eMedicine Specialties > Pediatrics: General Medicine > Allergy & Immunology

Severe Combined Immunodeficiency

Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School
Smeeta Sinha, MD, Staff Physician, Department of Dermatology, UMDNJ-New Jersey Medical School

Updated: Aug 18, 2009

Introduction

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 numerous 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.

Severe combined immunodeficiency is a pediatric emergency because survival depends on expeditious stem cell reconstitution, usually by bone marrow transplantation (BMT). Alternatively, 2 forms of severe combined immunodeficiency may be successfully treated with gene therapy: X-linked severe combined immunodeficiency (XL-SCID) and adenosine deaminase (ADA)–deficient 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.

Pathophysiology

Severe combined immunodeficiency results from mutations in one of more than 15 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 severely impaired, even when mature B cells are present due to lack of T-cell help. NK cells, a component of innate immunity, are variably affected. Classification of the etiologies of severe combined immunodeficiency is according to the corresponding phenotypic lymphocyte profiles: T-lymphocyte negative (T^-), B-lymphocyte positive (B⁺), and NK-negative (T^- B⁺ NK^-); T^- B^- NK^-; T^- B^- NK⁺; and T^- B⁺ NK⁺.

Most patients with severe combined immunodeficiency 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 may occur due to failure of clearing antigens appropriately.

Reticular dysgenesis is a variant of severe combined immunodeficiency characterized by bone marrow hypoplasia with resultant deficiency of both lymphocytes and hematopoietic cell lineages. Recently mutations in mitochondrial adenylate kinase 2 was revealed in patients with reticular dysgenesis.^{[1 ]} Cartilage-hair hypoplasia is also classified as severe combined immunodeficiency, although a significant proportion of patients have a less severe form not requiring stem cell reconstitution.

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

• Defective lymphokine signaling leading to failed cell proliferation and differentiation
  • An essential pathway to mature T-cell function is the γ chain/janus kinase 3 (JAK3) signaling sequence.
  • The cytokine receptors that share the common γ chain include interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Cytokine binding to the γ chain of these cytokines 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 γ chain or of the α chain of the IL-7 receptor, JAK3 cannot be activated in pro T cells in the bone marrow; thus, T-cell maturation/differentiation cannot occur. Similarly, mutations in JAK3 prevent proliferation and differentiation in pro T cells. The common γ chain is shared as a receptor of IL-15 which is a key growth factor for NK cells. Thus, defects in the common γ chain and JAK3 result in T^- B⁺ NK^- severe combined immunodeficiency, whereas IL-7 receptor a chain mutations result in T^- B^- NK⁺ severe combined immunodeficiency. 
• 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^- severe combined immunodeficiency.
• 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⁺ severe combined immunodeficiency. Deficiency of ZAP70 causes a preferential decrease of CD8 cells, causing an atypical severe combined immunodeficiency.
  • Likewise, CD3 deficiency presents with close-to-normal absolute lymphocyte count, albeit these T cells are dysfunctional. 
  • Defective expression of major histocompatibility complex (MHC) molecules disrupts antigen (Ag) presentation at pre-TCR level; these involve bare lymphocyte syndrome and mutations that cause defects in expression of MHCI or MHCII molecules, causing decreased CD8 and CD4 T cells, respectively.
• Defect in TCR and Ig gene rearrangement: Both T cell and B cell requires TCR and Ig gene rearrangement in early stage of their differentiation. Several recombinases play critical roles in TCR and Ig gene rearrangement; thus, deficiency of recombinases result in T^- B^- NK⁺ severe combined immunodeficiency. Mutations in RAG1, RAG2, and Artemis genes are now shown to cause this type of severe combined immunodeficiency.
• Thymic dysgenesis: Severe thymic dysgenesis results in lack of T cells, causing a T^- B⁺ NK⁺ severe combined immunodeficiency. This is typically seen in severe forms of DiGeorge syndrome and CHARGE association. 

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 severe combined immunodeficiency is notoriously underreported, several countries now maintain registries of patients with primary immunodeficiency diseases; the estimated prevalence of severe combined immunodeficiency 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, severe combined immunodeficiency occurs in 2.43 of every 100,000 live births.

Mortality/Morbidity

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

Early infancy is characterized by recurrent failure to thrive and common infections including otitis media, diarrhea, and opportunistic infections such as mucocutaneous candidiasis and cytomegalovirus (CMV) infection. If severe combined immunodeficiency is not recognized by age 6 months, opportunistic infections become more evident, especially Pneumocystis jiroveci pneumonia and invasive fungal infections. Common childhood viral illnesses may prove fatal in severe combined immunodeficiency patients. These include infections with varicella, respiratory syncytial virus (RSV), rotavirus, parainfluenza virus, CMV, Epstein-Barr virus (EBV), enterovirus, and adenovirus.

In classic cases, vaccination with the attenuated oral polio strain causes disseminated infection and resultant death.

Some patients with cartilage-hair hypoplasia, ADA deficiency, MHC class II, or a less severe mutation in XL-severe combined immunodeficiency survive longer. The former variant is associated with a high incidence of non-Hodgkin lymphoma.

Race

Severe combined immunodeficiency 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 Athabaskan descent. RAG-1/RAG-2 –deficient severe combined immunodeficiency 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 severe combined immunodeficiency cases is caused by XL-severe combined immunodeficiency, mutations in the common γ chain shared by several cytokine receptors. Only about one third of males with common γ chain mutations have a positive family history, indicating that patients with de novo mutations represent a significant group of people with severe combined immunodeficiency. The remainder of severe combined immunodeficiency cases are composed of various 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 severe combined immunodeficiency cases present in patients younger than 3 months. Patients with ADA-deficient severe combined immunodeficiency seem to have less severe mutations; some are not identified until adulthood. Patients with common γ chain mutation may reveal less severe mutations and present in the second year of life but this occurs rarely. Finnish patients with cartilage-hair hypoplasia may survive until later childhood or adulthood when cancer becomes an increased risk.

Clinical

History

Patients with severe combined immunodeficiency (SCID) may present with multiple severe or recurrent illnesses such as otitis media, diarrhea, and dermatitis during the first 3 months of life before failure to thrive develops. Mucocutaneous candidiasis is often more severe than expected and is resistant to treatment. Bacterial otitis media and pneumonia are common. Viral infections include varicella, herpes simplex, respiratory syncytial virus (RSV), rotavirus, adenovirus, enterovirus, parainfluenza virus, Epstein-Barr virus (EBV), and cytomegalovirus (CMV).

• In the past, severe combined immunodeficiency was often diagnosed after children developed serious infections such as 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 is also reported frequently. Diarrhea resembling Crohn Disease complicates some types of SCID, such as major histocompatibility complex (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 severe combined immunodeficiency, multiple deaths during infancy due to infection, or unexplained deaths in male infants.
• Asking the mother for risk factors for infection with human immunodeficiency virus (HIV) is important. Infants with transplacental infection with HIV may present very similar to those with severe combined immunodeficiency.

Physical

Examination findings are specific for the various superimposed infections and not for severe combined immunodeficiency itself. These include but are not limited to fever, tachypnea, failure to thrive, and signs of dehydration. Patients with severe combined immunodeficiency fail to manifest palpable lymphadenopathy or tonsillar hypertrophy. Lack of recognizable peripheral lymphoid organs should raise suspicion of severe combined immunodeficiency 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 T cells that are reacting host cells in the absence of opposing host T cells.
  • The dermatologic disorders of incontinentia pigmenti and hypohidrotic ectodermal dysplasia are associated with severe pneumococcal infections and progressive bronchiectasis, even with immunoglobulin replacement.
  • Dermatophytosis is uncommon in these patients, although one was recently described with widespread tinea corporis due to Trichophyton mentagrophytes.^{[2 ]}
  • Children with Artemis-deficient severe combined immunodeficiency additionally suffer from numerous oral and genital ulcers.
  • Some patients with a mild form of JAK3-deficient severe combined immunodeficiency may present with extensive cutaneous transitory warts.
• Adenosine deaminase (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. Hypomorphic heterozygous mutations in IKBA causes autosomal recessive ectodermal dysplasia with immunodeficiency (AD-EDA-ID) with impaired NFkB signaling pathways; however, this defect also causes severely impaired T-cell receptor (TCR) signaling with resultant clinical phenotype of severe combined immunodeficiency.
• Unique features of Omenn syndrome (OS) and the Omennlike syndrome caused by GVHD include erythroderma, lymphoid hyperplasia, hypereosinophilia, and hepatosplenomegaly. Growing numbers of leaky severe combined immunodeficiency mutations are now shown to manifest OS; thus, OS is now considered to be dysregulated inflammatory processes revealed in leaky severe combined immunodeficiency.

Causes

Mutational analysis pinpoints many types of severe combined immunodeficiency. 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 severe combined immunodeficiency.

Severe combined immunodeficiency is most commonly due to an X-linked mutation of the gene coding for common γ chain, which is common to the receptors for interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15, and IL-21. X-linked (XL) severe combined immunodeficiency accounts for approximately 50% of all cases of severe combined immunodeficiency, and the lymphocyte profile is T^- B⁺ NK^-. Mutations in the intracellular tail of the common γ chain are associated with a less severe form of XL severe combined immunodeficiency. Defective expression of common γ chain can be detected by flow cytometry

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

• ADA deficiency is the second most frequent type of severe combined immunodeficiency, 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 black, Amish, and Mennonite populations.
• Mutation of the IL-7 receptor a chain causes 10% of cases, making it the third most common type of severe combined immunodeficiency. The gene for the IL-7 receptor α 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 severe combined immunodeficiency 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 severe combined immunodeficiency. The genes map to chromosome band 11p13, and one case series estimates that RAG mutations account for 3% of severe combined immunodeficiency cases.
• CD45 mutations map to genes on chromosome band 1q31-1q32, resulting in the lymphocyte phenotype T^- B⁺ NK^-. This autosomal recessive etiology of severe combined immunodeficiency is very rare.
• Artemis gene mutations on chromosome band 10p13 account for approximately 1% of severe combined immunodeficiency cases. The lymphocyte phenotype is T^- B^- NK⁺.
• Mutations of ZAP-70, another tyrosine kinase, cause the CD8-deficient severe combined immunodeficiency variant.
• CD3 g, e, and d mutations are on chromosome band 11q23. CD3 mutations collectively account for about 1% of severe combined immunodeficiency cases. The lymphocyte phenotype is T^- B⁺ NK⁺.
• MHC class II deficiency caused by mutations of components of the transcription factors of MHCII including CIITA. CIITA is located on chromosome band 16p13; the RFX5 (another component of MHCII transcription factor) 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 and genes associated with this severe combined immunodeficiency localized to chromosome 9p.

Differential Diagnoses

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 severe combined immunodeficiency (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 severe combined immunodeficiency. 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 severe combined immunodeficiency; the former has normal populations of mature T cells, B cells, and NK cells, unlike most variants of severe combined immunodeficiency. Table 1. Primary Immunodeficiency Diseases With T-Lymphocyte Dysfunction

Workup

Laboratory Studies

• Lymphopenia is the classic hallmark of severe combined immunodeficiency (SCID); however, normal or even elevated lymphocyte counts can be seen in a significant proportion of patients. 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 severe combined immunodeficiency, including X-linked (XL) severe combined immunodeficiency, 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.
• Severe combined immunodeficiency is typically 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 proliferation, concanavalin A directed at T-cell proliferation, and pokeweed mitogen directed at T-cell and 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. Healthy young infants may not respond well to these specific antigens due to lack of exposure and/or immature T-cell functions.
  • Another T cell function used for screening is their ability to proliferate in response to allogeneic cells; this response aids in defining the type of severe combined immunodeficiency 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 or anti-CD3 and anti-CD28.
• Measurement of leukocyte adenosine deaminase (ADA) enzyme activity is both sensitive and specific for the detection of ADA deficiency severe combined immunodeficiency.
• Even when severe combined immunodeficiency 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 severe combined immunodeficiency in which autoimmune phenomena are present. Hypoplastic anemia occurs in cartilage-hair hypoplasia.
• Patients with severe combined immunodeficiency 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, cytomegalovirus (CMV) and associated viruses, and P jiroveci, are usually interpreted by immunologists as defining a T-cell defect, even in the presence of apparently adequate mitogen responses (eg, IKK-γ deficiency for which impaired T-cell receptor [TCR]–mediated signaling is present despite normal mitogen responses).
• Somech and Roifman suggest mutation analysis in patients with apparently normal immunologic tests to diagnose atypical cases of gC deficiency.^{[3 ]}
• 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 (Jeffrey Modell Foundation) or they can assist in contacting other research facilities.
• Prenatal diagnosis may be attempted when the family history is positive for severe combined immunodeficiency. Available DNA tests allow for the identification of mutations in genes for ADA, RAG1/RAG2, JAK3, gC, IL-7R, Artemis and many other gene mutations associated with SCID phenotype.
  • 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 severe combined immunodeficiency 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 severe combined immunodeficiency. Patients with severe combined immunodeficiency 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 radiography.

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 severe combined immunodeficiency 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 and/or other GI symptoms.

Histologic Findings

• In classic severe combined immunodeficiency, 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 graft versus host disease (GVHD) or in Omenn syndrome, they may be hyperplastic, with histiocytes and eosinophils.
• Hemophagocytic lymphohistiocytosis is reported in XL severe combined immunodeficiency and cartilage-hair hypoplasia.

Treatment

Medical Care

• Bone marrow or other stem cell reconstitution is the first-line emergent therapy specific for almost all forms of severe combined immunodeficiency. With early transplantation and aggressive monitoring and treatment of infections, survival rates may be as high as 97%.
  • In the largest series of patients with severe combined immunodeficiency, bone marrow transplantation (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 major histocompatibility complex (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 severe combined immunodeficiency 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 cytomegalovirus (CMV), HIV, and hepatitis.
  • In utero BMT into the fetal peritoneal cavity is successful, with reconstitution of T-cells in X-linked (XL) severe combined immunodeficiency and in one case of severe combined immunodeficiency due to IL-7R α-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 severe combined immunodeficiency or adenosine deaminase (ADA) deficiency severe combined immunodeficiency who have no human leukocyte antigen (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 severe combined immunodeficiency for which gene therapy was attempted, and efficacy has been reported in 4 patients.
  • In 1999, a clinical trial for XL severe combined immunodeficiency gene therapy began, and data suggest that in cases of successful gene insertion, functional T cells developed within 18 weeks and were detectable as long as 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.^{[4 ]}
• Specific therapy for dermatitis and eosinophilia in severe combined immunodeficiency is immunosuppression with cyclosporine and possible addition of interferon (IFN)-γ. 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 is customarily 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 severe combined immunodeficiency 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 handwashing.
• The earlier practice of putting patients in reverse isolation ("bubble") with such precautions as special diets is no longer advocated.

Medication

First-line therapy for severe combined immunodeficiency (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 have also been successful; however, the risk for graft failure, graft versus host disease (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 acyclovir, foscarnet, or ganciclovir for varicella-zoster virus (VZV), herpes simplex virus, and cytomegalovirus (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.

X-linked (XL) severe combined immunodeficiency and adenosine deaminase (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.

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 immunoglobulin (Ig)G levels greater than 500 mg/dL is desirable. Patients with X-linked agammaglobulinemia and 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, every 2-3 wk) 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 US Food and Drug Administration (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 orally [PO] every 6-8 h), acetaminophen (15 mg/kg/dose PO), diphenhydramine (1 mg/kg/dose PO), and/or hydrocortisone (6 mg/kg/dose, not to exceed 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 BUN 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. Caution should be exercised in those patients with IgA deficiency (<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^{[5,6,7,8 ]}

*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).

Enzyme replacement

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

Pegademase bovine (Adagen)

Modification of ADA by PEG conjugation of bovine ADA increases the half-life of the enzyme and reduces the immunogenicity of the protein.

Dosing

Adult

30 U/kg IBW IM twice weekly

Pediatric

Administer as in adults

Interactions

Pentostatin decrease effect of pegademase bovine; vidarabine is a substrate for ADA and may alter effect

Contraindications

Theoretical allergic reaction to foreign protein; severe thrombocytopenia

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Possible need for higher doses in younger children, who clear enzyme more rapidly; adjust until patient clinically stable with improved immune functions (lymphocyte count and proliferative responses to mitogens in vitro); therapeutic ADA levels have been established by measuring trough levels

Antiviral agents

Herpes simplex virus, CMV, and VZV are treated with acyclovir. PO 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.

Acyclovir (Zovirax)

High dose of 45-60 mg/kg/d, or 1500 mg/m²/d divided q8h is used for CNS infection. Good hydration is essential, and lower doses must be calculated in the presence of renal compromise.

Dosing

Adult

1500 mg/m²/d IV divided q8h for 10-14 d

Pediatric

Administer as in adults

Interactions

Concomitant use of probenecid or zidovudine prolongs half-life and increases CNS toxicity of acyclovir

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Lower doses with renal impairment; caution with premature infants; poor hydration increases risk for precipitation in renal tubules; headaches, encephalopathy, GI irritation, rashes, arthralgias, fever, and bone marrow suppression

Ganciclovir (Cytovene)

DOC for CMV and is used for HSV and VZV resistant to acyclovir.

Dosing

Adult

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 (PO absorption is poor)

Pediatric

>3 months: Administer as in adults for treatment; IV infusion is over 1 h or longer
Prevention: 5 mg/kg IV qd

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

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

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

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.

Fluconazole (Diflucan)

Fungistatic activity. Synthetic PO antifungal (broad-spectrum bistriazole) that selectively inhibits fungal CYP450 and sterol C-14 alpha-demethylation, which prevents conversion of lanosterol to ergosterol, thereby disrupting cellular membranes. Requires a loading dose on day 1 followed by maintenance at 50% of the loading dose. May be administered by either IV or PO routes with similar efficacy. Length of treatment is a minimum of 10 d; longer courses are determined individually, considering other risk factors such as ongoing broad-spectrum antibiotics.

Dosing

Adult

Loading dose: 400 mg PO/IV followed by 200 mg PO/IV qd

Pediatric

Loading dose: 10 mg/kg PO/IV followed by 3-6 mg/kg PO/IV qd

Interactions

Levels may increase with thiazide diuretics; fluconazole levels may decrease with long-term coadministration of rifampin; coadministration of fluconazole may decrease phenytoin clearance; fluconazole is a potent inhibitor of CYP450 3A isoenzyme and may increase concentrations of theophylline, tolbutamide, glyburide, and glipizide; effects of anticoagulants may increase with fluconazole coadministration; increases in cyclosporine concentrations may occur when administered concurrently

Contraindications

Documented hypersensitivity; cardiac arrhythmias may occur with cisapride, terfenadine, and astemizole

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Adjust dose for renal insufficiency; monitor closely if rashes develop and discontinue drug if lesions progress; may cause clinical hepatitis, cholestasis, and fulminant hepatic failure (including death) with underlying medical conditions (eg, AIDS, malignancy) and while taking multiple concomitant medications; not recommended for breastfeeding mothers

Itraconazole (Sporanox)

Used most commonly to prevent Aspergillus infection. PO solution, 10 mg/mL, is administered on an empty stomach; capsules, 100 mg, are taken with food.

Dosing

Adult

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

5-10 mg/kg/d PO qd or divided bid

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)

Contraindications

Documented hypersensitivity; coadministration with cisapride may cause adverse cardiovascular effects (possibly death)

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in hepatic insufficiencies; GI symptoms, headaches, rash, and hypokalemia

Amphotericin B (Amphocin, Fungizone)

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).

Dosing

Adult

1 mg/kg/d or 1.5 mg/kg qod IV

Pediatric

Administer as in adults

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

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Monitor renal function, serum electrolytes (eg, magnesium, potassium), liver function, CBC count, and hemoglobin concentrations; resume therapy at lowest level (eg, 0.25 mg/kg) when therapy is interrupted for more than 7 d

Lipid amphotericin B products

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.

Dosing

Adult

3-5 mg/kg/d infused IV over 2 h

Pediatric

Administer as in adults

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

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Premedicate with acetaminophen and diphenhydramine; monitoring of renal, electrolyte, hepatic, and hematologic status essential

Follow-up

Further Inpatient Care

• Coordinating medical management of severe combined immunodeficiency (SCID), including 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.
• Bone marrow transplantation (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.
• Although allogeneic hematopoietic stem cell transplantation (HCST) is curative for severe combined immunodeficiency, the long-term outcome in a 90-patient cohort followed for 2-34 years showed almost half experienced one or more significant clinical events, including persistent chronic graft versus host disease (GVHD), autoimmune and inflammatory manifestations, opportunistic and nonopportunistic infections, and a requirement for nutritional support.^{[9 ]} These late-onset complications suggest the need for prevention and careful follow-up.

Inpatient & Outpatient Medications

• 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 single-strand conformation polymorphism (SSCP) and dideoxy fingerprinting (ddF); actual sequencing of DNA to detect the mutation may be required in some situations. Linkage analysis and restriction fragment length polymorphism (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 varicella-zoster virus (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. Cytomegalovirus (CMV), VZV, and herpes simplex virus 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 severe combined immunodeficiency 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 severe combined immunodeficiency, 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 severe combined immunodeficiency) 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 severe combined immunodeficiency rarely survives. However, gene therapy for XL severe combined immunodeficiency and adenosine deaminase (ADA) deficiency may be viable alternatives for patients unable to find donors if the complication of acute lymphoblastic leukemia is effectively prevented.
• Patients with less severe mutations in ADA have survived into adulthood; optional treatment for ADA deficiency is polyethylene glycol–treated (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 severe combined immunodeficiency 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 severe combined immunodeficiency 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 severe combined immunodeficiency and ADA severe combined immunodeficiency.
• 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. 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 10017, also provides educational support for families and patients (1-800-JEFF-844).

Miscellaneous

Medicolegal Pitfalls

• Mutational analysis must be offered, and the opportunity for prenatal diagnosis must be discussed with the family. The risk for occurrence of X-linked (XL) severe combined immunodeficiency (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 severe combined immunodeficiency places siblings at a 1 in 4 risk for severe combined immunodeficiency.
• Misdiagnosing severe combined immunodeficiency as hypogammaglobulinemia is a common error.
• Administration of nonirradiated blood products or live-virus vaccines to a patient suspected of having severe combined immunodeficiency or undergoing a workup for severe combined immunodeficiency is another potentially fatal error if that patient turns out to have severe combined immunodeficiency.
• Dismissing an infant's death 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 graft versus host disease (GVHD) in the recipient after transplantation.

Multimedia

Media file 1: 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.

Media file 2: 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.

Media file 3: 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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Keywords

severe combined immunodeficiency, SCID, X-linked SCID, XL-SCID, MHC class II deficiency, bare lymphocyte syndrome, adenosine deaminase–deficient SCID, ADA-deficient SCID, recurrent infections, failure to thrive, dermatitis, bone marrow transplantation, DiGeorge syndrome, CHARGE syndrome, hematopoietic stem cell transplantation, HSCT, otitis media, cytomegalovirus infection, CMV, varicella, respiratory syncytial virus, RSV, rotavirus, parainfluenza virus, Epstein-Barr virus, EBV, enterovirus, adenovirus, non-Hodgkin lymphoma, herpes simplex virus, cryptosporidiosis, Crohn disease, HIV infection, graft versus host disease, GVHD, Omenn syndrome, treatment, diagnosis

Contributor Information and Disclosures

Author

Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School
Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and Sigma Xi
Disclosure: Nothing to disclose.

Coauthor(s)

Smeeta Sinha, MD, Staff Physician, Department of Dermatology, UMDNJ-New Jersey Medical School
Smeeta Sinha, MD is a member of the following medical societies: Alpha Omega Alpha, Phi Beta Kappa, and Sigma Xi
Disclosure: Nothing to disclose.

Medical Editor

James M Oleske, MD, MPH, François-Xavier Bagnoud Professor of Pediatrics, Director, Division of Pulmonary, Allergy, Immunology and Infectious Diseases, Department of Pediatrics, New Jersey Medical School
James M Oleske, MD, MPH is a member of the following medical societies: Academy of Medicine of New Jersey, American Academy of Pediatrics, American Public Health Association, American Society for Microbiology, Infectious Diseases Society of America, and Pediatric Infectious Diseases Society
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

David J Valacer, MD, Consulting Staff, Hoffman La Roche Pharmaceuticals
David J Valacer, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American Association for the Advancement of Science, American Thoracic Society, and New York Academy of Sciences
Disclosure: Nothing to disclose.

CME Editor

David Pallares, MD, Clinical Assistant Professor, Department of Pediatrics, Division of Allergy and Immunology, University of Louisville
David Pallares, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology
Disclosure: Nothing to disclose.

Chief Editor

Harumi Jyonouchi, MD, Associate Professor, Division of Pulmonary Allergy/Immunology and Infectious Diseases, Department of Pediatrics, UMDNJ-New Jersey Medical School
Harumi Jyonouchi, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American Association of Immunologists, American Medical Association, Clinical Immunology Society, New York Academy of Sciences, Society for Experimental Biology and Medicine, Society for Mucosal Immunology, and Society for Pediatric Research
Disclosure: Nothing to disclose.

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.

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