Severe Combined Immunodeficiency (SCID)

Practice Essentials

Severe combined immunodeficiency (SCID) is a group of medical disorders that result from genetic defects in both cellular and humoral immunity. Those immune defects lead to infections with bacterial, viral, and fungal pathogens that begin during infancy and, if untreated, result in a fatal outcome in the first few years of life.^[1]  

There has been a considerable gain in knowledge of the pathologic conditions of the immune system since the recognition of primary immunodeficiency as an entity in 1950, highlighted by the discovery of X-linked agammaglobulinemia, congenital neutropenia, and SCID. Over 200 diseases with more than 300 genetic etiologies have been described, which has provided opportunities for diagnosis and genetic counseling.^[2]  

Moreover, an understanding of the pathogenesis of primary immunodeficiencies has paved the way for immunologic interventions and new treatments, such as immunoglobulin G (IgG) replacement, bone marrow transplantation, and gene therapy. The discovery of the HLA system in 1968 led to successful bone marrow transplantations, and patients with immunodeficiency syndromes were the first to benefit from this novel therapy.

For patient education information, see the Immunodeficiency Disorders Directory.

• References

Pathophysiology

B and T cells, type 2 dendritic cells, and natural killer (NK) cells share a common ancestor: the common lymphoid progenitor (CLP). CLP differentiates into 2 intermediate progenitors, termed early B cells and T/NK/DC trilineage cells. Both intermediate progenitors continue their development in the bone marrow through primary lymphopoiesis, which is an antigen-independent process. Secondary B-cell lymphopoiesis is an antigen-dependent process that occurs in the germinal centers of peripheral lymphoid organs with specific antibody production. Secondary T-cell lymphopoiesis is also antigen-dependent and occurs in the thymus.

The earlier the defect, the more devastating the effect on lymphopoiesis. Defects occurring at the CLP stage or those affecting processes common to B- and T-cell development result in SCID involving B, T, and NK cells. According to the type of defect that leads to a SCID phenotype, Combined B- and T-cell disorders can be divided into specific groups with unique pathophysiologies that invariably result in an absence of nonfunctional B cells and absence of T cells (see Table 1).

Table 1. Classification of SCID

View Table

See Table

Adapted from Cavazzana-Calvo M, Fischer A. Gene therapy for severe combined immunodeficiency: are we there yet? J Clin Invest. Jun 2007;117(6):1456-65.^[3]

In other circumstances, the defect can affect later events in lymphopoiesis; a major loss or dysfunction in T cells can cause secondary B-cell deficiency, resulting in a clinical disorder that manifests as a combined B- and T-cell deficiency.

There are 4 characterized pathways that can result in SCID, as follows:

• Premature cell death caused by the accumulation of purine metabolites (seen in adenosine deaminase (ADA) deficiency)
• Defective V(D)J rearrangements of the T-cell and B-cell receptor genes (accounts for 30% of SCID cases)
• Defective cytokine-dependent survival signaling in T-cell precursors and sometimes NK-cell precursors (accounts for more than 50% of SCID cases)
• Defective pre-TCR and TCR signaling. Pure T-cell deficiencies are caused by defects in either a CD3 subunit (such as CD3 δ, CD3 ζ, CD3 ε ) or in CD45 tyrosine phosphatase, key proteins involved in pre-TCR and/or TCR signaling at the positive selection stage.

Defects in purine pathway enzymes that result in buildup of metabolites toxic to lymphocytes

ADA is an enzyme of the purine salvage pathway that is responsible for the deamination of adenosine to inosine and the deamination of deoxyadenosine to deoxyinosine. The deficiency of this enzyme leads to the accumulation of deoxyadenosine triphosphate (dATP) and 2'-deoxyadenosine. An increase in the intracellular levels of dATP is toxic to lymphocytes because it inhibits the enzyme ribonucleotide reductase, leading to suppression of DNA synthesis, whereas 2'-deoxyadenosine inhibits the enzyme S- adenosyl-L-homocysteine (SAH) hydrolase, which results in accumulation of SAH, a potent inhibitor of all cellular methylation reactions. Both B and T cells are affected, leading to SCID.

Defects in recombination of the antigen receptor genes (RAG) of B-cells and T-cells

Immunoglobulin gene rearrangement begins with heavy-chain gene rearrangement, which is followed by light-chain gene rearrangement. Once the rearrangement process is finished, recombination signal sequences that served to approximate the different genes from each other are removed with the help of the RAG1 and RAG2 proteins. RAG1/RAG2 deficiency is responsible for the B- and T-cell maturation defects in some persons with SCID.

Omenn syndrome is a rare, inherited disorder with a pooly understood pathogenesis. In this condition, mutations in the genes coding for the recombinases (ie, RAG1 and RAG2) cause a defect in the VDJ rearrangement that is needed for mature B-cells and T-cells to develop, resulting in a paradoxical combination of immunodeficiency and immune dysregulation.

In study by Khiong et al, the authors identified a C57BL/10 mouse with a spontaneous mutation in and reduced activity of RAG1.^[4] Mice bred from this animal exhibited major manifestations of Omenn syndrome, including high numbers of memory-phenotype T cells, hepatosplenomegaly and eosinophilia, oligoclonal T cells, and elevated levels of IgE. When the CD4+ T cells in the mice were depleted, a reduction in their IgE levels resulted. Thus, Khiong et al concluded that these "memory mutant" mice may be a model for human Omenn syndrome, and that many manifestations of the murine disease were direct results of the RAG hypomorphism, whereas some were caused by malfunctions of their CD4+ T-cells.^[4]

Artemis deficiency (with mutations in the Artemis protein that result in defective VDJ recombination) decreases both B and T cells and can be considered part of a subset of SCIDs. DNA ligase IV deficiency likewise results in defective circulating T- and B-cells and serum immunoglobulins.

Bloom syndrome, or congenital telangiectatic erythema, results from a mutation in the helicase enzyme called BLM RecQ. This mutation leads to defects in DNA repair and is characterized by an increased risk of malignancy and radiation sensitivity.

Defects in cytokine receptors and/or cytokine signaling (B cells are generally present but nonfunctional)

An extensive number of disorders with SCID manifestations belong to this category in which defects in cytokine receptors and/or cytokine signaling are present. Many cytokine receptors (eg, interleukin [IL], IL-2, IL-4, IL-7, IL-9, IL-15) share a common gamma chain, which is necessary for the normal signaling from the receptors after binding with their ligands.^[5]

After binding of IL-2 to its receptor (ie, IL-2R), JAK3 is recruited to the cytoplasmic tail of the receptor and then phosphorylated. In turn, JAK3 phosphorylates a docking site for src homology-containing (SHC) signal transducer and activator of transcription (STAT) proteins. Subsequent phosphorylation and dimerization of STAT with its translocation into the nucleus results in gene transcription and/or activation.

The gene that encodes the gamma chain is located on band Xq13. Approximately 100 mutations have been described in this gene, resulting in an abnormal (two thirds of cases) or absent (one third of cases) gamma C-chain. The absence of the gamma-C chain or the presence of aberrant forms affect signaling events that are mediated via various cytokine receptors, thus explaining the multiple cell types that are affected in X-linked SCID, which include T, NK, and B cells.

X-linked SCID is characterized by the absence of T and NK cells but a normal number of dysfunctional B cells (T– B+ NK– SCID). The development of T cells is dependent on functional IL-7/IL-7R, and that of NK cells is dependent on functional IL-15/IL-15R, whereas the abnormalities of IL-2 and IL-4 pathways affect the function of B cells.

The gene encoding JAK3 is located on band 19p13. JAK3 deficiency results in a rare SCID syndrome that is also associated with absent T and NK cells but a normal number of dysfunctional B cells (T–B+NK–SCID).

The Wiskott-Aldrich syndrome protein (WASP) is encoded by a gene located on band Xp11.22–11.23. This protein has a dual role: (1) it affects immune cell motility and trafficking through its binding with CDC42H2 and rac, members of the Rho family of GTPases, which then results in changes in actin polymerization; and (2) it relays external signals into the nucleus. The mutated gene encodes a WASP that lacks the hydrophobic transmembrane domain and results in defective immune cell trafficking and motility. The abnormality affects all immune cells, including dendritic cells, macrophages, and B and T cells, leading to abnormal initiation and regulation of the immune response and, ultimately, to ineffective secondary lymphopoiesis.

In common variable immunodeficiency (CVID), mature B cells are normal in number and morphology, but they fail to differentiate into plasma cells because of defective interaction between the B and T cells, mostly caused by a T-cell defect. This defect is thought to be related to a decreased number and/or function of CD4+ T lymphocytes or, occasionally, to an increased number of CD8+ T lymphocytes; however, abnormal responses of B cells to many usual stimuli have also been identified in vitro.

In selective IgM deficiency, the underlying abnormality is a defect of helper T cells and excessive suppressor T-cell activity. The condition is characterized by a low IgM level. IgG) levels are normal, but the IgG response is usually decreased.

T-helper lymphocyte deficiency has been incriminated in the pathogenesis of transient hypogammaglobulinemia of infancy (THI) and immunodeficiency with thymoma.

Primary B-cell disorders result in a complete or partial absence of one or more immunoglobulin isotypes. Regardless of the primary cause, the clincal manifestations depend on the type and severity of the immunoglobulin deficiency and the association of cell-mediated immunodeficiency. In general, severe immunoglobulin deficiency results in recurrent infections with specific microorganisms at certain anatomic sites.

Immunoglobulins play a dual role in the immune response by recognizing foreign antigens and triggering a biologic response that culminates in the elimination of the antigen. Their role in the fight against bacterial infections has been recognized for many years. Emerging evidence from animal and clinical studies suggests a more important role for humoral immunity in the response to viral infections than was initially thought.

IgM plays a pivotal role in the primary immune response. It is the first immunoglobulin class produced in a primary response to an antigen. IgM binds the C1 component of complement and activates the classical pathway, leading to opsonization of antigens and cytolysis. Binding of IgM to the polyimmunoglobulin receptor brings IgM to mucosal surfaces.

IgG represents the major component of serum antibodies (ie, approximately 85%). By binding to the Fc receptors, they mediate many functions, including antibody-dependent cell-mediated cytotoxicity, phagocytosis, and clearance of immune complexes. IgG1 is the major component of the response to protein antigens (eg, antitetanus/diphtheria antibodies); IgG2 is produced in response to polysaccharide antigens (eg, antipneumococcal antibodies); and IgG3 seems to play an important role in the response to respiratory viruses.

Complement fixation and activation is carried out by IgG1, IgG3, IgM, and, to a lesser degree, IgG2. IgA and, to a lesser extent, IgM, produced locally and secreted by mucous membranes, are the major determinants of mucosal immunity.

IgG antibodies are the only immunoglobulin class that crosses the placenta. These placental antibodies provide the infant with effective humoral immunity during the first 7-9 months of life.

Deficiency of the expression of major histocompatibility complex (MHC) class I and II cellular proteins also commonly manifests in early infancy with classic expressions of SCID. Manifestations in affected patients indicate the crucial involvement of MHC proteins in the immune recognition of self and non-self.

In other B- and T-cell disorders, additional anomalies may predominate, and clinical manifestations suggestive of immunodeficiency may occur late in life. Patients with short-limbed skeletal dysplasia with cartilage-hair hypoplasia (CHH) can also have either a T-cell or combined defect.

Combined immunodeficiency due to caspase-8 deficiency presents as recurrent sinopulmonary bacterial infections, poor growth, lymphadenopathy and splenomegaly, asthma, and herpesvirus infection. Caspases are a family of proteases that play roles in signal transduction by inflammatory cytokine receptors (eg, IL-1 and IL-18) as well as in pathways leading to apoptosis. The percentage of CD4+ T cells is low (about 25% of lymphocytes) and the CD4/C8 ratio is 0.5. T cells showed decreased proliferation and IL-2 production in vitro with mitogens, and NK cell function is also impaired.

There are 2 autosomal recessive syndromes that indicate some interaction of the immune system with neurologic function: ataxia-telangiectasia (AT) and Nijmegen breakage syndrome (NBS). These involve various mutations of DNA proteins. AT is a rare, autosomal recessive, neurodegenerative disorder in which the diagnosis is based on the presence of both ataxia and telangiectasia; combined immunodeficiency can be quite variable in this condition. Other multisystemic manifestations of AT include motor impairments secondary to a neurodegenerative process, oculocutaneous telangiectasia, sinopulmonary infections, and hypersensitivity to ionizing radiation.

NBS is also an autosomal recessive chromosomal instability syndrome in which patients have increased susceptibility to infection or lymphatic tumor development due to defects in humoral and cellular immune functions. NBS is also characterized by microcephaly with growth retardation, normal or impaired intelligence, and birdlike facies. Nearly all patients with NBS are homozygous for the same founder mutation: deletion of 5 bp (657del5) in the NBS1 gene, which encodes the protein nibrin.

Both AT and NBS are associated with decreased circulating levels of T cells and often decreased levels of the IgA, IgE, and IgG subclasses, whereas circulating levels of B cells are normal.

• References

Epidemiology

Frequency

United States

The accurate incidence of SCID in the United States is unknown, but it has been estimated to be in 1 per 50,000-100,000 births across all ethnic groups. A postulated reason for the lack of exact epidemiologic information is that infants with SCID may die of infections without having been diagnosed with the condition.

With implementation of SCID newborn screening in unbiased populations, Kwan et al reported that 1 in 58,000 infants (95% CI 1/46,000–80,000) are born with SCID or leaky SCID (ie, forms of SCID, such as Omenn syndrome, characterized by normal or elevated levels of nonfunctional T cells, in contrast to the low or absent T cell counts of typical SCID). That prevalence rate is nearly twice the previous estimates based on population data or experience of centers performing hematopoietic cell transplantation therapy for SCID.^[6]

The approximate frequency of the most common forms of SCID is as follows:

• X-linked SCID -  42%
• Autosomal recessive SCID - 22%
• ADA deficiency - 15%
• JAK3 deficiency - 6%

The incidence of reticular dysgenesis and CHH are less than 1% each. In approximately 14% of cases, the etiology remains unknown.^[7]

International

Estimates for Europe are thought to approximate those in the United States. CHH may be more frequent in Finland. SCID is underreported, but several countries now maintain registries of patients with primary immunodeficiency diseases.

The estimated prevalence of SCID in specific countries is as follows^[8] :

• Australia - 0.15 cases per 100,000 population
• Norway - 0.045 cases per 100,000 population
• Switzerland - 0.47 cases per 100,000 population
• Sweden, 2.43 of every 100,000 live births

Mortality/Morbidity

SCID is a devastating disease with a high risk of early death in infancy or childhood: a large number of patients die during their first year of life, and most do not survive beyond their second year.

The condition is notable for recurrent failure to thrive and common infections (eg otitis media, diarrhea, mucocutaneous candidiasis). Moreover, if infants are not diagnosed by age 6 months, opportunistic infections follow, especially Pneumocystis jirovecii pneumonia and invasive fungal infections, and mortality may ensue from infections with common viruses, such as the following^{[7, 9]} :

• Varicella-zoster virus (VZV)
• Respiratory syncytial virus (RSV)
• Rotavirus
• Parainfluenza virus
• Cytomegalovirus (CMV)
• Epstein-Barr virus (EBV) 
• Enterovirus 
• Adenovirus

Race-, sex-, and age-related demographics

Although there is no racial predilection for combined B-cell and T-cell disorders, some forms of combined immunodeficiency have been reported more in some ethnic groups, such as the following^[7] :

• JAK3 mutations in Italy
• MHC class II deficiency of North African origin
• ADA-SCID in the Somali population has an incidence of 1 in 5,000^[10]
• ZAP70 mutations in the Mennonite population
• Artemis gene product–deficiency in Navajo Indians of Athabasca descent has a reported incidence of 1 in 2,000^[10]
• RAG1/RAG2–deficient SCID in Europe
• CHH in the Finnish population and the old Amish order in the United States

The disorders associated with the X chromosome typically manifest only in males, whereas females are carriers. Approximately 50% of SCID cases are X-linked.

Most patients with these disorders become symptomatic with recurrent infections, failure to thrive, or both in the first months of life.

• References

History

The clinical hallmarks of severe combined immunodeficiency (SCID) are repetitive and frequent bacterial, viral, and fungal infections that persist despite standard medical treatment. These result from the profound degree of immune compromise in SCID.

Patients with primary T-cell deficiency SCID begin having infections soon after birth (ie, age 3-4 mo) compared with those that have pure B-cell disorders, who do not have an increased incidence of bacterial infections until 7-9 months after birth, when placental antibodies fall to undetectable levels.

Clinicians should focus attention on the family history, site of infection, type of microorganisms, and any adverse reactions to transfusion of blood products, which may provide clues to the significance and type of immune deficiency. It is also important to inquire about consanguineous relationships because consanguinity increases the risk of immune disorders that have autosomal recessive inheritance patterns (eg, some forms of SCID or chronic granulomatous disease [CGD]). In addition, a careful family history of risk factors for human immunodeficiency virus (HIV) should be obtained to rule out secondary forms of immunodeficiency.

Upper and lower respiratory tract infections, skin infections, meningitis, bacteremias, and abscesses are common in persons with B-cell disorders. Pneumonia with Pneumocystis jirovecii or cytomegalovirus (CMV), disseminated bacillus Calmette-Guerin (BCG) infection,^[11] or atypical mycobacterial infection and recurrent or persistent skin candidiasis are suggestive of T-cell disorders or SCID. Diarrhea with failure to thrive in children with SCID is usually related to infections with viruses such as rotaviruses and adenoviruses. Although antibody deficiency is associated with recurrent encapsulated bacteria infections, T-cell disorders or SCID are associated with opportunistic infections with fungi, viruses, or intracellular bacteria.

Reactions to blood products or vaccines should raise the suggestion of an underlying immunodeficiency, particularly IgA deficiency. Transfusion with blood products can result in significant graft versus host disease (GVHD) in SCID patients.

After a detailed inquiry, a SCID disorder should be suspected if the patient falls into one of the following groups:^{[12, 13, 14, 15]}

• Prenatal diagnosis
• Neonate with a family history of a known immunologic disorder
• Failure to thrive
• Recurrent upper and lower respiratory tract infections that do not respond to appropriate antibiotics
• Recurrent skin infections and delayed wound healing

X-linked severe combined immunodeficiency

X-linked severe combined immunodeficiency (XSCID) is by far the most common form of SCID, accounting for almost 50% of cases.^[16]  As the affected gene is located in the X chromosome (X13q band), the disease is limited to males. Because of a defective common gamma chain (a component of cytokine receptors for interleukin-2 [IL-2], IL-4, IL-7, IL-9, and IL-15), signal transduction cannot proceed normally, which results in SCID characterized by absent T and NK cells and dysfunctional B cells. The phenotype is T–B+NK–.

Infections begin in the first months of life, affecting the upper and lower respiratory tracts, gastrointestinal tract, and skin, whereas X-linked agammaglobulinemia (XLA) does not manifest clinically until the second half of an infant's first year of life. Persistent opportunistic infections with Candida albicans or P jirovecii and viral infections with varicella-zoster virus, CMV, and Epstein-Barr virus are common. The risk of GVHD is high in these patients because of their inability to reject foreign antigens

X-linked immunodeficiency with hyper IgM syndrome 

X-linked immunodeficiency with hyper IgM syndrome (XHM) is a part of the hyper-IgM syndromes that includes a group of disorders characterized by recurrent bacterial infections and low serologic levels of IgG, IgA, and IgE, with relatively elevated levels of IgM. XHM affects only boys and is the result of mutations in the gene that encodes the CD40 ligand (CD40L or CD154) located on chromosome X. Clinical manifestations of XHM are as follows:

• Recurrent infections of the upper and lower respiratory tracts beginning during the first 2 years of life; susceptibility to infection from P jirovecii and Clostridium parvum, both opportunistic pathogens controlled by cellular immunity, may be explained by the nature of the defect underlying this disease, which involving T-cell CD40L
• A high incidence of liver disease and sclerosing cholangitis (approximately 20% of patients in a series reported by Levy et al^[17] ; others report 80% by age 20 y), as well as liver and gastrointestinal malignancies
• Oral and rectal ulcers are common in patients with chronic neutropenia (approximately 50% of cases).
• Autoimmune diseases such as arthritis, nephritis, and hematologic disorders have also been reported.

Adenosine deaminase (ADA) deficiency

ADA is an enzyme of the purine salvage pathway. Deficiency leads to the accumulation of dATP and 2'-deoxyadenosine. dATP is lymphocytotoxic because of its ability to inhibit DNA synthesis via inhibition of ribonucleotide reductase. The nucleoside 2'-deoxyadenosine inhibits the enzyme S-adenosyl-L-homocysteine (SAH) hydrolase, which results in accumulation of SAH, a potent inhibitor of all cellular methylation reactions. Both B and T cells are affected. The phenotype is T–B–NK–.

ADA deficiency is an autosomal recessive disorder in which the age at presentation varies. Failure of the immune system is progressive and may not fully manifest in certain individuals until adulthood.

This disease has the same symptoms of XSCID, that is, recurrent infections, persistent opportunistic infections, and GVHD susceptibility. Clinically, ADA deficiency differs from XSCID by (1) the presence of skeletal and chest wall abnormalities involving the vertebral bodies and the chondrocostal junctions and (2) the possible presence of thymic differentiation with rare Hassall concentric corpuscles.

JAK3 deficiency

JAK3 is an intracellular enzyme that is activated as a result of the binding of cytokines with their cognate receptors. The gene encoding JAK3 is located on band 19p13, and the disorder is autosomal recessive. The phenotype is T–B+NK–.

The symptoms of this condition are similar to those observed in persons with XSCID and include upper and lower respiratory tract infections, persistent infections with opportunistic microorganisms, and increased susceptibility to GVHD.

RAG1 and RAG2 deficiency

In patients deficient in the RAG proteins 1 and 2, the lymphocytes cannot rearrange the antigen receptors, thus leading to B- and T-lymphocyte deficiency. Phenotypically, the numbers of B and T cells are decreased, whereas the number of NK cells is normal.

Clinically, these patients present with increased susceptibility to infection with encapsulated and intracellular bacteria, viruses, and fungi. On laboratory studies, this syndrome is characterized by high serum IgE levels, decreased levels of the other immunoglobulins, and hypereosinophilia.

RAG1 deficiency is observed in patients with cartilage-hair hypoplasia (CHH) and is characterized by the following:

• Short hands
• Metaphysial chondroplasia
• Hyperextensibility of the distal joints of hands and feet
• Fine, light hair

CHH

CHH manifests in early infancy as chronic diarrhea, failure to thrive, and an erythematous rash with desquamation. Hepatosplenomegaly is common. Patients die in the first few months of life unless successful allogeneic bone marrow transplantation is performed.

Reticular dysgenesis

Reticular dysgenesis is a rare disorder that is characterized by an almost complete lack of granulocytes and lymphocytes. Most patients die in early infancy or the newborn period because of severe and overwhelming infection. The molecular basis of the disease is not known

Wiscott-Aldrich syndrome

Wiskott-Aldrich Syndrome (WAS) is an X-linked recessive disorder resulting from mutation in a gene that encodes for the WAS protein (WASP). WASP is a key regulator of actin polymerization in hematopoietic cells. Structural studies of the WASP protein have identified 5 domains that are involved in signaling, cell locomotion, and immune synapse formation. WASP regulates nuclear factor kappaB (NF-KB) activity by promoting the nuclear translocation of NF-KB. In addition, WASP plays not only an important role in lymphoid development, but also in the maturation of myeloid monocytic cells.

Clinically, the syndrome is characterized by the triad of thrombocytopenic purpura, eczema, and increased susceptibility to infections. Symptoms begin in the first year of life, with recurrent upper and lower respiratory tract infections with encapsulated bacteria. P jirovecii pneumonia and herpes infections become a problem later in life

Most patients die of serious infections at approximately age 11 years. If these patients survive to adulthood, they are at high risk for autoimmune diseases, such as cytopenias and vasculitis, and for cancer, particularly non-Hodgkin lymphomas.

The discovery of the Wiskott-Aldrich gene made possible the identification of carriers of the gene in families of WAS patients with an incomplete syndrome. Some of these patients have only the thrombocytopenia (X-linked thrombocytopenia) with no skin involvement or immunodeficiency despite inheriting the same gene mutation.

• References

Physical

The physical examination may identify nonspecific signs of acute or chronic infections and those more specifically related to certain disease entities. Consider the following:

• Growth and development may be delayed as a result of recurrent infections. Dysmorphic syndromes such as short-limbed dwarfism may occur. Hair abnormalities are observed in persons with CHH.
• Lymphoid tissue and organs such as the tonsils, adenoids, and peripheral lymph nodes are underdeveloped in persons with XLA and those with various forms of SCID. Diffuse lymphadenopathy is observed in persons with CVID, XHM, and Omenn syndrome.
• Permanent cutaneous scars follow skin infections. A desquamating erythematous rash is observed in persons with Omenn syndrome.
• After recurrent episodes of otitis media, evidence of past perforations, scarring, and dull tympanic membranes are observed. Purulent nasal discharge, a cobblestone pattern of the pharyngeal mucosa, and postnasal exudate may be evident. Note the presence or absence of tonsillar tissue.
• Evaluate for signs such as a loud pulmonic heart sound, right ventricular heave, and tricuspid regurgitation murmur. If present, these signs support the diagnosis of pulmonary hypertension. Jugular venous distention, tender hepatomegaly, and lower-extremity edema suggest cor pulmonale. Pulmonary rales, rhonchi, wheezing, and digital clubbing may be encountered.
• Paralytic poliomyelitis may follow vaccination in patients with antibody deficiency.
• Deep sensory loss with decreased vibratory sense and position of limb segments are observed in persons with pernicious anemia.

• References

Causes

SCID disorders are the result of specific genetic alterations in key regulators of B-cell, T-cell, and/or natural killer (NK)-cell activation, proliferation, or differentiation. The genetic alterations have been identified in the following disorders, which has led to the investigation of gene therapy as an attractive intervention to treat such conditions:

• XSCID – Genetic defects in the gamma C gene, leading to defects in various cytokine receptors
• ADA deficiency – Genetic mutations in the ADA enzyme
• JAK3 deficiency – Defects in the Janus signaling kinase that interacts with the intracellular portion of the common gamma chain of various cytokine receptors
• RAG1 and RAG2 deficiency – Specific mutations and genetic defects in the RAG1 and RAG2 enzyme
• Omenn syndrome
• CHH – Mutations in RMRP, the RNA component of the ribonucleoprotein complex. RNase MRP consists of an RNA molecule bound to several proteins (as described by Ridanpaa et all, it has at least 2 functions: cleavage of RNA in mitochondrial DNA synthesis and nucleolar cleaving of pre-rRNA.^[18] This group of investigators recently identified several mutations in RMPR in patients with CHH.)
• Reticular dysgenesis
• Wiskott-Aldrich syndrome (WAS) - Rare X-linked disorder with variable clinical phenotypes that correlate with specific mutations in the WAS protein (WASP) gene

• References

Approach Considerations

Screening

In the United States as of December 2018, all 50 states, as well as the District of Columbia, the Navajo Nation, and Puerto Rico, conduct population-wide newborn screening (NBS) for SCID.^[19]  T-cell receptor excision circles (TRECs), a biomarker for T lymphopoiesis, can be measured by polymerase chain reaction (PCR) using DNA isolated from infant dried blood spots (DBS).^{[6, 10]}  

A systematic review of the diagnostic performance of published algorithms for TREC-based NBS for SCID concluded that a using a TREC cutoff value of maximal 25 TRECs/μl and incorporating the collection of a repeat DBS from neonatal intensive care unit patients with an abnormal screening result in the screening algorithm would be most effective in screening newborns for primary immunodeficiencies with T cell lymphopenia.^[20]

• References

Laboratory Studies

The diagnosis of SCID should be suspected in children with any of the following conditions:

• Unexplained lymphopenia
• Failure to thrive
• Chronic diarrhea
• Recurrent severe episodes of infection with respiratory syncytial virus (RSV), herpes simplex virus (HSV), varicella-zoster virus (VZV), measles, influenza, or parainfluenza
• A family history of SCID

Patients with suspected SCID require complete evaluation of specific humoral and cellular immunity, which includes measurement of immunoglobulin levels, antibody titers, lymphocyte subsets, and assessment of T-cell function. This can be done via evaluating the responses to mitogens in vitro.

The probable diagnosis of SCID is based on the following:

• A T-cell count less than 20% of lymphocytes, an absolute lymphocyte count of less than 3,000 cells/mm³, and a response to mitogens of less than 10% of the control or maternal T cells in the circulation
• At this point, establish a molecular diagnosis and also consider the sex, family history, and phenotype of the patient.
• Quantitative measurement of the serum immunoglobulins and IgG subclasses is necessary to confirm the diagnosis of B-cell deficiency. If, despite normal results, humoral immunodeficiency is suggested, the antibody response to specific antigens (polysaccharide or protein antigens) should be evaluated further. In patients with SCID presenting with recurrent infections in the first months of life, immunoglobulin levels are not helpful in the diagnosis, owing to the presence and persistence of maternal antibodies.

Levels of serum immunoglobulin are determined by serum protein electrophoresis.

Quantitative methods are used for the precise measurement of each immunoglobulin isotype. Enzyme-linked immunosorbent assays (ELISAs) are used for IgE quantitation.

Compare values to age-standardized reference ranges for each laboratory. The following are examples of values that are used for the adult population:

• IgG1 – 500-1200 mg/dL
• IgG2 – 200-600 mg/dL
• IgG3 – 50-100 mg/dL
• IgG4 – 20-100 mg/dL
• IgM – 50-150 mg/dL
• IgA1 – 50-200 mg/dL
• IgA2 – 0-20 mg/dL
• IgD – 0-40 mg/dL
• IgE – 0-0.2 mg/dL
• In most disorders involving IgG, the level is less than 200-250 mg/dL. Levels of the other immunoglobulins vary depending on the underlying disease.
• Immunoglobulin subclass deficiency is defined as a decrease of an IgG subclass greater than 2 standard deviations (SDs) below the normal mean for age.

Antibody response after immunization may be absent.

• Check the antitetanus/diphtheria antibodies (IgG1), antipneumococcal polysaccharide antibodies (IgG2), and antirespiratory virus antibodies (IgG3) if the titers for the total immunoglobulins are within the reference ranges and the patient is unable to produce antibodies to specific antigens.
• Antibody response is evaluated by measuring antitetanus and antipneumococcal titers 3-4 weeks after vaccination; a rise of 4-fold for antitetanus and 2-fold for antipneumococcal titers is considered normal.

The absence of isohemagglutinins is a significant finding that is suggestive of an immunoglobulin production problem. Evaluate IgM antibodies to A and B blood group antigens (isohemagglutinins) if the other test findings are within reference ranges and the patient is unable to mount a response to specific antigens.

Peripheral blood lymphocyte levels should be measured.

• The lymphocyte count is higher in infancy and childhood than in adulthood. An absolute lymphocyte count of less than 280 per microliter (ie, 2 SDs below the mean) is abnormal.
• The association of a low lymphocyte count with recurrent infections is very suggestive of immunodeficiency.

Lymphocyte phenotyping using flow cytometry analysis is the next step. The absolute number of B-cells, T-cells, and natural killer (NK) cells is more useful than percentages.

Measuring T-lymphocyte numbers and function may be necessary. Lymphocyte activation (CD45 RA/RO isoformic antigens) and T-cell receptor phenotype (TCR ab/gd lineage) determination may provide additional information regarding the type of immunodeficiency. For example, Omenn syndrome is characterized by a high number of T cells carrying TCRgd or CD45+. Determination of the helper (CD4) to suppressor (CD8) T-cell ratio is sometimes useful.

Cutaneous delayed-type hypersensitivity testing is used to evaluate the anamnestic response of cellular immunity to previously encountered antigens.

• The test results are not reliable in children younger than age 1 year, and the response is frequently suppressed following viral and bacterial infections and after glucocorticoid therapy.
• The results are determined by measuring the induration 48-72 hours following an intradermal injection of 0.1 mL of tetanus toxoid (at 1:100 dilution, 0.2 Loeffler U/0.1 mL), mumps skin test antigen, candidal antigen (at 1:100 dilution; if no reaction is present, use 1:10 dilution), tuberculin (0.1 mL containing 2-10 IU of purified protein derivative [PPD]), and trichophytin (1:30 dilution).
• The test result is considered positive if the induration is greater than 5 mm (or > 2 mm in children).
• This test can be complemented by in vitro study of lymphocyte proliferation to different mitogens.

Results in specific disorders

XHM:

• IgM levels are markedly increased, frequently to higher than 1000 mg/dL. Note: Normal levels do not exclude the diagnosis; in one \study, normal levels were present in 29 of 55 patients with genetically proven XHM.^[17]
•  IgG, IgA, and IgE levels and the number of lymphocytes bearing these antibodies are decreased.
• An IgM response to antigen exposure is possible, but the IgG and IgA responses are absent or diminished.
• Cell-mediated immunity is defective in some patients despite a normal T-lymphocyte count.
• Chronic neutropenia may be present in some patients.

ADA deficiency:

• The erythrocyte deoxy-ATP level is increased. The values in carriers are half to two thirds of normal.
• Lymphopenia is more severe than in other SCID syndromes (ie, < 500/μ L).
• Although the number of B-cells and NK cells is decreased, their function is quasinormal, and they normalize completely after bone marrow transplantation without pretransplantation chemotherapy.

RAG1 and RAG2 deficiency:

• B and T lymphocytes are completely absent.
• NK cells are the only circulating lymphocytes.
• Immunoglobulin levels are severely decreased.

• References

Imaging Studies

Chest radiography

Sometimes, recurrent or chronic infections may lead to abnormal chest radiographic findings, such as interstitial infiltrates, bronchiectasis, emphysema, and scarring. Note: Normal chest radiographic findings do not exclude the presence of structural abnormalities.

Absence of a thymic shadow is a very common finding in SCID. Patients with DiGeorge syndrome and other T-cell defects may also lack thymic tissue. However, the presence of thymic tissue does not exclude SCID. For example, patients with SCID who have mutations in ZAP70 or CD3 typically have normal-sized thymuses.

Chest radiographs in patients with ADA deficiency typically show inferior scapular angle squaring and spurring and costochondral cupping. Verhagen et al reported that these findings can reliably differentiate ADA deficiency from other forms of SCID, in children younger than approximately 7 months of age.^[21]

• References

Other Tests

For a prenatal diagnosis, restriction fragment length polymorphism (RFLP)can help detect genetic defect carriers of XHM, WAS, and ADA deficiency using fetal blood, amnion cells, or chorionic villus tissue. Umbilical cord blood can be used in the prenatal diagnosis of some of these disorders.

T cells are absent in persons with XSCID. B cells and T cells are absent in patients with autosomal recessive SCID. "Bald" lymphocytes found on scanning electron microscopy are diagnostic of WAS. Red blood cell ADA is decreased in fetuses with ADA deficiency.

ADA deficiency can be evaluated by demonstrating the following:

• Absent ADA levels in lysed erythrocytes
• A marked increase in dATP levels in erythrocytes
• A significant decrease in ATP concentration in red blood cells
• Absent or extremely low levels of N-adenosylhomocysteine hydrolase in red blood cells
• An increase in 2'-deoxyadenosine in urine and plasma

In AT, chromosomal karyotyping should reveal reciprocal translocations between chromosomes 7 and 14. Chromosomal instability testing is done to confirm AT and NBS to assess spontaneous and induced breakage. Diagnostic findings are absence or dysfunction of the ATM protein and mutations in the ATM gene.

• References

Procedures

See the list below:

• Bronchoscopy should be performed frequently for recurrent pulmonary infections.
• Endoscopic biopsies should be performed to look for the extent and to identify the cause of the diarrhea.
• Lymph node biopsy is not necessary for the diagnosis, although findings may indicate a paucity of T- and B-cells and a lack of germinal centers^[22]

• References

Approach Considerations

Intravenous immunoglobulin (IVIG) replacement therapy may benefit patients with combined immunodeficiencies, such as severe combined immunodeficiency (SCID), X-linked immunodeficiency with hyper IgM syndrome (XHM), Good syndrome, and Wiskott-Aldrich syndrome (WAS). Appropriate supportive care, such as early identification of opportunistic infections or nutritional support, are necessary.

In WAS, other than prophylactic antibiotics and IVIG, splenectomy for thrombocytopenia and platelet transfusion in acute life-threatening bleeding can be used.

Note: Do not immunize these patients with live attenuated vaccines. Focus efforts on the treatment of infections, allergic reactions, and autoimmune and gastrointestinal diseases. Aggressive and prolonged antibiotic therapy covering Streptococcus pneumoniae and Haemophilus influenzae is indicated. Prophylactic antibiotic therapy has been recommended for patients with frequent infections. A course of metronidazole may result in dramatic improvement of the diarrhea and, to a certain extent, of malabsorption syndrome in these patients. Prophylactic antibiotic therapy may significantly decrease the incidence of infections.

Patients with adenosine deaminase (ADA) deficiency may benefit from adenosine deaminase enzyme replacement therapy with pegademase or elapegademase. The maximum effect on immunologic function does not occur for several months.

Allogeneic bone marrow or hematopoietic stem cell transplantation (HSCT) may be helpful for patients with SCID. Survival rates in these previously fatal conditions are around 90% in some case series.

This treatment strategy is highly successful when a human leukocyte antigen (HLA)–matched sibling donor is available; if such a donor is not available, however, few therapeutic options exist. Gene-modified, autologous bone marrow transplantation can circumvent the severe immunologic complications that occur when a related HLA-mismatched donor is used and thus represents an attractive alternative (see below). 

Allogeneic bone marrow transplantation has become the standard of care for certain patients with SCIDs (eg, X-linked severe combined immunodeficiency [XSCID], ADA deficiency). Patients with other immunodeficiency syndromes may benefit from bone marrow transplantation or HSCT, including those with WAS or XHM.

Many groups are exploring the potential benefits of HSCT based on alternative donors. Umbilical cord blood stem cell transplantation (UCBSCT) offers several advantages, including ready availability of the unit, a lower risk of transmitting viral diseases, no risk to the donor, and a lower risk of GVHD even in the absence of a perfect HLA match.

Another possibility for patients without a suitable sibling donor is a matched unrelated donor (MUD) HSCT. But in clinical practice, this therapy is limited due to high rates of graft versus host disease (GVHD) and transplant-related mortality.

Identification of a suitable MUD has been facilitated by recent advances, including the following: 

1.  Continuous growth of volunteer donors worldwide
2. High-resolution molecular techniques for HLA typing, which permits a better selection of donors
3. Advances in critical care that have resulted in a significant decrease in MUD-HSCT transplant–related mortality and an increase in the survival of SCID infants who are severely infected at the time of diagnosis.

Early diagnosis before the development of permanent lung and liver damage and referral to a specialized center for bone marrow transplantation/HSCT are essential for therapeutic success.

Bertrand et al reported on a European experience with 178 patients in 18 centers who were treated with HLA, nonidentical, T-cell–depleted bone marrow transplantation.^[23]  With a median follow-up of 57 months, disease-free survival was shown to be significantly better for patients with B-positive SCID (60%) than for patients with B-negative SCID (35%).^[23]

Buckley et al found that the survival rate was not affected by the genetic type, but it was affected by race (ie, more white patients than black or Hispanic patients survived [P < 0.001]) and sex (all girls survived [P = 0.047]).^[24]

Another report noted the inefficacy of bone marrow transplantation in correcting Job syndrome.^[25]

Gene therapy

Despite the success that has been seen in some SCID patients treated with bone marrow transplantation, other patients experince failure to restore B-cell function or failure or rejection of the graft over time. A novel alternative strategy to circumvent graft failure/rejection is the use of gene transfer into autologous stem cells using retroviruses.

Gene therapy is a viable therapeutic option; advances in biotechnology have enabled the performance of this highly complex treatment for several immunodeficiency syndromes.^{[26, 27]}

Cavazzana-Calvo et al published reports of the successful results of gene therapy for SCID-X1 disease in 2 children, opening new horizons for the future of these patients.^[5]  This therapy resulted in complete immune reconstitution of the lymphoid system, with T-, B-, and NK-cell counts comparable to age-matched controls.^[5]  An update on these 2 patients by the same authors and a report on 3 others confirmed the previous results.

Patients with ADA deficiency were the first to be enrolled in gene therapy trials. Since 2000, over 100  patients with ADA-SCID have been treated with gamma-retrovirus or lentivirus-mediated autologous hematopoietic stem cell gene therapy (HSC-GT), and the excellent safety and efficacy observed in these cases has established HSC-GT as an equal alternative to HSCT for these patients.^[28]

In addition to ADA deficiency, , SCID-X1, WAS, RAG1 deficiency, and CD3 deficiency have been successfully treated with gene-modified autologous HSC-GT. In this technique, RNA viruses are the vectors most commonly used to introduce genetic information into hematopoietic stem cells and/or progenitor cells. It has been demonstrated that several T-cell precursors that carry a wild-type sequence of the disease-causing gene or a less harmful mutation can mature into functional mature T cells that provide adequate immunity. 

• References

Consultations

Consultations should be obtained with specialists from the following specialties:

• Bone marrow transplantation
• Gastroenterology
• Nutrition
• Infectious diseases

• References

Diet

In view of the presence of chronic diarrhea, patients often require enteral or parenteral supplementation.

• References

Activity

Physical activity should be encouraged. Patients may need isolation to decrease the risk of common viral and bacterial infections, such as avoiding crowded places. Strict hygienic practices are important.

• References

Medication Summary

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

• References

Immune globulin, intravenous (Gamimune, Gammagard, Sandoglobulin, Gammar-P)

• Dosing, Interactions, etc.

Clinical Context:  Provide an immediate rise of antibodies that have a proven protective effect against bacterial and viral infection (passive immunity). Because antibodies are not produced by the host, these products must be readministered monthly. This treatment may increase CSF IgG (10%).

• References

Class Summary

Blood products/immunoglobulins provide immediate passive immunity. These agents can be used as replacement therapy in patients with antibody-deficiency states.

• References

Elapegademase (Revcovi, Elapegademase-lvlr)

• Dosing, Interactions, etc.

Clinical Context:  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.

• References

Pegademase bovine (Adagen)

• Dosing, Interactions, etc.

Clinical Context:  ADA is an enzyme of the purine salvage pathway that is responsible for adenosine and deoxyadenosine deamination to inosine and deoxyinosine, respectively. ADA deficiency leads to accumulation of the metabolites dATP and 2'-deoxyadenosine, both of which are toxic to lymphocytes.

Treatment is indicated in patients with SCID secondary to ADA deficiency whose conditions proved refractory to bone marrow transplantation or who are not candidates for transplantation. Individualize therapy (based on plasma levels) to achieve the following: trough plasma levels of 15-35 mmol/h/mL and a decline in erythrocyte dATP to < 0.005-0.015 mmol/mL packed erythrocytes or to < 1% of total erythrocyte adenine nucleotide content (ATP + dATP). Plasma levels >35 mmol/h/mL are not associated with additional clinical benefit. This treatment has no role in preparatory regimen for bone marrow transplantation.

• References

Class Summary

Adenosine deaminase (ADA) enzyme replacement can reduce potentially serious, life-threatening infections in ADA deficient patients.

• References

Further Outpatient Care

Regularly monitor the following in patients with severe combined immunodeficiency:

• Growth and development
• Chest radiographs
• Pulmonary function
• Immunoglobulin trough levels
• Liver function

Imunoglobulin trough levels of 400 mg/dL or higher are considered satisfactory. Occasionally, levels greater than 500 mg/dL are required to clear certain viral infections, such as enterovirus meningoencephalitis. Trough levels may need to be titrated in individual patients to determine the level that is needed to prevent recurrent infection.

If abnormalities are identified on liver function tests, imaging studies of the liver and biliary tree are necessary to exclude malignancies or sclerosing cholangitis (the latter is observed in patients with X-linked immunodeficiency with hyper IgM syndrome [XHM]).

• References

Inpatient & Outpatient Medications

See the list below:

• Once initiated, IVIG therapy can be self-administered by the patient.

• References

Transfer

See the list below:

• Specialists in the diagnosis and treatment of these patients should be consulted for their initial evaluation and treatment.

• References

Deterrence/Prevention

See the list below:

• The liberal use of antibiotics helps to decrease the frequency of infections in these patients. Some experts use a rotating regimen of antibiotics on a monthly basis.

• References

Complications

See the list below:

• Bronchiectasis and cor pulmonale complicate chronic/recurrent lower respiratory tract infections.
• Hearing loss due to chronic otitis media or meningoencephalitis may affect as many as one third of patients with XLA.
• The risk of GVHD is high in patients with SCID because of their inability to reject foreign antigens.
• EBV-associated smooth muscle tumors may occur in patients who are partially reconstituted after bone marrow transplantation for SCID and who may not require surgery or chemotherapy.^[29]
• Central nervous system viral infection is one of the most potentially devastating complications of immunodeficiency, but this is a rare presentation in patients with SCID.
• Complications related to IVIG therapy include the following:

  • Increased serum viscosity and thromboembolic events, increased risk of migraine attacks, aseptic meningitis (10%), urticaria, pruritus, or petechiae (2-5 d postinfusion to 30 d postinfusion) can occur.
  • The most common adverse reactions are nonanaphylactic in nature and are characterized by back and abdominal pain, nausea, vomiting, chills, fever, and myalgias. Discontinue the infusion until the symptoms subside; then restart at a slower rate.
  • True anaphylactic reactions are rare and occur seconds to hours after the infusion is started. Typical symptoms consist of flushing, facial swelling, dyspnea, and hypotension. Stop the infusion, and administer epinephrine, steroids, and antihistamines together.
  • The risk of renal tubular necrosis is increased in elderly patients and in patients with diabetes, volume depletion, and preexisting kidney disease.
  • Transmission of hepatitis C virus (HCV) is much less common now than in the past. Most patients who are HCV RNA–positive contracted their infection in the 1980s when serologic testing of blood donors for this infection was not available. Chronic liver disease in these patients is characterized by a severe clinical course, particularly in those with CVID.
    • Hepatitis B virus (HBV) and hepatitis G virus (HGV) seem to play minor roles in the pathogenesis of chronic liver disease in these patients.
    • A milder form of chronic liver disease with negative serology for HCV, HBV, and HGV infections has been described in these patients. This form occurs, on average, 36 months after the beginning of IVIG therapy, and it is thought to be related to immune phenomena or to a viral infection not yet described.
    • A few non-HCV, non-HBV, and non-HGV patients have a particularly severe course, and granulomatous disease of the liver has been identified in most of them.
    • Lymphoma, especially Burkitt lymphoma, has been reported in patients with ADA deficiency, including those who received prolonged PEG-ADA replacement therapy.

   

  

   

• References

Prognosis

See the list below:

• Without treatment, most of the patients with combined B-cell and T-cell disorders die within the first 6 months.
• Patients who are well nourished, uninfected, and younger than 6 months before transplantation have the best outcomes.
• Patients with SCID barely survive without stem cell reconstitution. However, gene therapy is an alternative for those cases in which donors are unavailable.
• Patients with less severe mutations in the ADA gene have survived into adulthood.

• References

Patient Education

See the list below:

• Inform patients and their families about the risk of overwhelming infection and the need for immediate intervention.
• Encourage the use of antibiotics in case symptoms of infection arise, along with immediate referral to the nearest medical facility for evaluation.

• References