Pediatric Severe Combined Immunodeficiency

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. Without intervention, SCID usually results in severe infection and death in children by age 2 years.

A committee of experts, initially sponsored by the World Health Organization (WHO), meets every 2 years with the goal to classify the group of primary immunodeficiency diseases according to current understanding of the pathways that become defective in the immune system.[1] Eight classification groups have been determined, with SCID being one of the best studied. Over the past few decades, the diverse molecular genetic causes of SCID have been identified with progress from studies of the immune system.[2]

SCID is considered a pediatric emergency because survival depends on expeditious stem cell reconstitution, usually by bone marrow transplantation (BMT). Appropriate diagnosis is essential because instituting proper treatment is lifesaving. Despite the heterogeneity in the pathogenesis of immune defects, common cutaneous manifestations and typical infections can provide clinical clues in diagnosing this pediatric emergency.[3]

Skin manifestations were prevalent in primary immunodeficiency disorders studied in 128 pediatric patients in Kuwait; skin infections were the most prevalent findings, seen in 39 patients (30%), followed by dermatitis in 24 (19%).[4] Skin infections were significantly more prevalent in those with congenital defects in phagocyte number, function, or both, as well as in those with well-defined immunodeficiencies.

Dermatitis was evident in all patients with hyper–immunoglobulin (Ig) E syndrome and Wiskott-Aldrich syndrome.[4] Erythroderma of infancy with diffuse alopecia was seen exclusively in patients with SCID disorders, and telangiectasia in patients with ataxia telangiectasia; and partial albinism with silvery gray hair was associated with Chediak-Higashi syndrome.

With the advances in BMT and gene therapy, patients now have a better likelihood of developing a functional immune system in a previously lethal genetic disease. However, once an infant develops serious infections, intervention is rarely successful.

Genetic defects

SCID results from mutations in any of more than 15 known genes. These molecular defects interfere with lymphocyte development and function, blocking 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, because of the lack of T-cell help. NK cells, a component of innate immunity, are variably affected. Sequencing and other techniques may reveal the actual genetic defects in these patients.[5] Ideally, SCID can be detected in a newborn before the onset of infections, with one well-documented example by screening of T-cell–receptor excision circles.[6]

SCID can be broadly classified into 2 groups: SCID with B cells (70% of patients with SCID) and SCID without B cells. Beyond this basic grouping, SCID may be categorized according to phenotypic lymphocyte profiles that include both B-cell status (B+ or B–) and NK-cell status (NK+ or NK–) in addition to T-cell status (T–, because there is always a T-cell deficiency in SCID).

The most common genetic condition responsible for SCID is a mutation of the common γ chain of the interleukin (IL) receptors shared by the receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 (T– B+ NK–).[7] This protein is encoded on the X chromosome; therefore, this variant of SCID is X-linked (and is sometimes referred to as X-linked SCID [XL-SCID]). These patients account for approximately 50% of all patients with SCID. A novel pathogenic mutation on the interleukin-7 receptor has been described in a newborn.[8]

In X-linked SCID, loss of IL-2 receptor (IL-2R) function leads to the loss of a lymphocyte proliferation signal. Loss of IL-4R function leads to the inability of B cells to class switch. Loss of IL-7R function leads to the loss of an antiapoptotic signal, resulting in a loss of T-cell selection in the thymus. Loss of IL-7R function is also associated with the loss of a T-cell receptor (TCR) rearrangement. Loss of IL-15R function leads to the ablation of NK-cell development.[7, 9, 10]

Autosomal recessive SCID (formerly known as Swiss-type agammaglobulinemia) includes the following deficiencies:

• Janus-associated kinase 3 (JAK3) deficiency (T– B+ NK–)[9, 10, 11, 12]

• Adenosine deaminase (ADA) deficiency (T– B– NK+/–)[13]

• Bare lymphocyte syndrome (a somewhat milder SCID)[14, 15, 16]

• ζ chain–associated protein (ZAP)-70 deficiency[17]

• Reticular dysgenesis

• IL-7R α chain deficiency

• Deficiency of the recombination-activating genes RAG1 and RAG2 (T– B– NK+)[18]

• Ligase 4 deficiency (T– B– NK+)[19]

• CD45 deficiency[20]

JAK3 is a protein tyrosine kinase (PTK) that associates with the common γ chain of the IL receptors. Deficiency of this protein results in the same clinical manifestations as those of XL-SCID.[11, 12]

ADA is an enzyme that breaks down purines. When it is absent, deoxyadenosine triphosphate (dATP) builds up and inhibits the enzymes necessary for lymphocyte proliferation. It causes B-, T-, and NK-cell deficiency.[13]

Bare lymphocyte syndrome is a deficiency of major histocompatibility complex (MHC). MHC type II is decreased on mononuclear cells. MHC type I levels may be decreased, or MHC type I may be absent entirely. The defect occurs in a gene regulating expression of MHC type II.[14, 15]

In ZAP-70 deficiency, a mutation occurs in the gene coding for this tyrosine kinase, which is important in T-cell signaling and is critical in positive and negative selection of T cells in the thymus. A selective absence of CD8+ T cells and an abundance of nonfunctioning CD4+ T cells occur. ZAP-70 is apparently needed in the selection of CD8+ T cells and is necessary for T cell functioning—hence the nonfunctioning CD4+ cells.[17]

Reticular dysgenesis is a rare variant of SCID arising from the lack of appropriate stem cell development and characterized by agranulocytosis in addition to a lack of both B cells and T cells in the adaptive immune system. Mutations in mitochondrial adenylate kinase 2 have been revealed in patients with reticular dysgenesis.[21] Cartilage-hair hypoplasia is also classified as SCID, although a significant proportion of patients have a less severe form not requiring stem cell reconstitution.

Several deficiencies of the CD3 complex (CD3γ, ε, δ, and ζ) are associated with SCID.[22, 23] Omenn syndrome results from mutations that impair the function of Ig and TCR recombinase genes. These include the Artemis mutation[24] (an enzyme that opens DNA hairpin during variable diversity joining [VDJ] rearrangement) and RAG1 and RAG2 deficiencies.[18, 25, 26]

Purine nucleotide phosphorylase (PNP) deficiency and IL-2 deficiency are severe enough in nature to be classified as SCID, and other defects are identified every year.[27] The exact molecular defect involved in IL-2 production deficiency is unknown, but this defect is often associated with other cytokine production defects.

These are the most common and best characterized forms of SCID, but not all of the genetic conditions leading to SCID are well characterized. Infants with SCID usually present with infections that are secondary to the lack of T-cell function (eg, Pneumocystis jiroveci (carinii) pneumonia [PCP], systemic candidiasis, generalized herpetic infections, severe failure to thrive secondary to gut infections or diarrhea). Graft versus host disease (GVHD) from nonirradiated blood products is an important cause of morbidity.

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 may occur due to failure of clearing antigens appropriately.

Human phosphoglucomutase 3 mutations cause a congenital severe immunodeficiency disorder associated with skeletal dysplasia.[28]

Pathogenetic mechanisms

The pathogenesis of SCID may be further divided into the following 5 mechanisms on the basis of the stage or stages at which lymphopoiesis is arrested.

Defective lymphokine signaling

An early block may occur within the T-cell differentiation pathway. The most common form of SCID, occurring in 40-60% of patients, is XL-SCID, which arises from defects in the common γ chain of interleukin receptors. This molecular defect results in absent T-cell and NK-cell maturation, although evidence suggests that the γ chain is also involved in B-cell development.

The cytokine receptors that share the common γ chain include IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. These function to increase cytokine binding affinity and signal transduction.[29, 30] Cytokine binding to the γ chain of these cytokines activate the signaling pathway that includes the intracellular tyrosine kinase JAK3. JAK3 is upregulated 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 the common γ chain or of the alpha chain of the IL-7 receptor, JAK3 cannot be activated in pro-T cells in the bone marrow; thus, T-cell maturation and 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– SCID, whereas IL-7 receptor alpha-chain mutations result in T– B– NK+ SCID.

In addition, defects in signaling molecules that associate with the T-cell receptor can lead to SCID; examples include mutations in the LCK and ZAP70 genes. Another cytokine receptor–associated gene is JAK1, which, when defective, can lead to SCID.

Apoptosis secondary to accumulation of toxic metabolites

Abnormal purine metabolism may be involved in the pathogenesis of SCID. ADA and PNP are required for purine salvage pathways. Defects in ADA and PNP can lead to apoptosis, resulting in T– B– NK– SCID.

ADA deficiency accounts for 20% of all SCID cases. It leads to the accumulation of intermediates (eg, adenosine diphosphate, guanosine triphosphate, and dATP), which results in lymphocyte toxicity, particularly with immature thymic lymphocytes. PNP deficiency is mechanistically similar to ADA deficiency in that the accumulation of an intermediate (in this case, deoxyguanosine triphosphate [dGTP]) exerts a lymphotoxic effect. In both conditions, T-cell function is most severely affected.

Defective cell signaling at and before level of TCR

CD45, a tyrosine phosphatase found in the cell membranes of hematopoietic cells, is essential in regulating the transmission of cell surface signals in B cells and T cells. Deficiency of CD45 can lead to in T– B+ NK– SCID.

CD3 is a complex of transmembrane proteins (δ, γ, ε, and ζ) that forms a heterodimer with the TCR; upon ligand binding by the TCR, the immunoreceptor tyrosine-based activation motifs (ITAMs) of CD3 become activated, and these then activate the kinase ZAP-70 to propagate downstream signaling events.

Deficiency of CD3δ is associated with defective pre-TCR signaling, whereas the lack of CD3ε results in the absence of mature TCRs in the periphery; both are associated with T– B+ NK+ SCID. Deficiency of ZAP-70 causes a preferential decrease of CD8 cells, causing an atypical SCID. Likewise, CD3 deficiency presents with close-to-normal absolute lymphocyte count, although these T cells are dysfunctional.

Defective expression of MHC molecules disrupts antigen (Ag) presentation at the pre-TCR level, leading to bare lymphocyte syndrome, which then results in an inability of the T cells to function. Patients with this condition can have defects in the regulatory region of the MHC class II gene or a defect in a transcription regulator, CTIIA, which is responsible for controlling the expression of MHC class II genes.

Defective TCR and Ig gene rearrangement

Abnormal TCR and Ig gene rearrangement may occur. Both B-cell maturation and T-cell maturation involve a process of recombination in which various combinations of VDJ genes are assembled to create unique and specific antigen receptors. Several recombinases play critical roles in this process.

RAG1 and RAG2, which mediate initial DNA double-strand breaking at specific sequences, enable subsequent joining of the various gene segments. Mutations in RAG1 and RAG2 result in a T– B– NK+ SCID phenotype and Omenn syndrome, in which residual VDJ recombination activity occurs.[26]

The ARTEMIS gene, located on chromosome 10, encodes a product that plays a role in VDJ recombination and is associated with SCID that develops from an early block in B- and T-cell development. Artemis splice defects may cause atypical relatively mild combined immunodeficiency.[24]

The gene DNA-PK is a DNA-dependent serine-threonine protein kinase that is required for correct recombination. Mutations in this gene are autosomal recessive and can also lead to combined deficiency. DNA from the cells of these patients is associated with an increased radiosensitivity.

Thymic dysgenesis

Severe thymic dysgenesis results in lack of T cells, causing a T– B+ NK+ SCID. This is typically seen in severe forms of DiGeorge syndrome and CHARGE association.

Genetic mutations

Mutational analysis pinpoints many types of SCID: more than 20 genetic loci are referenced in the Online Mendelian Inheritance in Man (OMIM) database. Large deletions of chromosomal material are not seen, and this limits 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.

Overall, SCID is characterized by profound abnormalities in T-cell, B-cell, and NK-cell functions. The genetic mutations can be X-linked, autosomal recessive, or sporadic, depending on the location of the gene affected. Although the list of gene defects is extensive, the disease can be stratified according to absence of T-cell function with or without the loss of B- and NK-cell host defenses (see Table 1 below).

Table 1. Common Causes of SCID, Cellular Defects, and Inheritance Pattern (Open Table in a new window)

SCID is most commonly due to an X-linked mutation of the gene coding for the γ chain that 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. Mutations in the intracellular tail of the common γ chain are associated with a less severe form of XL-SCID. Defective expression of the common γ chain can be detected by flow cytometry. SCID has also been described due to compound heterozygous mutations in the MTHFD1 gene.[31] Hydroxocobalamin and folate therapy provided partial immune reconstitution.

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

• ADA and PNP deficiencies

• Mutation of the IL-7R α chain

• IL-2 production defects

• Mutation of JAK3

• Null mutations in RAG1 and RAG2

• Artemis gene mutations

• CD45 mutations

• Mutations of ZAP70

• CD3γ, ε, and δ mutations

• MHC class II deficiency caused by mutations of components of the transcription factors of MHC II, including CIITA

• Bare lymphocyte syndrome

• Deficiency in p56lck (a tyrosine kinase–signaling molecule in the IL-2–mediated JAK-STAT pathway)

• Cartilage-hair hypoplasia

Opportunistic infections

Loss of immunity results in severe and opportunistic infections that instigate the rapid downhill course of SCID. Essentially, most infectious organisms can cause disease, but the following are the more common infections in SCID:

• Viral infections – Cytomegalovirus (CMV) (pneumonia, hepatitis); parainfluenza virus 3, respiratory syncytial virus (RSV), and adenovirus (pneumonia); enterovirus and rotavirus (diarrhea); varicella zoster virus (VZV), herpes simplex virus (HSV), and human herpesvirus 6 (extensive cutaneous disease, meningitis)

• Candida albicans infections – Thrush; diaper dermatitis progressing to diffuse skin involvement; renal and biliary candidiasis

• Cutaneous fungal infections

• Cryptosporidial infections

• Aspergillus infections (pneumonia)

• Bacterial infections -Staphylococcus aureus, streptococci, and enterococci (pyodermas, recurrent furunculosis, impetigo); Pseudomonas aeruginosa (ecthyma gangrenosum); Pneumocystis jiroveci (pneumonia); atypical mycobacteria; Pneumococcus and other common bacteria; Haemophilus influenzae and Listeria, Legionella, and Moraxella species

• Protozoan infections (diarrhea)

Exacerbating factors

A number of exacerbating factors may be present in patients with SCID. In most cases, the presence of maternal T cells is asymptomatic; however, approximately 30-40% of infants with SCID develop mild changes, such as erythema with skin T-cell infiltration, eosinophilia, elevated liver enzyme levels, and periportal T-cell infiltration. However, no cases of maternal graft-versus-host disease (GVHD) fatality have been reported.

GVHD can occur after engraftment of allogeneic immunocompetent lymphocytes because of incompatible bone marrow grafts or transfusion of blood products. Signs and symptoms include necrotizing erythroderma, gut mucosal abrasion, and biliary epithelium destruction.

In the past, when infants were routinely immunized with vaccinia virus, many infants with SCID died of vaccinia gangrenosa or progressive vaccinia. The bacille Calmette-Guérin (BCG) vaccine is still widely used in many countries; it can lead to a disseminated, fatal infection, revealing SCID.[32] Live vaccines, such as BCG and varicella vaccines, must not be administered to patients with SCID.

United States statistics

The incidence was previously reported at approximately 1 in 100,000, but improved early identification of affected subjects revealed that the true incidence is higher than previously believed (closer to 1 case per 50,000-75,000 births). To the author’s knowledge, no population surveys have been performed. However, interest has been garnered in implementing screening to identify affected newborns.[33]

Approximately 50% of all SCID cases are X-linked (ie, mutation of the common γ chain); the remaining 50% are various forms of autosomal recessive SCID. Approximately 25% of the patients with an autosomal recessive SCID are JAK3-deficient, and 40% are ADA-deficient. The other disorders make up the remaining 35% of autosomal recessive patients.

International statistics

International frequency is similar to that of the United States. XL-SCID, like other X-linked disorders, has a higher frequency in populations with increased consanguinity.

Although SCID is notoriously underreported, several countries now maintain registries of patients with primary immunodeficiency diseases. In Australia, the estimated prevalence of SCID 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.

Age-related demographics

The great majority of SCID cases present in patients younger than 3 months (average age at symptom onset, 2 months; mean age at diagnosis, 6.5 months). Patients with ADA-deficient SCID 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.

Sex-related demographics

About 50% of SCID cases are X-linked (ie, occurring only in males). Only about one third of males with common γ chain mutations have a positive family history, which indicates that de novo mutations account for a significant percentage of SCID cases. The remaining SCID cases are caused by various autosomal recessive mutations that affect males and females equally. Seek a family history of consanguinity or of an inbred population. Homologous mutations are more common in these circumstances. Thus, the overall male-to-female ratio is 3:1.

Race-related demographics

No racial predisposition exists for most forms of SCID, but most patients with ZAP-70 deficiency and CD3δ are Mennonites. The Artemis gene deficiency is seen predominately in Navajo and Apache Native Americans. JAK3 mutations have been reported more frequently in Italy. MHC II deficiency is usually reported in North African individuals. RAG1/RAG2 -deficient SCID occurs more commonly in Europe. Cartilage-hair hypoplasia affects a Finnish population and the old Amish order in the United States.

Without treatment, death from infection usually occurs within the first 2 years of life. Diagnosis must be made before severe life-threatening infections occur so that the immunity can be restored with enzyme replacement or BMT; such treatment can lead to long-term survival. With bone marrow and other stem cell reconstitution techniques, many patients with SCID are fully reconstituted without complications.

GVHD from maternal cell engraftment can occur in any SCID case. The transfusion of nonirradiated blood products is an important cause of GVHD in all forms of SCID. 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, pretransplant immunosuppression is not necessary.

Patients who are well-nourished, uninfected, and younger than 6 months before transplantation have the best outcomes. Allogeneic hematopoietic stem cell transplantation (HSCT) in patients younger than 3-4 months of age is associated with better outcomes.

Patients with common γ chain (XL-SCID) or JAK3 mutations have an increased risk of hypogammaglobulinemia after transplantation because of the retention of recipient B cells that do not respond adequately to donor T-cell communication.

Although patients with SCID rarely survive without stem cell reconstitution, gene therapy may be a viable alternative for XL-SCID and ADA deficiency in patients who are unable to find donors if the complication of acute lymphoblastic leukemia is effectively prevented.

Patients with less severe ADA mutations have survived into adulthood. An optional treatment for ADA deficiency is polyethylene glycol (PEG)-treated ADA replacement, although this does not return immune function to normal.

Cartilage-hair hypoplasia, particularly in the Finnish population, may be less severe.

Early infancy is characterized by recurrent failure to thrive and a number of common infections, including otitis media, diarrhea, and opportunistic infections such as mucocutaneous candidiasis and CMV infection. If SCID is not recognized by age 6 months, opportunistic infections become more evident, especially P jiroveci pneumonia and invasive fungal infections. Common childhood viral illnesses may prove fatal in SCID. These include infections with VZV, 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-SCID survive longer. The former variant is associated with a high incidence of non-Hodgkin lymphoma.

Families must be informed about the risks of infection so that appropriate steps to avoid exposure to infection are instituted. They must be cautioned not to ignore a fever, rashes, or malaise in an affected child; these may indicate a serious infection.

Parents should be instructed to ensure that the child does not receive live virus vaccines, especially polio or BCG. Vaccinating children with SCID prior to treatment is not only futile, because they cannot make antibody, but is also very dangerous. The live attenuated virus can be deadly and can lead to disease in these immunocompromised hosts.

Genetic counseling is an essential part of medical care for the family, and the opportunity for prenatal diagnosis must be discussed. Parents must be informed of the risk of SCID in subsequent children, depending on X-linked or autosomal etiology. The risk that XL-SCID will occur in another child is 50% for male infants; female infants are not affected, but they have a 50% risk of being carriers. Any autosomal recessive mutation causing SCID places siblings at a 1 in 4 risk for the disorder.

With respect to informed consent, stem cell reconstitution must be discussed carefully with the family, particularly because the donor may be a sibling who is 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 essential that families are made aware of the high risk of fatal infection or GVHD in the recipient after transplantation. 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.

When patients with SCID fail to engraft or develop GVHD after transplantation, other forms of stem cell reconstitution may be considered, including cord cell transplantation. Gene therapy is an option for XL-SCID and ADA-deficient 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; 877-666-0866. Some US states have local chapters.

The Jeffrey Modell Foundation also provides educational support for families and patients. It is located at 747 3rd Avenue, New York, NY 10017; 800-JEFF-844 (800-533-3844).

Patients with severe combined immunodeficiency (SCID) may present with multiple severe or recurrent illnesses during the first months of life. Initially, growth appears normal, but failure to thrive with severe emaciation ensues secondary to diarrhea and chronic infections. In the past, SCID was often diagnosed after children acquired serious infections, such as pneumonia due to P jiroveci (carinii). Today, most infants should be recognized before the development of failure to thrive or Pneumocystis infection.

Within the first 3 months of life, infants with SCID present with persistent and recurrent diarrhea, otitis media, thrush, and respiratory infections (see the image below). In this setting, a thorough medical and family history, with particular attention to recurrent infections, should be obtained. The history should include questions about the following:

• Family history of consanguinity

• Sibling death in infancy (eg, multiple deaths during infancy due to infection or unexplained deaths in male infants) or previous miscarriages in the mother

• Family history of SCID or other primary immunodeficiency

• Poor feeding and poor weight gain

• Chronic diarrhea

• Previous infections, especially pneumonia

See the image below.

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.

Patients with SCID have repeated infections, which are typically more severe than comparable infections occurring in children with normal immunity. The frequency may be greater than 8 per year. Patients may require antibiotics for longer than 2 months; at times, intravenous (IV) antibiotics may be necessary. Patients with SCID may have recurrent deep skin or organ abscesses.

Mucocutaneous candidiasis is often more severe than expected and is resistant to treatment. Bacterial otitis media and pneumonia are common. Viral infections caused by varicella zoster virus (VZV), herpes simplex virus (HSV), respiratory syncytial virus (RSV), rotavirus, adenovirus, enterovirus, parainfluenza virus, Epstein-Barr virus (EBV), and cytomegalovirus (CMV) are seen. Asking the mother about risk factors for HIV infection is important; infants with transplacental HIV infection may present in much the same fashion as SCID.

Dismissing an infant’s death caused by an overwhelming common bacterial or viral infection without further investigation is a mistake. Whenever an infant with a history of unusually frequent and severe common infections dies of infection, an autopsy should be performed to assess lymphoid and thymic tissue. Peripheral blood lymphocytes can survive for several days; thus, blood should be saved for assessment of T-cell and B-cell markers by flow cytometry and for responses to mitogens.

Defects in the cell-mediated immune system become more apparent because breastfeeding may mask the humoral immune defects during the early neonatal period. T-cell defects, such as candidiasis affecting the esophagus, may occur. For example, cytomegalovirus (CMV) infection, measles, and varicella, which are usually self-limited, infect the lungs and the brain, resulting in life-threatening pneumonia, meningitis, and sepsis. Pulmonary involvement with P jiroveci (carinii) pneumonia (PCP) can also be severe.

Autoimmune phenomena, especially hemolytic anemia and neutropenia, are more common in CD3 deficiency and MHC class II mutations. The absolute lymphocyte count is less than 3000/μL, and the proliferative response of the lymphocytes to mitogens activation is less than 10% of control values.

Physical findings are multisystemic. The abnormal findings are primarily related to the various superimposed infections or to graft-versus-host disease (GVHD) rather than to SCID itself. The patient may present with the following:

• Failure to thrive, manifesting as decreased weight, height, and head circumference

• Dehydration from chronic diarrhea

• Recurrent, painful otitis media, which may be more severe than typical, is common

• Eczematous rash from GVHD, which may be mistaken for atopic dermatitis, especially in Omenn syndrome

• Increased respiratory rate and effort and crepitations secondary to pneumonia (especially PCP)

• Fever from sepsis, systemic fungal infections, or generalized herpes

• Absent lymphatic tissue, including tonsils; lack of recognizable peripheral lymphoid organs should raise suspicion of SCID in children with multiple aggressive infections

• Lymphadenopathy and hepatosplenomegaly in Omenn syndrome or bare lymphocyte syndrome

• Neurologic sequelae and developmental regression (loss of developmental milestones), especially in purine nucleotide phosphorylase (PNP) deficiency (the cause of which is genetic, not infectious); neurologic perturbation also occurs secondary to central nervous system (CNS) infection

• Abdominal findings, including tenderness secondary to gastrointestinal (GI) infections and hepatomegaly from viral hepatitis

• Candidiasis

Infants with SCID have an extensive and diverse group of cutaneous disorders. Recurrent skin abscesses are present. Extensive candidiasis in the mouth and diaper area may persist beyond the neonatal period and may involve the rest of the skin. Severe seborrheic dermatitis is observed over the scalp, ears, and nasolabial folds. Intractable eczemalike dermatitis is noted. Impetigo and severe skin infections with deep ulcers in the perineum, tongue, and buccal mucosa are observed. Recurrent furunculosis may develop.

A generalized herpetic dermatitis may also be noted. Cutaneous manifestations of GVHD may also be present from maternally derived T cells that are reacting host cells in the absence of opposing host T cells. Such manifestations include the following:

• In the acute setting, a maculopapular or morbilliform rash can occur and progress to erythroderma and exfoliative dermatitis

• In chronic GVHD, lichenoid or sclerodermoid lesions are described

The dermatologic disorders of incontinentia pigmenti and hypohidrotic ectodermal dysplasia are associated with severe pneumococcal infections and progressive bronchiectasis, even with immunoglobulin (Ig) replacement.

Dermatophytosis is uncommon in SCID patients, although a case has been described with widespread tinea corporis due to Trichophyton mentagrophytes.[34] Children with Artemis-deficient SCID additionally suffer from numerous oral and genital ulcers. Some patients with a mild form of JAK3-deficient SCID 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 SCID patients. Hypomorphic heterozygous mutations in IKBA causes autosomal dominant ectodermal dysplasia with immunodeficiency (AD-EDA-ID) with impaired nuclear factor kappa B (NFκB) signaling pathways; however, this defect also causes severely impaired T-cell receptor (TCR) signaling with the resultant clinical phenotype of SCID.

Unique features of Omenn syndrome and the Omennlike syndrome caused by GVHD include erythroderma, lymphoid hyperplasia, hypereosinophilia, and hepatosplenomegaly. Growing numbers of leaky SCID mutations have been shown to manifest Omenn syndrome; accordingly, this syndrome is now considered to consist of dysregulated inflammatory processes revealed in leaky SCID.

Patients are at risk for infections from inadequate immune reconstitution from bone marrow transplantation (BMT) or enzyme replacement. Opportunistic infections usually follow more common infections. P jiroveci and fungal pneumonias cause death in classic cases. CMV, VZV, and HSV infections typically occur in infants who have already had treatable infections. Neurologic compromise from polio and other enteroviruses precludes stem cell reconstitution.

Ensure that the child does not receive any live virus vaccines until after BMT engraftment, especially polio or bacille Calmette-Guérin (BCG) vaccine. Vaccinating children with SCID is not only futile, because they cannot make antibody, but also dangerous, because they can develop disease (eg, poliomyelitis) from attenuated viruses and may even die after exposure to these vaccines.

Graft failure with BMT and posttransplant GVHD are well recognized, although both have decreased with improved BMT preparatory techniques. GVHD) may ensue if the blood products given before BMT are not depleted of white blood cells by filtration or irradiation. Ensure that all blood products are also negative for CMV to avoid systemic CMV disease.

Gene therapy has been associated with virus-induced malignancies. Cancer, usually non-Hodgkin lymphoma, is seen in patients with cartilage-hair hypoplasia who survive beyond early childhood.

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. Failure to make the diagnosis because the child is not frankly lymphopenic may present a problem, particularly in patients with Omenn syndrome, bare lymphocyte syndrome, and interleukin (IL)–2 deficiency. Obtaining lymphocyte markers and test results of antibody and lymphocyte proliferation can help physicians to avoid this pitfall.

Other laboratory studies can be performed on the basis of clinical judgment, depending on the nature of the infection and the organ system involved. Specifically, assays that measure the ability of lymphocytes to respond to activating agents, such as pokeweed mitogen and phytohemagglutinin, are valuable. Imaging studies are not useful for diagnosis of the primary condition; however, obtaining a chest radiograph may be necessary to evaluate pneumonia secondary to SCID.

Conduct a complete blood count (CBC) with differential to help detect lymphopenia. Children with SCID have a lymphocyte count lower than 3000/µL; however, a normal number of lymphocytes does not rule out SCID, because the lymphocytes may be nonfunctional. An absolute lymphocyte count lower than 2500/µL in an infant definitely warrants further workup, but any infant with severe infection or opportunistic infection should have the full initial workup.

Obtain total serum immunoglobulin (Ig) levels, including IgG, IgA, IgM, and IgE. Immunoglobulin levels, especially IgM levels, can be low. However, soon after birth, IgG levels may be falsely elevated because of maternal IgG.

Draw lymphocyte markers at the same time as the CBC to obtain percentages and absolute counts of CD3+ T cells, CD4+ T cells, CD8+ T cells, CD19+ B cells, and natural killer (NK) cell markers (CD16 and CD56).

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.

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 X-linked SCID (XL-SCID), in which all the lymphocytes are B cells. DiGeorge syndrome is another example in which lymphocyte counts may be higher than 2000/µL with no T-cell function, or, conversely, normal T-cell function may be observed in spite of lymphopenia.

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 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 or anti-CD3 and anti-CD28.

Cellular hallmarks that help differentiate between various forms of SCID, as well as other combined immune deficiencies that are sometimes severe enough to be classified as SCID, are as follows:

• X-linked SCID - Lymphopenia occurs primarily from the absence or near absence of T cells (CD3+) and NK cells; variable levels of B cells occur, which do not make functional antibodies

• JAK3 deficiency - Lymphopenia occurs primarily from the absence or near absence of T cells (CD3+) and NK cells; normal or high levels of B cells occur, which do not make functional antibodies

• Adenosine deaminase (ADA) deficiency - Lymphopenia occurs from the death of T and B cells secondary to the accumulation of toxic metabolites in the purine salvage pathway; functional antibodies are decreased or absent

• ZAP-70 deficiency - Lymphopenia occurs because of the absence of CD8+ T cells; as in all types of SCID, no antibody formation is present

• Reticular dysgenesis - Lymphopenia occurs from the absence of myeloid cells in the bone marrow; red blood cells and platelets are present and functioning

• Omenn syndrome - Normal or elevated T-cell numbers are present, but these are of maternal, not fetal, origin; B cells are usually undetectable, NK cells are present, and the total Ig level is markedly low with poor antibody production; eosinophils are elevated, as is total IgE

• Purine nucleoside phosphorylase (PNP) deficiency - Lymphopenia occurs from the death of T cells secondary to the accumulation of toxic metabolites in the purine salvage pathway; this deficiency differs from ADA deficiency because circulating B cells are normal in number, but B-cell function is poor, as evidenced by the lack of antibody formation; PNP deficiency can be severe enough to be classified as SCID

• Bare lymphocyte syndrome - The lymphocyte count is normal or mildly reduced, CD4+ T cells are decreased, and CD8+ T cells are normal or mildly increased; B-cells are normal or mildly decreased, but the ability to make antibodies is decreased; bare lymphocyte syndrome is sometimes classified as SCID

• IL-2 deficiency - Normal, or near normal, numbers of T cells exist (both CD4+ and CD8+), but they fail to proliferate in vitro when stimulated with mitogens unless IL-2 is added to the culture medium; production of functional antibody is decreased; IL-2 deficiency may be severe enough to be classified as SCID

Determine the ADA and PNP levels in lymphocytes, erythrocytes, or fibroblasts. Measurement of leukocyte ADA enzyme activity is both sensitive and specific for the detection of ADA-deficient SCID.

Consider X-inactivation studies to determine whether the SCID is X-linked. Approximately 50% of patients have sporadic mutations with no history of affected family members.

Perform molecular studies to identify any specific known genetic defects or to identify new defects. These tests are now commercially available. If identifying a laboratory to perform these tests is difficult, consult a referral center for primary immune deficiency to assist in this matter.

Even when SCID is not suspected until the infant’s death, lymphocyte markers, mitogen responses, and DNA studies can still 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 1 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 γC deficiency.[35]

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.

To exclude HIV infection, perform HIV-DNA testing using polymerase chain reaction (PCR) testing; because of maternal antibody, anti-HIV tests are of no value in this setting. To help exclude congenital infection, perform serum testing of IgM against any suspected infection.

Advanced assays of lymphocytes, if present, include measurements of the proliferative response of B cells and T cells to mitogens and lymphocyte subset analysis with flow cytometry. Analysis of specific genes associated with immunodeficiency may be helpful.

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.

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-sized 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. In ADA deficiency, chest radiographs show typical cupping and flaring of the costochondral junction.

Prenatal diagnosis may be attempted when the family history is positive for SCID. Available DNA tests allow for the identification of mutations involving ADA, RAG1/RAG2, JAK3, γC, IL-7 receptor, and Artemis, as well as many other gene mutations associated with the SCID phenotype.

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.

Fetal blood sampling for fluorocytometric testing, mitogen responses, and enzyme levels can establish the diagnosis when DNA analysis is not available. Percutaneous umbilical blood sampling is performed to examine fetal blood for T-cell deficiency, as well as ADA enzyme levels.

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.

When the exact mutation cannot be found, linkage analysis and restriction fragment length polymorphism (RFLP) studies may be performed within families. With the advent of specific mutation analysis, these options are needed less frequently.

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.

The newborn screening test for T-cell receptor excision circles (TRECs) has been used to identify infants with T-cell lymphopenia. No TRECs were detected in newborns with SCID.[36]

The newborn screening testing-and-referral algorithm in Massachusetts works for all gestational ages, with a low naïve T-cell percentage being associated with a higher risk of SCID/CID, documenting the value of memory/naïve T-cell phenotyping as part of follow-up flow cytometry.[37]

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 other GI symptoms.

In classic SCID, the thymus is small with few thymocytes, and it lacks corticomedullary distinction and Hassall corpuscles (see the image below). The epithelium is normal.

The skin and gut may show infiltration with histiocytes, eosinophils, or activated dysfunctional T cells. The epidermis can have foci of hyperkeratosis with parakeratosis or irregular acanthosis with spongiosis and exocytosis. The papular dermis has edema and a diffuse perivascular infiltrate with some eosinophils.

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. The spleen is depleted of lymphocytes. Although a lymph node biopsy is not necessary for diagnosis, findings may indicate a paucity of T and B cells and a lack of germinal centers. The tonsils, adenoids, and Peyer patches are underdeveloped or absent.

Hemophagocytic lymphohistiocytosis is reported in XL-SCID and cartilage-hair hypoplasia.

Drug therapy is not a major part of treatment of the primary disease. Surgical intervention is customarily not indicated for severe combined immunodeficiency (SCID) and also is not part of the primary treatment.

Conventional care for any patient with SCID includes isolation to avoid infection and meticulous skin and mucosal hygienic care while the patient is awaiting stem cell reconstitution. Parenteral nutrition is customarily provided to children with diarrhea and failure to thrive. Blood product transfusions must be lymphocyte-depleted and irradiated to prevent transfusion-associated graft-versus-host disease (GVHD).

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 during the wait for the results of cultures and body fluid analysis. Consider prophylactic treatment with nystatin to prevent mucocutaneous candidiasis.

SCID is a pediatric emergency and must be addressed expeditiously. Intravenous immunoglobulin (IVIg) should be administered promptly, and evaluation for bone marrow transplantation (BMT) should be started. Patients with SCID who are treated with BMT before age 3.5 months have better survival rates. BMT is the primary treatment of choice for most types of SCID when an appropriate donor is found. Pretreatment with ablative chemotherapy is controversial. If B cells do not engraft, monthly IVIg replacement therapy may be required.

Administration of nonirradiated blood products or live-virus vaccines (especially polio or bacille Calmette-Guérin [BCG]) to a patient suspected of having SCID or undergoing a workup for SCID is an error that may prove dangerous if the patient turns out to have SCID. These children can develop disease from attenuated viruses and may even die after exposure to these vaccines.

Because T cells are absent, dysfunctional, or both, administer P jiroveci (carinii) pneumonia (PCP) prophylaxis to all patients until T-cell function is restored by means of BMT or other therapy. Trimethoprim-sulfamethoxazole is the drug of choice and can be administered in a patient who is older than 2 months or in whom neonatal jaundice is no longer a concern.

In individual cases, prophylaxis with antiviral agents (eg, acyclovir) or antibiotics also may be appropriate. After exposure to varicella zoster virus (VZV), prophylaxis with varicella zoster immune globulin (VZIG) should be administered within 48 hours, if possible; VZIG may be efficacious up to 96 hours after exposure. Beyond that interval, acyclovir has been administered and may prevent or modify the severity of VZV infection.

The consensus among clinical immunologists is that an IVIg dose of 400-600 mg/kg each month or a dose that maintains trough serum immunoglobulin (Ig) G levels above 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 weeks) 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.

Numerous IVIg preparations are available.[38, 39, 40, 41] For replacement therapy in patients with primary immune deficiency, all brands of IVIg are probably equivalent, though viral inactivation processes differ (eg, solvent detergent vs pasteurization and ready-to-use liquid vs lyophilized powder requiring reconstitution). Additional knowledge of IgA content of a particular brand may be necessary depending on the particular patient. The choice of brands may be dependent on the hospital or home care formulary and the local availability and cost. The Immune Deficiency Foundation provides a useful resource that describes the characteristics of immunoglobulin products.

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 older than 65 years) and those who use nephrotoxic drugs, the recommended doses should not be exceeded and the infusion rates and concentrations should be at the minimum practicable levels.

Initial IVIg treatment should be administered under the close supervision of experienced personnel. The risk of adverse reactions at this point is high, especially in patients with infections and those who form immune complexes. In patients with active infection, infusion rates may have to be reduced and the dose halved (ie, 200-300 mg/kg), with the remainder of the dose given the next day. Treatment should not be discontinued. Once normal serum IgG levels are reached, 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 every 6-8 hours), acetaminophen (15 mg/kg/dose orally), diphenhydramine (1 mg/kg/dose orally), 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 of this 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 (BUN) and creatinine levels before starting the treatment and before 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.

Although treatment of the acute infectious process is critical, the only cure for almost all forms of SCID is bone marrow transplantation or other stem cell reconstitution.[42, 43] This approach is successful if the disease is diagnosed within the first 3 months of life. Early transplantation before 3.5 months is associated with better overall survival.[44] With early transplantation and aggressive monitoring and treatment of infections, survival rates may be as high as 97%. No live vaccines should be administered before BMT.

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, GVHD, and inadequate B-cell function is higher. Neither pretransplant chemoablation nor GVHD prophylaxis is required for successful engraftment with an identical donor; however, the former is necessary with nonidentical HLA-matched donors.

Pretransplant evaluation routinely includes testing of the recipient and the donor for infectious agents, such as cytomegalovirus (CMV), HIV, and hepatitis viruses. After BMT, medication therapy to prevent GVHD must be maintained.[45] All blood products must receive 25-Gy irradiation to prevent fatal GVHD.

BMT is the primary therapy for purine nucleotide phosphorylase (PNP) deficiency and bare lymphocyte syndrome when an appropriate donor is available. It is also the primary treatment for Omenn syndrome; however, pretreatment ablative chemotherapy is necessary because of maternal cell engraftment.

In the largest series of patients with SCID, BMT was successful in 80% of patients. T-cell function has been adequate in approximately 90% of patients who survive 6 months after transplantation, 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.

In utero BMT into the fetal peritoneal cavity is successful, with reconstitution of T-cells in X-linked SCID (XL-SCID) and in 1 case of due to interleukin (IL)-7 receptor α chain deficiency. Cord blood stem cell transplantation from related or unrelated donors is an option.

Enzyme replacement

The primary treatment for adenosine deaminase (ADA) deficiency is ongoing polyethylene glycol–conjugated ADA (PEG-ADA) replacement therapy. Patients need to have their immune function monitored and prophylaxis provided, depending on their immune status. Enzyme replacement therapy typically yields improvement in patients with ADA-deficient SCID, but not complete reconstitution of immune function.

The bovine-derived ADA replacement enzyme pegademase (Adagen) was approved by the FDA in 1990. However, pegademase was discontinued in 2019 from the market owing to a permanent shortage of the active ingredient. In October 2018, the FDA approved elapegademase (Revcovi), a recombinant adenosine deaminase based on bovine amino acid sequence, for treatment of adenosine deaminase severe combined immune deficiency (ADA-SCID) in adults and children. Enzyme replacement helps prevent potentially serious, life-threatening infections in this patient population.

Interleukin replacement

Intravenous IL-2 replacement is the primary therapy, and a BMT is an alternative if an appropriate donor is available.

Cyclosporine and interferon

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.

Gene therapy is a viable option for patients with XL-SCID or ADA-deficient SCID who have no HLA-identical sibling. Treatment is optimally provided early enough to reduce the risks of failed gene transduction and leukemia. Murine studies suggest that gene therapy may work for JAK3 and RAG2 mutations as well. Several gene therapy clinical trials have been utilized, including a CD34+ cells transduced with retroviral vector-based gene therapy (Strimvelis; Orchard Therapeutics) that was approved in Europe in 2016 and is currently in phase 3 trials in the US for ADA-SCID.[46, 47, 48, 49]

An investigational ex vivo autologous gene therapy, simoladagene autotemcel (OTL-101; Orchard Therapeutics), is in phase 3 clinical trials as of May 2020 for ADA-SCID in the US.[50]   

A clinical trial of gene therapy for XL-SCID found that in cases of successful gene insertion, functional T cells developed within 18 weeks and were detectable as long as 5 years later.[51] 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.

ADA deficiency was the first form of SCID for which gene therapy was attempted, and efficacy has been reported; it remains in the experimental phase. Although some long-term benefits of gene therapy have been reported for ADA-deficient patients with SCID, complications have arisen in some cases of gene therapy in patients with common γ chain deficiency.

The development of leukemia is a complication of gene therapy and appears to be related to the site of insertion of the transgene. Some suggest that better outcomes may occur with different vectors or more specific insertion sites.[52] A greater risk of cognitive abnormalities and emotional and behavioral problems has also been reported in patients with ADA-deficient SCID who received long-term enzyme replacement therapy.[53]

In general, no dietary limitations are necessary. However, 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. Undernutrition decreases the success rate for stem cell reconstitution and increases the risk of opportunistic infections.

In general, activity is limited only by any infections that may develop secondary to the immune deficiency; the disease itself does not require limitation of physical 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 handwashing. The earlier practice of putting patients in reverse isolation (ie, in a “bubble”) with such precautions as special diets is no longer advocated.

SCID is under consideration for population-based newborn screening.[54] Screening tests do not prevent SCID but can identify infants early, before complications develop, thereby permitting earlier initiation of treatment. Diagnosis at birth may allow for better protection of babies with SCID from infection and improve transplantation outcome, significantly, improving the outcome in this otherwise potentially devastating condition.[55]

Newborn screening to identify SCID is currently performed in several American states using polymerase chain reaction (PCR) of DNA from universally collected, dried blood spots.[56]

Some states now screen all neonates for the most common forms of SCID by identifying T-cell receptor excision circles (TRECs). TRECs are a normal byproduct of T-cell receptor rearrangement. They can be detected in a newborn dried blood spot by using a unique molecular assay as a primary screen. In healthy neonates, they are made in large numbers, whereas in infants with SCID, they are barely detectable.

The pronounced deficiency of TRECs in patients with SCID makes identification of TRECs a reasonable screening test for the disease. Ideally, such screening will allow diagnosis and BMT before the infants become ill, thereby greatly increasing their chance of survival.[57, 58]

Microarray technology has also been proposed as a screening tool to detect the most common genetic defects leading to SCID.[58, 52] A combination of these therapies may be the eventual solution to the dilemma of screening for SCID.

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

Management of SCID required the participation of a number of different specialists, and coordinating their efforts can be challenging.

The need for excellent laboratory and radiology support mandates hospitalization in tertiary pediatric medical centers. Laboratory studies for stem cell reconstitution must be initiated promptly with the BMT team. In the meantime, gastroenterology and nutrition consultations provide important support.

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.

Consultation with an internal medicine specialist and an infectious disease specialist is important in the management and prevention of infection.

BMT should be coordinated between immunology/hematology and the BMT team. Admit the patient to an immunology/hematology clinic for IVIg therapy, IL-2 infusion, or PEG-ADA therapy, as necessary.

Ensure regular follow-up visits to monitor the immune system, with specialist physicians monitoring the SCID patient. 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 SCID, the long-term outcome in a 90-patient cohort followed for 2-34 years showed that almost half experienced 1 or more significant clinical events, including persistent chronic GVHD, autoimmune and inflammatory manifestations, opportunistic and nonopportunistic infections, and a requirement for nutritional support.[59] These late-onset complications suggest the need for prevention and careful follow-up.

In October 2018, the FDA approved elapegademase (Revcovi) for treatment of adenosine deaminase severe combined immune deficiency (ADA-SCID) in adults and children. The drug had been available as an orphan drug prior to approval. Enzyme replacement helps prevent potentially serious, life-threatening infections in this patient population.

Trimethoprim-sulfamethoxazole is prescribed routinely after the second month of life in children with severe combined immunodeficiency (SCID) until after bone marrow transplant (BMT) engraftment for Pneumocystis jiroveci prophylaxis. Intravenous immunoglobulin (IVIg) is used to prevent infection before BMT and, in selected patients, after BMT, if B-cell function remains poor.

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 (HSV), and cytomegalovirus (CMV). Antifungal therapy includes fluconazole for mucocutaneous candidiasis; amphotericin B is first-line therapy for invasive fungal infections such as Aspergillus.

Class Summary

IVIg is the usual choice. It is derived from human plasma and is composed of all 4 immunoglobulin G (IgG) subclasses. The antibody distribution of IVIg is approximately the same as that of human serum. IVIg can be used to restore antibody levels until the B-cell system is restored with BMT. However, long-term use fails to change the terminal course of SCID.

Immune globulin IV (IGIV) (Asceniv, Bivigam, Carimune)

IVIg is a human serum fraction that contains IgG. It provides IgG antibodies that the patient cannot make. The therapeutic function is passive immunization to prevent infection.

Class Summary

Replacement enzymes are used in patients with adenosine deaminase (ADA) deficiency and SCID who benefit from BMT. Improved immune function and clinical response are observed with polyethylene glycol–conjugated ADA (PEG-ADA) replacement therapy for ADA deficiency.

Elapegademase (Revcovi)

Elapegademase a recombinant adenosine deaminase based on bovine amino acid sequence and conjugated to PEG. It is indicated for treatment of ADA severe combined immune deficiency (ADA-SCID) in pediatric and adult patients.

Class Summary

Antibiotics are used in the primary treatment and prophylaxis of Pneumocystis jiroveci (carinii) pneumonia (PCP).

Trimethoprim-sulfamethoxazole (Septra DS, Bactrim DS, Cotrim DS)

Trimethoprim-sulfamethoxazole is used because of low levels of T cells or poor T-cell function in children with SCID. It inhibits bacterial growth by inhibiting synthesis of dihydrofolic acid. Its antibacterial activity affects common urinary tract pathogens, except Pseudomonas aeruginosa. Each 5 mL vial for intravenous (IV) administration contains 80 mg of trimethoprim and 400 mg of sulfamethoxazole. Each 5 mL vial must be added to 125 mL of 5% dextrose in water. Please consult the hospital pharmacist when preparing this medication.

Class Summary

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 varicella zoster immune globulin (VZIG) is effective at 50% of the therapeutic dose.

Acyclovir (Zovirax)

Acyclovir is given in a high dose of 45-60 mg/kg/day or 1500 mg/m2/day divided every 8 hours for central nervous system (CNS) infection. Good hydration is essential, and lower doses must be calculated in the presence of renal compromise.

Ganciclovir (Cytovene)

Ganciclovir is the drug of choice for CMV infection and is used for HSV and VZV infections that are resistant to acyclovir.

Class Summary

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 infections that are resistant to fluconazole may be accomplished effectively with itraconazole.

Fluconazole (Diflucan)

Fluconazole has fungistatic activity. It is a synthetic oral antifungal (a broad-spectrum bistriazole) that selectively inhibits fungal cytochrome P-450 and sterol C-14 alpha-demethylation, which prevents conversion of lanosterol to ergosterol, thereby disrupting cellular membranes.

A loading dose is given on day 1, followed by maintenance at 50% of the loading dose. Fluconazole may be administered either IV orally with similar efficacy. Length of treatment is a minimum of 10 days; longer courses are determined individually, with other risk factors (eg, ongoing broad-spectrum antibiotic therapy) taken into account.

Itraconazole (Sporanox)

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

Amphotericin B deoxycholate (amphotericin B conventional)

A test dose of 0.1 mg/kg is recommended by the manufacturer but is often omitted. Infusion of the total dose over 2-4 hours has been recommended, but infusion over 1 hour 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 normal saline before each dose is used to decrease the risk of nephrotoxicity.

Premedication with acetaminophen and diphenhydramine 30 min before and 4 hours after infusion decreases the typical adverse effects of fever, chills, hypotension, nausea, and vomiting. Hydrocortisone may be admixed to the IV solution (1 mg to 1 mg of amphotericin, not to exceed 25 mg).

The 3 lipid amphotericin products are 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, gastrointestinal irritation, chills, and headache. It is unclear whether their renal toxicity is lower.

Amphotericin B lipid complex (ABLC, Abelcet)

This agent is amphotericin B in phospholipid complexed form; it is a polyene antibiotic with poor oral availability. Amphotericin B is produced by a strain of Streptomyces nodosus; it can be fungistatic or fungicidal. The drug binds to sterols (eg, ergosterol) in the fungal cell membrane, causing leakage of intracellular components and fungal cell death. Toxicity to human cells may occur via this same mechanism.

Amphotericin B, liposomal (AmBisome)

This is a lipid preparation consisting of amphotericin B within unilamellar liposomes. It delivers higher concentrations of the drug, with a theoretical increase in therapeutic potential and decreased nephrotoxicity.

Amphotericin B is a polyene antibiotic with poor oral availability. It is produced by a strain of Streptomyces nodosus, and it can be fungistatic or fungicidal. The drug binds to sterols (eg, ergosterol) in the fungal cell membrane, causing leakage of intracellular components and fungal cell death. Toxicity to human cells may occur via this same mechanism.

Amphotericin B colloidal dispersion (Amphotec)

Amphotericin B colloidal dispersion is a lipid preparation consisting of amphotericin B attached to lipid discoid structures. Amphotericin B is a polyene antibiotic with poor oral availability. It is produced by a strain of Streptomyces nodosus, and it can be fungistatic or fungicidal. The drug binds to sterols (eg, ergosterol) in the fungal cell membrane, causing leakage of intracellular components and fungal cell death. Toxicity to human cells may occur via this same mechanism.