Push to expand newborn screening for SCID

The Centers for Disease Control and Prevention announced on April 1 the availability of funding opportunities to expand newborn screening for severe combined immunodeficiency, also known as SCID.

Currently, only 12 states regularly test for SCID as part of their newborn screening programs. With the availability of a highly specific and low-cost test that measures a biomarker for a T-cell deficiency associated with SCID that can easily be added to current routine newborn screening, patient advocacy groups as well as state and federal governments are working to spur more widespread adoption of newborn SCID screening.

"Severe combined immunodeficiency is a pediatric emergency," medical geneticist Amy Brower, Ph.D., said at the NYU Annual Pediatric Rheumatology Update. "We need to get the message out to pediatricians and ob.gyns. that talking about newborn screening should begin prenatally. ... Unfortunately, surveys find that ob.gyns. do not have time for that conversation, and parents don’t remember it. We want physicians to know that there is a new test for SCID that has been vetted, is evidence based, and is available that can identify children before they become gravely ill."

Dr. Brower also suggests that parents should be made aware that even if their state does not offer SCID screening, they can request to have a newborn dried blood spot sample sent to a commercial lab for SCID analysis.

SCID is known colloquially as "bubble boy syndrome" because poor immune systems make these children vulnerable to infections. While babies born with SCID appear normal at birth, they stand a high risk of developing life-threatening viral, bacterial, and fungal infections. Right after birth, they are still protected by transplacentally derived maternal IgG antibodies, but soon lose that protection. If the condition is detected early and treated, survival rates are excellent. If treated before 3.5 months of age, 95% of affected babies will have long-term survival, but the survival rate falls below 70% if SCID is diagnosed after 3.5 months, even with intensive care and intervention (Public Health Rep. 2010;125:88-95).

Treatments include hematopoietic cell transplantation, enzyme replacement in cases of adenosine deaminase (ADA) deficiency, and gene therapy.

"Newborn screening for SCID is cost-effective, leads to years of productive life, and prevents the real negative outcomes associated with having one of this group of conditions," said Michael Watson, Ph.D., director of the American College of Medical Genetics and Genomics (ACMG) and principal investigator of the Newborn Screening Translational Research Network (NBSTRN). "Bone marrow transplant costs about $50,000-plus, but when these babies start getting infections and need hospitalization, the costs can be $1 to 1.2 million."

Using an estimated cost of SCID screening of $7.10 per baby, a medical model developed by the Washington State Department of Health reported a potential benefit:cost ratio of 4.93, meaning that almost $5 in benefits would accrue from every dollar of costs to provide SCID screening (Thompson JD, Glass M. Guide to the newborn screening cost-benefit model for adding severe combined immunodeficiency, 2012).

In January 2010, the U.S. Secretary of Health and Human Services approved SCID as the 30th core condition of the Recommended Uniform Screening Panel and the first immunological disorder. In May 2010, HHS Secretary Kathleen Sebelius endorsed newborn screening for SCID as the standard of care. However, there has been a wide disparity of adoption among states. "Currently no states are doing all newborn screening recommended by the secretary of HHS’s Advisory Committee, which now consists of 31 core conditions, including SCID and congenital heart screening," said Dr. Brower, project manager for the NBSTRN.

States that have screening programs in place for SCID are California, Colorado, Connecticut, Delaware, Florida, Massachusetts, Michigan, Minnesota, Mississippi, New York, Texas, and Wisconsin (also Puerto Rico).

Figure 1 from the NBSTRN shows the estimated number of newborns screened throughout the United States up until Dec. 31, 2012. Screening in the small area of New Mexico and Arizona reflects the high rate of SCID in Navajo Native Americans: In 2012, about 45% of all newborns were screened for SCID, and the hope is to reach 65% by 2014, Dr. Brower said at the meeting sponsored by New York University.

The Centers for Disease Control and Prevention (CDC) has been instrumental in trying to expand SCID newborn screening capability to more states, and contributed funding to pilot projects in Massachusetts and Wisconsin. The new CDC program is known as the Program to Support New Implementation of State or Territorial Public Health Laboratory Capacity for Newborn Bloodspot Screening of Severe Combined Immunodeficiency (SCID). Eligibility is restricted to states, special districts, and territorial governments that do not currently conduct SCID newborn screening. The total funds available are $1.8 million and it is anticipated that three awards will be made of $300,000 each year for 2 years. The application deadline is May 28, 2013, for funding that can begin on Aug. 1.

"Implementation of newborn screening for SCID is going slowly," agreed Dr. Watson. One challenge is the disparity of processes necessary for approval. Some states require legislative action, some need approval by the governor, and others require a go-ahead from the state’s department of health, which sometimes requires completion of a pilot program despite evidence collected from other states. Funding to properly outfit labs to carry out the new technology also can be a barrier.

Dr. Watson says that most of the states that initially began offering SCID screening already had the molecular assay technology in place from other programs, such as second-tier testing for cystic fibrosis. But even labs with the technical capability to conduct limited testing were not prepared to handle the high volume necessary for newborn screening. A possible cost-saving solution is that instead of having testing facilities available in every state, Dr. Watson suggests regionalized test centers, as is now done in New England, state partnerships, or even the use of commercial labs. Once a lab becomes equipped to handle SCID newborn screening, it often has the capacity to handle more than its own state’s needs, said Dr. Brower. Right now, Wisconsin and Massachusetts have the capacity to offer screening for other states.

Another limiting factor facing states considering adding SCID newborn screening can be the lack of a proper response mechanism. If a child screens positive for SCID, the child’s pediatrician must be prepared to shepherd the family through the next steps of diagnosis and arrange for immediate treatment, said Dr. Brower. To better inform pediatricians and other primary care physicians about SCID, the American College of Medical Genetics and Genomics offers an ACT sheet on SCID management aimed for the primary care provider. Dr. Watson also advises primary care providers to establish relationships with specialists in immunology, so that if a SCID baby is identified, the primary care provider can reach out for support regarding medical management, as well as for dealing with parental concerns.

The SCID newborn screening test is effective. Wisconsin was the first state to begin newborn screening for SCID. Between January 2008 and December 31, 2012, 5 infants with SCID or other forms of severe T-cell lymphopenia were detected out of almost 208,000 infants screened. No infants with SCID were missed during the screening period. The specificity of the assay used was 99.98%, with a false-positive rate of 0.018%. (Pediatrics 2012;130:S50-1). In California, the test had 99.91% specificity. Of 11 infants identified with SCID, all were able to be treated, with more than 90% alive at 6-21 months. In Colorado, a child with SCID was identified within the first week the SCID screening program began.

As part of the ACMG, the NBSTRN (www.nbstrn.org) maintains several SCID resources for investigators, including links to patient registries, a virtual repository of dried blood spot samples, and a longitudinal pediatric data resource. It also was involved with the National SCID Pilot Study that screened newborns in California, Louisiana, New York, and Puerto Rico. The ACMG operates the NBSTRN as part of funding it receives from the Eunice Kennedy Shriver National Institute of Child Health and Human Development for research into new therapeutics, technologies, and other aspects of newborn screening.

The NBSTRN also holds monthly conference calls for stakeholders, including scientists, clinicians, public health specialists, administrators, and patient advocates, to discuss SCID-related developments. "After decades of living with SCID children, some of whom we have already lost, mothers with children like mine who are older and were late transplants understand the urgency. They push us to think, what else can we be doing?" said Dr. Brower. Those interested in helping to broaden SCID screening may consult the Immune Deficiency Foundation’s SCID Newborn Screening Toolkit for Advocates or attend its national conference in Baltimore on June 27-29.

Screening for SCID

SCID is a group of conditions characterized by blocks in T-cell development, leading to functional deficiencies in both T cells and B cells.

Fortunately, a screening test able to detect low levels of a DNA biomarker of normal T-cell development has proven successful at identifying individuals before symptoms appear. The test, developed by Dr. Jennifer M. Puck of the University of California, San Francisco, measures T-cell receptor excision circles (TRECs) using a polymerase chain reaction (PCR) process in samples of dried blood spots commonly taken from infants that are used for other screening purposes. Infants with SCID or related disorders have very low or undetectable levels of TRECs.

Being able to measure TRECs "was a real game changer for SCID," said Dr. Brower. It fit well into ongoing public health programs that utilized dried blood spot collections. "This was a technology developed at [the National Institutes of Health] that was developed and translated into clinical care with clear public health benefits." At the NBSTRN, Dr. Brower leads similar efforts to take genomic advances from bench to bedside.

The Wisconsin screening program uses a cutoff of 25 TRECs/mcL. Most screening programs have an algorithm in place for dealing with abnormal results. In Wisconsin, the first step is to redo the TREC assay. If the results are still positive, a physician member of the screening program is notified, who then contacts the newborn’s primary care physician. A decision is then made to either do another filter-paper specimen analysis or have a whole-blood specimen sent for T-cell enumeration by flow cytometry. A full workup for SCID is then recommended if results are still abnormal. (Curr. Opin. Pediatr. 2011;23:667-73).

In the first 18 months of the California screening program, 116 babies had samples sent for flow cytometry. Of those, 81 were normal. There were 10 cases of typical SCID, 1 child with Omenn syndrome (leaky SCID), 4 with variants of SCID, 8 with low T cell syndromes, and 7 with secondary causes of low T cells. There were 5 preterm births.

Children with leaky SCID may have a later onset of symptoms, with rash, adenopathy, and poorly functioning T cells. SCID variants include cartilage-hair hypoplasia, CHARGE syndrome (coloboma, heart defect, atresia choanae [also known as choanal atresia], retarded growth and development, genital abnormality, and ear abnormality), Down syndrome, or DiGeorge syndrome.

SCID newborn screening also could be helpful to children with non-SCID, secondary causes of T-cell lymphopenia who might also be vulnerable to serious opportunistic infections. Just recently, abnormal TREC findings led investigators to diagnose ataxia telangiectasia in two infants (J. Clin. Immunol. 2013;33:540-9).

Dr. Brower and Dr. Watson both said that they had no relevant financial disclosures.

[email protected]

The Centers for Disease Control and Prevention announced on April 1 the availability of funding opportunities to expand newborn screening for severe combined immunodeficiency, also known as SCID.

Currently, only 12 states regularly test for SCID as part of their newborn screening programs. With the availability of a highly specific and low-cost test that measures a biomarker for a T-cell deficiency associated with SCID that can easily be added to current routine newborn screening, patient advocacy groups as well as state and federal governments are working to spur more widespread adoption of newborn SCID screening.

"Severe combined immunodeficiency is a pediatric emergency," medical geneticist Amy Brower, Ph.D., said at the NYU Annual Pediatric Rheumatology Update. "We need to get the message out to pediatricians and ob.gyns. that talking about newborn screening should begin prenatally. ... Unfortunately, surveys find that ob.gyns. do not have time for that conversation, and parents don’t remember it. We want physicians to know that there is a new test for SCID that has been vetted, is evidence based, and is available that can identify children before they become gravely ill."

Dr. Brower also suggests that parents should be made aware that even if their state does not offer SCID screening, they can request to have a newborn dried blood spot sample sent to a commercial lab for SCID analysis.

SCID is known colloquially as "bubble boy syndrome" because poor immune systems make these children vulnerable to infections. While babies born with SCID appear normal at birth, they stand a high risk of developing life-threatening viral, bacterial, and fungal infections. Right after birth, they are still protected by transplacentally derived maternal IgG antibodies, but soon lose that protection. If the condition is detected early and treated, survival rates are excellent. If treated before 3.5 months of age, 95% of affected babies will have long-term survival, but the survival rate falls below 70% if SCID is diagnosed after 3.5 months, even with intensive care and intervention (Public Health Rep. 2010;125:88-95).

Treatments include hematopoietic cell transplantation, enzyme replacement in cases of adenosine deaminase (ADA) deficiency, and gene therapy.

"Newborn screening for SCID is cost-effective, leads to years of productive life, and prevents the real negative outcomes associated with having one of this group of conditions," said Michael Watson, Ph.D., director of the American College of Medical Genetics and Genomics (ACMG) and principal investigator of the Newborn Screening Translational Research Network (NBSTRN). "Bone marrow transplant costs about $50,000-plus, but when these babies start getting infections and need hospitalization, the costs can be $1 to 1.2 million."

Using an estimated cost of SCID screening of $7.10 per baby, a medical model developed by the Washington State Department of Health reported a potential benefit:cost ratio of 4.93, meaning that almost $5 in benefits would accrue from every dollar of costs to provide SCID screening (Thompson JD, Glass M. Guide to the newborn screening cost-benefit model for adding severe combined immunodeficiency, 2012).

In January 2010, the U.S. Secretary of Health and Human Services approved SCID as the 30th core condition of the Recommended Uniform Screening Panel and the first immunological disorder. In May 2010, HHS Secretary Kathleen Sebelius endorsed newborn screening for SCID as the standard of care. However, there has been a wide disparity of adoption among states. "Currently no states are doing all newborn screening recommended by the secretary of HHS’s Advisory Committee, which now consists of 31 core conditions, including SCID and congenital heart screening," said Dr. Brower, project manager for the NBSTRN.

States that have screening programs in place for SCID are California, Colorado, Connecticut, Delaware, Florida, Massachusetts, Michigan, Minnesota, Mississippi, New York, Texas, and Wisconsin (also Puerto Rico).

Figure 1 from the NBSTRN shows the estimated number of newborns screened throughout the United States up until Dec. 31, 2012. Screening in the small area of New Mexico and Arizona reflects the high rate of SCID in Navajo Native Americans: In 2012, about 45% of all newborns were screened for SCID, and the hope is to reach 65% by 2014, Dr. Brower said at the meeting sponsored by New York University.

The Centers for Disease Control and Prevention (CDC) has been instrumental in trying to expand SCID newborn screening capability to more states, and contributed funding to pilot projects in Massachusetts and Wisconsin. The new CDC program is known as the Program to Support New Implementation of State or Territorial Public Health Laboratory Capacity for Newborn Bloodspot Screening of Severe Combined Immunodeficiency (SCID). Eligibility is restricted to states, special districts, and territorial governments that do not currently conduct SCID newborn screening. The total funds available are $1.8 million and it is anticipated that three awards will be made of $300,000 each year for 2 years. The application deadline is May 28, 2013, for funding that can begin on Aug. 1.

"Implementation of newborn screening for SCID is going slowly," agreed Dr. Watson. One challenge is the disparity of processes necessary for approval. Some states require legislative action, some need approval by the governor, and others require a go-ahead from the state’s department of health, which sometimes requires completion of a pilot program despite evidence collected from other states. Funding to properly outfit labs to carry out the new technology also can be a barrier.

Dr. Watson says that most of the states that initially began offering SCID screening already had the molecular assay technology in place from other programs, such as second-tier testing for cystic fibrosis. But even labs with the technical capability to conduct limited testing were not prepared to handle the high volume necessary for newborn screening. A possible cost-saving solution is that instead of having testing facilities available in every state, Dr. Watson suggests regionalized test centers, as is now done in New England, state partnerships, or even the use of commercial labs. Once a lab becomes equipped to handle SCID newborn screening, it often has the capacity to handle more than its own state’s needs, said Dr. Brower. Right now, Wisconsin and Massachusetts have the capacity to offer screening for other states.

Another limiting factor facing states considering adding SCID newborn screening can be the lack of a proper response mechanism. If a child screens positive for SCID, the child’s pediatrician must be prepared to shepherd the family through the next steps of diagnosis and arrange for immediate treatment, said Dr. Brower. To better inform pediatricians and other primary care physicians about SCID, the American College of Medical Genetics and Genomics offers an ACT sheet on SCID management aimed for the primary care provider. Dr. Watson also advises primary care providers to establish relationships with specialists in immunology, so that if a SCID baby is identified, the primary care provider can reach out for support regarding medical management, as well as for dealing with parental concerns.

The SCID newborn screening test is effective. Wisconsin was the first state to begin newborn screening for SCID. Between January 2008 and December 31, 2012, 5 infants with SCID or other forms of severe T-cell lymphopenia were detected out of almost 208,000 infants screened. No infants with SCID were missed during the screening period. The specificity of the assay used was 99.98%, with a false-positive rate of 0.018%. (Pediatrics 2012;130:S50-1). In California, the test had 99.91% specificity. Of 11 infants identified with SCID, all were able to be treated, with more than 90% alive at 6-21 months. In Colorado, a child with SCID was identified within the first week the SCID screening program began.

As part of the ACMG, the NBSTRN (www.nbstrn.org) maintains several SCID resources for investigators, including links to patient registries, a virtual repository of dried blood spot samples, and a longitudinal pediatric data resource. It also was involved with the National SCID Pilot Study that screened newborns in California, Louisiana, New York, and Puerto Rico. The ACMG operates the NBSTRN as part of funding it receives from the Eunice Kennedy Shriver National Institute of Child Health and Human Development for research into new therapeutics, technologies, and other aspects of newborn screening.

The NBSTRN also holds monthly conference calls for stakeholders, including scientists, clinicians, public health specialists, administrators, and patient advocates, to discuss SCID-related developments. "After decades of living with SCID children, some of whom we have already lost, mothers with children like mine who are older and were late transplants understand the urgency. They push us to think, what else can we be doing?" said Dr. Brower. Those interested in helping to broaden SCID screening may consult the Immune Deficiency Foundation’s SCID Newborn Screening Toolkit for Advocates or attend its national conference in Baltimore on June 27-29.

Screening for SCID

SCID is a group of conditions characterized by blocks in T-cell development, leading to functional deficiencies in both T cells and B cells.

Fortunately, a screening test able to detect low levels of a DNA biomarker of normal T-cell development has proven successful at identifying individuals before symptoms appear. The test, developed by Dr. Jennifer M. Puck of the University of California, San Francisco, measures T-cell receptor excision circles (TRECs) using a polymerase chain reaction (PCR) process in samples of dried blood spots commonly taken from infants that are used for other screening purposes. Infants with SCID or related disorders have very low or undetectable levels of TRECs.

Being able to measure TRECs "was a real game changer for SCID," said Dr. Brower. It fit well into ongoing public health programs that utilized dried blood spot collections. "This was a technology developed at [the National Institutes of Health] that was developed and translated into clinical care with clear public health benefits." At the NBSTRN, Dr. Brower leads similar efforts to take genomic advances from bench to bedside.

The Wisconsin screening program uses a cutoff of 25 TRECs/mcL. Most screening programs have an algorithm in place for dealing with abnormal results. In Wisconsin, the first step is to redo the TREC assay. If the results are still positive, a physician member of the screening program is notified, who then contacts the newborn’s primary care physician. A decision is then made to either do another filter-paper specimen analysis or have a whole-blood specimen sent for T-cell enumeration by flow cytometry. A full workup for SCID is then recommended if results are still abnormal. (Curr. Opin. Pediatr. 2011;23:667-73).

In the first 18 months of the California screening program, 116 babies had samples sent for flow cytometry. Of those, 81 were normal. There were 10 cases of typical SCID, 1 child with Omenn syndrome (leaky SCID), 4 with variants of SCID, 8 with low T cell syndromes, and 7 with secondary causes of low T cells. There were 5 preterm births.

Children with leaky SCID may have a later onset of symptoms, with rash, adenopathy, and poorly functioning T cells. SCID variants include cartilage-hair hypoplasia, CHARGE syndrome (coloboma, heart defect, atresia choanae [also known as choanal atresia], retarded growth and development, genital abnormality, and ear abnormality), Down syndrome, or DiGeorge syndrome.

SCID newborn screening also could be helpful to children with non-SCID, secondary causes of T-cell lymphopenia who might also be vulnerable to serious opportunistic infections. Just recently, abnormal TREC findings led investigators to diagnose ataxia telangiectasia in two infants (J. Clin. Immunol. 2013;33:540-9).

Dr. Brower and Dr. Watson both said that they had no relevant financial disclosures.

[email protected]

The Centers for Disease Control and Prevention announced on April 1 the availability of funding opportunities to expand newborn screening for severe combined immunodeficiency, also known as SCID.

Currently, only 12 states regularly test for SCID as part of their newborn screening programs. With the availability of a highly specific and low-cost test that measures a biomarker for a T-cell deficiency associated with SCID that can easily be added to current routine newborn screening, patient advocacy groups as well as state and federal governments are working to spur more widespread adoption of newborn SCID screening.

"Severe combined immunodeficiency is a pediatric emergency," medical geneticist Amy Brower, Ph.D., said at the NYU Annual Pediatric Rheumatology Update. "We need to get the message out to pediatricians and ob.gyns. that talking about newborn screening should begin prenatally. ... Unfortunately, surveys find that ob.gyns. do not have time for that conversation, and parents don’t remember it. We want physicians to know that there is a new test for SCID that has been vetted, is evidence based, and is available that can identify children before they become gravely ill."

Dr. Brower also suggests that parents should be made aware that even if their state does not offer SCID screening, they can request to have a newborn dried blood spot sample sent to a commercial lab for SCID analysis.

SCID is known colloquially as "bubble boy syndrome" because poor immune systems make these children vulnerable to infections. While babies born with SCID appear normal at birth, they stand a high risk of developing life-threatening viral, bacterial, and fungal infections. Right after birth, they are still protected by transplacentally derived maternal IgG antibodies, but soon lose that protection. If the condition is detected early and treated, survival rates are excellent. If treated before 3.5 months of age, 95% of affected babies will have long-term survival, but the survival rate falls below 70% if SCID is diagnosed after 3.5 months, even with intensive care and intervention (Public Health Rep. 2010;125:88-95).

Treatments include hematopoietic cell transplantation, enzyme replacement in cases of adenosine deaminase (ADA) deficiency, and gene therapy.

"Newborn screening for SCID is cost-effective, leads to years of productive life, and prevents the real negative outcomes associated with having one of this group of conditions," said Michael Watson, Ph.D., director of the American College of Medical Genetics and Genomics (ACMG) and principal investigator of the Newborn Screening Translational Research Network (NBSTRN). "Bone marrow transplant costs about $50,000-plus, but when these babies start getting infections and need hospitalization, the costs can be $1 to 1.2 million."

Using an estimated cost of SCID screening of $7.10 per baby, a medical model developed by the Washington State Department of Health reported a potential benefit:cost ratio of 4.93, meaning that almost $5 in benefits would accrue from every dollar of costs to provide SCID screening (Thompson JD, Glass M. Guide to the newborn screening cost-benefit model for adding severe combined immunodeficiency, 2012).

In January 2010, the U.S. Secretary of Health and Human Services approved SCID as the 30th core condition of the Recommended Uniform Screening Panel and the first immunological disorder. In May 2010, HHS Secretary Kathleen Sebelius endorsed newborn screening for SCID as the standard of care. However, there has been a wide disparity of adoption among states. "Currently no states are doing all newborn screening recommended by the secretary of HHS’s Advisory Committee, which now consists of 31 core conditions, including SCID and congenital heart screening," said Dr. Brower, project manager for the NBSTRN.

States that have screening programs in place for SCID are California, Colorado, Connecticut, Delaware, Florida, Massachusetts, Michigan, Minnesota, Mississippi, New York, Texas, and Wisconsin (also Puerto Rico).

Figure 1 from the NBSTRN shows the estimated number of newborns screened throughout the United States up until Dec. 31, 2012. Screening in the small area of New Mexico and Arizona reflects the high rate of SCID in Navajo Native Americans: In 2012, about 45% of all newborns were screened for SCID, and the hope is to reach 65% by 2014, Dr. Brower said at the meeting sponsored by New York University.

The Centers for Disease Control and Prevention (CDC) has been instrumental in trying to expand SCID newborn screening capability to more states, and contributed funding to pilot projects in Massachusetts and Wisconsin. The new CDC program is known as the Program to Support New Implementation of State or Territorial Public Health Laboratory Capacity for Newborn Bloodspot Screening of Severe Combined Immunodeficiency (SCID). Eligibility is restricted to states, special districts, and territorial governments that do not currently conduct SCID newborn screening. The total funds available are $1.8 million and it is anticipated that three awards will be made of $300,000 each year for 2 years. The application deadline is May 28, 2013, for funding that can begin on Aug. 1.

"Implementation of newborn screening for SCID is going slowly," agreed Dr. Watson. One challenge is the disparity of processes necessary for approval. Some states require legislative action, some need approval by the governor, and others require a go-ahead from the state’s department of health, which sometimes requires completion of a pilot program despite evidence collected from other states. Funding to properly outfit labs to carry out the new technology also can be a barrier.

Dr. Watson says that most of the states that initially began offering SCID screening already had the molecular assay technology in place from other programs, such as second-tier testing for cystic fibrosis. But even labs with the technical capability to conduct limited testing were not prepared to handle the high volume necessary for newborn screening. A possible cost-saving solution is that instead of having testing facilities available in every state, Dr. Watson suggests regionalized test centers, as is now done in New England, state partnerships, or even the use of commercial labs. Once a lab becomes equipped to handle SCID newborn screening, it often has the capacity to handle more than its own state’s needs, said Dr. Brower. Right now, Wisconsin and Massachusetts have the capacity to offer screening for other states.

Another limiting factor facing states considering adding SCID newborn screening can be the lack of a proper response mechanism. If a child screens positive for SCID, the child’s pediatrician must be prepared to shepherd the family through the next steps of diagnosis and arrange for immediate treatment, said Dr. Brower. To better inform pediatricians and other primary care physicians about SCID, the American College of Medical Genetics and Genomics offers an ACT sheet on SCID management aimed for the primary care provider. Dr. Watson also advises primary care providers to establish relationships with specialists in immunology, so that if a SCID baby is identified, the primary care provider can reach out for support regarding medical management, as well as for dealing with parental concerns.

The SCID newborn screening test is effective. Wisconsin was the first state to begin newborn screening for SCID. Between January 2008 and December 31, 2012, 5 infants with SCID or other forms of severe T-cell lymphopenia were detected out of almost 208,000 infants screened. No infants with SCID were missed during the screening period. The specificity of the assay used was 99.98%, with a false-positive rate of 0.018%. (Pediatrics 2012;130:S50-1). In California, the test had 99.91% specificity. Of 11 infants identified with SCID, all were able to be treated, with more than 90% alive at 6-21 months. In Colorado, a child with SCID was identified within the first week the SCID screening program began.

As part of the ACMG, the NBSTRN (www.nbstrn.org) maintains several SCID resources for investigators, including links to patient registries, a virtual repository of dried blood spot samples, and a longitudinal pediatric data resource. It also was involved with the National SCID Pilot Study that screened newborns in California, Louisiana, New York, and Puerto Rico. The ACMG operates the NBSTRN as part of funding it receives from the Eunice Kennedy Shriver National Institute of Child Health and Human Development for research into new therapeutics, technologies, and other aspects of newborn screening.

The NBSTRN also holds monthly conference calls for stakeholders, including scientists, clinicians, public health specialists, administrators, and patient advocates, to discuss SCID-related developments. "After decades of living with SCID children, some of whom we have already lost, mothers with children like mine who are older and were late transplants understand the urgency. They push us to think, what else can we be doing?" said Dr. Brower. Those interested in helping to broaden SCID screening may consult the Immune Deficiency Foundation’s SCID Newborn Screening Toolkit for Advocates or attend its national conference in Baltimore on June 27-29.

Screening for SCID

SCID is a group of conditions characterized by blocks in T-cell development, leading to functional deficiencies in both T cells and B cells.

Fortunately, a screening test able to detect low levels of a DNA biomarker of normal T-cell development has proven successful at identifying individuals before symptoms appear. The test, developed by Dr. Jennifer M. Puck of the University of California, San Francisco, measures T-cell receptor excision circles (TRECs) using a polymerase chain reaction (PCR) process in samples of dried blood spots commonly taken from infants that are used for other screening purposes. Infants with SCID or related disorders have very low or undetectable levels of TRECs.

Being able to measure TRECs "was a real game changer for SCID," said Dr. Brower. It fit well into ongoing public health programs that utilized dried blood spot collections. "This was a technology developed at [the National Institutes of Health] that was developed and translated into clinical care with clear public health benefits." At the NBSTRN, Dr. Brower leads similar efforts to take genomic advances from bench to bedside.

The Wisconsin screening program uses a cutoff of 25 TRECs/mcL. Most screening programs have an algorithm in place for dealing with abnormal results. In Wisconsin, the first step is to redo the TREC assay. If the results are still positive, a physician member of the screening program is notified, who then contacts the newborn’s primary care physician. A decision is then made to either do another filter-paper specimen analysis or have a whole-blood specimen sent for T-cell enumeration by flow cytometry. A full workup for SCID is then recommended if results are still abnormal. (Curr. Opin. Pediatr. 2011;23:667-73).

In the first 18 months of the California screening program, 116 babies had samples sent for flow cytometry. Of those, 81 were normal. There were 10 cases of typical SCID, 1 child with Omenn syndrome (leaky SCID), 4 with variants of SCID, 8 with low T cell syndromes, and 7 with secondary causes of low T cells. There were 5 preterm births.

Children with leaky SCID may have a later onset of symptoms, with rash, adenopathy, and poorly functioning T cells. SCID variants include cartilage-hair hypoplasia, CHARGE syndrome (coloboma, heart defect, atresia choanae [also known as choanal atresia], retarded growth and development, genital abnormality, and ear abnormality), Down syndrome, or DiGeorge syndrome.

SCID newborn screening also could be helpful to children with non-SCID, secondary causes of T-cell lymphopenia who might also be vulnerable to serious opportunistic infections. Just recently, abnormal TREC findings led investigators to diagnose ataxia telangiectasia in two infants (J. Clin. Immunol. 2013;33:540-9).

Dr. Brower and Dr. Watson both said that they had no relevant financial disclosures.

[email protected]