Basics
Description
Severe combined immunodeficiency (SCID) is a primary immunodeficiency characterized by functional defects in both the humoral and cellular immune systems. Most babies present with lymphopenia. Even the suspicion of SCID constitutes a pediatric emergency. Untreated, SCID is universally fatal, usually within the 1st year of life.
Epidemiology
Most patients present in the 1st year of life as immunity from maternal antibody wanes.
Incidence
- Estimated to be 1 in 100,000 births but may be underreported because of early infant mortality
- Highest in regions where consanguineous marriages take place
- SCID due to Artemis defects occurs in 1 in 2,500 births in the Navajo and Apache populations because of a founder mutation.
Genetics
- At least 13 known genetic defects that cause SCID
- Approximately 50% of cases are X-linked (mutation in the IL2 gamma chain); the others are autosomal recessive or de novo mutations.
- Classified by the lymphocytes subsets affected (e.g., T ’ B+ NK+, T ’ B ’ NK+, etc.)
Etiology
Caused by mutations in genes required for T-cell growth and development, purine salvage pathway function (e.g., adenosine deaminase), and expression of histocompatibility (HLA) antigens.
Diagnosis
History
- Failure to thrive
- Chronic diarrhea
- Chronic thrush or candidal diaper rash
- Frequent and/or severe infections with common pathogens
- Rotaviral infection after immunization
- Opportunistic infections
- Consanguinity
- Family history of SCID or unexplained infant deaths
Physical Exam
- Emaciated or wasted appearance
- Atypical morbilliform rash
- Absence of lymphoid tissue (small or absent tonsils and lymph nodes)
- Evaluation for infection
- Thrush or diaper dermatitis
- Manifestations of graft-versus-host disease (skin rash, conjunctivitis, hepatitis, diarrhea) secondary to transplacental alloreactive maternal T cells or T cells from unirradiated blood products
Diagnostic Tests & Interpretation
- CBC with differential to assess for lymphopenia: should suspect SCID if absolute lymphocyte count (ALC) <3,000 per microliter in the neonatal period or if ALC is < 1,000 per microliter in any child <3 years of age
- Lymphocyte subsets: All populations are generally decreased, but T cells are almost always severely decreased.
- Serum immunoglobulins (IgG, IgA, IgM): usually low or absent, but IgG may be normal in first 4 months of life because of placental transfer
- T-cell receptor excision circles (TRECs) are part of newborn screening from Guthrie cards (now legally mandated by many states in the United States).
- Identifies lymphopenia in the newborn
- TRECs are absent in infants with SCID.
- TRECs may be reduced in premature infants.
- Lymphocyte proliferation assay: Cells do not proliferate to antigenic stimulation.
- Appropriate cultures to identify pathogens
- Identification of causative mutation is necessary to allow for genetic counselling.
Differential Diagnosis
- HIV infection
- DiGeorge (22q11 deletion) syndrome
- Iatrogenic lymphopenia (e.g., steroid therapy)
- Other primary immunodeficiency (e.g., X-linked agammaglobulinemia, ataxia telangiectasia)
Treatment
- The only curative treatment is stem cell transplant.
- Success rates >70% have been reported and increase to 96% when the transplant is done before the age of 3 1/2 months.
- Preconditioning is generally not required because of the lack of T-cell function, but reduced intensity conditioning is often done to ensure engraftment.
- In patients with adenosine deaminase (ADA) " deficient SCID, for whom there is no identical stem cell match, enzyme replacement therapy with pegylated ADA (Adagen) can be given.
Ongoing Care
- Pretransplant Supportive Care
- Pneumocystis prophylaxis with trimethoprim/sulfamethoxazole
- Immunoglobulin replacement therapy (intravenous every 3 " 4 weeks, subcutaneously every 1 " 2 weeks)
- Aggressive and early treatment of infections
- Nutritional support
- Avoidance of crowds and persons with symptoms of infection (fever, cough, etc.)
- Routine immunization is unnecessary, as patients are unable to mount antibody responses.
- Live viral vaccines are absolutely contraindicated.
- If blood transfusion is required, only irradiated, CMV negative blood products should be used.
- Nontransplant treatment
- Gene therapy trials are ongoing for patients with ADA-deficient and X-linked SCID.
- Post transplant care
- Close monitoring for signs of graft-versus-host disease, engraftment failure, infection
- Immunoglobulin replacement therapy may still be required if B-cell reconstitution is absent or impaired.
- Genetic counseling for parents
Complications
- Pre- or posttransplant graft-versus-host disease
- Engraftment failure
- Omenn syndrome caused by clonal autoreactive T cells, resembling graft-versus-host disease seen in patients with RAG1 or RAG2 mutations
- Increased risk for lymphoreticular cancers
- Radiation sensitivity in patients with SCID caused by DNA repair syndromes (Artemis, Ligase-4, DNA-PKcs, Cernunnos)
- Growth failure and hearing impairment in patients with ADA-deficient SCID
Additional Reading
- Buckley RH. Transplantation of hematopoietic stem cells in human severe combined immunodeficiency: long-term outcomes. Immunol Res. 2011;49(1 " 3):25 " 43. [View Abstract]
- Cavazzana-Calvo M, Fischer A, Hacien-Bey-Abina S, et al. Gene therapy for primary immunodeficiencies: part I. Curr Opin Immunol. 2012;24(5):580 " 584. [View Abstract]
- Chinen J, Notarangelo LD, Shearer WT. Advances in basic and clinical immunology in 2012. J Allergy Clin Immunol. 2013; 131(3):675 " 682. [View Abstract]
- Puck JM. Laboratory technology for population-based screening for severe combined immunodeficiency in neonates: the winner is T-cell receptor excision circles. J Allergy Clin Immunol. 2012;129(3):607 " 616. [View Abstract]
Codes
ICD09
- 279.2 Combined immunity deficiency
ICD10
- D81.9 Combined immunodeficiency, unspecified
- D81.1 Severe combined immunodeficiency w low T- and B-cell numbers
- D81.2 Severe combined immunodef w low or normal B-cell numbers
- D81.89 Other combined immunodeficiencies
SNOMED
- 31323000 Severe combined immunodeficiency disease (disorder)
- 49555001 Severe combined immunodeficiency due to absent T cell receptor (disorder)
- 190997006 severe combined immunodeficiency with low T- and B-cell numbers (disorder)
- 190998001 severe combined immunodeficiency with low or normal B-cell numbers (disorder)
- 203592006 X-linked severe combined immunodeficiency (disorder)
FAQ
- Q: What should I do if I am notified that a newborn screen has identified a low number of TRECs?
- A: As a precaution while the child is being evaluated, prevent the infant 's exposure to sick contacts and public places or places with large crowds (day care centers, malls, churches, large family gatherings). Consider the need for pneumocystis prophylaxis and immunoglobulin replacement therapy while the evaluation proceeds. Send blood for enumeration of T-cell subsets (CD4 and CD8), B-cells (CD19), and NK cells (CD 16/56) and refer the child to a clinical immunologist.
- Q: What vaccines should be given to a child with SCID or suspected SCID?
- A: Children with SCID do not benefit from immunizations, and live viral vaccines of any type (rotavirus, MMR, varicella, and BCG) are absolutely contraindicated.
- Q: What is the chance of another child in the family being affected with SCID?
- A: The answer to this question depends of the cause of SCID. If a child has X-linked SCID, then there is a 50% chance of SCID in any male child born to the mother. In other forms of SCID, the risk is 25% for any male or female. It is crucial that a genetic diagnosis is made for each case of SCID so that families can be given accurate information about recurrence risk, they can be offered prenatal testing, and other affected children can be identified as soon as possible after birth.
- Q: Is there gene therapy for SCID?
- A: There are active research protocols for treating children with X-linked SCID and children with ADA deficiency. These protocols are still investigative and not standard therapy. Bone marrow transplantation remains the standard of care at this point.