Q&A: Newborn screenings improve severe immunodeficiency survival rates
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Key takeaways:
- Survival rates improved from 72% to 73% before newborn screenings to 87% afterward.
- Positive results at birth enable providers to begin the search for donors and take immediate prophylactic measures.
Between 40 and 80 infants are born with severe combined immunodeficiency disorder each year in the United States and Canada. The disease is fatal without bone marrow transplants as infections overwhelm compromised immune systems.
Five-year survival rates for infants with severe combined immunodeficiency disorder (SCID) who received transplants from sources other than a genetically matched sibling remained steady at 72% to 73% from 1982 to 2009.
Between 2010 and 2018, however, rates jumped up to 87%. Researchers attributed this increase to widespread availability of newborn screening for SCID, first introduced in the United States in 2008 and in Canada in 2013.
These screenings enable health care providers to immediately begin the search for a donor and take rapid steps to delay or prevent infections, accelerating successful treatment and driving higher survival rates.
Healio spoke with Luigi D. Notarangelo, MD, chief of the NIAID Laboratory of Clinical Immunology and Microbiology, about the history of SCID treatment, how screenings enable survival, and what needs to be done to see their use expand around the world.
Healio: Can you provide some background about SCID diagnosis and treatment?
Notarangelo: Basically, SCID is not one disorder. It is several genetic disorders, all of which profoundly compromise the immune function. These babies are born with a lack of an immune system. In particular, they lack T cells, which are the essential components of white blood cells in fighting infections. Because of that, babies with SCID would succumb to infections very early in life, within the first few months or within the first couple of years. Before 1968, all these babies would inevitably die, no matter what you were doing to them. Then, 1968 was the first time ever that bone marrow transplantation was done successfully in a baby with SCID. That has changed the landscape of SCID and, in particular, outcomes for these babies.
Healio: How have these transplants evolved?
Notarangelo: For many years, you could only survive if you had a genetically matched sibling, which only happens in 15% to 20% of patients. All other patients would die. They tried bone marrow transplants from parents, but in those cases the T cells from the father or mother would react against the baby’s body. That would cause a fatal disease called graft-versus-host-disease. Then it became possible to manipulate the bone marrow of the parents and remove T cells, or purify the stem cells. That would allow these babies to receive paternal or maternal bone marrow as well as bone marrow transplants from unrelated donors.
If you had a matched sibling donor, you would have had a very high chance of survival, up to 85% or 90%. This has been true across multiple decades. But if you didn’t have a matched sibling, you would still be able to survive in a significant proportion of cases, but not in all cases. Survival was around 70% to 75% in those cases.
Healio: What prompted the current study into survival rates?
Notarangelo: In the United States and Canada, the Primary Immune Deficiency Treatment Consortium (PIDTC) gathers together all of the major centers that care for patients with severe forms of immune deficiency including SCID. The purpose of this consortium, which has been funded by the NIH since 2009, has been to collect data and analyze which factors drive survival and which factors affect in a negative manner the outcomes of these babies.
Healio: What did the current study find?
Notarangelo: For SCID, we appreciated that there are two main factors that really play a critical role. One is the age at the time of transplantation. Babies who received transplants within the first 3, 3.5 months of life did much better in terms of survival than babies with transplants later in life. The other fact that really mattered was the infectious status of the patient at the time of transplantation. If you had never had an infection before the transplant, your chance of surviving as a SCID baby was much higher. If you went to transplant with an ongoing infection, your chance of surviving would be much, much lower.
Now, obviously, when you think about it, age at transplant and infectious status are somewhat related to each other. Because these babies don’t have a good immune system, the longer you wait until they’re transplanted, the more likely it is that they’re going to catch an infection. But how could we go around this problem where a significant number of babies arrived at transplant either later in life or with an ongoing infection? We have to fix this.
Healio: So, what was the solution?
Notarangelo: When Jennifer M. Puck, MD, [professor of pediatrics, division of allergy/immunology and blood and marrow transplantation, department of pediatrics, University of California, San Francisco] was at the NIH, she thought that a molecular assay developed at the NIH would potentially help save those babies.
The assay measures a byproduct of what happens in the thymus when the T cells are being generated, and they do a cut-and-paste of a specific loci in the DNA called the T cell receptor (TCR) loci. The T cells express the TCR to bind and fight against any foreign antigen or pathogen. The expression of that TCR is the result of this cut and paste of DNA. During this process of cut and paste, there is some DNA that forms a circle (and for this reason are called T cell receptor excision circles, or TRECs) and is maintained within the developing T lymphocytes so that when they are released from the thymus into the circulation, you can actually measure the levels of these TRECs. By quantifying the level of TRECs in peripheral blood, it is possible to know whether that baby was producing T cells or not producing T cells.
Babies with SCID are born with undetectable TRECs. Dr. Puck proposed that a newborn screening could be attempted, measuring TRECs in the DNA extracted from the dry blood spots that are collected at birth from every newborn for a variety of disorders. One could take a punch of that dry blood spot and extract the DNA and measure the amount of TREC levels within that DNA.
The United States started newborn screening state by state, initially in Wisconsin in 2008, and then Massachusetts followed in 2009. By December 2018, all 50 states and two territories were screening all babies for SCID using the TRECS assay. Canada has also started screening, with several provinces now doing it.
Healio: What are the advantages of newborn screenings?
Notarangelo: You can identify a baby with SCID at birth before the baby catches an infection. Babies with SCID look absolutely healthy at birth. In most cases, babies with SCID don’t have any somatic features, dysmorphisms or malformation. Unless you do a proper test, you wouldn’t know whether the baby has SCID or not, and the only way to know without a test is after they catch a serious infection. Then you start testing their immune system and find out they don’t have T cells. But that’s often too late because they’ve already caught an infection, so that puts them already at a disadvantage in terms of surviving after a transplant. Now with newborn screening, you can identify these babies at birth. You know that a baby has SCID. You can do confirmatory tests, of course, and you should. But once you know that the baby has SCID, you can do two things.
First, you can protect the baby. You isolate the baby. You provide prophylactic medications, antibiotics, antivirals and antifungals. You can administer intravenous immunoglobulins (antibodies) to help prevent infections. Next, you immediately search for potential donors within the family and worldwide. You accelerate the timing of a bone marrow transplant.
Healio: Were there any challenges in promoting these screenings?
Notarangelo: From the very beginning, it was thought that newborn screening could help save the lives of babies with SCID. But you need to prove it. In fact, many countries worldwide have been reluctant to initiate newborn screening for SCID, because the politicians and other authorities were questioning how cost effective these screenings would be. They wanted to see that these newborn screenings would improve outcomes for these babies. This is exactly what our paper shows. Taking advantage of the data that PIDTC has collected over the decades, we analyzed survival decade by decade up to the most recent decade, which is 2010 to 2018, and that is the time when all 50 states were screening for SCID at birth. Our anticipation was that if we were going to see an effect of newborn screening on survival, we would see it in that decade.
In previous decades, survival had remained pretty stable around 70%, 75%. Not much changed in spite of progress in terms of medications, intensive care and nutritional support. It was only in the last decade after newborn screening became available that we could see a jump in survival, almost reaching 90% for an otherwise inevitably fatal condition. Then we looked into the factors associated with this improved survival, and what we found was that babies went to transplant sooner and they went to transplant more often without infections. That’s exactly what we expect from newborn screening.
Healio: Are there any findings in these results you would like to highlight?
Notarangelo: When we looked at the babies who received transplants in the last decade, because not every state started screening at the same time, we found three different types of SCID babies: those who were identified because of newborn screening, those who were identified because newborn screening was not yet available in their state so they caught infections and were recognized later, and those who had a positive family history. If that happens, you know it is genetic and you look for SCID in the next baby.
Among these three different groups of babies, the babies who were diagnosed because of newborn screening and those who were diagnosed because of family history were able to go to transplant sooner and without infections compared with the babies who did not have newborn screening because it was not available in their state.
Healio: What impact will this data have on policy?
Notarangelo: These are important data because they provide the first formal evidence that newborn screening is indeed cost effective. It does save lives. It does improve survival in an otherwise fatal condition. We hope that these data will also inform policies in other countries worldwide. Several other countries have now started newborn screening. They recognize the importance of newborn screening for SCID.
Healio: Are there objections to these screenings?
Notarangelo: It varies from country to country, and the costs may be slightly different, but on average the screening costs around $4 per baby. It’s not very expensive. Multiply that by the number of newborns, and people may say it’s too much money. They want to see that it works. But if you delay the diagnosis, the baby will catch an infection, potentially a life-threatening one, because SCID babies do not have good immune responses. Very often, they end up being in the ICU, and you know how much every single day in an ICU costs.
I don't expect implementation of newborn screening for SCID will be a problem in countries that have adequate healthcare and economical resources. Already, several countries in Europe are using newborn screening. Israel is using newborn screening. In settings where health care is very solid and patients need treatment, they will get treatment. I don't anticipate any difference compared with the data we obtained in North America.
Healio: Are there any other obstacles in screenings and care?
Notarangelo: There is still much to do, because survival, even with newborn screening, is not 100%. We know that there are still factors that we have to work out. For instance, Black or African-American race is associated with lower survival after bone marrow transplantation for SCID in North America even in the newborn screening era. There is still a problem of access to care.
Also there are many other fatal conditions of the immune system (besides SCID) that the current newborn screening does not detect. In the future, we hope that other disorders can also be diagnosed at birth so the lives of these babies can also be saved. But the results obtained with implementation of newborn screening for SCID are already a first important step forward, and they tell us how important it is when science goes hand in hand with public health and the implementation of public health measures.
Healio: What’s the next step in this research?
Notarangelo: There are many, many different steps. First, the PIDTC is an NIH-funded initiative. We are not just working on bone marrow transplants for SCID. We’re interested in gene therapy. We’re also interested in other forms of severe immunodeficiencies. Our goal is to help physicians across the country and in North America to become familiar with these disorders, to recognize them more promptly and to treat them more effectively.