Severe combined immunodeficiency: causes, symptoms, diagnosis, treatment

Severe combined immunodeficiency is characterized by the absence of T cells and low, high, or normal numbers of B cells and natural killer cells. Most infants develop opportunistic infections within 1 to 3 months of life. The diagnosis is made by lymphopenia, the absence or very low number of T cells, and impaired lymphocyte proliferation when exposed to a mitogen. Patients must be kept in a protected environment; the only treatment is a bone marrow stem cell transplant.

Severe combined immunodeficiency (SCID) results from mutations in at least 10 different genes, resulting in 4 forms of the disease. In all forms, T cells are absent (T-); however, depending on the form of SCID, the number of B cells and natural killer cells may be low or absent (B-, NK-), or normal or high (B+, NK+). However, even if the B cell count is normal, the T cells are absent and they cannot function normally. The most common form is X-linked. This form is characterized by the absence of the y chain in the IL2 receptor protein molecule (this chain is a component of at least 6 cytokine receptors); this is the most severe form with a T-, B+, NK- phenotype. Other forms are inherited in an autosomal recessive manner. The two most common forms result from a deficiency of adenosine deaminase ADA, which leads to apoptosis of B-, T-lymphocyte precursors and natural killers; the phenotype of this form is T-, B-, NK-. In the other form, there is a deficiency of the alpha chain in the IL7 receptor protein molecule; the phenotype of this form is T-, B+, NK+.

Most children with severe combined immunodeficiency develop candidiasis, pneumonia, and diarrhea by 6 months, leading to developmental disabilities. Many develop graft-versus-host disease after maternal lymphocyte infusion or blood transfusion. Others survive to 6 to 12 months. Exfoliative dermatitis may develop as part of Omenn syndrome. ADA deficiency may lead to bone abnormalities.

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Treatment of severe combined immunodeficiency

The diagnosis is based on lymphopenia, low or absent T-lymphocytes, lack of lymphocyte proliferation in response to mitogen stimulation, absence of radiographic thymic shadow, and impaired lymphoid tissue development.

All forms of severe combined immunodeficiency are fatal unless diagnosed and treated early. Adjuvant treatments include immunoglobulin and antibiotics, including prophylaxis against Pneumocystis jiroveci (formerly P. carinii). Bone marrow stem cell transplantation from an HLA-identical, mixed leukocyte culture-matched sibling is indicated for 90–100% of patients with severe combined immunodeficiency and its forms. If an HLA-identical sibling cannot be matched, haploidentical T-cell-washed bone marrow from one of the parents is used. If severe combined immunodeficiency is diagnosed before 3 months of age, the survival rate after bone marrow transplantation by any of the above methods is 95%. Preimplantation chemotherapy is not used because the recipient lacks T cells and therefore cannot reject the transplant. Patients with ADA deficiency who are not candidates for bone marrow transplantation are given polyethylene glycol, a modified bovine ADA, once or twice a week. Gene therapy is successful in X-linked severe combined immunodeficiency but can cause T-cell leukemia, which limits its use.