Severe Combined Immunodeficiency

Author and Editor Disclosure

Synonyms and related keywords: SCID, T-cell dysfunction, T cell dysfunction, B-cell dysfunction, B cell dysfunction, graft versus host disease, GVHD, graft-versus-host disease, graft-vs-host disease, severe infection, Swiss-type agammaglobulinemia, Janus-associated kinase 3 deficiency, JAK3 deficiency, adenosine deaminase deficiency, ADA deficiency, purine nucleoside phosphorylase deficiency, PNP deficiency, bare lymphocyte syndrome, interleukin-2 deficiency, IL-2 deficiency, ZAP-70 protein tyrosine kinase deficiency, PTK deficiency, reticular dysgenesis, Omenn syndrome, Pneumocystis carinii pneumonia, PCP, systemic candidiasis, generalized herpetic infections

INTRODUCTION

Background

Severe combined immunodeficiency (SCID) is a disorder that results from any of a heterogenous group of genetic conditions affecting the immune system. SCID leads to severe T- and B-cell dysfunction. Without intervention, the severe T- and B-cell dysfunction results in severe infection and death in children by age 2 years.

The most common genetic condition responsible for SCID is a mutation of the common gamma chain of the interleukin (IL) receptors shared by the receptors for IL-2, IL-4, IL-7, IL-9, and IL-15. This protein is encoded on the X chromosome, and this variant of SCID is, therefore, X-linked (and sometimes referred to as X-linked SCID). These patients account for approximately 50% of all patients with SCIDs.

Autosomal recessive SCID (formerly known as Swiss-type agammaglobulinemia) includes Janus-associated kinase 3 (JAK3) deficiency, adenosine deaminase (ADA) deficiency, purine nucleoside phosphorylase (PNP) deficiency, bare lymphocyte syndrome, IL-2 deficiency, ZAP-70 protein tyrosine kinase (PTK) deficiency, reticular dysgenesis, and Omenn syndrome.

These are the most common and best characterized forms of SCID, but not all of the genetic conditions leading to SCID are well characterized. Infants with SCID usually present with infections that are secondary to the lack of T-cell function (eg, Pneumocystis carinii pneumonia [PCP], systemic candidiasis, generalized herpetic infections).

Pathophysiology

The pathophysiology and molecular biology vary; however, the lack of T- and B-cell function is the common endpoint in all forms of SCID.

Cellular hallmarks that help differentiate between various forms of SCID are as follows:

X-linked SCID: Lymphopenia occurs primarily from the absence or near absence of T cells (CD3⁺) and natural killer (NK) cells. Variable levels of B cells occur, which do not make functional antibodies.
JAK3 deficiency: Lymphopenia occurs primarily from the absence or near absence of T cells (CD3⁺) and NK cells. Normal or high levels of B cells occur, which do not make functional antibodies.
ADA deficiency: Lymphopenia occurs from the death of T and B cells secondary to the accumulation of toxic metabolites in the purine salvage pathway. Functional antibodies are decreased or absent.
PNP deficiency: Lymphopenia occurs from the death of T cells secondary to the accumulation of toxic metabolites in the purine salvage pathway. This deficiency differs from ADA deficiency because circulating B cells are normal in number. However, B-cell function is poor, as evidenced by the lack of antibody formation.
Bare lymphocyte syndrome: The lymphocyte count is normal or mildly reduced, the CD4⁺ T cells are decreased, and the CD8⁺ T cell numbers are normal or mildly increased. The B-cell numbers are normal or mildly decreased, but the ability to make antibodies is decreased.
IL-2 deficiency: Normal, or near normal, numbers of T cells exist (both CD4⁺ and CD8⁺). The T cells fail to proliferate in vitro when stimulated with mitogens, unless IL-2 is added to the culture medium. The production of functional antibody is decreased.
ZAP-70 PTK deficiency: Lymphopenia occurs because of the absence of CD8⁺ T cells. As in all types of SCID, no antibody formation is present.
Reticular dysgenesis: Lymphopenia occurs from the absence of myeloid cells in the bone marrow. Red blood cells and platelets are present and functioning.
Omenn syndrome: Normal or elevated T-cell numbers are present, but these are of maternal not fetal origin. The B cells are usually undetectable, NK cells are present, and the total immunoglobulin level is markedly low with poor antibody production. Eosinophils are elevated, and the total serum immunoglobulin E (IgE) level is elevated.

Molecular abnormalities in various forms of SCID are as follows:

X-linked SCID: Mutation of the common gamma chain (IL-2R, IL-4R, IL-7R, IL-9R, IL-15R) of the IL receptors occurs, resulting in loss of cytokine function. Loss of IL-2R function leads to the loss of a lymphocyte proliferation signal. Loss of IL-4R function leads to the inability of B cells to class switch. Loss of IL-7R function leads to the loss of an antiapoptotic signal, resulting in a loss of T-cell selection in the thymus. Loss of IL-7R function is also associated with the loss of a T-cell receptor (TCR) rearrangement. Loss of IL-15R function leads to the ablation of NK cell development.
JAK3 deficiency: JAK3 is a PTK that associates with the common gamma chain of the IL receptors. Deficiency of this protein results in the same clinical manifestations as those of X-linked SCID.
IL-2 production deficiency: The exact molecular defect is unknown, but it is often associated with other cytokine production defects.
Bare lymphocyte syndrome: This is a deficiency of major histocompatability complex (MHC). MHC type II is decreased on mononuclear cells. MHC type I levels may be decreased, or MHC type I may be absent. The defect occurs in a gene regulating expression of MHC type II.
ZAP-70 PTK deficiency: A mutation occurs in the gene coding for this tyrosine kinase, which is important in T-cell signaling and is critical in positive and negative selection of T cells in the thymus.
Omenn syndrome: A mutation that impairs the function of immunoglobulin and TCR recombinase genes (ie, Rag1, Rag2 genes) is now believed to be responsible for this syndrome.

Frequency

United States

SCID occurs in approximately 1 in 100,000 births. Some groups report a higher incidence, 1 in 50,000-75,000 births, probably because of better identification of affected subjects. Approximately 50% of all SCID cases are X-linked (ie, mutation of the common gamma chain). The remaining 50% are various forms of autosomal recessive SCID. Approximately 25% of the patients with an autosomal recessive SCID are JAK3 deficient and 40% are ADA deficient. The other disorders make up the remaining 35% of autosomal recessive patients.

Mortality/Morbidity

Without treatment, death from infection usually occurs within the first 2 years of life. Graft versus host disease (GVHD) from maternal cell engraftment can occur in any SCID case, but it is more prone to occur in cases of Omenn syndrome.

Race

No racial predisposition exists for most forms of SCID, but most patients with ZAP-70 deficiency are Mennonites.

Sex

Approximately 50% of SCID cases are X-linked (ie, occurring only in males). No sexual predisposition is associated with autosomal recessive SCID.

Age

The average age at the onset of symptoms is 2 months.

CLINICAL

History

Family history of consanguinity
Sibling death in infancy and/or previous miscarriages in mother
Family history of SCID
Poor feeding and poor weight gain
Chronic diarrhea
Previous infections, especially pneumonia

Physical

Abnormal physical findings are primarily due to infection or GVHD and are not directly due to the primary immunodeficiency. The patient may present with the following:

Failure to thrive, manifesting as decreased weight, height, and head circumference
Dehydration from chronic diarrhea
Eczema from GVHD, especially in Omenn syndrome
Increased respiratory rate and effort and crepitations secondary to pneumonia (especially PCP)
Fever from sepsis, systemic fungal infections, or generalized herpes
No lymphadenopathy or increased tonsillar tissue despite serious infections
Lymphadenopathy and hepatosplenomegaly in Omenn syndrome or bare lymphocyte syndrome
Neurological sequelae and developmental regression (loss of developmental milestones), especially in PNP deficiency (the cause of which is genetic, not infectious)

Causes

Genetic (molecular defects)
- X-linked SCID: Mutation of the common gamma chain shared by multiple receptors (ie, IL-2R, IL-4R, IL-7R, IL-9R, IL-15R) occurs, resulting in loss of cytokine function. Loss of IL-2R function leads to the loss of a lymphocyte proliferation signal. Loss of IL-4R function leads to the inability of B cells to class switch. Loss of IL-7R function leads to the loss of an antiapoptotic signal, resulting in a loss of T-cell selection in the thymus. Loss of IL-7R function is also associated with the loss of a TCR rearrangement. Loss of IL-15R function leads to the ablation of NK cell development.
- JAK3 deficiency: JAK3 is a PTK that associates with the common gamma chain shared by the multiple receptors listed above. This deficiency has the same clinical manifestations as those of X-linked SCID.
- ADA and PNP deficiencies: These are associated with enzyme deficiencies in the purine salvage pathway; toxic metabolites are responsible for the destruction of lymphocytes that cause the immune deficiency.
- Bare lymphocyte syndrome: This is associated with a molecular defect in the gene regulating MHC type II expression.
- IL-2 production defects: These occur secondary to poorly defined defects in IL-2 production.
- Omenn syndrome: This is associated with abnormalities in the Rag1 and Rag2 genes that are responsible for TCR and immunoglobulin rearrangement.
- X-linked SCID: This is, of course, X-linked, while the other forms of SCID are autosomal recessive.
Usual pathogens
- Pneumocystis carinii pneumonia
- Atypical mycobacterium
- Herpes viruses
- Candidiasis and other systemic fungal infections
- Cryptosporidium
- Pneumococcus and other common bacteria

DIFFERENTIALS

Combined B-Cell and T-Cell Disorders

WORKUP

Lab Studies

Initial workup
- Conduct a complete blood cell (CBC) count with differential to help detect lymphopenia.
- Draw lymphocyte markers at the same time as the CBC count to obtain percentages and absolute counts of CD3⁺ T cells, CD4⁺ T cells, CD8⁺ T cells, CD19⁺ B cells, and NK cell markers (CD16 and CD56).
- Obtain total serum immunoglobulin levels of immunoglobulin G (IgG), immunoglobulin A (IgA), immunoglobulin M (IgM), and IgE.
- To test lymphocyte function, look for antibodies to standard protein vaccines (eg, diphtheria and tetanus; children <2 y cannot adequately make antibody to polysaccharide so only antibody against protein is relevant) with preimmunization and postimmunization titers. If maternal antibody is still present, which is likely, remember that this confounds the results. Check isohemagglutinins (IgM against blood group antigens), and check mitogen stimulation of lymphocytes. Patients with SCID essentially have no antibody formation and have very poor proliferation of lymphocytes. Children with IL-2 deficiency have proliferation of lymphocytes if IL-2 is added to their lymphocytes. Children with combined immune deficiency that is not severe may be difficult to differentiate from SCID in these initial evaluations.
- To help exclude HIV infection, perform HIV-DNA testing using polymerase chain reaction because antibody tests for HIV are of no value in this setting due to maternal antibody. To help exclude congenital infection, perform serum testing of IgM against any suspected infection. Children with complete DiGeorge syndrome have normal B-cell function, but T cells are absent or nearly absent and, if present, function poorly.
Confirmatory tests
- After finding abnormalities consistent with SCID, perform confirmatory tests to determine the type of SCID that is responsible.
- Determine the ADA and PNP levels in lymphocytes, erythrocytes, or fibroblasts.
- Conduct X-inactivation studies to determine whether the SCID is X-linked, which is the most common form of SCID. Approximately 50% of patients have sporadic mutations with no history of affected family members.
- Perform molecular studies to identify any specific known genetic defects. These tests are not commercially available and are performed in only a few molecular immunology research labs.

Imaging Studies

Imaging studies are not useful for diagnosis of the primary condition; however, obtaining a chest x-ray film may be necessary to evaluate pneumonia secondary to SCID.

Procedures

Only blood studies are necessary to make the initial diagnosis.

Histologic Findings

Although a lymph node biopsy is not necessary for diagnosis, findings may indicate a paucity of T and B cells and a lack of germinal centers.

TREATMENT

Medical Care

Prophylaxis
- Because T cells are absent and/or dysfunctional, administer PCP prophylaxis to all patients until T-cell function is restored by a bone marrow transplant or other therapy.
- Trimethoprim-sulfamethoxazole is the drug of choice and can be administered when the patient is older than 2 months or in whom neonatal jaundice is no longer a concern.
X-linked SCID and JAK3 PTK deficiency
- A bone marrow transplant is the primary treatment of choice for most types of SCID when an appropriate donor is found. Pretreatment with ablative chemotherapy is controversial.
- If B cells do not engraft, the patient may require monthly intravenous immunoglobulin (IVIG) replacement therapy.
ADA deficiency
- The primary treatment is ongoing polyethylene glycol–conjugated ADA replacement (PEG-ADA) therapy.
- Gene therapy is in the experimental phase.
PNP deficiency and bare lymphocyte syndrome: A bone marrow transplant is the primary therapy when an appropriate donor is available.
IL-2 production defects: Intravenous IL-2 replacement is the primary therapy, and a bone marrow transplant is an alternative if an appropriate donor is available.
Omenn syndrome: A bone marrow transplant is the primary treatment; however, pretreatment ablative chemotherapy is necessary because of maternal cell engraftment.

Surgical Care

Surgical care is not part of the primary treatment.

Consultations

Immunologist for diagnosis and treatment
Hematology/immunology transplant team for an anticipated bone marrow transplant

Diet

No diet limitations are necessary.

Activity

Only infections secondary to the immune deficiency limit activity. The disease itself does not require limitation of physical activity. Keep children with SCID in reverse isolation until bone marrow transplant or other therapy is initiated.

MEDICATION

Drug therapy is not a major part of therapy for the primary disease. Only trimethoprim-sulfamethoxazole is prescribed routinely after the second month of life in children with SCID. This is PCP prophylaxis. IVIG is used in selected patients after bone marrow transplant if B-cell function remains poor.

Drug Category: Antibiotics

These agents are used as prophylaxis against PCP.

Drug Name	Trimethoprim-Sulfamethoxazole (Bactrim, Bactrim DS, Septra, Septra DS)
Description	Used because of low levels of T cells or poor T-cell function in children with SCID.
Adult Dose	1 DS tab PO bid
Pediatric Dose	5-10 mg/kg PO divided bid 3 times per wk (Mon, Wed, Fri or Mon, Tue, Wed)
Contraindications	Documented hypersensitivity; G-6-PD deficiency, children <2 mo, porphyria
Interactions	May increase PT when used with warfarin (perform coagulation tests and adjust dose accordingly); coadministration with dapsone may increase blood levels of both drugs; coadministration of diuretics increases incidence of thrombocytopenia purpura in elderly; phenytoin levels may increase with coadministration; may potentiate effects of methotrexate in bone marrow depression; hypoglycemic response to sulfonylureas may increase with coadministration; may increase levels of zidovudine
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Can cause bone marrow suppression; hypersensitivity; hemolysis in patients with G-6-PD deficiency; use with caution in renal or hepatic failure

Drug Category: Immune globulins

IVIG is the usual choice. It is derived from human plasma and is composed of all 4 IgG subclasses. The antibody distribution of IVIG is approximately the same as human serum.

Drug Name	Intravenous immunoglobulins (Gammaimmune, Gammagard, Sandoglobulin)
Description	Pooled human immunoglobulin provides IgG antibodies the patient cannot make.
Adult Dose	400-500 mg/kg IV titrating trough IgG level to 900-1000 mg/dL
Pediatric Dose	Not established; administer as in adults
Contraindications	Documented hypersensitivity; IgA deficiency; anti-IgE/IgG antibodies
Interactions	Interferes with efficacy of MMR vaccine, but this should not be an issue in a child who does not make antibody since no vaccines are administered to these children; the IVIG replaces antibodies that vaccines would stimulate the production of in a healthy child; furthermore, live viral vaccines are contraindicated in these patients
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Check serum IgA before IVIG (use an IgA-depleted product, eg, Gammagard S/D); infusions may increase serum viscosity and thromboembolic events; infusions may increase risk of migraine attacks, aseptic meningitis (10%), urticaria, pruritus, or petechiae (2-5 d postinfusion to 30 d) Increases risk of renal tubular necrosis in elderly patients and in patients with diabetes, volume depletion, and preexisting kidney disease; lab result changes associated with infusions include elevated antiviral or antibacterial antibody titers for 1 mo, 6-fold increase in ESR for 2-3 wk, and apparent hyponatremia

FOLLOW-UP

Further Outpatient Care

Admit the patient to an immunology/hematology clinic for IVIG therapy, IL-2 infusion, or PEG-ADA therapy, as necessary.
Frequently monitor the patient for acquired infections.

Deterrence/Prevention

Genetic counseling is necessary. If the family wishes to have other children, suggest that they obtain prenatal testing (eg, chorionic villus sampling) if the genetic defect is known.

Complications

GVHD may ensue if the blood products given prior to a bone marrow transplant are not depleted of white blood cells by filtration or irradiation. Ensure that all blood products are also negative for cytomegalovirus to avoid systemic cytomegalovirus disease.
Ensure that the child does not receive any live virus vaccines, especially polio or bacille Calmette-Guérin (BCG). Vaccinating children with SCID is not only futile, because they cannot make antibody, but is also dangerous, because they can develop disease from attenuated viruses and may even die after exposure to these vaccines.

Prognosis

Without treatment, death is expected to occur within 2 years. Following a successful bone marrow or other transplant, the patient may survive to adulthood.

Patient Education

Parents of children with any immune deficiency can obtain information from the Immune Deficiency Foundation .
Parents must not ignore a fever, rashes, or malaise in an affected child. These may indicate a serious infection.
Instruct parents to ensure that the child does not receive live virus vaccines, especially polio or BCG. Vaccinating children with SCID prior to treatment is not only futile, because they cannot make antibody, but is also very dangerous. The live attenuated virus can be deadly and can lead to disease in these immunocompromised hosts.
For excellent patient education resources, visit eMedicine's Yeast and Fungal Infections Center. Also, see eMedicine's patient education article Candidiasis (Yeast Infection).

MISCELLANEOUS

Medical/Legal Pitfalls

Failure to make the diagnosis because the child is not frankly lymphopenic may present a problem, particularly in patients with Omenn syndrome, bare lymphocyte syndrome, and IL-2 deficiency. Obtaining lymphocyte markers and test results of antibody and lymphocyte proliferation can help physicians to avoid this pitfall.
Ensure that the child does not receive any live virus vaccines, especially polio or BCG. Vaccinating children with SCID is futile and may be very dangerous because these children can develop disease from attenuated viruses, and they may even die after exposure to these vaccines.