Severe Combined Immunodeficiency

Severe combined immunodeficiency is a group of inherited disorders with absent or severely deficient T-cell function, and variable B-cell and natural killer cell involvement. It is a paediatric emergency and is fatal in the first 1 to 2 years without definitive treatment.

The estimated incidence is about 1 in 50 000 to 60 000 live births. It is more common where consanguinity is frequent. Genetic types include X-linked (IL2RG, around 40% of cases), ADA deficiency, JAK3, IL7R, RAG1, RAG2, DCLRE1C (Artemis), and reticular dysgenesis.

Types are classified by lymphocyte phenotype: T-B+NK- (IL2RG, JAK3), T-B+NK+ (IL7R, CD3 defects), T-B-NK- (ADA, reticular dysgenesis), and T-B-NK+ (RAG1, RAG2, DCLRE1C).

Pathophysiology.

Defects in lymphocyte development, signalling or receptor rearrangement block T-cell maturation, so there is no cellular immunity, and B cells are unable to make antibodies without T-cell help.

In ADA deficiency, accumulating toxic metabolites kill lymphocytes. Maternal T cells may engraft and cause graft-versus-host disease.

• Onset in the first months, once maternal antibodies wane: failure to thrive, persistent diarrhoea, and chronic oral candidiasis.
• Severe or opportunistic infections: Pneumocystis jirovecii pneumonia, cytomegalovirus, adenovirus, respiratory syncytial virus, parainfluenza virus and disseminated BCG after vaccination.
• Skin rash from maternal engraftment or Omenn syndrome (erythroderma, lymphadenopathy, eosinophilia and hepatosplenomegaly).
• Absent lymphoid tissue (no tonsils or lymph nodes) and absent thymic shadow on chest X-ray. In ADA deficiency, bony abnormalities and deafness.

Red flags.

• Lymphopenia on a full blood count (under 2.5 x 10^9/L in an infant).
• Opportunistic infection, persistent candidiasis, or failure to thrive with diarrhoea.
• Family history of early infant death, or a severe reaction to a live vaccine.

• Full blood count with lymphocyte count (lymphopenia in most), lymphocyte subsets (CD3, CD4, CD8, CD19, CD16/56) with naive T cells (CD45RA), and immunoglobulins. Newborn screening by T-cell receptor excision circles where available.
• Lymphocyte proliferation to mitogens (absent or very low), with maternal engraftment testing.
• Genetic testing to identify the defect, and adenosine deaminase enzyme activity.
• Chest X-ray, and infection screening including Pneumocystis jirovecii, cytomegalovirus, adenovirus and respiratory viruses.

Differential diagnosis. HIV infection, transient lymphopenia, DiGeorge syndrome, other primary immunodeficiencies, malnutrition, secondary lymphopenia from drugs or infection, and Omenn syndrome mimics such as atopic dermatitis and graft-versus-host disease.

Immediate measures.

• Protective isolation, and admission to a specialist unit. No live vaccines (BCG, rotavirus), no breastfeeding if the mother is cytomegalovirus positive, and avoidance of contact with infection.
• Irradiated, leucodepleted, cytomegalovirus safe blood products only.
• Prophylaxis: co-trimoxazole 5 mg/kg/day of the trimethoprim component in 2 divided doses on 3 days each week for Pneumocystis jirovecii, fluconazole 3 to 6 mg/kg once daily for fungal infection, and immunoglobulin replacement 0.4 to 0.6 g/kg every 3 to 4 weeks.
• Treat infections early and aggressively with specific antimicrobials. For Omenn syndrome, give immunosuppression (corticosteroids and ciclosporin) before transplant.

Definitive treatment.

• Haematopoietic stem cell transplantation, ideally in the first 3 to 4 months of life before infection, from a matched sibling or the best available donor. Survival exceeds 90% when transplanted early and without active infection.
• Gene therapy for X-linked, ADA and Artemis deficiencies in specialist centres. Enzyme replacement as a bridge in ADA deficiency.

Monitoring. Lymphocyte counts and reconstitution, chimerism, immunoglobulin levels and infections after transplant, with long term follow up for growth, autoimmunity and late effects.

Referral and escalation. Contact a paediatric immunology and transplant centre at once for any suspected case.

Special groups. Siblings and newborns of families with SCID need early testing and protective measures from birth.