Guidance for primary care clinicians receiving a positive newborn screen result
Other Names
- Adenosine Deaminase deficiency
- Cartilage-Hair Hypoplasia
- CD3/T cell receptor complex disorders with immunodeficiency
- Combined immunodeficiency syndromes
- Reticular dysgenesis
- SCID with intestinal atresia (TTC7A SCID)
- Syndromic immunodeficiency
- T-B+NK+ SCID (IL7Ra SCID)
- T-B+NK- SCID (IL2RG or JAK3 SCID)
- T-B-NK+ SCID (RAG1, RAG2 or DCLRE1C SCID)
- T-B-NK- SCID (ADA or AK2 SCID)
- X-linked severe combined immunodeficiency (X-SCID)
Disorder Category
Inborn error of immunity (IEI), immunodeficiency disorder
Newborn Screening for SCID
Abnormal Finding
Absent or reduced T-cell receptor excision circles (TRECs), which are produced during normal T-cell maturation
Tested By
- TREC test; PCR-based assay that detects the number of copies of TRECs
- Additional testing should be done to confirm the diagnosis and determine the subtype and genotype of SCID, which will determine next steps in management.
Description
Severe combined immunodeficiency (SCID) includes a group of rare but serious and potentially fatal inherited immune disorders in which T lymphocytes fail to develop, and B lymphocytes may be absent or compromised. Impairment of both B and T cells leads to the term “combined.” In certain presentations, NK cells may also be affected in about 50% of patients with SCID. Untreated patients develop life-threatening infections.
Newborn screening also identifies infants with low TREC numbers who do not have SCID but nonetheless have few T lymphocytes in the peripheral blood, which is termed T-cell lymphopenia (TCL). Although most of these infants have recognized conditions, such as thymic hypoplasia seen in DiGeorge syndrome, others have secondary TCL due to another condition, such as preterm birth or heart surgery. There are also infants who have TCL with no apparent underlying cause, often termed idiopathic. Establishing a definitive diagnosis and managing these infants are new challenges for physicians, who must recognize the level of TCL that is medically significant, select diagnostic tests, and apply appropriate interventions.
Not all serious disorders of T cells are identified by using TREC screening; combined immunodeficiencies that are associated with intact T-cell development beyond the point of T-cell receptor gene recombination in the thymus, including Zap-70 deficiency and MHC class I and II nonexpression, can have normal numbers of TRECs, even though T-cell function is severely impaired.
Clinical Characteristics
Babies with SCID are at high risk for life-threatening infections that can begin as early as 1 month after birth. Most patients are asymptomatic shortly after birth before increasingly severe infections develop.
Without treatment for SCID, individuals suffer from frequent and increasingly severe infections that result in chronic diarrhea, growth faltering, and eventually death within the first 1 or 2 years of life.
Treatment approach depends on the subtype and genotype of SCID. Curative treatment modalities include hematopoietic cell transplantation (HCT) using a matched or haploidentical related donor or a matched unrelated donor or gene therapy (currently an investigational treatment in the United States). Other treatments include enzyme replacement therapy (ERT) (for adenosine deaminase deficiency SCID)1–6. Infants who receive hematopoietic transplant to reconstitute the immune system prior to 3.5 months of age and before onset of infection have an 80-95% chance of 5-year survival4,7. Transplantation survival decreases to less than 80% after 3.5 months of age, usually because of complications resulting from infections8.
Early signs of SCID include:
- Frequent, severe infections caused by common bacteria, viruses, or opportunistic infections, such as Pneumocystis jirovecii
- Infections that do not respond appropriately to antibiotic treatment
- Recurrent fevers
- Unexplained lymphopenia
- Chronic diarrhea
- Poor weight gain or growth faltering
- Persistent thrush (candidiasis) in the mouth or throat, mouth ulcers, infections with RSV, HSV, VZV, measles, influenza, or parainfluenza viruses
- Infections from live viral vaccines (rotavirus, MMR, and varicella vaccines)
- Severe eczematous rash from birth that does not respond to treatment
Incidence
The incidence of SCID is approximately 1:58,0009.
Inheritance
There are several types of SCID; the most common form is X-linked recessive, affecting only males, while other forms are autosomal recessive.
Primary Care Management
Next Steps After a Positive Screen
- Contact the family to inform them of the newborn screening result. The Department of Health can also connect the infant’s primary care provider to pediatric immunology and HCT specialists experienced in diagnosing and treating children with SCID, and they will help advise with next steps. Point out that additional confirmatory tests are required to determine whether the baby actually has an immune deficiency. Only a small proportion of infants with an abnormal initial TREC result will ultimately be diagnosed with SCID. The remainder of abnormal screening tests may include infants with mild-to-moderate immune defects, those with transient delays in T-cell maturation, or those with false-positive tests.
- Refer the patient to a pediatric hospital where pediatric immunologists and HCT providers work collaboratively to manage infants with SCID.
- Until testing is complete, avoid exposing the infant to those who are sick and to large groups.
- If the infant has any signs of illness, refer to a pediatric hospital right away for evaluation and potential administration of immune globulin and antibiotics.
- If the infant requires transfusion of any blood product, be sure that only leukocyte-reduced, irradiated products that are negative for cytomegalovirus (CMV) are used.
- There is a risk of transferring CMV from breastmilk. Some treatment centers recommend stopping breastfeeding/breastmilk unless the mother is known to be CMV-negative and continuing to monitor the mother for potential CMV infections when using breastmilk.
- DO NOT give live attenuated rotavirus vaccine, which could cause infection and prolonged diarrhea in a baby with SCID. This vaccine is to be given only after an immunologist confirms that the baby’s immune system function is normal.
Confirming the Diagnosis
To confirm the diagnosis of SCID, work with:
- Newborn Screening Services
- Pediatric Immunology and Hematopoietic Cell Transplantation teams – patients with positive newborn screening for SCID need to be referred to pediatric immunology and HCT specialists for further workup and management.
Confirmatory testing done by the pediatric immunology and HCT group after an abnormal screening result will include extended lymphocyte subset enumeration of T, B, and NK cells, along with naïve and memory T cells.
If there are further concerns of SCID or other immune deficiency states, a comprehensive immune function testing will be obtained including complete blood count with differential, repeat extended lymphocyte subset enumeration of T, B, and NK cells, transplacental maternal T cell engraftment, T cell diversity, lymphocyte proliferation to mitogens, quantitative immunoglobulin levels, ADA enzyme level and molecular genetic testing for genetic variants associated with SCID.
If the Diagnosis is Confirmed
- After a positive newborn screening test for SCID, the patient will be connected with the pediatric immunology and HCT group who will be able to assist the family with the initial SCID counseling. They will also go over next steps in management and treatment options and, if needed, discuss HCT.
- Educate the family about signs, symptoms, and the need for urgent care when the infant becomes ill before being seen by the immunology and HCT group.
- Provide the family with basic information about SCID and T-cell lymphopenia.
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
References
1. Thakar MS, Logan BR, Puck JM, et al. Measuring the effect of newborn screening on survival after haematopoietic cell transplantation for severe combined immunodeficiency: a 36-year longitudinal study from the Primary Immune Deficiency Treatment Consortium. Lancet Lond Engl. 2023;402(10396):129-140. doi:10.1016/S0140-6736(23)00731-6
2. Dvorak CC, Haddad E, Heimall J, et al. The diagnosis of severe combined immunodeficiency (SCID): The Primary Immune Deficiency Treatment Consortium (PIDTC) 2022 Definitions. J Allergy Clin Immunol. 2023;151(2):539-546. doi:10.1016/j.jaci.2022.10.022
3. Cuvelier GDE, Logan BR, Prockop SE, et al. Outcomes following treatment for ADA-deficient severe combined immunodeficiency: a report from the PIDTC. Blood. 2022;140(7):685-705. doi:10.1182/blood.2022016196
4. Haddad E, Logan BR, Griffith LM, et al. SCID genotype and 6-month posttransplant CD4 count predict survival and immune recovery. Blood. 2018;132(17):1737-1749. doi:10.1182/blood-2018-03-840702
5. Chinn IK, Shearer WT. Severe Combined Immunodeficiency Disorders. Immunol Allergy Clin North Am. 2015;35(4):671-694. doi:10.1016/j.iac.2015.07.002
6. van der Burg M, Mahlaoui N, Gaspar HB, Pai SY. Universal Newborn Screening for Severe Combined Immunodeficiency (SCID). Front Pediatr. 2019;7:373. doi:10.3389/fped.2019.00373
7. Heimall J, Logan BR, Cowan MJ, et al. Immune reconstitution and survival of 100 SCID patients post-hematopoietic cell transplant: a PIDTC natural history study. Blood. 2017;130(25):2718-2727. doi:10.1182/blood-2017-05-781849
8. Myers LA, Patel DD, Puck JM, Buckley RH. Hematopoietic stem cell transplantation for severe combined immunodeficiency in the neonatal period leads to superior thymic output and improved survival. Blood. 2002;99(3):872-878. doi:10.1182/blood.v99.3.872
9. Kwan P, Arzimanoglou A, Berg AT, et al. Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia. 2010;51(6):1069-1077. doi:10.1111/j.1528-1167.2009.02397.x
Article History
This article was originally published on the Medical Home Portal and updated before publication on TRiP. The Medical Home Portal, retired in July 2024, provided diagnosis and management information for pediatric conditions, guidance for immediate steps after a positive newborn screen result, and in-depth family education to improve outcomes for children with complex medical care needs. The full archive can be found at the Medical Home Portal Archive.
Topical Reviews in Pediatrics (TRIP) includes archival and updated content from the Medical Home Portal and features new, contemporary topics in pediatrics.
- 2017 revision: Karin Chen, MDRA
- 2013 revision: Karin Chen, MDRA
- 2012 first publication: Nicole Tattersall, RN BSNAA
AAuthor; CAContributing Author; SASenior Author; RReviewer
