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Understanding primary immunodeficiency (PI)
Understanding PI
The more you understand about primary immunodeficiency (PI), the better you can manage it. Learn about PI diagnoses and treatment options.
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Living with PI
Living with PI
Living with primary immunodeficiency (PI) can be challenging, but you’re not alone—many people with PI lead full and active lives. With the right support and resources, you can, too.
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Get involved
Get involved
Be a hero for those with PI. Change lives by promoting primary immunodeficiency (PI) awareness and taking action in your community through advocacy, donating, volunteering, or fundraising.
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Advancing research and clinical care
Advancing research and clinical care
Whether you’re a clinician, researcher, or an individual with primary immunodeficiency (PI), IDF has resources to help you advance the field. Get details on surveys, grants, and clinical trials.
Key points:
- Newborn screening is a set of tests done soon after birth for babies born in all 50 U.S. states, as well as D.C., Puerto Rico, Guam, and the Navajo Nation.
- Newborn screening helps healthcare providers identify babies who may have serious but treatable conditions early so that these babies can be treated before they develop any health problems. Babies with many of these conditions do not show outward signs of illness and appear healthy at birth.
- Newborn screening tests do not provide a diagnosis but rather flag babies for further testing and evaluation by healthcare providers for a possible health condition. The newborn screening test for severe combined immune deficiency (SCID), TREC, also flags babies who have low T cell numbers for other reasons.
- All babies with an abnormal TREC or ADA result need additional testing and evaluation by a clinical immunologist.
How is newborn screening done?
Newborn screening has three different parts: the heel stick; the hearing screen; and the pulse oximetry test.
The heel stick determines if a newborn might have one of many serious health conditions, including severe combined immunodeficiency (SCID). A small blood sample is taken from a baby’s heel, or sometimes through a vein, and placed on a newborn screening card. The hospital sends the newborn screening card with the dried blood spot to the state public health laboratory for testing.
The hearing screening determines if a newborn might have hearing loss. Two different tests can be done to screen for hearing loss. Both tests involve earphones or earbuds to check the baby’s hearing, usually while the baby is asleep.
The pulse oximetry test checks if a newborn might have certain heart conditions. A painless sensor placed on the baby’s skin monitors the amount of oxygen in their blood.
These tests all happen within 24-48 hours and before discharge for babies born in the hospital. For babies born at home or in birthing centers, licensed midwives can perform the blood test and hearing screening, or families can make an appointment with their pediatrician or local hospital to have the tests done [3]. Note that you may need to call several providers/facilities to find one who can do the testing. The newborn screening hearing and pulse oximetry test results are ready immediately, and the blood screening results are available within a week.
How does the screening test for SCID work?
Beginning in December 2018, after 10 years of advocacy work [4], every state in the U.S., as well as Washington, D.C., Puerto Rico, Guam, and the Navajo Nation, now screens every newborn for SCID as part of the baby’s blood screening.
To screen for SCID, the public health laboratory measures the number of T cell receptor excision circles (TRECs) in the baby’s blood. TRECs are created when a type of white blood cell called a T cell matures in a small organ called the thymus. As T cells develop, they cut out a small piece of DNA that forms a circle inside the cell—this is the TREC. The number of TRECs correlates with how many T cells a baby has. The TREC screening results are either normal or abnormal.
- A normal TREC result, also called negative, in-range, or low-risk depending on the state, means that it is unlikely that a baby has a health condition affecting their T cells.
- An abnormal TREC result, also called positive, out-of-range, or high-risk depending on the state, means that a baby needs more testing to see if they have a health condition affecting their T cells.
If the results are normal, families are often not notified, but it is always important to ask the baby’s primary healthcare provider about their newborn screening results. State newborn screening offices can also provide information for parents or caregivers if they have questions.
If the results are abnormal, the baby’s healthcare provider will contact the family. An abnormal TREC test means that the baby might have no or very low numbers of T cells. T cells are a very important part of the immune system that prevent life-threatening infections. Low or no T cells means the baby’s immune system may not work.
In addition to the TREC test, some states, including Alabama, Connecticut, Michigan, and Minnesota use an additional test to screen for a specific type of SCID called adenosine deaminase deficiency SCID (ADA-SCID) [5]. Babies with ADA-SCID don’t have working adenosine deaminase, which is a protein that helps the body break down adenosine. Adenosine is toxic to T cells and other white blood cells and kills them if it builds up.
Some babies with ADA-SCID have normal TREC screening results because their T cell numbers are not low when they are born [6]. The additional screening for ADA-SCID is called tandem mass spectrometry (TMS) for ADA and measures the amount of adenosine in a baby’s blood. If a baby has a high level of adenosine, they may have ADA deficiency, which can cause ADA-SCID or a combined immune deficiency that is less severe than SCID. These babies require the same precautions as babies who have an abnormal TREC test and need additional testing and evaluation by an immunologist or other healthcare provider.
Abnormal TREC results could mean a child has no or low numbers of T cells, which is a condition called T cell lymphopenia or T cell deficiency. T cell deficiency can be caused by SCID, sometimes known as the bubble boy disease, or it could mean a child has another health condition. In some cases, a repeat TREC screening or additional diagnostic testing shows good levels of T cells, and the baby likely does not have a T cell deficiency.
As states expand into testing specifically for ADA-SCID, it is important for babies that get an abnormal result for ADA, without or without an abnormal TREC, to receive additional testing. Immunologists will often order the same tests as they would for those that have an abnormal newborn screening for TREC.
It is important to remember that TREC and ADA testing are very useful for screening for low T cells, but don’t provide a diagnosis—they only identify that something may be wrong. Additional testing and evaluation by healthcare providers determine if the child has a T cell deficiency and why.
Confirming T cell deficiency
Follow-up testing to confirm T cell deficiency in a baby with an abnormal TREC or ADA result differs from state to state. Some states perform another test with a different blood sample, while others go directly to other diagnostic tests.
To find out if the number of T cells in the baby’s blood is actually low, healthcare providers order a follow-up test, called immunophenotyping by flow cytometry, on another blood sample from the baby. This test counts T cells and other types of white blood cells, including B cells and natural killer (NK) cells, directly. Experts recommend also measuring the number of naïve versus memory T cells during immunophenotyping to see if any detected T cells could be from the baby’s mother (T cells from the baby should be mostly naïve T cells).
If the baby has no or low numbers of T cells by immunophenotyping, or the T cells they do have are likely from their mother, they are confirmed to have T cell deficiency. Again, further testing and evaluation have to be done to figure out why the baby has a T cell deficiency.
Some babies with T cell deficiency are ultimately diagnosed with a type of SCID. However, in most cases, the T cell deficiency is caused by another condition. Other conditions that may cause low T cell numbers include:
- Birth defects of the heart or digestive tract, which often require surgery.
- Premature birth (mainly infants born before 30 weeks).
- Other primary immunodeficiencies.
- Transient lymphopenia of infancy.
- Idiopathic T cell lymphopenia.
- Combined immunodeficiencies or ‘leaky’ SCID.
- Syndromes such as DiGeorge/22q11.2 deletion syndrome, CHARGE syndrome, and Jacobsen syndrome.
- Ataxia-telangiectasia.
- DOCK8 deficiency.
- FOXN1 gene variant causing poor thymus development, but not complete deficiency of the FOXN1 protein.
- Lymphatic system disorders, which can cause T cells to leak out of the lymphatic system and the bloodstream.
- Temporary immune system suppression from maternal medication or exposure to certain viruses during pregnancy.
- Other factors that can impact the development of the baby’s thymus such as maternal diabetes.
- Down syndrome (trisomy 21).
- Edwards syndrome (trisomy 18).
- VACTERL association.
- Leukemia.
- HIV/AIDS.
Other conditions that can cause low T cells and abnormal TREC results are often not as severe as SCID, but it's important to learn about and test for them. If your child is diagnosed with T cell deficiency and it’s not SCID, continue to pursue diagnosis and medical treatment. Keep in mind that some of the medical steps taken overlap those for SCID, at least in the beginning.
Importance of seeing a clinical immunologist
Babies with confirmed T cell deficiency—both those with SCID and those with non-SCID T cell deficiency—need to be seen and followed by a clinical immunologist. Clinical immunologists have specialized training in recognizing, diagnosing, and treating disorders associated with low T cells. In the meantime, the healthcare team may start the baby on medications to prevent infections such as immunoglobulin (Ig) replacement therapy or antimicrobials (which may include antibiotics, antivirals, or antifungals).
Some babies who have abnormal TREC results and confirmed T cell deficiency at birth eventually make enough T cells to protect themselves, without suffering from serious infections or poor health outcomes. However, all babies with T cell deficiency should be evaluated by a clinical immunologist to help caregivers and pediatricians decide the best treatment and monitoring plan for each baby’s individual needs.
For help finding a clinical immunologist, use Immune Deficiency Foundation’s Clinician Finder [7] or the Primary Immune Deficiency Treatment Consortium (PIDTC) website [3].
Further diagnostic testing
If a baby has a confirmed T cell deficiency, healthcare providers will do additional testing to diagnose the issue. These tests can include measures of how well the baby’s T cells work, determining whether any T cells in the baby’s blood are from the mother, and genetic tests.
If the TREC test shows low T cells instead of no T cells at all, a test of how well the T cells work, called lymphocyte proliferation to mitogens, may be done. Mitogens are chemicals made by plants that encourage healthy, working T cells to divide and multiply. By measuring the T cells’ ability to divide when mixed with the mitogen, the test helps determine if the baby’s T cells are working.
Since low T cells can be caused by chromosomal problems (such as Down syndrome or DiGeorge/22q11.2 deletion syndrome), healthcare providers may order blood tests to look at the size, shape, and number of the baby’s chromosomes. Tests that can diagnose chromosomal problems include karyotype, fluorescence in situ hybridization (FISH), multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray.
Your healthcare provider may order genetic testing, especially if there is a high suspicion of SCID or another genetic cause for the T cell deficiency. Most genetic testing laboratories offer a SCID panel, a broader PI panel, or your provider may order more comprehensive genetic testing such as whole exome (looks for variants in all of the baby’s genes) or whole genome sequencing (looks for variants in all of the baby’s DNA). Your provider will base the type of genetic testing on your child’s overall evaluation, including findings from any previous testing.
Your healthcare provider may need to get prior authorization from your insurance provider before some tests can be performed. If denied, some testing companies offer assistance with the cost of these tests.
Latest newborn screening resources
This page contains general medical and/or legal information that cannot be applied safely to any individual case. Medical and/or legal knowledge and practice can change rapidly. Therefore, this page should not be used as a substitute for professional medical and/or legal advice. Additionally, links to other resources and websites are shared for informational purposes only and should not be considered an endorsement by the Immune Deficiency Foundation.
Adapted from the IDF Patient & Family Handbook for Primary Immunodeficiency Diseases, Sixth Edition.
Copyright ©2019 by Immune Deficiency Foundation, USA
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