AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

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

INTRODUCTION

Section 2 of 10  

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

Background

Immunodeficiency is the genetic or acquired failure of the patient's innate or adaptive immunity, resulting in an increased frequency and severity of infections that may lead to catastrophic morbidity, early death, or both.

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 severe combined immunodeficiency (SCID). The description of over 200 diseases with more than 100 genetic etiologies has been described, which has provided opportunities for diagnosis and genetic counseling. 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.

Combined B-cell and T-cell immunodeficiencies, or SCID, is a group of medical disorders that are the result of genetic defects in both cellular and humoral immunity. The defects in humoral and cellular immunity have an early clinical presentation and, if untreated, result in a fatal outcome in the first few years of life. This article focuses only on SCID disorders and outlines recent advances in therapeutics options for patients.

The profound degree of immune compromise in SCID leads to infections with bacterial, viral, and fungal pathogens that cause significant morbidity and eventually mortality in patients.

For excellent patient education resources, visit eMedicine's Immune System Center, Bacterial and Viral Infections Center, and Yeast and Fungal Infections Center. Also, see eMedicine's patient education articles HIV/AIDS and Pneumonia.

Related eMedicine topics:
Bone Marrow Aspiration and Biopsy
Pure B-Cell Disorders

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Resource Center Sepsis
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Human Embryonic Stem Cells: A Potential Source of Transplantable Neural Progenitor Cells
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The Role of the Thymus in HIV Infection: A 10-Year Perspective
SCID Patient Has Leukaemia After UK Gene Therapy

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

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 are the following:

• Premature cell death caused by the accumulation of purine metabolites (seen in adenosine deaminase (ADA) deficiency)
• Defective V(D)J rearrangements of the TCR and B-cell receptor genes (BCR) (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 CD3δ, CD3ε, or CD3ζ) 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 adenosine deamination to inosine and deoxyadenosine deamination 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. This condition produces a paradoxical combination of immunodeficiency and immune dysregulation, which is the result of mutations in the genes coding for the recombinases (ie, RAG1 and RAG2) that cause a defect in the VDJ rearrangement that is needed for mature B-and T-cells to develop.  

In study by Khiong et al, the authors identified a C57BL/10 mouse with a spontaneous mutation in and reduced activity of RAG1.² Mice bred from this animal exhibited major symptoms of Omenn syndrome, including having high numbers of memory-phenotype T cells, experiencing hepatosplenomegaly and eosinophilia, having oligoclonal T cells, and demonstrating 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 the these "memory mutant" mice may be a model for human Omenn syndrome, and many symptoms of the murine disease were direct results of the RAG hypomorphism, whereas some were caused by malfunctions of their CD4+ T-cells.²

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.³

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.

The underlying abnormality in selective IgM deficiency 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 symptoms 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. 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 in the secretions of mucous membranes, are the major determinants of mucosal immunity.

IgG antibodies are the only immunoglobulin class that crosses the placenta and provides 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 symptoms of SCID. Symptoms 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 with recurrent sinopulmonary bacterial infections, poor growth, lymphadenopathy and splenomegaly, ataxia-telangiectasia (AT) and Nijmegen breakage syndrome (NBS). These are part of 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, ie, 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.

Related eMedicine topics:
Immunoglobulin A Deficiency
Immunoglobulin G Deficiency
Immunoglobulin M Deficiency

Related Medscape topics:
Resource Center Genomic Medicine
Specialty Site Allergy & Clinical Immunology
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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.

X-linked SCID is the most common form of this disorder (approximately 42%), followed by autosomal recessive SCID (22%), ADA deficiency (approximately 15%), and JAK3 deficiency (6%).

The incidence of reticular dysgenesis and CHH are less than 1% each. In approximately 14% of cases, the etiology remains unknown.⁴

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 Australia is 0.15 cases per 100,000; in Norway, 0.045 cases per 100,000; in Switzerland, 0.47 cases per 100,000; in Sweden, 2.43 of every 100,000 live births.⁵

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 carinii pneumonia and invasive fungal infections, and mortality may ensue from common viral illnesses (eg, infections with varicella (VZV), respiratory syncytial virus (RSV), rotavirus, parainfluenza virus, cytomegalovirus (CMV), Epstein-Barr virus (EBV), enterovirus, adenovirus).⁴

Related Medscape topics:
Resource Center Sepsis
Resource Center Vaccines
Specialty Site  Infectious Diseases
Specialty Site Pediatrics

Race

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 following⁴:

• JAK3 mutations in Italy
• MHC class II deficiency of North African origin
• ZAP70 mutations in the Mennonite population
• Artemis gene product–deficiency in Navaho Indians of Athabasca descent
• RAG1/RAG2–deficient SCID in Europe
• CHH in the Finnish population and the old Amish order in the United States

Sex

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

Age

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

Related Medscape topics:
Resource Center Neonatal Medicine
Specialty Site Pediatrics

CLINICAL

Section 3 of 10  

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

History

The clinical manifestation landmarks of SCID are secondary to the profound degree of immune compromise leading to repetitive and frequent bacterial, viral, and fungal infections that persist despite standard medical treatment.

Patients with primary T-cell deficiency or 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 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 P carinii or CMV, disseminated bacille Calmette-Guérin (BCG) infection, 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:

• 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 immunodeficiency with hyper IgM syndrome (XHM)
• • XHM is a part of the hyper-IgM syndromes that includes a group of disorders characterized by recurrent bacterial infections, 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.
  • Patients with XHM present with recurrent infections of the upper and lower respiratory tracts beginning during the first 2 years of life. The susceptibility to P carinii and Clostridium parvum, both opportunistic infections controlled by cellular immunity, may be explained by the nature of the defect underlying this disease, involving T-cell CD40L.
  • These patients have a high incidence of liver disease and sclerosing cholangitis (approximately 20% of patients in a series reported by Levy et al⁶; 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.
• X-linked severe combined immunodeficiency (XSCID)
• • XSCID is by far the most common form of SCID, accounting for almost 50% of the cases. 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 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 symptoms in patients with X-linked agammaglobulinemia (XLA) do not manifest symptoms until the second half of an infant's first year of life.Persistent opportunistic infections with Candida albicans or P carinii and viral infections with VZV, CMV, and EBV are common.The risk of GVHD is high in these patients because of their inability to reject foreign antigens.
• 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 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.
• • This syndrome is characterized by high serum IgE levels, decreased levels of the other immunoglobulins, and hypereosinophilia.
  • RAG1 deficiency is observed in patients with CHH. This condition is characterized by short hands; metaphysial chondroplasia; hyperextensibility of the distal joints of hands and feet; and fine, light hair.
• CHH
• • CHH manifests in early infancy with 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
• • This 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
• Wiskott-Aldrich Syndrome
• • WAS affects only males because it is transmitted by an X-linked recessive 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 the 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 carinii 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.

Physical

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

• 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 are observed following skin infections. A desquamating erythematous rash is observed in persons with Omenn syndrome.
• Evidence of past perforations, scarring, and dull tympanic membranes are observed after recurrent episodes of otitis media. 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 be present in patients with antibody deficiency following vaccination.
• Deep sensory loss with decreased vibratory sense and position of limb segments are observed in persons with pernicious anemia.

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Resource Center Vaccines
Specialty Site  Cardiology
Specialty Site Hematology-Oncology
Specialty Site Pulmonary Medicine

Causes

SCID disorders are the result of specific genetic alterations in key regulators of B-, T- and/or NK-cell activation, proliferation, or differentiation. The genetic alterations had been identified in some of these 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.⁷ This group of investigators recently identified several mutations in RMPR in patients with CHH.)
• Reticular dysgenesis
• WAS – Rare X-linked disorder with variable clinical phenotypes that correlate with the type of mutations in the WAS protein (WASP) gene

DIFFERENTIALS

Section 4 of 10  

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

Other Problems to Be Considered

Patients with combined B-cell and T-cell disorders present with symptoms similar to those of patients with pure B-cell disorders; however, the association of infections controlled by cellular immunity should point to the possibility of a combined deficiency in both humoral and cellular immunity. Exclude HIV infection with appropriate testing.

Related Medscape topics:
Resource Center Antiretroviral Drug Resistance and Testing
Resource Center Antiretroviral Therapy
Resource Center HIV Pathogenesis
Resource Center HIV Transmission & Prevention

WORKUP

Section 5 of 10  

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

Lab 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 RSV, HSV, VZV, measles, influenza, or parainfluenza
• A family history of SCID

There is no population screening for SCID at present.

The probable diagnosis of SCID is based on the following:

• A T-cell count less than 20% of the 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/µL (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, T, and 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 related to specific disorders are as follows:

• XHM
• • The IgM measurement is markedly increased to levels frequently higher than 1000 mg/dL. Note: Normal levels do not exclude the diagnosis (in a study, normal levels were present in 29 of 55 patients with genetically proven XHM⁶). 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 in patients with ADA deficiency. The values in carriers are half to two thirds of the normal values of erythrocyte deoxy ATP. Lymphopenia is more severe than in other SCID syndromes (ie, <500/µL). Although the number of B 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.

Related Medscape topics:
Specialty Site Hematology-Oncology
Specialty Site Pathology & Lab Medicine

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.
  • A very common finding in SCID can be absence of a thymic shadow. (DiGeorge syndrome and other T-cell defects may also lack thymic tissue, but the presence of thymic tissue does not exclude SCID. Moreover, patients with SCID who have mutations in ZAP70 or CD3 typically have normal-sized thymuses.)
  • Patients with ADA deficiency typically show cupping and flaring of the costochondral junctions.

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.

Procedures

• 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 centers⁸

TREATMENT

Section 6 of 10  

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

Medical Care

Patients with combined immunodeficiencies, such as SCID, XHM, Good syndrome, and WAS, may benefit from intravenous immunoglobulin (IVIG) replacement therapy. 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 patients' diarrhea and, to a certain extent, of malabsorption syndrome. Prophylactic antibiotic therapy may significantly decrease the incidence of infections.
• Patients with ADA deficiency may benefit from substitution with pegademase bovine ADA. The maximum effect on immunologic function does not occur for several months. (see the package insert for details.)
• Inherited and acquired diseases of the hematopoietic system can be cured by allogeneic hematopoietic stem cell transplantation. 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). Bone marrow transplantation 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.

• • The discovery of the HLA system in 1968 led to successful bone marrow transplantations. Patients with immunodeficiency syndromes were the first to benefit from this novel therapy.
  • Allogeneic bone marrow transplantation has become the standard of care for certain patients with SCIDs (eg, XSCID, ADA deficiency). Patients with other immunodeficiency syndromes may benefit from bone marrow transplantation or HSCT, including those with WAS or XHM.
  • • There are many groups that are exploring the potential benefits of HSCT based on alternative donors. There are several advantages of umbilical cord blood stem cell transplantation (UCBSCT), which include 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 GVHD and transplant-related mortality.
    • To facilitate the identification of a suitable MUD, there have been recent advances, including the following:
    • • The continuous growth of volunteer donors worldwide
      • High-resolution molecular techniques for HLA typing, which permits a better selection of donors
      • Advances in critical care 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.⁹ 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%).⁹
  • 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]).¹⁰
  • Another report noted the inefficacy of bone marrow transplantation in correcting Job syndrome.¹¹
• Despite the success that has been seen in some SCID patients treated with bone marrow transplantation, in some cases, failure to restore B-cell function or failure or rejection of the graft over time occurrence. 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.
• • 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.³ This therapy resulted in complete immune reconstitution of the lymphoid system, with T-, B-, and NK-cell counts comparable to age-matched controls.³ 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. Until recently, no successful sustained expression of ADA occurred in treated patients. A trial conducted by Kohn et al is under way.¹²
  • Novel forms of gene therapy are being tested in clinical studies.^{5, 13} One approach known as gene-modified autologous HSCT has shown some promising results; this therapy has the potential to circumvent the significant limitations of allogeneic bone marrow transplantation and gene therapy by using postthymic differentiated cells.

    RNA viruses are the most commonly used vectors to introduce genetic information into hematopoietic stem cells and/or progenitor cells. There have been reports of spontaneous, partial corrections of the phenotype of severe T-cell immunodeficiencies (eg, ADA deficiency, SCID-X1, WAS, RAG1 deficiency, CD3 deficiency) within the past decade. It has been demonstrated that several T-cell precursors which carry a wild-type sequence of the disease-causing gene or mutation with less harmful effects can mature into functional mature T cells that provide adequate immunity. The selective advantage conferred by the expression of either gamma C or ADA in lymphocyte progenitors was confirmed in 3 gene therapy clinical trials.

    It is striking to note that gene therapy for ADA deficiency was only successful in patients who did not concomitantly receive polyethylene glycol–ADA (PEG-ADA) enzymatic substitution.¹⁴

Consultations

Consultations should be obtained with specialists from the following specialties:

• Bone marrow transplant
• Gastroenterology
• Nutrition
• Infectious diseases

Diet

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

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.

Related Medscape topics:
Resource Center Exercise and Sports Medicine
Resource Center Patient Safety
Resource Center Sepsis
Resource Center Vaccines

MEDICATION

Section 7 of 10  

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

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

Drug Category: Blood Products/Immunoglobulins

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

Drug Category: Metabolic Enzymes

Metabolic enzymes are used to replace ADA.

FOLLOW-UP

Section 8 of 10  

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

Further Outpatient Care

• Regularly monitor patients for the following parameters:
• • Growth and development
  • Chest radiographs
  • Pulmonary function
  • Immunoglobulin trough levels
  • • levels greater than or equal to 400 mg/dL 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.
• Liver function tests should be performed. If abnormalities are identified, imaging studies of the liver and biliary tree are necessary to exclude malignancies or sclerosing cholangitis (the latter is observed in patients with XHM).

In/Out Patient Meds

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

Transfer

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

Deterrence/Prevention

• 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.

Complications

• 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.¹⁵
• Central nervous system viral infection is one of the most potentially devastating complications of i