Severe combined immunodeficiency

PPT ON SEVERE COMBINED IMMUNODEFICIENCY. USEFUL FOR MD/DNB PEDIATRICS/MEDICINE EXAMS.

1. SEVERE COMBINED IMMUNODEFICIENCY Dr.Himanshu S Dave Dept of Pediatrics NRCH, New Delhi

2. Severe combined immunodeficiency ( SCID ) is caused by diverse genetic mutations that lead to absence of T- and B-cell function. Patients with this group of disorders have the most severe immunodeficiency.

3. PATHOGENESIS SCID is caused by mutations in genes crucial for lymphoid cell development. All patients with SCID have very small thymuses; contain no thymocytes and lack corticomedullary distinction or Hassall corpuscles .

4. The thymic epithelium appears histologically normal. Both the follicular and the paracortical areas of the spleen are depleted of lymphocytes. Lymph nodes, tonsils, adenoids, and Peyer patches are absent or extremely underdeveloped .

5. CLINICAL MANIFESTATIONS SCID is included in the newborn screening program in many areas. Thus, infants are identified prior to symptoms, which has dramatically improved the survival of infants with SCID. A few genetic types of SCID are not detected by newborn screening, and there are a few states where newborn screening for SCID is not yet performed.

6. SCID most often present with infection . Diarrhea , pneumonia, otitis media, sepsis, and cutaneous infections are common presentations. Infections with a variety of opportunistic organisms, either through direct exposure or immunization, can lead to death.

7. Potential threats include Candida albicans , Pneumocystis jiroveci , parainfluenza 3 virus, adenovirus,RSV , rotavirus vaccine,CMV , EBV, varicella -zoster virus , measles virus, MMRV (measles, mumps, rubella, varicella ) vaccine, or bacille Calmette-Guérin (BCG) vaccine.

8. Affected infants also lack the ability to reject foreign tissue and are therefore at risk for severe or fatal graft-versus-host disease (GVHD) from T lymphocytes in non irradiated blood products or maternal immuno competent T cells that crossed the placenta while the infant was in utero .

9. This devastating presentation is characterized by expansion of the allogeneic cells, rash, hepatosplenomegaly and diarrhea . A 3rd presentation is often called Omenn syndrome , in which a few cells generated in the infant expand and cause a clinical picture similar to GVHD. The difference in this case is that the cells are the infant's own cells.

10. A key feature of SCID is that almost all patients will have a low lymphocyte count . A combination of opportunistic infections and a persistently low lymphocyte count is an indication to test for SCID.

11. The diagnostic strategy both for symptomatic infants and those detected by newborn screening is to perform flow cytometry to quantitate the T, B, and natural killer (NK) cells in the infant. The CD45RA and CD45RO markers can be helpful to distinguish maternal engraftment and Omenn syndrome.

12. T-cell function is also often assessed by measuring proliferative responses to stimulation . All genetic types of SCID are associated with profound immunodeficiency . A small number have other associated features or atypical features that are important to recognize.

13. Adenosine deaminase (ADA) deficiency can be associated with pulmonary alveolar proteinosis and chondro osseous dysplasia. Adenylate kinase 2 (AK2) deficiency causes a picture referred to as reticular dysgenesis where neutrophils , myeloid cells, and lymphocytes are all low. This condition is also often associated with deafness.

14. TREATMENT SCID is a true pediatric immunologic emergency. Unless immunologic reconstitution is achieved through hematopoietic stem cell transplantation ( HSCT ) or gene therapy, death usually occurs during the 1st yr of life and almost invariably before 2 yr of age.

15. HSCT in an infant prior to infection is associated with a 95% survival rate . ADA-deficient SCID and X-linked SCID have been treated successfully with gene therapy.

16. ADA-deficient SCID can also be treated with repeated injections of polyethylene glycol–modified bovine ADA ( PEG-ADA ), although the immune reconstitution achieved is not as effective as with stem cell or gene therapy .

17. GENETICS The 4 most common types of SCID are: - The X-linked form, caused by mutations in CD132 - Autosomal recessive RAG1 and RAG2 deficiencies and -ADA deficiency .

18. For X-linked SCID and ADA deficiency, gene therapy exists , but genetic counseling is the most compelling reason for genetic sequencing to identify the gene defect. Several specific gene defects are associated with increased sensitivity to radiation and chemotherapy , and their early identification can lead to a better transplant experience .

19. Sequencing is often done by requesting a SCID gene panel. Hypomorphic mutations in genes most often associated with SCID can lead to varied phenotypes. This condition is often referred to as leaky SCID.

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