Diagnosis of Severe Combined Immunodeficiency

The SCID newborn screening test, originally developed at NIH, measures T cell receptor excision circles (TRECs), a byproduct of T-cell development. Because SCID infants have few or no T cells, the absence of TRECs may indicate SCID. To confirm a SCID diagnosis, a doctor will evaluate the numbers and types of T and B cells present and their ability to function.

Source: NIAID (NIH)1

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Back to: « Severe Combined Immunodeficiency

Back to: « Combined Immunodeficiency

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With the introduction of newborn screening for SCID in a number of states in the United States and in Ontario in Canada, young infants are increasingly being diagnosed with SCID soon after birth, before the onset of serious infections.

Source: RDCRN (NCATS/NIH)2

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How is SCID Diagnosed?

The frequency and severity of infections are the most helpful clues that a patient may have a problem with their immune system. For patients with symptoms suggestive of SCID, the following tests can be helpful in making a definitive diagnosis:

  • Complete Blood Counts (CBC with differential) -often shows low lymphocyte counts (although in some situations, the total lymphocyte count may be in the normal range, and sometimes, even higher than normal). Patients with SCID are susceptible to infections because they are missing one or more types of lymphocytes.
  • T cell, B cell, and NK cell counts -T cells are absent or dysfunctional in all forms of SCID. B cells and NK cells may be absent depending on which type of SCID a patient has.
  • Immunoglobulin levels (IgG, IgM, IgA, IgE) - Immunoglobulins (antibodies) are made by the lymphocytes so they are usually low in SCID.
  • Specific genetic testing - There are at least 20 known genetic causes of SCID, making it possible to identify an underlying genetic defect in about 90% of cases. Mutations in different genes are accompanied by characteristic immune abnormalities that can assist in making the diagnosis.
  • A growing number of states are currently performing newborn screening for SCID with the TREC assay. As of May 2015, about 70% of all newborns in the United States are screened at birth. As this process expands to other states, most children with SCID will be diagnosed very early in life, increasing their chances for successful treatment.

Source: RDCRN (NCATS/NIH)3

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How is SCID diagnosed?

Clinical diagnosis is difficult without positive family history of SCID, or characteristic infection history. Blood tests for SCID typically reveal significantly lower-than-normal levels of T cells and a lack of germ-fighting antibodies. Genetic testing generally provides with specific diagnosis.

Source: RDCRN (NCATS/NIH)4

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How is SCID diagnosed?

Early diagnosis of SCID is rare because doctors do not routinely count each type of white blood cell in newborns. As a result, the average age at which babies are diagnosed with SCID is just over six months, usually because of recurrent infections and failure to thrive.

Blood tests for SCID typically reveal significantly lower-than-normal levels of T cells and a lack of germ-fighting antibodies. Even if B cells are present in the blood of SCID patients, they do a poor job of producing antibodies. Low antibody levels and lack of specific antibodies after vaccination or a natural infection are characteristic features of SCID.

Source: NHGRI (NIH)5

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Can SCID be detected before birth (prenatally)?

If the mutation leading to SCID in a family is known, an at-risk pregnancy can be tested by sequencing DNA from the fetus. However, SCID is so rare that prenatal testing of a baby with no family history is probably not justified because the test is so expensive.

Source: NHGRI (NIH)6

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Is SCID diagnosis in the newborn period possible and beneficial?

Newborns with SCID generally appear healthy because they are protected for a few weeks by antibodies produced by the mother and then transferred into the baby's blood. In addition, newborns have not been exposed to infections. Diagnosis and treatment before the onset of infections and the complications they cause in immune-compromised babies reduces costly hospitalizations and leads to better outcomes. Testing immediately after birth can be done, either by sequencing DNA if the family mutation is known or by counting the numbers of T and B cells and assessing their function. However, the current tests to confirm SCID must be applied to individual blood samples and take hours to prepare.

The high cost of current testing has prohibited newborn screening on a population-wide basis. To make screening for all newborns affordable, an automated screening method that could process hundreds of samples every day with minimal hands-on requirements would need to be developed. In addition, the results would have to be made quickly available to doctors for patient follow-up.

Source: NHGRI (NIH)7

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Diagnosis

A diagnosis of severe combined immunodeficiency (SCID) may be suspected if a baby shows any of the following persistent symptoms within the first year of life:[2]

Eight or more ear infections

Two or more cases of pneumonia

Infections that do not resolve with antibiotic treatment for two or more months

Failure to gain weight or grow normally

Infections that require intravenous antibiotic treatment

Deep-seated infections, such as pneumonia that affects an entire lung or an abscess in the liver

Persistent thrush in the mouth or throat

A family history of immune deficiency or infant deaths due to infections

Diagnosis can be confirmed by blood tests. Blood tests show significantly lower-than-normal levels of T cells and antibodies.[2]

For further details on diagnosis see the following Web pages:

The Primary Immunodeficiency Resource Center provides further details regarding diagnosis of SCID. Click on the embedded link to view the page.

An article from Medscape Reference provides detailed information on the diagnosis of SCID. Click on eMedicine Journal to view the page. You may need to register to view the article, but registration is free.

Last updated: 5/28/2014

Source: GARD (NIH)8

Screening Tests for Severe Combined Immunodeficiency

However, development of a newborn screening test has made it possible to detect SCID before symptoms appear, helping ensure that affected infants receive life-saving treatments.

Source: NIAID (NIH)9

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Can SCID be detected before birth (prenatally)?

If the presence of SCID in the family’s history is known, and the type of SCID genetic mutation has been identified, prenatal testing can be performed. Sequencing DNA from the fetus can be tested in an at-risk pregnancy via chorionic villus sampling (CVS) by removing and testing cells from the placenta or by amniocentesis in which a sample of the fluid surrounding the baby is removed and tested. Even when the gene mutation is not known, the diagnosis can be made in the fetus by sampling a small amount of fetal blood at around 18-20 weeks of gestation.

Source: RDCRN (NCATS/NIH)10

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What is Newborn Screening for SCID?

Until recently, infants with SCID would present to their doctors’ offices or hospitals with signs and symptoms of an infection. Often this would occur many times, or the infection would become quite serious before it was recognized by doctors that the patient had SCID. Once a serious infection was occurring, it may have already been too late to perform a transplant (or gene therapy); or, the infection made the transplant process more complicated. One thing the PIDTC has confirmed is that infants with SCID who are transplanted before 3 months of age do better than infants who are transplanted later in life, in part because younger infants have had fewer infections.

This led researchers to search for a test that could alert doctors to a patient with SCID early on in life (within the first week or two after birth), before the patient developed severe infections. This test was discovered and is called the T-Cell Receptor Excision Circles test (TRECs for short). As SCID is a rare disease and babies would need to be screened for TRECs before they had signs of infection, large populations of babies would all need to be tested right after birth in order to pick up the rare baby who would be affected by SCID.

In all states (US) and provinces (Canada), newborn screenings for a variety of diseases (other than SCID) have been around for many years. Each state/ province screens for different rare diseases. At birth, all babies have a prick done on their heels (called the “heel prick” test) as part of the newborn screening. In certain states and provinces newborn screenings now include the TREC test to screen for SCID. As of May 2015, about 70% of all newborn babies in the US are screened for SCID. These babies will be diagnosed early on (often in the first few weeks of life) before the onset of serious infections. The other 30% of newborns are not screened because some states have not yet implemented newborn screening for SCID. A future goal is to have 100% of newborns screened for SCID.

It seems likely that newborn screenings for SCID will significantly improve outcomes for this rare disorder in the future. One of the goals of the PIDTC is to continue to study how newborn screenings improve transplant and gene therapy outcomes, as well as to lobby for all states and provinces to adopt newborn screenings for SCID.

Source: RDCRN (NCATS/NIH)11

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References

  1. Source: NIAID (NIH): niaid.nih.gov/ diseases-conditions/ scid-symptoms-diagnosis
  2. Source: RDCRN (NCATS/NIH): rarediseasesnetwork.org/ cms/ pidtc/ Learn-More/ Disorder-Definitions
  3. ibid.
  4. ibid.
  5. Source: NHGRI (NIH): genome.gov/ 13014325/ learning-about-severe-combined-immunodeficiency-scid/ 
  6. ibid.
  7. ibid.
  8. Source: GARD (NIH): rarediseases.info.nih.gov/ diseases/ 7628/ severe-combined-immunodeficiency
  9. Source: NIAID (NIH): niaid.nih.gov/ diseases-conditions/ severe-combined-immunodeficiency-scid
  10. Source: RDCRN (NCATS/NIH): rarediseasesnetwork.org/ cms/ pidtc/ Learn-More/ Disorder-Definitions
  11. Source: RDCRN (NCATS/NIH): rarediseasesnetwork.org/ cms/ pidtc/ Learn-More/ Newborn-Screening

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