change.
extremely poor. In recent years, though, new
As compelling as this evidence is, though, variation
treatments have managed to cure a disease which
in screening methodologies can lead to differences
might once have been deadly. Unfortunately, these
in their effectiveness. Not all types of PID can be
miracle cures can’t be administered unless the
detected using conventional newborn tests. They
disease is first detected.
can also vary in their speed and accuracy with some
Our opening article comes from ImmunoIVD,
tests still showing relatively high rates of misdiagnosis.
manufacturers of the SPOT-itTM Screening kits,
Much depends, therefore, on how screening is
which provide early detection of various forms of
implemented and the choice of test.
primary immunodeficiency diseases (PID). They
As James Butler discovers, the development of
explain how biomarkers can be used to detect
advanced kits capable of detecting a wider variety
immunodeficiencies at birth and why newborn
of conditions is bringing about significant changes.
screening has the potential to transform outcomes
Many existing kits are only capable of detecting
for patients and families.
T-cell related types of PID which leaves patients
Elsewhere in the Report, we’ll look at the
with missing B-cells undetected. He looks at how
development of exciting new treatments such
new screening assays such as SPOT-it™ TREC &
as gene therapy and Haematopoietic Stem Cell
KREC Screening Kit can detect both T- and B-cell
Transplantation (HSCT). These treatments offer
deficiencies, while also offering faster and more
patients, whose life expectancies would have been
effective tests.
severely limited, the prospect of a full and active life.
These new tests will be crucial to the future treatment
Even so, their effectiveness will be severely
of immunodeficiencies. The ability of health services
compromised if the condition is not identified quickly.
to treat PIDs is improving rapidly, but none of these
Newborn screening for the most serious conditions
developments will mean much unless there is a
such as Severe Combined Immunodeficiency
similar improvement in their ability to detect the
(SCID), is only just making its way onto the lists of
disease at birth.
approved tests for newborns. Jo Roth looks at why some health services have been comparatively slow to make the transition
Tom Cropper Editor
Tom Cropper, has produced articles and reports on various aspects of global business over the past 15 years. He has also worked as a copywriter for some of the largest corporations in the world, including ANZ Bank, ING and KPMG.
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SPECIAL REPORT: SCREENING FOR PRIMARY IMMUNODEFICIENCY DISORDERS IN INFANTS
Enhanced Screening for Immunodeficiency Diseases ImmunoIVD
TREC (T-CELL RECEPTOR EXCISION CIRCLES) AND KREC (KAPPA-DELETING RECOMBINATION EXCISION CIRCLES) ARE BY-PRODUCTS OF T-CELL AND B-CELL MATURATION. VERY LOW NUMBERS OF TREC AND KREC REQUIRE FURTHER INVESTIGATION AND POTENTIALLY TREATMENT FOR SCID.
N
EONATAL SCREENING programs have been used since the sixties, but it is only in recent years that it has become possible to screen for severe primary immunodeficiencies. This is a major development. Between two and eight babies per 100,000 births have diseases which require immediate treatment and, unless that treatment is delivered quickly, the condition can be devastating. Symptoms are often vague and hard to identify which means neonatal screening is often the only chance infants have to halt the disease before it’s too late. The most serious form of inherited primary immunodeficiency disease is Severe Combined Immunodeficiency (SCID), a rare group of disorders caused by mutations in different genes involved in the development of infection-fighting immune cells. Most patients with SCID have absent T-cells and may also be categorised with absent B or NK cells. Diagnosis should be considered a clinical emergency. Even a short delay in identifying it can be fatal, but diagnosis is challenging. Late diagnosis may also reduce the effectiveness of treatment options. If children can be screened successfully for SCID at birth, they stand a better chance of receiving treatment before the condition becomes too serious.
The Burden of Delay A delay in diagnosis can be deadly. Babies will appear healthy at birth and the disease will remain clinically silent for the first few months until
maternal antibodies, which provide a measure of protection, have left the body. A child affected by SCID will be unable to develop T-cells leaving the body open to infection. The condition can be cured with Hematopoietic stem cell transplantation (HSCT) or early enzyme replacement in the case of ADA-deficient SCID. These treatments can be extremely effective. HSCT has a clinical survival rate of 95%. However, it is most successful when initiated before overwhelming complications occur. If a child is not screened at birth, it will suffer from recurring infections and the chances of survival will be dramatically reduced. The benefits, therefore, are clear. Early intervention not only reduces mortality and morbidity but can be curative, allowing patients to enjoy a full and active quality of life. Because the disease is rare, there is a lack of clear data about exactly how prevalent it is. However, early data from pilot screening programs in the USA suggest that one in 30,000 to 50,000 infants may be born with SCID. Incidence rates are comparable to disorders of fatty acids which are routinely screened in most EU countries. The evidence, therefore, suggests that health services would benefit from screening.
SPOT-it
TM
Developing Newborn Screening The search for a suitable biomarker for T-cell and B-cell development has been long and exhausting. The concept was initially proposed in the 1990s by Puck and Buckley who suggested
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SPECIAL REPORT: SCREENING FOR PRIMARY IMMUNODEFICIENCY DISORDERS IN INFANTS
Early intervention not only reduces mortality and morbidity but can be curative, allowing patients to enjoy a full and active quality of life
NORMAL DISTRIBUTION OF TREC (LEFT) AND KREC (RIGHT) COPIES FROM DRIED BLOT SPOT (DBS) ANALYSIS IN 1200 HEALTHY NEWBORNS AS WELL AS 10 SAMPLES FROM PATIENTS WITH LOW TREC AND/OR KREC COPY NUMBERS. THIS FIGURE IS FROM THE SPOT-IT TM TREC & KREC KIT.
that a complete differential blood count might help to diagnose the disease based on a lower lymphocyte count in the blooda. This approach could be effective but lacked practical application. It was only effective in fresh blood samples and these logistical difficulties prevented its large-scale implementation. Equally, T/B- and NK forms of SCID could yield false results. Meanwhile, bead capture CD3 complex and CD45 have been in development, but these have resulted in false results in patients with maternal engraftment or oligoclonal T-cells. There was more success with tests for T-cell receptors. Normal T-cell development requires the production of precursor T-cells in the bone marrow and processing of T-cells in the thymus. During normal thymic processing, T-cells undergo receptor gene splicing and rearrangement leading to the intracellular accumulation of DNA by products known as T-cell receptor excision circles (TRECs). These can provide a marker indicating a newborn’s capacity to produce T-cells which will be compromised in SCID patients. As such, TREC assays became possible based on DNA extracted from a dry blood spot collected at birth.
A similar method can be used to screen for B-cell defects, such as agammaglobulinaemia, by using Kappa-deleting recombination excision circles (KRECs). Combining these two markers in a single assay allows for simultaneous detection of both T- and B-cell presence.
The SPOT-itTM TREC & KREC Screening Platform As things stand, T-cell screening is not standardised which leads to variations in different types of screening programs. This can result in significant discrepancies in the number of patient recalls and diagnostic procedures of up to tenfold in some cases. Our SPOT-itTM screening algorithm offers an opportunity to harmonise newborn screening efforts for newborns. It is the only commercially available screening system which can detect both T-cell and B-cell defects. All infants will undergo screening by the TREC & KREC Screening Kit assays. If results come back normal, no further action will be taken. For infants with TREC or KREC levels below the cut off, the first screening card will be retested for TREC and/or KREC as well as DNA amplification by quantifying beta-actin levels. If these are
THE PROTOCOL INVOLVES DNA ELUTION AND QPCR TO QUANTIFY TREC AND KREC. IT IS DESIGNED TO BE RAPID, EFFICIENT AND TO REDUCE PIPETTING STEPS.
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SPECIAL REPORT: SCREENING FOR PRIMARY IMMUNODEFICIENCY DISORDERS IN INFANTS
PLATES ARE PRE-FILLED FOR EASE OF USE AND ALREADY INCLUDE STANDARD CURVE SAMPLES FOR QUANTIFICATION. CONTROL SAMPLES AND ALL REQUIRED REAGENTS COME WITH EVERY SHIPMENT.
below normal, the primary care provider can be contacted for two separate scenarios. 1. Where no TREC and/or KREC can be detected the infant needs urgent confirmatory testing and treatment by a clinical immunologist. 2. If TRECs and/or KRECs are detectable but below the established cut off value, retesting of a second testing card can be performed. These infants can be tracked. The first action for the tracking procedure is to contact the obstetric unit and the parents of the newborn will be informed about the child’s status. The parents should be given a detailed explanation of the significance of the test results. Subsequently a specialised treatment centre should be selected close to home. In the case of suspected T- and B-cell lymphopenia, intensive hygiene measures and possibly strict isolation may be needed to prevent infection. If patients are to receive gene therapy or HSCT, they may need to be transferred to a specialised transplant centre. The SPOT-it™ TREC & KREC Screening Kit is a leap forward over and above other available tests. As well as being the only available test capable of B- and T-cell detection, it offers an all-in-one solution which uses real time PCR. Based on the experience of those health services which
have already used the system, results tend to be returned faster and recall rates are lower than other assays.
Clinical and Financial Benefits The assay is a life saver. It leads to the early detection of disorders and allows patients to be treated before the onset of symptoms. At the same time, it can produce significant economic benefits for hard pressed health services. Early detection of SCID leads to curative interventions and avoids the occurrence of complications which could have required costly and prolonged intensive care management. This allows patients who would otherwise have suffered from a fatal genetic disorder to recover and lead full and active lives. The social benefits of this are almost inestimable. There is more to come. Multiplexing the TREC & KREC screening assay could lead to population-based screening and may allow for multiple biomarkers to be tested using the same dried blood sample. Automated processes can further accelerate the process while research continues to extend such tests to other biomarkers. Moving towards more comprehensive neonatal screening, therefore, is vital if the disease is to be picked up in time for treatment.
SPOT-it
TM
References a.
Stem Cell Transplantation for Immunodeficiency: https://link.springer.com/article/10.1007/BF00792603
b.
Retrospective Analysis of TREC Based Screening: https://www.ncbi.nlm.nih.gov/pubmed/24610337
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Treating Immunodeficiency Disease Tom Cropper, Staff Writer The development of advanced treatments for various forms of SCID have improved dramatically the prospects of patients living with the disorder but, to be effective, symptoms must be identified early.
HSCT remains the most common type of curative treatment, but advances in gene therapy have also yielded impressive results. This is a relatively new field and involves correcting the defect in the gene and replacing faulty genes with healthy copies
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S
EVERE PRIMARY immunodeficiencies (PID) can be catastrophic, but new treatments have transformed the lives of many patients. Thanks to stem cell transplants and new forms of gene therapy, the condition can often be cured completely. But one problem remains - many children die from the disease before it is identified.
Treating Immunity Deficiencies There are many different types of diseases caused by genetic defects within cells of the immune system. Research from the International Union of Immunological Societies indicates that, to date, there are more than 300 diseases with X-linked, autosomal recessive and autosomal dominant inheritance with new types being continuously identified. The number is growing. The report indicates that more than 30 new gene defects had been reported since the previous update1. In the past, patients may have been treated in a number of different ways. •M edication: Antibiotics, antiviral and antifungal medications would be used to protect against serious infection. •B lood transfusions: Blood, platelets or plasma can be donated, but this requires precautions. Blood must be specially irradiated and not contain viruses such as CMV which could cause problems for patients. • I mmunoglobin therapy: Immunoglobin can be administered to replace the missing antibodies. These antibodies will have been purified from a healthy donor and can be administered intravenously to provide temporary protection. However, this in itself carries a small risk of infection from the donor blood. It is also only a temporary solution and patients will require repeated injections. The effectiveness of injections can wear off. These treatments can manage the condition to a certain extent, but in recent years, a range of new treatments have become available which offer the prospect of a cure.
Hematopoietic stem cell transplantation (HSCT) aims to replace the defective immune system with one from a healthy donor. A unique type of stem cell which has the capacity to develop into immune cells is taken either from bone marrow, blood or umbilical blood and transfused into the vein of the affected child. Stem cells find their way from the bloodstream into the bone marrow where they start to develop healthy blood cells. Success rates for HSCT in SCID can be as high as 95%, but it does have risks2. The outcome can be affected by graft-versus-host complications and incomplete stem cell engraftment. A study into the outcomes of HSCT found that some patients developed signs of asthma, delayed speech, poor growth and eczema3. The high success rate, though, relies on early treatment. To have the best chance of success, patients need to be treated before symptoms have manifested themselves.
Developments of Gene Therapy HSCT remains the most common type of curative treatment, but advances in gene therapy have also yielded impressive results. This is a relatively new field and involves correcting the defect in the gene and replacing faulty genes with healthy copies. In 1990, a four year old girl called Ashanthi4 received a pioneering form of life saving gene therapy from IDF Medical Director R. Michael Blaese. She had been receiving ADA injections, but these had become ineffective. Blaese took samples of blood and inserted a functioning ADA gene using a modified virus as the delivery vehicle. A few months later the procedure was used on another child, Cindy Kisik, who was also born with the rare ADA form of SCID. The therapy was so successful that, more than 20 years later, both girls were able to attend the IDF National Conference to highlight the progress of gene therapy. New treatments are constantly being trialled which have the potential to transform the
SPECIAL REPORT: SCREENING FOR PRIMARY IMMUNODEFICIENCY DISORDERS IN INFANTS
prospects for children with immune deficiencies. New conditioning regimens can reduce the risks of HSCT and new methods of stem cell manipulation have the potential to guarantee donors for all patients. Genetic counselling is becoming increasingly effective at identifying and correcting the genetic defect which causes PIDs. Treatments such as Strimvelis have also been shown to be successful. This uses autologous gene corrected HSC taken from a patient’s own bone marrow and genetically modified with gamma-retroviral vector to replace the defective gene with a functioning copy. NICE states that, despite some uncertainties surrounding clinical evidence, data suggests that more patients may survive with Strimvelis than with HSCT5.
The Need for Better Screening However, for advanced treatments to work, early interventions are vital. The effectiveness of HSCT drops off dramatically after 3.5 months. A study by Wahlstrom et. al. demonstrates that infants treated without infection have survival rates of more than 90%. The figures were especially high for younger infants (94%) but procedures in older infants without infection
were still effective in 90% of cases. However, the probability of success plummeted to 50% for patients with infections6. Because of the difficulties involved with identifying immunodeficiencies symptomatically, many patients risk dying before they are diagnosed and can be treated. For the future, therefore, newborn screening for all forms of PID will be crucial for advanced treatments to have their desired impact. Screening also plays an important role in research. A study of advances in severe immunodeficiency disease by Andrew Gennery argues that, as well as improving outcomes, screening can focus ‘research on safer and less toxic treatment strategies, which result in durable and sustainable immune function without adverse effects.’ For a number of reasons, therefore, early diagnosis is crucial to delivering better treatment and improving outcomes. Even so, PID is not universally recommended for newborn screening. Doubts remain over the cost and effectiveness of such tests but failing to test at birth leaves any child with PID at serious risk. The next generation of exciting treatments will only be useful if infants at risk are quickly and accurately identified.
SPOT-it
TM
Success rates for HSCT in SCID can be as high as 95%, but it does have risks. The outcome can be affected by graft-versus-host complications and incomplete stem cell engraftment immunoivd.com
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Why Newborn Screening for SCID is Vital Jo Roth, Staff Writer Momentum is growing to increase neonatal screening for SCID, but what does the evidence say?
Currently the main method for identifying SCID is through family history, but although it is a genetic disease, family history is only a useful indicator in about 20% of cases
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VERY NEWBORN baby will receive a number of tests in the first few days of their life. A nurse will take a small sample of blood to test for a range of conditions including cystic fibrosis or sickle cell disease. Unfortunately, one is currently missing from the list. It’s an exemption which potentially deprives many children of the chance to live a full and active life. Severe Combined Immunodeficiency Disease (SCID) is one of the most serious forms of primary immunodeficiency diseases (PIDs). Its effects can be devastating. It first came to prominence in the 1970s and 80s when a child called David Vetter was born with the condition. In most cases SCID, once it has become manifest, is fatal in the first two years of life, but Vetter managed to live until the age of 12 encased in a bubble to protect him from the outside world. His story became the inspiration for a made for TV movie – ‘The Boy in the Plastic Bubble’. Cases such as David’s are rare, but they can be devastating. Currently the main method for identifying SCID is through family history, but although it is a genetic disease, family history is only a useful indicator in about 20% of cases.7 Without newborn screening, the majority of children with SCID will be difficult to diagnose before it is too late. Symptoms tend not to show because babies receive a measure of protection while maternal antibodies are still present. Even when symptoms do appear, they can be vague and difficult to pinpoint.
Campaigning for Change For this reason, there have been a number of campaigns to promote newborn screening for SCID. In the US, the Immune Deficiency Foundation (IDF) has been campaigning to have SCID accepted as a recommended newborn screening test in all 50 States, and it is universal as of 2018. Several other countries are also moving to adopt newborn screening for SCID. Israel implemented it in 20108, prompted by calls from
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the scientific community. New Zealand recently implemented it after a consultation period9. Programs are now in place in Spain, France, Sweden, Norway, Italy, Denmark, Germany and Switzerland and there has been a sustained campaign for the UK to follow suit. In 2017, PID UK which helps families affected by immune deficiency diseases, hosted a parliamentary reception to build political support, which resulted in a ‘call to action’ for the Government to include it on the screening list10. Demand is growing and health services are beginning to heed it.
More Evidence Needed Even so, there is still some reluctance. The case against screening for SCID is familiar. Tests, so the argument goes, will incur a cost and there is still widespread concern about the possible impact of false positives. This could cause unnecessary angst for parents and lead to patients receiving an inappropriate course of treatment. These concerns are understandable, but the overall evidence increasingly points to the value of newborn screening programs.
Effectiveness of Neonatal Screening Studies into the prospects of those babies who are diagnosed at birth because of their family conditions show a survival rate of more than 90%11. The inevitable conclusion is that applying neonatal screening to all cases would significantly improve outcomes in what would otherwise be a devastating condition12. A study into the effectiveness of TREC screening found that the survival rate of children identified early was 87% compared to 54% for late identified infants13. An analysis conducted in Washington State found that an additional 1.19 newborns were detected preclinically through screening in addition to those who would have been detected through family history. On average, the study found that screening would have prevented 0.40
SPECIAL REPORT: SCREENING FOR PRIMARY IMMUNODEFICIENCY DISORDERS IN INFANTS
deaths per year and would lead to a cost saving of $35,311 per life saved and a cost benefit ratio of either 5.31 or 2.7114. Given such numbers, the case for newborn screening appears to be clear. Although SCID is a rare disease, and affects only comparatively few children every year, screening can save lives and reduce the cost of treatment per patient. From both a financial and clinical perspective, newborn screening is beneficial. Momentum is building and the market for newborn screening is likely to grow rapidly over the next few years. According to data from Zion Research, the newborn screening market will grow by 11.5% year on year between 2019 and 2025 from $739 million to $1,584
million. The report states that growth will be facilitated by the growing neonatal population, increasing cases of congenital diseases, favourable government policies and technological advancements15. Investigations around the world tend to demonstrate the value of neonatal screening for SCID and other rare genetic conditions. The most serious problems, such as the risks of false positives and cost of unnecessary treatment, are being mitigated by the development of new, more sensitive, tests and procedures. The main question managers should be asking is not ‘if’ neonatal screening is clinically beneficial, but ‘how’ it should be implemented.
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According to data from Zion Research, the newborn screening market will grow by 11.5% year on year between 2019 and 2025 from $739 million to $1,584 million
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SPECIAL REPORT: SCREENING FOR PRIMARY IMMUNODEFICIENCY DISORDERS IN INFANTS
Choosing Neonatal Screening for SCID Tom Cropper, Editor Screening for severe primary immunodeficiencies has been shown to be highly effective - how can the procedure be implemented widely?
Estimates of the prevalence of SCID vary. Approximately one case in between 10,000 and 50,000 births occur in the USA, which equates to between 80 to 400 new cases each year
T
HERE IS growing agreement that neonatal screening for serious immunodeficiencies such as Severe Combined Immunodeficiency (SCID) can be beneficial, but doubts remain. The key to overcoming these issues lies in understanding how to implement screening procedures. Estimates of the prevalence of SCID vary. Approximately one case in between 10,000 and 50,000 births occur in the USA, which equates to between 80 to 400 new cases each year16. However, it is possible that these figures are underestimated because of a lack of research. One study suggests that there may be double the number of SCID cases than was previously thought17. Several calls have been made for SCID to be screened at birth18. In 2017 the UK Government launched a consultation on whether SCID screening should be tried in the NHS19. The main concerns around SCID testing, in the past, have revolved around the perceived lack of sensitivity in some tests. The risks of false positives may limit the value of the tests. This was the rationale behind UK NSC’s reply to calls for a trial period of SCID screening. Although they agreed there was enough evidence that screenings could be beneficial, they argued that there were still concerns about false results and the type of treatment which would be provided once the condition had been identified. Professor Anne Mackie, Director of Programmes for the UK National Screening Committee (UK NSC), said: “There is still uncertainty whether screening for SCID would lead to babies who are well being diagnosed with the condition and receiving unnecessary treatment. It is also unclear what would be the best care and treatment to offer babies who don’t have SCID but are found to have other immune deficiency conditions20.”
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recommendations, others are more sceptical. Those which have not so far added it to the list cite the initial cost of implementing a screening service as being their main concern. However, a retrospective economic analysis by the report’s authors suggests a positive return on investment. Over the course of five years, they compared the results of early screening (less than 3.5 months) with later screenings. Mean charges for those centres adopting late treatment were approximately four times higher ($1.43million) than early treatment ($365,785). SCID screening not only allows for earlier treatment; it also increases the number of cases which will respond to treatment. This treatment is curative, meaning patients will no longer be a burden to health services. In comparison, a patient who is diagnosed late may require intensive care and prolonged treatment at a higher cost to health services. Meanwhile, the social benefit is vast. Patients face the difference between a disease which can be cured and one which is fatal. If they receive appropriate treatment, they can go on to enjoy a full life free from any complications. Attitudes are shifting and even the NSC, despite its reservations, agrees that the fiscal case is compelling22. For this reason, they recommended it be tested.
Choosing the Best Screening Tests For those health services that do decide to screen at birth, there is another issue: how can they select the best method? There is currently no standardised approach for SCID screening which means performances vary depending on the type of assay used. When choosing an assay, clinicians should look at a number of factors including: •C ost: In a resource constrained environment, a system’s upfront cost will be an important consideration. They will need to demonstrate a clear return on investment as well as positive clinical value.
SPECIAL REPORT: SCREENING FOR PRIMARY IMMUNODEFICIENCY DISORDERS IN INFANTS
•S peed: Time is of the essence. The most advanced test kits have the capacity to provide same day results and retesting. •E ase of use: How much training will clinicians need to use the test? Much of this also depends on the quality of the company providing the test. Some offer a more personal service than others and can provide dedicated training for staff after purchase. • Sophistication: Ongoing research means new methodologies are being developed to improve testing performance. These systems can detect a wider range of conditions simultaneously. •A ccuracy: False positives have been a serious problem for newborn screening. Tests which can be shown to reduce errors, with less retesting, will be highly sought after. Customer service is also proving to be valuable. Different suppliers vary in terms of the quality of support they can offer. For best results, a personalised service can be extremely helpful, but this is something larger organisations often struggle to provide. However, there are
several smaller manufacturers entering the market. Despite their small size they do enjoy some advantages over their larger competitors. They can provide a more dedicated and bespoke service, helping to tailor the test to the user’s requirements. Because they are smaller operations, they are also more agile adapting swiftly to changing circumstances to deliver added value to clients. As the market for neonatal screening strengthens, new tests are coming to market and demonstrating their value. They are faster, more sensitive, require less training and can identify the presence of a wider range of genetic defects. Each of these cases are rare, and there is an understandable tendency for health services to withhold expenditure on conditions which are perceived to affect only a small proportion of the population, but the evidence is clear. Early interventions have been shown to be curative and to save lives. It is less a case of managing the condition; it’s a case of achieving a full recovery.
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As the market for neonatal screening strengthens, new tests are coming to market and demonstrating their value. They are faster, more sensitive, require less training and can identify the presence of a wider range of genetic defects
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SPECIAL REPORT: SCREENING FOR PRIMARY IMMUNODEFICIENCY DISORDERS IN INFANTS
The Evolution of Neonatal Tests James Butler, Staff Writer Evidence shows that screening for PIDs, including SCID, is is clinically beneficial. However, just screening for T-cells alone is insufficient.
Momentum for universal neonatal screening is gathering. In the US several states have added screening for SCID to the list of recommended tests for neonatal screening and Europe appears to be moving in the same direction
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P
RIMARY IMMUNE deficiencies (PIDs) is a wide-ranging term. It encompasses more than 350 dif ferent deficiencies including phagocyte disorders, complement deficiencies, T-cell defects and antibody deficiencies. Identifying these issues from symptoms alone is extremely difficult and, even then, diagnosis often happens too late. Neonatal screening is often the only way to identify diseases before they advance too far, but this also presents challenges. Each of these conditions is different and many of the available tests will miss certain conditions.
Universal New-Born Screening Momentum for universal neonatal screening is gathering. In the US, all states now screen for Severe Combined Immunodeficiency (SCID), and many European countries have already implemented neonatal screening including Switzerland, Germany and Sweden, while the Netherlands is partially screening. The change is driven by a series of studies which appear to demonstrate the value of newborn screening of additional severe PIDs. In 2010, a screening program in California showed that tests designed to detect the presence of T-cell receptor excision circles (TREC) could identify SCID and other forms of T-cell lymphopenia facilitating further treatment before the onset of serious symptoms23. Where America leads, Europe is following. In 2017, Europe’s first universal screening program for SCID took place in Spain. All babies born between January 2017 and December 2018 were screened using a test which quantifies T-cell receptors in the blood. The results provided further evidence that newborn screening could identify the presence of SCID24. One patient was diagnosed with SCID which equates to an incidence rate of one in 130,903 births for Catalonia. 13 had clinically significant T-cell lymphopenia (non SCID), which represented 43% of positive detections. However, while both
these studies demonstrate the effectiveness of T-cell screening, they also show their limitations. The tests produced a total of nine false positives - something which has also been a concern for those who are still wary of the TREC methodology. More importantly, testing for TREC alone fails to identify some forms of SCID. For example, in Manitoba, Canada, the overall incidence of SCID is three times the national average. Studies showed that it was overrepresented in two groups: Mennonites and First Nations of Northern Cree ancestries. Although T-cell receptor tests are being increasingly used to test for primary immunodeficiency conditions in Canada, the majority of patients in Manitoba are T-cell positive. A retrospective analysis of blood samples taken from SCID patients confirmed that the TREC assay only successfully identified those patients with a specific T-cell deficiency25. Existing TREC assays, therefore, are limited. They may have demonstrated their value in detecting disorders associated with T-cell deficiencies but failed to identify cases where the issue is related to B-cells. The goal now is to develop more tests capable of detecting B-cell related cases.
The Search for Combined T-cell and B-cell Tests There has been considerable progress. Tests using kappa-deleting recombination excision circles (KREC) have also been used to identify the presence of some forms of SCID. KRECs form during B-cell maturation in the bone marrow. Similarly to TRECs, KREC concentrations can be used as a biomarker for immune deficiencies in which B-cells are missing. They are used with real time quantitative PCR using dried blood spot samples. By testing for both KREC and TREC, clinicians can achieve positive detection for those non-T-cell immunodeficiencies.
SPECIAL REPORT: SCREENING FOR PRIMARY IMMUNODEFICIENCY DISORDERS IN INFANTS
MORE AND MORE COUNTRIES WORLDWIDE ARE IMPLEMENTING SCID SCREENING, AND WE ARE LEARNING MORE ABOUT THE DISEASE PREVALENCE IN DIFFERENT COMMUNITIES. IN MANY COUNTRIES, BABIES WITH SCID ARE NOW BEING IDENTIFIED AND TREATED AS SOON AS POSSIBLE, OFTEN THROUGH BONE MARROW TRANSPLANTS OR ENZYME REPLACEMENT THERAPY.
Considerable efforts have been made to develop combined tests for both B- and T-cells to reduce the cost and time taken for newborn screening. It is only recently that the first commercially available test assay capable of testing both B- and T-cells has made it to market. The SPOT-itTM test from ImmunoIVD, which was specially developed for national newborn screening programs, is currently the only TREC and KREC combined assay. It is available in two variants to accommodate different neonatal screening directives. One can be used for TREC quantification, while the second quantifies both TREC and KREC. The system has been designed to be fast, easy to use and sensitive. It employs regular 3.2 mm Guthrie spot cards and uses the qPCR test method. The suggested cut off values for use have been optimised to make the system more effective at identifying the most severe forms of PID such as SCID and agammaglobulinemia.
Faster More Accurate Tests An important advantage of this test is that it can produce fast turnarounds. It requires only two pipetting steps; workflows are typically 2.5 hours; it can run approximately 500 samples each day and has the capacity for same day reruns. It is also highly sensitive and comparative tests against other commercially available assays have shown it to require fewer retests26. This is an example of how newborn screening is evolving. New methodologies can produce faster and more accurate results. They are more sensitive, can pick up a wider range of conditions and reduce instances of false positives. Although primary immunodeficiencies only affect a relatively small proportion of the population, the impact on sufferers and their families can be devastating. For them, the use of newborn screening can make the difference between a child with minimal chances of living beyond their early years and one who goes on to enjoy a full and active life.
SPOT-it
TM
Considerable efforts have been made to develop combined tests for both B- and T-cells to reduce the cost and time taken for newborn screening. It is only recently that the first commercially available test assay capable of testing both B- and T-cells has made it to market immunoivd.com
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SPECIAL REPORT: SCREENING FOR PRIMARY IMMUNODEFICIENCY DISORDERS IN INFANTS
References: Primary Immunodeficiency Diseases: http://bit.ly/2PDTctf
1 2
Immune Deficiency Foundation. Stem Cell and Gene Therapy: https://primaryimmune.org/treatment-information/stem-cell-and-gene-therapy
Outcomes of Patients with Severe Combined Immunodeficiency When Treated with Hematopoietic Stem Cell Transplantation: https://www.jacionline.org/article/S0091-6749(09)01323-2/pdf 3
4
First Gene Therapy Patients Attend IDF 2013 Conference: https://primaryimmune.org/first-gene-therapy-patients-attend-conference
Strimvelis For Treating Adenosine Deaminase Deficiency Severe Combined Immunodeficiency Disease: https://www.nice.org.uk/guidance/hst7/chapter/1-Recommendation 5
6
Haematopoietic Stem Cell Transplantation for Severe Combined Immunodeficiency: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4371740/
Screening for Primary Immunodeficiency Diseases: https://www.frontiersin.org/research-topics/9556/screening-for-primary-immunodeficiency-disorders-pidds-in-neonates 7
8
Newborn Screening for Severe Combined Immunodeficiency Disease: http://www.mdpi.com/2409-515X/3/2/13
9
Diagnosis and Management of Severe Combined Immunodeficiency: https://www.allergy.org.au/hp/papers/ascia-guidelines-scid-tapid
10
Call to Action. Newborn SCID Screening: http://www.piduk.org/static/media/up/CALL%20TO%20ACTION.pdf
11
Questions About Severe Combined Immunodeficiency Disease: https://primaryimmune.org/wp-content/uploads/2014/08/questions-about-SCID.pdf
12
Neonatal Diagnosis of Severe Combined Immunodeficiency Leads to Significantly Improved Outcomes: Severe Combined Immunodeficiency: https://www.ncbi.nlm.nih.gov/pubmed/21273302
13
Newborn Screening for Severe Combined Immunodeficiency: https://www.mdpi.com/2409-515X/3/2/14/htm
14
Cost Effectiveness of Newborn Screening: https://www.ncbi.nlm.nih.gov/pubmed/26876279
15
Global Newborn Screening Market: http://bit.ly/2PCQSCX
Addition of Severe Combined Immunodeficiency as a Contraindication For Administration of Rotavirus Vaccine: https://www.cdc.gov/mmwr/preview/mmwrhtml/mm5922a3.htm 16
17 18
SCID Prevalence Double Previous Estimates: https://www.medscape.com/viewarticle/830156 A Call to Include Severe Immunodeficiency deficiency in New-born Screening Programs: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3904476/
Screening Consultation on Rare but Serious Condition in Babies: https://www.gov.uk/government/news/screening-consultation-on-rare-but-serious-condition-in-babies 19
Expert Committee Recommends Trial Period to Test Babies for SCID: https://www.gov.uk/government/news/screening-committee-recommends-trial-of-testing-babies-for-scid 20
21
Fiscal Implications of New-born Screening: https://www.jaci-inpractice.org/article/S2213-2198(14)00265-7/fulltext
22
The UK NSC Recommendation on Severe Combined Immunodeficiency: https://legacyscreening.phe.org.uk/scid
23
New-born Screening for SCID: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3759317/
24
First Universal New born Screening Program in Europe: https://www.frontiersin.org/articles/10.3389/fimmu.2019.02406/full
Retrospective TREC Testing of New-borns With Severe Combined Immunodeficiency: https://www.sciencedirect.com/science/article/pii/S2214426914000457 25
26
Introducing New-born Screening for Severe Immunodeficiency in the Dutch Neonatal Screening Program: https://www.mdpi.com/2409-515X/4/4/40/htm
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