Severe Combined Immunodeficiency
Introduction
Severe combined immunodeficiency (SCID) covers a group of genetic conditions that severely compromise the body's immune system, i.e. its capacity to fight infection.[1][2]
These conditions block the development of immune cells in the bone marrow and thymus,[2] resulting in:[1]
- T lymphocytes: always absent or non-functional
- B lymphocytes: may be absent or non-functional
- Natural Killer (NK) cells: may be absent or non-functional
These conditions are among the most severe types of primary immunodeficiency and are often fatal if not diagnosed early enough.[2] Children born with this condition are born seemingly healthy, but develop recurrent infections very early in life.[2] If left untreated, SCID will lead to life-threatening infections, and ultimately the death of the infant mostly within the first one to two years.[1] [2]
Aetiology
SCID is caused by mutations in one of 20 known genes, though the specific cause remains unidentified in approximately 15% of cases.[3] The two patterns of inheritance of SCID are:[3][4]
- X-linked recessive: the most common form, accounting for roughly 50% of all cases.
- Autosomal recessive: meaning that it results from inheriting a mutated copy of the same gene from both parents[5]
Notably, over 80% of all cases present sporadically, meaning there is no prior family history of immunodeficiency, regardless of which genetic pattern is involved.[4]
SCID conditions are usually classified by their pathogenic mechanisms:[3][4]
- Toxic metabolite accumulation
- Adenosine deaminase deficiency: most common and severe form of SCID, with a prevalence of 15%.
- Defective survival of haematopoietic precursors (i.e. the formation of blood cellular components is impaired)
- T-cell and NK cells abnormalities
- Cytokine signalling abnormalities
- Recombinations and alterations in T-cell receptors
Epidemiology
Prevalence, meaning the risk of contracting SCID, ranges between 1/40,000 and 1/75,000 live births.[3]
Clinical Presentation
Frequent signs and symptoms of patients living with SCID include: [6]
- Repeated infections from diverse organisms that resist standard antibiotic treatments
- Viral and fungal illnesses beginning in the lungs and spreading to the mouth due to candidal infection
- Fever, coughing, general weakness, breathing difficulties, and sore throat
- Infections of the tonsils, eyes, and thyroid gland
- Seizures, muscle spasms (tetany), and muscular disorders
- Poor nutrient absorption leading to weight loss, stunted development, and retarded fetal growth
- Swollen lymph nodes, recurring abscesses, granulomas, and tumors
- Tuberculosis, lupus, kidney inflammation (glomerulonephritis), and amyloidosis
- Fragile bones, slow wound healing, and temperature sensitivity
- Genital abnormalities
These symptoms typically emerge within the first few weeks or months of life.[6]
Diagnosis
Given the critical need to diagnose SCID early and start treatment before infections or other complications occur, many countries have implemented new born screening programs.[1][3] This consists in a T-cell receptor excision circle screening (TREC), which are small DNA fragments produced only when healthy T cells develop.[7] Using a PCR test on dried blood spots, the screening looks for these fragments.[7] Since babies living with SCID cannot make T cells, they have no TRECs.[7] Therefore, a missing TREC result identifies the disease with high sensitivity.[7]
Medical Management
The different treatment options for SCID includes:[2][3][4]
- Haematopoietic Stem Cell Therapy (HSCT)
- Gene Therapy
- Enzyme Replacement Therapy (ERT)
Haematopoietic Stem Cell Therapy
HSCT, also known as bone marrow transplant, is the primary curative treatment for SCID. Survival rates reach 70–95%, with the best outcomes occurring when transplants happen before 3.5 months of age.[4] The procedure involves infusing immature cells that gradually develop into a functional immune system.[4]
Gene Therapy
Gene therapy treats SCID by correcting the patient’s own stem cells before returning them to the body.[4]
Procedure:
- Stem cells are drawn from the patient’s bone marrow, clinicians insert a correct gene copy using a deactivated virus, then multiplied and stored in a cryopreserved state.[4]
- The child then receives conditioning via chemotherapy or immunosuppressive agents before the corrected cells are inserted through a simple intravenous infusion.[4]
Safety issues:
- Early attempts restored T cell function but caused leukaemia in 25% of children because vectors inappropriately activated genes.[4]
- Modern techniques use modified vectors that are more efficient and have fewer complications.[4]
Enzyme Replacement Therapy
ERT consists of giving weekly intramuscular injection to patients living with ADA deficiency to temporarily replace the missing vital enzyme.[4] This treatment is not a cure but serves as a bridge to definitive therapies like HSCT or gene therapy.[4] It also boosts T cell levels to reduce infections while waiting for a lasting intervention.[4]
Multidisciplinary management
Recent evidence on the multidisciplinary management of SCID is scarce. However, since SCID is a form of Inborn Errors of Immunity (IEI),[9] guidelines and recommendations developed for IEI broadly may still offer relevant guidance for its management.
These highlight the importance of a multidisciplinary approach and early diagnosis.[9] Key measures include:[9]
- Antibiotics, antivirals, and antifungals to prevent infection
- Regular immunoglobulin infusions to support immune defences
- Strict isolation to reduce exposure to harmful germs
- Avoidance of live vaccines, though inactivated vaccines are safe
Lung problems are one of the most common features of IEI, frequently being the first sign of the condition.[10] This suggests that therapeutic interventions such as respiratory physiotherapy or long-term antibiotic therapy should be implemented early and prioritised.[10]
Summary
SCID is a group of severe genetic conditions that impair the immune system, leaving affected infants vulnerable to life-threatening infections from birth. The primary curative treatment is haematopoietic stem cell transplantation, with gene therapy and enzyme replacement therapy serving as alternatives or bridging options. Early diagnosis is critical to improve survival. While evidence on multidisciplinary management of SCID remains scarce, guidance can be drawn from broader IEI recommendations.
References
- ↑ 1.0 1.1 1.2 1.3 Lankester AC, Neven B, Mahlaoui N, von Asmuth EG, Courteille V, Alligon M, et al. Hematopoietic cell transplantation in severe combined immunodeficiency: the SCETIDE 2006-2014 European cohort. J Allergy Clin Immunol. 2022;149(5):1744-54.
- ↑ 2.0 2.1 2.2 2.3 2.4 2.5 Cirillo E, Giardino G, Gallo V, D'Assante R, Grasso F, Romano R, et al. Severe combined immunodeficiency—an update. Ann N Y Acad Sci. 2015;1356(1):90-106.
- ↑ 3.0 3.1 3.2 3.3 3.4 3.5 Kumrah R, Vignesh P, Patra P, Singh A, Anjani G, Saini P, Sharma M, Kaur A, Rawat A. Genetics of severe combined immunodeficiency. Genes Dis. 2020;7(1):52-61.
- ↑ 4.00 4.01 4.02 4.03 4.04 4.05 4.06 4.07 4.08 4.09 4.10 4.11 4.12 4.13 Justiz-Vaillant AA, Gopaul D, Akpaka PE, Soodeen S, Arozarena Fundora R. Severe combined immunodeficiency—classification, microbiology association and treatment. Microorganisms. 2023;11(6):1589.
- ↑ Cook J. Genes in families. In: Reference Module in Biomedical Sciences. Amsterdam: Elsevier; 2014. Available from: https://www.sciencedirect.com/science/chapter/referencework/abs/pii/B9780128012383054817
- ↑ 6.0 6.1 Wadbudhe AM, Meshram RJ, Tidke SC. Severe combined immunodeficiency (SCID) and its new treatment modalities. Cureus. 2023;15(10):e46695.
- ↑ 7.0 7.1 7.2 7.3 Blom M, Zetterström RH, Stray-Pedersen A, Gilmour K, Gennery AR, Puck JM, et al. Recommendations for uniform definitions used in newborn screening for severe combined immunodeficiency. J Allergy Clin Immunol. 2022;149(4):1428-36.
- ↑ Immune Deficiency Foundation. SCID Compass: Exploring Treatment Options [Internet]. YouTube; 2021 Jan 19 [cited 2026 Jun 27]. Available from: https://www.youtube.com/watch?v=AeW0l2KE9ZU
- ↑ 9.0 9.1 9.2 Pegoraro F, Voarino M, Gambineri E. Clinical Management of Severe Combined Immunodeficiencies. In: Severe Combined Immunodeficiency. Cham: Springer Nature Switzerland; 2024. p. 67-77.
- ↑ 10.0 10.1 Napiorkowska-Baran K, Cofta S, Treichel P, Tykwinska M, Lis K, Matyja-Bednarczyk A, et al. Pulmonary manifestations of inborn errors of immunity: diagnostic and therapeutic insights. Life. 2025;15(12):1838.