MED-NERD

Management of Severe combined immunodeficiency (SCID)

Management of SCID includes bone marrow transplant, gammaglobulins, antimicrobial treatment, gene therapy, and other treatment options.

1-Bone marrow transplant:

Bone marrow transplant may improve the outcomes of some types of SCID including ADA-SCID, Wiskott-Aldrich syndrome, RAG1/2 SCID, and Artemis SCID.

2-Gammaglobulins:

Gammmaglobulin may be used in various sub-types of SCID including Artemis SCID, ADA-SCID, MHC class II deficiency, RAG1/2 SCID, Bare lymphocyte syndrome, CD3 SCID, Jak 3 kinase deficiency, and X-linked SCID.

3-Supportive care:

Once SCID is suspected, isolation of patient to avoid infections and initiation of Trimethoprim/sulfamethoxazole as prophylaxis for PJP, as well as Ig replacement therapy. Long-term Ig replacement therapy may be required in about 25% in absence of donor B-lymphocyte engraftment.

Many centers recommend stopping breastfeeding as the main source of Cytomegalovirus (CMV) infection is breastfeeding unless proved negative CMV screening test.

4-Antimicrobial treatment:

Antimicrobial drugs include antibiotics, antifungal, antiviral, and antiparasitic.

Other treatment options including:

Transfer factor, vitamins, anti-inflammatory drugs, irradiated blood transfusions, and cytokines (e.g., IL-2 and gamma interferon).

5-Gene therapy:

Gene therapy emerged long time ago. Since the discovery of the biology of retroviruses, researchers used them as vectors to integrate a transgene into targeted cells Transduction of hematopoietic stem cells (HSCs) was first performed using murine retroviruses. The first indication for allogeneic HSC transplantation and the first disorder corrected by gene therapy was SCID. Treatment with allogeneic HSCT leads to correction of the T cell deficiency on the long-term and is considered the definitive treatment of SCID. Gene therapy was first used to correct adenosine deaminase (ADA) deficiency sub-group of SCID but failed due to poor technology. Understanding the genes defects in SCID and the pathophysiology of the disease helped to perform successful gene therapy. Due to graft-versus-host disease (GvHD), transplant from non-genoidentical donors in the early 1990s led to high mortality and morbidity rates.

Survival rates after HCT are between 85 and 90% recently. Matched sibling donor (MSD) is the main factor improving the survival after HSCT. The survival rate after HSCT with a MSD is usually >90%. Other factors affecting the survival after HSCT include genotype, age, race/ethnicity, and infection at HSCT. Survival in RAG mutations was better compared to DCLRE1C mutations (The Artemis gene) after HSCT.

Conditioning regimen is required to provide normal B-lymphocyte function post-HSCT in patients with deficient RAG1, RAG2, and DCLRE1C due to residual Natural Killer (NK) cell function and to avoid the inhibition of donor progenitor engraftment which is caused by thymic and bone marrow components and thus require emptying. It is also used non-functional B-lymphocytes such as JAK3 and IL2RG. The conditioning regimen in HSCT may be associated with chemotherapy-induced toxicity and increase the incidence of GvHD. Due to the long-term toxicity of conditioning regimen associated with DNA repair defects, anti-stem cell monoclonal antibody may be required. The conditioning regimen with myeloablative agents enables stem cell engraftment and allows better reconstitution of T and B lymphocytes. Better prognosis was found with T and B lymphocyte reconstitution.

A two-step approach can be used in case of active infection at transplantation: the first HCT is performed without conditioning regimen and after recovery from infection another HCT with conditioning regimen is performed. If conditioning regimen used in the first step in the presence of infection, it will be associated with poor prognosis.

In ADA-deficient SCID, enzyme replacement by PEG-ADA may be used as a short term therapy until definitive treatment by HSCT or gene therapy through providing sufficient T-lymphocyte function to prolong the survival.

Complications of SCID

Complications of SCID include life-threatening infections caused by multiple organisms, septic shock, anaphylactic shock, opportunistic malignancy, multi-organ failure, acute and chronic renal failure, cardiac failure, respiratory insufficiency, metabolic disturbances (e.g., acidosis, alkalosis), endocrinopathy, bleeding disorders, neurological complications ( e.g., seizures, coma), congenital disabilities, and premature death.

References:

(1)Justiz Vaillant AA, Mohseni M. Severe Combined Immunodeficiency. 2023 Jan 1. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan–.
https://www.ncbi.nlm.nih.gov/books/NBK539762/
(2)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. 2019 Jul 24;7(1):52-61.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7063414/
(3)Fischer A, Hacein-Bey-Abina S. Gene therapy for severe combined immunodeficiencies and beyond. J Exp Med. 2020 Jan 6;217(2):e20190607.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7041706/
(4)Puck JM. Newborn screening for severe combined immunodeficiency and T-cell
lymphopenia. Immunol Rev. 2019 Jan;287(1):241-252.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6324582/
(5)Haddad E, Hoenig M. Hematopoietic Stem Cell Transplantation for Severe Combined Immunodeficiency (SCID). Front Pediatr. 2019 Nov 19;7:481.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6877719/