AUTHOR AND EDITOR INFORMATION

Section 1 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

INTRODUCTION

Section 2 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Background

Severe combined immunodeficiency (SCID) is a life-threatening syndrome of recurrent infections, diarrhea, dermatitis, and failure to thrive. It is the prototype of the primary immunodeficiency diseases and is caused by a number of molecular defects that lead to severe compromise in the number and function of T cells, B cells, and occasionally natural killer (NK) cells. Clinically, most patients present before age 3 months with unusually severe and frequent infections by common or opportunistic pathogens. SCID is a pediatric emergency since survival depends upon expeditious stem cell reconstitution, usually by bone marrow transplantation (BMT). Alternatively, 2 forms of SCID may be successfully treated with gene therapy: X-linked SCID (XL-SCID) and adenosine deaminase (ADA)–deficient SCID.

Pathophysiology

SCID results from mutations in 1 of 10 known genes. These molecular defects block the differentiation and proliferation of T cells and, in some types, of B cells and NK cells. Antibody production is impaired severely, even when mature B cells are present. NK cells, a component of innate immunity, are affected variably. Classification of the etiologies of SCID is according to the corresponding phenotypic lymphocyte profiles: T-lymphocyte (T) negative, B-lymphocyte (B) positive, natural killer cell (NK)-negative (T^-B⁺NK^-), T^-B^-NK^-; T^-B^-NK⁺; and T^-B⁺NK⁺.

Most patients with SCID have atrophic thymuses populated by few lymphocytes and decreased or absent Hassall corpuscles. Peripheral lymphoid tissue is usually absent or severely decreased. In some circumstances, poorly functioning activated oligoclonal lymphocytes develop, perhaps because of increased antigen stimulation that is allowed by initial failure to clear antigens appropriately.

Reticular dysgenesis is a variant of SCID characterized by bone marrow hypoplasia with resultant deficiency of both lymphocytes and hematopoietic cell lineages. Cartilage-hair hypoplasia also is classified as SCID, although a significant proportion of patients have a less severe form not requiring stem cell reconstitution.

The pathogenesis of SCID may be further delineated based on the stage or stages at which lymphopoiesis is arrested. The following 5 mechanisms reflect the known causes of SCID:

(1) Defective lymphokine signaling leading to failed cell proliferation and differentiation: An essential pathway to mature T-cell function is the g chain/janus kinase 3 (JAK3) signaling sequence. The cytokine receptors that share the common g chain include interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Cytokine binding to the g chain IL-2 and IL-7 activate the signaling pathway that includes the intracellular tyrosine kinase, JAK3.

JAK3 is up-regulated as the T cell is activated; downstream signaling by JAK3 triggers 3 additional signaling pathways, including the signal transducers and activators of transcription (STATs). In the absence of common g chain or of the a chain of the IL-7 receptor, JAK3 cannot be activated; thus, cell proliferation and differentiation cannot occur. Similarly, mutations in JAK3 prevent proliferation and differentiation. Defects in the common g chain and JAK3 result in T^-B⁺NK^- SCID, whereas IL-7 receptor a chain mutations result in T^-B^-NK⁺ SCID.

(2) Apoptosis secondary to the accumulation of toxic metabolites:Adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP) are required for purine salvage pathways. Defects in ADA and PNP allow for the accumulation of adenosine, deoxyadenosine, and deoxyadenosine triphosphate, leading to lymphocyte toxicity and apoptosis. This results in T^-B^-NK^- SCID.

(3) Defective cell signaling at the level of the T-cell receptor (TCR) and pre-TCR: CD45, a tyrosine phosphatase found in the cell membranes of hematopoietic cells, functions in TCR and BCR signaling. Deficiency of CD45 results in T^-B⁺NK^- SCID. CD3 is a complex of transmembrane proteins (d, g, e, and z) that forms a heterodimer with the TCR; upon ligand binding by the TCR, the immunoreceptor tyrosine-based-activation motifs (ITAMs) of CD3 become activated, which then activate the z-associated kinase (ZAP70) to propagate downstream signaling events. Deficiency of CD3 d is associated with defective pre-TCR signaling, whereas the lack of CD3 e results in the absence of mature TCRs in the periphery; both are associated with T^-B⁺NK⁺ SCID. Defects in CD3 δ result in a less severe type of immunodeficiency.

(4) Aberrant transcription or expression of cell surface molecules: The absence of cell surface major histocompatibility complex (MHC) proteins prevents normal T-cell function and communication between T cells and other effector cells. MHC class I deficiency is the result of mutations in the transporters of antigenic peptides 1 and 2 (TAP1, TAP2), and in the TAP binding protein. Defective MHC class II expression is caused by mutations in 4 regulatory genes (RFX-ANK, RFX-5, RFX-associated protein [RFXAP], CIITA) that affect transcription or inducibility of class II proteins, not by mutations in the class II genes located on chromosome 6.

(5) Deficient clonal diversity at the level of V(D)J recombination: V(D)J recombination is the process that determines the diversification of the genes encoding T-cell antigen receptors (TCRs) and B-cell antigen receptors (BCRs or immunoglobulins). The recombination activating genes RAG-1 and RAG-2 initiate V(D)J recombination, and the recombinase complex requires the product of the Artemis gene for nonhomologous end joining repair. Mutations in RAG-1, RAG-2, or Artemis cause some T^-B^-NK⁺ forms of SCID. Another gene product required for DNA cross-link repair, DCLRE1C, has been identified.

In the Omenn syndrome variant of SCID, V(D)J recombination activity is reduced. Consequently, lymphocyte counts in patients with Omenn syndrome may be normal or elevated, but many of the lymphocytes have impaired response to antigens.

In the absence of normal regulation of T-cell functions, other cell types may proliferate in an unchecked manner and become activated. Activated, anergic, oligoclonal cells that are CD4⁺ develop in some patients with common g chain or JAK3 mutations. Oligoclonal T helper 2 cells are present in Omenn syndrome, which is caused by mutations in RAG-1 and RAG-2. Autoimmunity characterizes CD3 deficiency. Hemophagocytic lymphohistiocytosis also can complicate SCID.

Murine knockout or mutated models exist for the known human mutations causing SCID and for additional components of the pathways for lymphocyte differentiation, proliferation, and cell regulation. The "SCID mouse" is very well studied for its immunologic defects and is a useful model for research in cancer and transplantation. Common g chain-/- and JAK3-/- mice knockouts resemble human infants with SCID because abnormalities are restricted to the immune system. Murine knockouts also have been reconstituted successfully by gene transfer.

Frequency

United States

Prevalence has been estimated at 1 case per 50,000-75,000 births, but the actual incidence is not established.

International

Estimates for Europe are thought to approximate those in the United States. Cartilage-hair hypoplasia may be even more frequent in Finland.

Although SCID is notoriously underreported, several countries now maintain registries of patients with primary immunodeficiency diseases; the estimated prevalence of SCID in Australia is 0.15 case per 100,000; in Norway, 0.045 case per 100,000; and in Switzerland, 0.47 case per 100,000. In Sweden, SCID occurs in 2.43 of every 100,000 live births.

Mortality/Morbidity

Without stem cell reconstitution, most children die in the first year of life. Allogeneic hematopoietic stem cell transplantation in patients younger than 3-4 months is associated with better outcomes.

• Early infancy is marked by recurrent failure to thrive and common infections including otitis media, diarrhea, and mucocutaneous candidiasis. If SCID is not recognized by age 6 months, opportunistic infections follow, especially Pneumocystis jiroveci pneumonia and invasive fungal infections. Common childhood viral illnesses may prove fatal, including infections with varicella, respiratory syncytial virus (RSV), rotavirus, parainfluenza virus, cytomegalovirus (CMV), Epstein-Barr virus (EBV), enterovirus, and adenovirus.
• In classic cases, vaccination with the attenuated oral polio strain causes death.
• Some patients with cartilage-hair hypoplasia, ADA deficiency, MHC class II, or a less severe mutation in XL-SCID survive longer. The former variant is associated with a high incidence of non-Hodgkin lymphoma.

Race

SCID occurs in infants throughout the world. JAK3 mutations have been reported more frequently in Italy. ZAP70 mutations are more common in Mennonite populations. MHC class II deficiency is usually reported in North African individuals. Artemis gene product deficiency is often seen in Navaho Indians of Athabascan descent. RAG-1/RAG-2–deficient SCID occurs more commonly in Europe. Cartilage-hair hypoplasia affects a Finnish population and the old Amish order in the United States.

Sex

As noted above, 50% of SCID cases is caused by XL-SCID, mutations in the common g chain of the IL-2 receptor.

• Only about one third of males with common g chain mutations have a positive family history, indicating that patients with de novo mutations represent a significant group of people with SCID.
• The remainder of SCID cases is composed of a variety of autosomal recessive mutations; therefore, males and females are affected equally. Seek a family history of consanguinity or of an inbred population. Homologous mutations are more common in these circumstances.

Age

The great majority of SCID cases present in patients younger than 3 months.

• Patients with ADA-deficient SCID seem to have less severe mutations; some are not identified until adulthood.
• Rare patients with common g chain mutation have less severe mutations and present in the second year of life.
• Finnish patients with cartilage-hair hypoplasia may survive until later childhood or adulthood, when cancer becomes an increased risk.

CLINICAL

Section 3 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

History

SCID presents during the first 3 months of life with multiple severe or recurrent illnesses such as otitis media, diarrhea, dermatitis, and before failure to thrive is present. Mucocutaneous candidiasis often is more severe than expected and resistant to treatment. Bacterial otitis media and pneumonia are common. Viral infections include varicella, herpes simplex, RSV, rotavirus, adenovirus, enterovirus, parainfluenza virus, EBV, and CMV.

• In the past, SCID was diagnosed after children developed pneumonia due to P jiroveci. Today, most infants should be recognized before appearance of failure to thrive or Pneumocystis infection.
• Diarrhea may be caused by rotavirus, adenovirus, and enterovirus. Cryptosporidiosis also is reported frequently. Diarrhea resembling Crohn disease complicates some types of SCID, such as MHC class II deficiency.
• Autoimmune phenomena, especially hemolytic anemia and neutropenia, are more common in CD3 deficiency and MHC class II mutations.
• The family history may reveal relatives who were diagnosed with SCID, multiple deaths during infancy due to infection, or unexplained deaths in male infants.
• It is important to ask the mother for risk factors for infection with human immunodeficiency virus (HIV). Infants with transplacental infection with HIV may present very similarly as those with SCID.

Physical

Examination findings are specific for the various superimposed infections and not for SCID itself. These include but are not limited to fever, tachypnea, and signs of dehydration. Patients with SCID fail to manifest palpable lymphadenopathy or tonsillar hypertrophy, findings that should raise suspicion in children with multiple aggressive infections.

• Common cutaneous findings include eczematous dermatitis that resembles severe seborrheic dermatitis, recurrent furunculosis, extensive oral thrush, and candidiasis of the diaper area. A generalized herpetic dermatitis may also be noted. Cutaneous manifestations of graft versus host disease (GVHD) may also be present from maternally derived cells that are reacting unopposed to the neonatal cells.
• • The dermatologic disorders of incontinentia pigmenti and hypohidrotic ectodermal dysplasia are associated with severe pneumococcal infections and progressive bronchiectasis, even with immunoglobulin replacement.
  • Children with Artemis-deficient SCID additionally suffer from numerous oral and genital ulcers.
  • Some patients with a mild form of JAK3-deficient SCID may note the presence of extensive cutaneous transitory warts.
• ADA deficiency is accompanied by abnormalities to ribs and vertebrae caused by defects in cartilaginous structures.
• Sparse hair, abnormal dentition, and osteopetrosis are other manifestations in these patients. Mutations in IKK-g cause these disorders, and the mouse model has both T- and B-cell dysfunction.
• Unique features of Omenn syndrome and the Omenn-like syndrome caused by GVHD include erythroderma, lymphoid hyperplasia, hypereosinophilia, and hepatosplenomegaly.

Causes

Mutational analysis pinpoints many types of SCID. Large deletions of chromosomal material are not seen, limiting the techniques that can be applied for mutation detection. In general, specific mutations do not predict the degree of severity of a specific form of SCID.

SCID is most commonly due to an X-linked mutation of the gene for the IL-2 receptor g chain, which is common to the receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. XL-SCID accounts for approximately 50% of all cases of SCID, and the lymphocyte profile is T^-B⁺NK^-. Mutations in the intracellular tail of the common g chain are associated with a less severe form of XL-SCID.

The remainder of SCID cases is the result of the following autosomal recessive or, less commonly, sporadic mutations:

• ADA deficiency is the second most frequent type of SCID, comprising 16% of total cases. The ADA gene is found on chromosome band 20q13.11. The lymphocyte profile is T^-B^-NK^-. ADA mutations differ among African American, Amish, and Mennonite populations.
• Mutation of the IL-7 receptor a chain causes 10% of cases, making it the third most common type of SCID. The gene for the IL-7 receptor a chain is found on chromosome band 5p13, and the lymphocyte profile is T^-B⁺NK⁺.
• Mutation of the JAK-3 tyrosine kinase occurs in an estimated 7-14% of SCID cases. The JAK3 gene is located on chromosome band 19p13.1. The resultant lymphocyte profile is T^-B⁺NK^-.
• Null mutations in RAG-1 and RAG-2 underlie the autosomal recessive T^-B^-NKC⁺ form of SCID. The genes map to chromosome band 11p13, and one case series estimates that RAG mutations account for 3% of SCID.
• CD45 mutations map to genes on chromosome band 1q31-1q32, resulting in the lymphocyte phenotype T^-B⁺NK^-. This autosomal recessive etiology of SCID is very rare.
• Artemis gene mutations on chromosome band 10p13 account for approximately 1% of SCID cases. The lymphocyte phenotype is T^-B^-NK⁺.
• Mutations of ZAP-70, another tyrosine kinase, cause the CD8-deficient variant.
• CD3 g, e, and d mutations are on chromosome band 11q23. CD3 mutations collectively account for about 1% of SCID cases. The lymphocyte phenotype is T^-B⁺NK⁺.
• MHC class II deficiency caused by CIITA is a mutation located on chromosome band 16p13; the RFX5 mutation is on chromosome band 1q21; RFXAP is on 13q.
• A paucity of CD4⁺ T cells can be caused by the absence of the MHC class II (DR, DP, DQ) proteins, or by deficiency in p56lck, a tyrosine kinase–signaling molecule in the IL-2–mediated JAK-STAT pathway important for differentiation, activation, and proliferation of T cells.
• Cartilage-hair hypoplasia is an autosomal recessive disorder localized to chromosome arm 9p.

DIFFERENTIALS

Section 4 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Other Problems to be Considered

When patients first present with common bacterial infections such as otitis media and pneumonia, a diagnosis of agammaglobulinemia often is considered. In fact, early descriptions of SCID were termed Swiss agammaglobulinemia. In almost all cases, flow cytometry immediately distinguishes between B-cell deficiencies and lack of mature T cells. Other immunodeficiency syndromes, particularly DiGeorge syndrome, may lack T-cell function completely and look clinically like SCID. The nonimmunologic features of these T-cell disorders usually distinguish them. CD40 ligand (CD154) deficiency, that is, X-linked hypogammaglobulinemia with hyper–immunoglobulin M (IgM), may present with recurrent otitis media and Pneumocystis pneumonia as does SCID; the former has normal populations of mature T cells, B cells, and NK cells, unlike most variants of SCID.

Table 1. Primary Immunodeficiency Diseases With T-Lymphocyte Dysfunction

WORKUP

Section 5 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Lab Studies

• Lymphopenia is the classic hallmark of SCID; however, normal or even elevated lymphocyte counts can be seen in a significant proportion of patients. It is essential to emphasize that a complete absence of T-cell function by mitogen tests can occur in association with a normal lymphocyte count for age in some forms of SCID, including XL-SCID, in which all the lymphocytes are B cells. DiGeorge syndrome is another example in which lymphocytes may be more than 2000 cells/dL with no T-cell function, or, conversely, normal T-cell function may be observed in spite of lymphopenia.
• SCID typically is diagnosed by fluorocytometric analysis of T-cell, B-cell, and NK cell populations. See Table 1, which differentiates the lymphocyte profile of various T-cell disorders.
• Enumeration of lymphocytes is followed by DNA-sequencing of genes suggestive of the particular profile. Lymphocyte function should be assessed by measuring responses to phytohemagglutinin, a nonspecific stimulant of T-cell and B-cell proliferation, concanavalin A directed at T-cell proliferation, and pokeweed mitogen directed at B-cell proliferation.
• • Specific antigens, such as tetanus and Candida, stimulate lymphocyte proliferation and represent a later step in lymphocyte function than responses to the nonspecific mitogens.
  • An earlier T-cell function is the ability to proliferate in response to allogeneic cells; this response aids in defining the type of SCID but also is relevant to determining the need for immunosuppressive therapy in preparation for stem cell reconstitution.
  • Additional activators of lymphocyte proliferation are phorbol myristate acetate (PMA) with ionomycin and anti-CD3 and IL-2.
• Measurement of leukocyte ADA enzyme activity is both sensitive and specific for the detection of ADA deficiency SCID.
• Even when SCID is not suspected until the infant's death, lymphocyte markers, mitogen responses, and DNA studies can be carried out. Anticoagulated blood should be saved because lymphocytes are viable for at least 48 hours after death. An autopsy to assess the thymus and peripheral lymphoid tissues, including the spleen, gut, and tonsils, is needed.
• Compromise of other hematopoietic cell lines is observed in reticular dysgenesis, in which myeloid cells are decreased, and platelets and erythrocytes may be deficient. Autoimmune hemolytic anemia can complicate forms of SCID in which autoimmune phenomena are present. Hypoplastic anemia occurs in cartilage-hair hypoplasia.
• Patients with SCID are anergic. However, the reliability of delayed hypersensitivity skin testing depends on adequate exposure to the antigen. Candida and tetanus are the most useful antigens, but exposure requires 4-6 weeks, and more than one immunization is required in the case of tetanus. Mumps and Trichophyton antigens are of minimal use in infants.
• T-cell defects can be difficult to define. The clinical manifestations of T-cell–associated opportunistic infections, such as mycobacteria, CMV and associated viruses, and P jiroveci, usually are interpreted by immunologists as defining a T-cell defect, even in the presence of apparently adequate mitogen tests. An example is IKK-g deficiency for which the mouse model does show T-cell dysfunction. Somech and Roifman (2005) suggest mutation analysis in patients with apparently normal immunologic tests to diagnose certain atypical patients with gc deficiency. When a T-cell disorder is suspected, the Immune Deficiency Foundation has a consultative service for physicians. Laboratories in Seattle (the University of Washington), Boston (Children's Hospital), and New York City are funded to provide molecular analysis (JeffreyModellFoundation)or they can assist in contacting other research facilities.
• Prenatal diagnosis may be attempted when the family history is positive for SCID. Available DNA tests allow for the identification of mutations in genes for ADA, RAG1/RAG2, JAK3, the IL-2 receptor gamma chain, and Artemis.
• • Amniocentesis and chorionic villus sampling enable DNA analysis of fetal cells.
  • Percutaneous umbilical blood sampling is performed to examine fetal blood for T-cell deficiency as well as ADA enzyme levels.

Imaging Studies

• Chest radiographs in classic SCID show a small or absent thymus. However, infants who are immunologically normal may have no visible thymus if they have an overwhelming infection, such as sepsis or meningitis. Other T-cell defects, especially DiGeorge syndrome, also lack thymic tissue. Presence of thymic tissue does not exclude SCID. Patients with SCID who have mutations in ZAP70 or CD3 typically have normal size thymuses.
• • Chest radiographs are essential for early recognition of pneumonitis caused by viral pathogens and P jiroveci.
  • Patients with ADA deficiency and cartilage-hair hypoplasia may have bony abnormalities observed in the ribs and vertebrae on chest radiograph.

Other Tests

• Once lymphocyte populations are enumerated by flow cytometry, mutational analysis usually can be initiated based on the distribution of cell surface markers and clinical findings, including the sex of the infant. When the exact mutation cannot be found, linkage analysis and restriction fragment length polymorphism (RFLP) studies may be performed within families. The techniques for mutational analysis include screening by single-strand conformation polymorphism (SSCP), which detects about 85% of mutations, and dideoxy fingerprinting (ddF), a more sensitive test. The criterion standard to detect the exact DNA change is determination of genomic DNA; direct DNA sequencing must be carried out for some molecular defects, such as those at the 3‘ and 5‘ ends of exons and where the full exon-intron structure of the gene has not been delineated.
• Polymorphisms in the androgen receptor are used to define nonrandom inactivation of the X chromosome in the mother and other female relatives in families in which an infant boy has SCID but no extended family pedigree is informative.

Procedures

• Bronchoscopy frequently is indicated to identify the etiologic agent for pulmonary infection.
• Endoscopy and biopsies are important in delineating the extent and identifying the cause of diarrhea.

Histologic Findings

In classic SCID, thymic tissue is severely deficient with few Hassall corpuscles and rare lymphocytes. The skin and gut may show infiltration with histiocytes, eosinophils, and/or activated dysfunctional T cells. The spleen and peripheral lymph nodes are characteristically atrophic, but, in maternal and transfusion-mediated GVHD or in Omenn syndrome, they may be hyperplastic, with histiocytes and eosinophils. Hemophagocytic lymphohistiocytosis is reported in XL-SCID and cartilage-hair hypoplasia.

TREATMENT

Section 6 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Medical Care

Conventional care for any patient with SCID includes isolation to avoid infection and meticulous skin and mucosal hygienic care while awaiting stem cell reconstitution. Signs of sepsis and pulmonary infections may be subtle; fever mandates a detailed search for infectious agents. Empiric broad-spectrum antibiotics should be administered parenterally while awaiting the results of cultures and body fluid analysis. Consider prophylactic treatment with nystatin to prevent mucocutaneous candidiasis. In individual cases, prophylaxis with antiviral agents such as acyclovir or antibiotics, also may be appropriate. Parenteral nutrition is customarily provided to children with diarrhea and failure to thrive. Ancillary therapy includes intravenous immunoglobulin replacement. Live viral vaccines should not be used. Erythrocyte transfusions must be lymphocyte- depleted and irradiated to prevent transfusion-associated GVHD.

• Bone marrow or other stem cell reconstitution is first-line emergent therapy specific for almost all forms of SCID. With early transplantation and aggressive monitoring and treatment of infections, survival rates may be as high as 97%.
• • In the largest series of SCID patients, BMT was successful in 80% of patients. T-cell function has been adequate in approximately 90% of patients who survive 6 months posttransplant, and B-cell function has been adequate in 70% of these patients. Workup includes MHC typing to identify a fully matched sibling, or, in the case of consanguinity, possibly a parent. Reconstitution using a matched unrelated donor or haploidentical parent also have been successful, although GVHD occurs more frequently in these recipients. The lack of functional T cells in patients with SCID obviates the need for pretransplant myeloablative chemotherapy, thus reducing the toxicity of the procedure. Pretransplant evaluation routinely includes testing of the recipient and the donor for infectious agents, such as CMV, HIV, and hepatitis.
  • In utero BMT into the fetal peritoneal cavity is successful, with reconstitution of T-cells in XL-SCID and in one case of SCID due to IL-7 receptor alpha chain deficiency.
  • Cord blood stem cell transplantation from related or unrelated donors is an option.
• Gene therapy is a viable option in patients with XL-SCID or ADA deficiency SCID who have no HLA-identical sibling. Treatment is optimally given prior to age 4 months to reduce the risks of failed gene transduction and leukemia. Gene therapy is also predicted to work for JAK3 and RAG2 mutations based on murine studies.
  • ADA deficiency was the first form of SCID for which gene therapy was attempted, and efficacy has been reported in 4 patients.
  • In 1999, a clinical trial for XL-SCID gene therapy began, and data suggest that in cases of successful gene insertion, functional T cells developed within 18 weeks and were detectable up to 5 years later. Adverse events have included failure of gene insertion and acute lymphoblastic leukemia due to aberrant insertion within the LMO-2 gene, both of which occurred in older patients. Other studies have confirmed the risk for leukemia in patients who underwent gene therapy and attempts are underway to minimize it (Puck, 2006).
• Specific therapy for dermatitis and eosinophilia in SCID is immunosuppression with cyclosporine and possible addition of IFN-g. These modalities have been used to treat Omenn syndrome but theoretically should be effective in treating maternal or transfusion-induced GVHD.

Surgical Care

Surgical intervention customarily is not indicated.

Consultations

Laboratory studies for stem cell reconstitution must be initiated promptly with the BMT team. In the meantime, gastroenterology and nutrition consultations provide important support.

Diet

The presence of chronic diarrhea and failure to thrive requires consultation with gastroenterology and nutrition. Parenteral or enteral nutritional supplementation is often necessary to ensure adequate intake of calories, nutrients, and vitamins.

Activity

Infants with any form of SCID are isolated to decrease the risk of common viral and bacterial infections. Avoidance of crowds in such places as stores, doctors' offices, and hospitals is important, along with customary hygiene practices, like strict hand washing.

The earlier practice of putting patients in reverse isolation ("bubble") with such precautions as special diets is no longer advocated.

MEDICATION

Section 7 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

First-line therapy for SCID is allogeneic hematopoietic stem cell transplantation. The optimal bone marrow donor is a human leukocyte antigen (HLA)–matched sibling or parent if consanguinity is present. Haploidentical parent donors, HLA-matched unrelated donors, and HLA 5/6 allele–matched unrelated donors also have been successful; however, the risk for graft failure, GVHD, and inadequate B-cell function is higher.

Aggressive therapy for suspected or proven infection is essential. Antibiotic coverage typically must be broad-spectrum. Antiviral agents include pleconaril for enteroviruses and acyclovir, foscarnet, or ganciclovir for varicella-zoster virus (VZV), herpes simplex virus (HSV), and CMV. Antifungal therapy includes fluconazole for mucocutaneous candidiasis; amphotericin B is first-line therapy for invasive fungal infections such as Aspergillus.

Nutritional support is imperative because undernutrition decreases the success rate for stem cell reconstitution and increases the risk for opportunistic infections.

XL-SCID and ADA deficiency may alternatively be treated with gene therapy. Polyethylene glycol–treated (PEG) ADA replacement may be administered, with improvement but not complete reconstitution of immune function.

Replacement therapy with IVIG in patients with primary immune deficiencies

The overall consensus among clinical immunologists is that a dose of IVIG of 400-600 mg/kg/mo or a dose that maintains trough serum IgG levels greater than 500 mg/dL is desirable. Patients (X-linked agammaglobulinemia) with meningoencephalitis require much higher doses (1 g/kg) and perhaps intrathecal therapy. Measurement of preinfusion (trough) serum IgG levels every 3 months until a steady state is achieved and then every 6 months if the patient is stable may be helpful in adjusting the dose of IVIG to achieve adequate serum levels. For persons who have a high catabolism of infused IgG, more frequent infusions (eg, q2-3wk) of smaller doses may maintain the serum level in the reference range. The rate of elimination of IgG may be higher during a period of active infection; measuring serum IgG levels and adjusting to higher dosages or shorter intervals may be required.

For replacement therapy for patients with primary immune deficiency, all brands of IVIG are probably equivalent, although differences exist in viral inactivation processes (eg, solvent detergent vs pasteurization and liquid vs lyophilized). The choice of brands may be dependent on the hospital or home care formulary and the local availability and cost. The dose, manufacturer, and lot number should be recorded for each infusion in order to review for adverse events or other consequences. Recording all side effects that occur during the infusion is crucial.

Monitoring liver and renal function test results periodically, approximately 3-4 times a year, is also recommended. The FDA recommends that for patients at risk for renal failure (eg, those with preexisting renal insufficiency, diabetes, volume depletion, sepsis, paraproteinemia, those >65 y, and those who use nephrotoxic drugs) recommended doses should not be exceeded and infusion rates and concentrations should be the minimum levels that are practicable.

The initial treatment should be administered under the close supervision of experienced personnel. The risk of adverse reactions in the initial treatments is high, especially in patients with infections and those who form immune complexes. In patients with active infection, infusion rates may need to be slower and the dose halved (ie, 200-300 mg/kg), with the remaining dose given the next day to achieve a full dose. Treatment should not be discontinued. After achieving normal serum IgG levels, adverse reactions are uncommon unless patients have active infections.

With the new generation of IVIG products, adverse effects are greatly reduced. Adverse effects include tachycardia, chest tightness, back pain, arthralgia, myalgia, hypertension or hypotension, headache, pruritus, rash, and low-grade fever. More serious reactions are dyspnea, nausea, vomiting, circulatory collapse, and loss of consciousness. Patients with profound immunodeficiency or patients with active infections have more severe reactions.

Anticomplementary activity of IgG aggregates in the IVIG and the formation of immune complexes are thought to be related to the adverse reactions. The formation of oligomeric or polymeric IgG complexes that interact with Fc receptors and trigger the release of inflammatory mediators is another cause. Most adverse reactions are rate related. Slowing the infusion rate or discontinuing therapy until symptoms subside may diminish the reaction. Pretreatment with ibuprofen (5-10 mg/kg q6-8h), acetaminophen (15 mg/kg/dose), diphenhydramine (1 mg/kg/dose), and/or hydrocortisone (6 mg/kg/dose, maximum 100 mg) 1 hour before the infusion may prevent adverse reactions. In some patients with a history of severe side effects, analgesics and antihistamines may be repeated.

Acute renal failure is a rare but significant complication of IVIG treatment. Reports suggest that IVIG products using sucrose as a stabilizer may be associated with a greater risk for this renal complication. Acute tubular necrosis, vacuolar degeneration, and osmotic nephrosis are suggestive of osmotic injury to the proximal renal tubules. The infusion rate for sucrose-containing IVIG should not exceed 3 mg sucrose/kg/min. Risk factors for this adverse reaction include preexisting renal insufficiency, diabetes mellitus, dehydration, age older than 65 years, sepsis, paraproteinemia, and concomitant use of nephrotoxic agents. For patients at increased risk, monitoring blood urea nitrogen and creatinine levels before starting the treatment and prior to each infusion is necessary. If renal function deteriorates, the product should be discontinued.

IgE antibodies to IgA have been reported to cause severe transfusion reactions in IgA-deficient patients. A few reports exist of true anaphylaxis in patients with selective IgA deficiency and common variable immunodeficiency who developed IgE antibodies to IgA after treatment with immunoglobulin. In actual experience, however, this is very rare. In addition, this is not a problem for patients with X-linked agammaglobulinemia (Bruton disease) or severe combined immunodeficiency (SCID). Caution should be exercised in those IgA-deficient patients ( <7 mg/dL) who need IVIG because of IgG subclass deficiencies. IVIG preparations with very low concentrations of contaminating IgA are advised (see Table 2).

Table 2. Immune Globulin, Intravenous

*IVIG products containing sucrose are more often associated with renal dysfunction, acute renal failure, and osmotic nephrosis, particularly with preexisting risk factors (eg, history of renal insufficiency, diabetes mellitus, age >65 y, dehydration, sepsis, paraproteinemia, nephrotoxic drugs).

Contents of table are adapted from the following sources:

1. Manufacturers' literature.
2. Siegel J. The Product: All intravenous immunoglobulins are not equivalent. Pharmacotherapy. 2005; 25(11 Pt 2):78S-84S.
3. Shah S. Pharmacy consideration for the use of IGIV therapy. Am J Health-Syst Pharm. 2005; 62(Suppl 3):S5-11.

Drug Category: Enzyme replacement

Improved immune function and clinical response are observed with PEG-ADA replacement for ADA deficiency.

Drug Category: Antiviral agents

HSV, CMV, and VZV are treated with acyclovir. Oral absorption is poor; thus, most patients require IV administration. Ganciclovir is an alternative drug, also administered IV, for the same viral infections. Both drugs are used for prophylaxis after exposure to VZV beyond the 72- to 96-hour period within which VZIG is effective at 50% of the therapeutic dose.

Drug Name	Ganciclovir (Cytovene)
Description	DOC for CMV and is used for HSV and VZV resistant to acyclovir.
Adult Dose	Therapy: 10 mg/kg/d IV divided q12h for 14-21 d Maintenance: 5-6 mg/kg/d IV for 5-7 d/wk; infuse IV over 1 h or longer Prevention: 5-6 mg/kg/dose IV qd for 5-7 d/wk; alternatively, 1000 mg PO tid with food (oral absorption is poor)
Pediatric Dose	>3 months: Administer as in adults for treatment; IV infusion is over 1 h or longer Prevention: 5 mg/kg IV qd
Contraindications	Documented hypersensitivity
Interactions	Concomitant administration with cytotoxic drug (eg, dapsone, vinblastine, Adriamycin, pentamidine, flucytosine, vincristine, amphotericin B, trimethoprim/sulfamethoxazole, nucleoside analogs) may result in additive toxicity in bone marrow, spermatogonia, and germinal layers of skin and GI mucosa (coadminister only if potential benefits outweigh risks) Coadministration with imipenem-cilastatin may cause generalized seizures (use only if potential benefits outweigh risks); serum creatinine level may increase following concurrent use of ganciclovir with either cyclosporine or amphotericin B; in presence of probenecid, ganciclovir renal clearance is reduced; bioavailability may increase when didanosine is administered either 2 h before or simultaneously with ganciclovir; bioavailability of ganciclovir may decrease in presence of zidovudine, while bioavailability of zidovudine is increased in presence of ganciclovir
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Lower dosage with renal impairment; neutropenia, thrombocytopenia, confusion, and retinal detachment; reconstituted solutions of IV ganciclovir have a high pH (11); phlebitis or pain may occur at site of IV infusion, despite further dilution in IV fluids; administration of ganciclovir should be accompanied by adequate hydration; photosensitization (photoallergy or phototoxicity) may occur

Drug Name	Pleconaril
Description	Investigational antipicornavirus agent. Has resulted in 50% reduction of CNS symptoms in a placebo-controlled study in adults. Used for enteroviral meningoencephalitis and other severe enteroviral infections in immunodeficient patients, including those who have had bone marrow transplantation. It also is used for vaccine-associated paralytic poliomyelitis. Currently available on a compassionate plea basis from Viropharma at (610) 651-0200.
Adult Dose	200-400 mg PO tid for 7 d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in hepatic or renal dysfunction because elimination data are lacking; data lacking on adverse effect profile

Drug Category: Antifungal agents

Mucocutaneous candidiasis usually can be treated with fluconazole. Invasive Candida, Aspergillus, and other fungal infections require IV amphotericin B. Prevention of Aspergillus infection and treatment of certain Candida resistant to fluconazole may be performed effectively with itraconazole.

Drug Name	Itraconazole (Sporanox)
Description	Used most commonly to prevent Aspergillus infection. Oral solution, 10 mg/mL, is administered on an empty stomach; capsules, 100 mg, are taken with food.
Adult Dose	600 mg/24 h PO divided tid for 3-4 d; followed by 400 mg/d PO divided bid; in severe cases, initial high dose is continued for longer period
Pediatric Dose	5-10 mg/kg/d PO qd or divided bid
Contraindications	Documented hypersensitivity; coadministration with cisapride may cause adverse cardiovascular effects (possibly death)
Interactions	Antacids may reduce absorption of itraconazole; CYP450 3A isoenzyme inhibitor; edema may occur with coadministration of calcium channel blockers (eg, amlodipine, nifedipine); hypoglycemia may occur with sulfonylureas; may increase tacrolimus and cyclosporine plasma concentrations when high doses are used; rhabdomyolysis may occur with coadministration of HMG-CoA reductase inhibitors (lovastatin or simvastatin); coadministration with cisapride can cause cardiac rhythm abnormalities and death May increase digoxin levels; coadministration may increase plasma levels of midazolam or triazolam; phenytoin and rifampin may reduce itraconazole levels (phenytoin metabolism may be altered)
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in hepatic insufficiencies; GI symptoms, headaches, rash, and hypokalemia

Drug Name	Amphotericin B (Amphocin, Fungizone)
Description	Test dose of 0.1 mg/kg is recommended by manufacturer but often omitted. Infusion of total dose over 2-4 h has been recommended, but infusion over 1 h seems to be adequate. Because of the high incidence of toxicity, renal, hepatic, electrolyte, and hematologic status must be monitored closely. In particular, potassium and magnesium levels usually are monitored daily. Salt loading with 10-15 mL/kg of NS before each dose is used to decrease the risk of nephrotoxicity. Premedication with acetaminophen and diphenhydramine 30 min before and 4 h after infusion decreases the typical adverse effects of fever, chills, hypotension, nausea and vomiting. Hydrocortisone may be admixed to IV (1 mg/mg amphotericin, not to exceed 25 mg).
Adult Dose	1 mg/kg/d or 1.5 mg/kg qod IV
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Antineoplastic agents may enhance the potential of amphotericin B for renal toxicity, bronchospasm, and hypotension; corticosteroids, digitalis, and thiazides may potentiate hypokalemia; risk of renal toxicity is increased with cyclosporine
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Monitor renal function, serum electrolytes (eg, magnesium, potassium), liver function, CBC, and hemoglobin concentrations; resume therapy at lowest level (eg, 0.25 mg/kg) when therapy is interrupted for more than 7 d

Drug Name	Lipid amphotericin B products
Description	Three amphotericin products are available: amphotericin B lipid complex (Abelcet), amphotericin B cholesteryl sulfate (Amphotec), and amphotericin B liposomal (AmBisome). Lipid amphotericin B is used when toxicity from nonlipid amphotericin B is unacceptable. In some patients, lipid products seem to cause less fever, GI irritation, chills, and headache. Not clear whether renal toxicity is lower.
Adult Dose	3-5 mg/kg/d infused IV over 2 h
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Antineoplastic agents may enhance the potential of amphotericin B for renal toxicity, bronchospasm, and hypotension; corticosteroids, digitalis, and thiazides may potentiate hypokalemia; risk of renal toxicity is increased with cyclosporine
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Premedicate with acetaminophen and diphenhydramine; monitoring of renal, electrolyte, hepatic, and hematologic status essential

FOLLOW-UP

Section 8 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Further Inpatient Care

• Coordinating medical management between immunology, infectious disease, pulmonary, and gastroenterology specialists can be challenging.
• The need for excellent laboratory and radiology support mandates hospitalization in tertiary pediatric medical centers.
• BMT should be coordinated between immunology and the BMT team.

Further Outpatient Care

• Isolation to avoid transmission of infection is required. Usually, contacts are restricted to immediate family members and friends whose risks for infection can be monitored. Visits to doctors' offices and hospitals must be orchestrated carefully to avoid exposure to infection.

In/Out Patient Meds

• See Medical Care.

Transfer

• As with any primary immunodeficiency disease, subtle signs of infection, morbidity/mortality from common infections, and the need to offer stem cell transplantation reinforces the importance of frequent monitoring and management by a clinical immunologist.

Deterrence/Prevention

• Prenatal diagnosis is possible by chorionic villus sampling at 10 weeks' gestation (or later) by amniocentesis, using DNA methodology in families for whom the exact mutations have been established. Molecular techniques include SSCP and ddF; actual sequencing of DNA to detect the mutation may be required in some situations. Linkage analysis and RFLP are other options that are needed less frequently with the advent of specific mutation analysis. Fetal blood sampling for fluorocytometric testing, mitogen responses, and enzyme levels can establish the diagnosis when DNA analysis is not available.
• After exposure to VZV, prophylaxis with VZIG should be administered within 48 hours, if possible; VZIG may be efficacious up to 96 hours postexposure. Beyond that interval, acyclovir has been administered and may prevent or modify the severity of VZV.

Complications

• Opportunistic infections usually follow more common infections. P jiroveci and fungal pneumonias cause death in classic cases. CMV, VZV, and HSV are viral infections that typically occur in the infant who already has had treatable infections. Poliomyelitis from the attenuated oral vaccine is well recognized. Neurologic compromise from polio and other enteroviruses precludes stem cell reconstitution.
• Graft failure with BMT and posttransplant GVHD are well recognized, although both have decreased with improved BMT preparatory techniques.
• Cancer, usually non-Hodgkin lymphoma, is seen in patients with cartilage-hair hypoplasia who survive beyond early childhood.

Prognosis

• With bone marrow and other stem cell reconstitution techniques, many patients with SCID are fully reconstituted without complications. The risk for GVHD or graft failure has declined significantly with newer techniques that include T-cell depletion using monoclonal antibodies and, possibly, the use of cord blood CD34⁺ stem cells. In selected patients with SCID, pretransplantation immunosuppression is not necessary (see Medical Care).
• • Patients who are well-nourished, uninfected, and younger than 6 months before transplantation have the best outcomes.
  • Patients with common g chain (XL-SCID) or JAK3 mutations have an increased risk of hypogammaglobulinemia posttransplantation, based on retention of recipient B cells that do not respond adequately to donor T-cell communication.
• Without stem cell reconstitution, a patient with SCID rarely survives. However, gene therapy for XL-SCID and ADA deficiency are viable alternatives for patients unable to find donors.
• Patients with less severe mutations in ADA have survived into adulthood; optional treatment for ADA deficiency is PEG-ADA replacement, although this does not return immune function to normal.
• Cartilage-hair hypoplasia, particularly in the Finnish population, may be less severe.

Patient Education

• Families must be informed about the risks of infection so that appropriate steps to avoid exposure to infection are instituted. They should be aware that live viral vaccines are contraindicated.
• Genetic counseling is an essential part of medical care for the family. Parents must be informed of the risk of SCID in subsequent children depending on the X-linked or autosomal etiology. The risk for daughters to be carriers for X-linked immunodeficiencies also must be clarified.
• Communicate the high risk for life-threatening infection during the preparative immunosuppressive regimen (when indicated), in addition to the risk for failure to engraft and GVHD. Adequate informed consent for stem cell reconstitution must review these points. Although successful complete immune reconstitution from BMT is reported using fully matched related and unrelated donors or haploidentical parents, patients with SCID may fail to engraft or develop GVHD posttransplant. Other forms of stem cell reconstitution that can be offered include cord cell transplantation. Gene therapy is an option for XL-SCID and ADA-SCID.
• The Immune Deficiency Foundation is an important resource for education and support for patients and families with any primary immunodeficiency disease. The current address is 25 West Chesapeake Avenue, Suite 206, Towson, MD 21204, USA. Some US states have local chapters. For consultation, contact 1-877-666-0866 or www.primaryimmune.org. The Jeffrey Modell Foundation, located at 747 3rd Avenue, New York, NY, USA, 10017, also provides educational support for families and patients (1-800-JEFF-844).

MISCELLANEOUS

Section 9 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Medical/Legal Pitfalls

• Mutational analysis must be offered, and the opportunity for prenatal diagnosis must be discussed with the family. The risk for occurrence of XL-SCID in another child is 50% for male infants; female infants are not affected, but they have a 50% risk for being carriers. Any autosomal recessive mutation causing SCID places siblings at a 1 in 4 risk for SCID.
• Misdiagnosing SCID as an immunoglobulin deficiency is a common error.
• Administration of nonirradiated blood products or live-virus vaccines to a patient suspected of having SCID or undergoing a workup for for SCID is another potentially fatal error if that patient turns out to have SCID.
• Dismissing an infant's death as caused by an overwhelming common bacterial or viral infection without further investigation is another mistake. Any infant with the history of an unusual frequency and severity of common infections prior to death from infection should have an autopsy performed to assess lymphoid and thymic tissue. Peripheral blood lymphocytes can survive for several days; thus, blood should be saved for the assessment of T-cell and B-cell markers by flow cytometry and for responses to mitogens.
• Stem cell reconstitution must be discussed carefully with the family for informed consent, particularly since the donor may be a sibling too young to understand the risks and benefits of the procedure. Under these circumstances, a guardian outside the family may most effectively guide this decision. Furthermore, in weighing the likelihood of death unless stem cell reconstitution is attempted, it is equally essential that families are made aware of the high risk for fatal infection or GVHD in the recipient after transplantation.

ACKNOWLEDGMENTS

Section 10 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author Ann O'Neill Shigeoka, MD to the development and writing of this article.

MULTIMEDIA

Section 11 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Media file 1:  Severe combined immunodeficiency. This patient presented with fever and paralysis of his left arm 3 months after receiving his third oral poliovirus vaccine. Past history included chronic thrush presenting in the absence of antibiotic therapy or breastfeeding at 2 months, chronic diarrhea from 4 months, and recurrent otitis media. He was at the 90th percentile for height and weight, similar to his parents. Major histocompatibility complex (MHC) class II deficiency was diagnosed by immunologic tests.
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Media type:  Photo

Media file 2:  Severe combined immunodeficiency. This patient with an autosomal recessive type of severe combined immunodeficiency died of cytomegalovirus pneumonia when aged 22 months after prior infections that included recurrent otitis, pneumonia, and oral thrush. A CMV inclusion body is pictured in the upper left of the photo.
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Media type:  Photo

Media file 3:  Severe combined immunodeficiency. Histologically, the thymus in severe combined immunodeficiency usually lacks Hassall corpuscles and is depleted of lymphocytes. In this photo, a Hassall corpuscle is identified to the right of center.
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Media type:  Photo

REFERENCES

Section 12 of 12

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

• Bonilla FA, Geha RS. 2. Update on primary immunodeficiency diseases. J Allergy Clin Immunol. Feb 2006;117(2 Suppl Mini-Primer):S435-41. [Medline].
• Buckley RH. Primary immunodeficiency diseases due to defects in lymphocytes. N Engl J Med. Nov 2 2000;343(18):1313-24. [Medline].
• Buckley RH, Schiff SE, Schiff RI, et al. Hematopoietic stem-cell transplantation for the treatment of severe combined immunodeficiency. N Engl J Med. Feb 18 1999;340(7):508-16. [Medline].
• Buckley RH. Molecular defects in human severe combined immunodeficiency and approaches to immune reconstitution. Annu Rev Immunol. 2004;22:625-55. [Medline].
• Buckley RH. The multiple causes of human SCID. J Clin Invest. Nov 2004;114(10):1409-11.