Severe combined immunodeficiency (SCID): An overview

INTRODUCTION — 

The terms "primary immunodeficiency" and "inborn errors of immunity" denote diseases resulting from inherited defects of the immune system. Many distinct disorders have been described [1]. Combined immunodeficiency syndromes are a heterogeneous group of disorders arising from a disturbance in the development and function of both T and B cells (cellular and humoral immunity) and may also involve natural killer (NK) cells. Combined immunodeficiencies are termed "severe" when they lead to early death from overwhelming infection, typically in the first year of life. Severe combined immunodeficiency (SCID) can be categorized as typical SCID or, if less severe, leaky SCID based upon the severity of T cell qualitative and quantitative deficiency. (See "Inborn errors of immunity (primary immunodeficiencies): Classification".)

An overview of SCID, including clinical manifestations and diagnosis, is presented here. The major combined immunodeficiencies, including multiple causes of SCID, are discussed in detail separately:

●(See "Severe combined immunodeficiency (SCID): Specific defects".)

●(See "X-linked severe combined immunodeficiency (X-SCID)".)

●(See "Adenosine deaminase deficiency: Pathogenesis, clinical manifestations, and diagnosis".)

●(See "T-B-NK+ SCID: Pathogenesis, clinical manifestations, and diagnosis".)

●(See "Severe combined immunodeficiency (SCID) with JAK3 deficiency".)

●(See "ZAP-70 deficiency".)

●(See "Combined immunodeficiencies: An overview" and "Combined immunodeficiencies: Specific defects".)

●(See "CD3/T cell receptor complex disorders causing immunodeficiency".)

●(See "Syndromic immunodeficiencies".)

EPIDEMIOLOGY — 

A study using data from newborn screening for SCID from 11 states in the United States found an incidence of 1 in 58,000 live births (95% CI, 1 in 46,000 to 1 in 80,000) for SCID, inclusive of typical SCID, leaky SCID, and Omenn syndrome [2]. The incidence of autosomal recessive SCID is higher in cultures in which consanguineous marriage is common [3,4]. (See 'SCID classification' below and "Newborn screening for inborn errors of immunity".)

PATHOGENESIS — 

SCID is a syndrome caused by mutations in any of several genes whose products are crucial for the development and function of T cells, with some also impacting development of B cells and natural killer (NK) cells (table 1) [1]. However, serious T cell dysfunction precludes effective humoral immunity since B cells require signals from T cells to produce antibody.

NK cells, a non-T, non-B lymphocyte subset exhibiting cytotoxic activities, develop via a pathway distinct from B and T cells. NK cells are present in approximately 50 percent of patients with SCID and may provide a degree of protection against bacterial and viral infections in these patients. Determining the presence or absence of NK cells is also helpful in guiding mutation analysis of patients with SCID. (See "T-B-NK+ SCID: Pathogenesis, clinical manifestations, and diagnosis".)

The pathogenesis of SCID is reviewed in greater detail in specific SCID topics.

While typical SCID is characterized by complete or near-complete absence of T cell function, with variable intrinsic defects of B and NK cells, the related clinical entities Omenn syndrome and leaky SCID occur in individuals in whom T cells are significantly reduced in number and diversity. Hypomorphic defects in any of the genes associated with typical SCID can cause Omenn syndrome or leaky SCID.

GENETICS — 

A list of known gene defects that cause SCID is presented in the first two sections of the table (table 1). The most common genetic form of typical SCID is mutation in the X-linked gene IL2RG, encoding the interleukin 2 receptor gamma chain, also called the common cytokine receptor gamma chain (gamma-c).

All other causes of SCID are also autosomal recessive in inheritance and are due to mutations in genes associated with proteins that mediate cytokine signaling; signaling through the T cell antigen receptor (TCR); recombination of the variable, joining and diversity (V(D)J) regions of the TCR and immunoglobulin genes; and certain cellular metabolic pathways. Other commonly identified autosomal recessive genetic defects causing SCID occur in the interleukin 7 receptor alpha chain gene (IL7R), Janus kinase 3 gene (JAK3), deoxyribonucleic acid (DNA) cross-link repair protein 1C gene or Artemis (DCLRE1C), and adenosine deaminase (ADA) gene. Autosomal recessive pathogenic variants in recombination-activating genes 1 and 2 (RAG1 and RAG2) more commonly cause leaky SCID than typical SCID.

In a report by the Primary Immune Deficiency Treatment Consortium (PIDTC) of 100 SCID patients diagnosed and followed prospectively through transplant, 87 percent had an identified genetic defect, and 12 different involved genes were reported amongst the 100 patients [5].

SCID CLASSIFICATION — 

In the past, SCID syndromes were classified as T-B+NK+, T-B+NK-, T-B-NK+, or T-B-NK- based on lymphocyte subset profiles. Patients with typical SCID have low-to-absent numbers of autologous T cells, while numbers of B and natural killer (NK) cells, regardless of the functional status of these cells, generally fall into the above categories (table 1). However, presence of nonautologous maternal T cells transferred transplacentally to the infant can mask low intrinsic T cell numbers. In addition, patients with Omenn syndrome may have normal or high absolute numbers of autologous T cells with limited diversity and a memory phenotype (CD45RO+). Leaky SCID (also called atypical SCID) likewise is associated with low to normal T cell numbers that prove insufficient to sustain immune function over time. The definitions of SCID types were updated by the US Primary Immune Deficiency Treatment Consortium (PIDTC) in 2022 to clarify these distinctions [6,7].

The mutated gene responsible can now be determined for a majority of cases of SCID since genetic sequence-based diagnosis is readily available [8]. Thus, it is appropriate to refer to SCID according to the specific molecular defect once it is identified, particularly since the genotype can impact decisions regarding treatment protocol and also has implications for risks of posttreatment complications and/or gene defect-specific nonimmune manifestations. (See 'Genetics' above and "Severe combined immunodeficiency (SCID): Specific defects".)

CLINICAL FEATURES

Clinical presentation — In infants identified to have SCID via newborn screening, most are well appearing at the time of first assessment [9].

In the absence of population-based newborn screening, the diagnosis is often delayed by several months since infants with SCID outwardly appear normal, maternally derived immunoglobulin G (IgG) antibodies transferred prenatally provide some protection for the first months of life, and very young infants are likely to be relatively isolated from exposure to infection [10].

The classic symptoms of typical SCID not diagnosed at birth are recurrent, increasingly severe infections, opportunistic infections, chronic diarrhea, and failure to thrive (FTT) [11]. Increased resting energy expenditure (hypermetabolism) is common in SCID patients with FTT and may contribute to its development [12]. SCID, by definition, is universally fatal in the first year or two of life if not treated with immune function-restoring therapy. (See 'Definitive therapy' below.)

Physical examination of infants with SCID may reveal a focus of infection, such as oral thrush. In countries that employ live Bacillus Calmette–Guérin (BCG) vaccination at birth as a protective measure against tuberculosis, prolonged local and disseminated infection with BCG can occur in infants with SCID. In addition, discernible peripheral lymphoid tissue (tonsils, adenoids, axillary/inguinal nodes) is absent, except in Omenn syndrome, in which adenopathy and an erythroderma rash may be found. (See "Recognition of immunodeficiency in the first three months of life".)

Increased susceptibility to infection — The absence of both specific cellular and humoral immunity in patients with SCID leads to a profound susceptibility to infection [5,10,13]:

●Persistent mucocutaneous candidiasis is a common early finding.

●Infections with common viral pathogens, such as adenovirus, cytomegalovirus (CMV), Epstein-Barr virus (EBV), rotavirus, norovirus, respiratory syncytial virus (RSV), varicella zoster virus (VZV), herpes simplex virus (HSV), measles virus, influenza viruses, and parainfluenza 3 virus, are severe and frequently fatal.

●Opportunistic infections with normally nonpathogenic organisms, such as Pneumocystis jirovecii, occur frequently.

●Live-attenuated vaccine organisms, such as oral polio vaccine virus, attenuated live rotavirus, varicella vaccine, measles/mumps/rubella (MMR) vaccine, and BCG, may cause severe, disseminated, or fatal infection [14]. (See "Immunizations in patients with inborn errors of immunity", section on 'Live vaccines'.)

Absence of thymic shadow — The absence of a thymic shadow on chest radiography (image 1) is a typical finding in infants with SCID but is not considered a necessary component of the evaluation following an abnormal T cell receptor excision circle (TREC) based SCID newborn screen [2,15-18]. Additionally, several genetic forms of SCID are associated with radiosensitivity; therefore, it is not recommended to universally obtain chest radiography of all infants suspected to have SCID. Furthermore, the presence of a thymic shadow does not rule out SCID, since the thymus may sometimes be visible in rare forms of SCID (eg, coronin 1A and CD3 delta deficiencies) [19]. Moreover, infants who do not have SCID but who have malnutrition or metabolic stress due to serious or overwhelming infection or other severe illness may have involution of the thymus such that it is no longer apparent on chest radiograph. Nevertheless, an absent thymic shadow warrants an immune evaluation.

Graft-versus-host disease — Patients with SCID may also suffer from graft-versus-host disease (GVHD) prior to definitive treatment with transplant due to [20,21]:

●Transplacental passage of alloreactive maternal T cells

●Transfusion of nonirradiated blood, erythrocytes, or platelet products containing viable lymphocytes, which can lead to rapidly fatal GVHD

Laboratory abnormalities

Typical findings — A low total lymphocyte number on a complete and differential blood count is a hallmark of SCID but may not occur in SCID with high numbers of B and/or natural killer (NK) cells, with maternal engraftment, or with leaky SCID or Omenn syndrome [22]. In the United States and other countries and regions that include testing for SCID on population-based newborn screening, the most common initial sign of SCID is low TRECs detected in DNA from dried blood spots (DBS) [5].

The laboratory abnormalities observed in typical SCID include low-to-absent T cell numbers, as measured by T cell enumeration by flow cytometry; low-to-absent proportions of naïve T cells, which bear the cell surface marker CD45RA; and functional variants in known SCID genes [2,6,7,15-17]. Presence of maternal T cells is a strong indication of SCID [23,24]. Laboratory studies necessary to confirm the diagnosis are discussed below. (See "Newborn screening for inborn errors of immunity", section on 'Screening for SCID and other T cell defects' and 'Confirmatory studies' below.)

Ancillary studies — Other laboratory studies performed as part of the evaluation but that are not required for the initial diagnosis of SCID include the following (see "Laboratory evaluation of the immune system"):

●B and NK cell counts – These counts may be low, depending upon the specific defect, and should also be quantified by flow cytometry [2,6,7,15-17]. (See "Flow cytometry for the diagnosis of inborn errors of immunity", section on 'B cells' and "Flow cytometry for the diagnosis of inborn errors of immunity", section on 'Natural killer cells'.)

●Assessment of radiosensitivity – This assessment is performed in patients found to have variants of undetermined significance in genes associated with SCID and radiosensitivity [6,7,16]. The presence of radiosensitivity can have implications for safety of imaging modalities as well as choice of conditioning regimen that may be used for hematopoietic cell transplant (HCT). (See "T-B-NK+ SCID: Pathogenesis, clinical manifestations, and diagnosis", section on 'Evaluation for radiation sensitivity'.)

●Quantitative immunoglobulin levels – Hypogammaglobulinemia is often found but may be obscured due to the presence of maternal IgG in the blood in early infancy if only IgG is measured [25]. Serum levels of immunoglobulin M (IgM) and immunoglobulin A (IgA) are usually very low, although they may be low due to other causes, such as transient hypogammaglobulinemia of infancy or other primary antibody defects. IgE ranges from undetectable in typical SCID to markedly elevated in Omenn syndrome, a form of leaky SCID in which partial gene function is retained, leading to dysregulated immune manifestations. (See "Transient hypogammaglobulinemia of infancy" and "T-B-NK+ SCID: Pathogenesis, clinical manifestations, and diagnosis", section on 'Additional features'.)

●Specific antibody responses to antigens – Specific antibody responses are severely impaired [26]. However, it is not useful to test them if SCID is suspected in an infant, since the results in infants under six months of age are confounded by the presence of maternal IgG antibodies. In addition, false-positive responses are found in infants who have received immune globulin replacement therapy. (See "Laboratory evaluation of the immune system", section on 'Measurement of antibody function'.)

●T cell antigen responses – Cutaneous anergy to recall antigens is universal, but this test is not reliable under one year of age [27]. In vitro tests of T cell antigen response, such as proliferative response to tetanus toxoid, may be used only after the infant has been immunized. Thus, testing for antigen response is not usually required in the context of evaluation for SCID. (See "Laboratory evaluation of the immune system", section on 'T cell function proliferation assays'.)

DIAGNOSIS

When to suspect SCID — Prior to the widespread use of newborn screening in the United States, most patients were identified based on either clinical symptoms of infection or a positive family history of SCID [5]. The diagnosis of SCID should be suspected in children with any of the following [28] (see "Approach to the child with recurrent infections", section on 'Clinical features suggestive of an inborn error of immunity'):

●Positive newborn screening result for SCID (see "Newborn screening for inborn errors of immunity", section on 'Screening for SCID and other T cell defects')

●Unexplained lymphopenia

●Recurrent fevers

●Failure to thrive (FTT)

●Chronic diarrhea

●Opportunistic infections, such as with Pneumocystis jirovecii, or infectious complications following live vaccines, such as Bacillus Calmette-Guérin (BCG), rotavirus vaccine, or varicella vaccine

●Recurrence of episodes of thrush, mouth ulcers, or infections with respiratory syncytial virus (RSV), herpes simplex virus (HSV), varicella zoster virus (VZV), measles virus, influenza viruses, or parainfluenza 3 virus

●A family history of SCID (seen in <20 percent of cases)

Confirmatory studies — Laboratory studies necessary to confirm the diagnosis include the following:

●Absolute lymphocyte count (compared with age-adjusted reference range) – There is usually a low absolute lymphocyte count (<2500 cells/microL) [29] since the thymus is generally small and devoid of lymphocytes. Occasionally, the absolute lymphocyte count is normal. This can be due to a high number of B cells or the presence of transplacentally transferred maternal T cells. (See "Laboratory evaluation of the immune system", section on 'Complete blood count with differential and blood smear'.)

●CD3+ T cell count – Abnormalities of lymphocyte subpopulations as determined by flow cytometry may vary depending upon the specific molecular defect (table 1). Autologous CD3+ T cells are <50 cells/microL in typical SCID and usually between 50 to <1000 cells/microL in leaky/atypical SCID [24]. The T cell count may be normal or high in some cases due to the presence of maternal T cells in typical SCID or abnormal clonal expansion of a small number of autologous cells, as in Omenn syndrome. (See "Laboratory evaluation of the immune system", section on 'Flow cytometry for cell populations'.)

●Proportion of naïve T cell populations – Assessment of naïve T cell populations using flow cytometry-based methods, most commonly assessing the proportion of CD4/CD45RA+ T cells relative to either memory T cells (CD4/CD45RO+) or the total CD4 count [6,7]. Regardless of the underlying genetic defect, T cells in SCID exhibit a predominance of memory cells. (See "Laboratory evaluation of the immune system", section on 'Flow cytometry for cell populations'.)

●Genetic testing – Genetic testing to determine if pathologic variants in specific genes associated with SCID are present [6,7]. This is most commonly accomplished via commercially available, panel-based testing. In cases where panel-based testing is not diagnostic, an unbiased whole exome or whole genome testing, both of which are becoming increasingly available, can be applied. (See "Genetic testing in patients with a suspected primary immunodeficiency or autoinflammatory syndrome".)

●Testing for transplacental maternal engraftment (TME) – This testing is typically performed in conjunction by human leukocyte antigen (HLA) typing laboratories at centers that perform hematopoietic cell transplantation (HCT) [6,7]. Clinically, the presence of maternal engraftment may lead to maternal graft-versus-host disease (GVHD) affecting the infant's skin, liver, and/or other organs and requiring immunosuppressive treatment prior to HCT or gene therapy. (See "Laboratory evaluation of the immune system", section on 'Advanced tests'.)

●Testing for oligoclonality of the T cell receptor (TCR) – Either spectratyping or sequence-based assessment of the diversity of the TCR beta-chain variable region (TCRV beta) repertoire can be used. Flow cytometric determination of proportions of TCRV beta families is sometimes measured, but this is less informative than sequence-based assessments [6,7]. (See "CD3/T cell receptor complex disorders causing immunodeficiency", section on 'Overview of T cell receptor biology'.)

●T cell proliferative responses to mitogen or anti-CD3 – T cell proliferative responses may be low, and this is one of the criteria that can be used in confirming a diagnosis of leaky SCID. However, poor proliferation to the mitogen phytohemagglutinin (PHA) may merely reflect low T cell number and is no longer a requirement for diagnosing typical SCID [2,23,24,30-32]. (See "Laboratory evaluation of the immune system", section on 'T cell function proliferation assays'.)

Diagnostic criteria for typical SCID — The Primary Immune Deficiency Treatment Consortium (PIDTC) developed updated diagnostic parameters in 2022 based upon the prospective assessment of infants with SCID [6,7,33].

To diagnose typical SCID, patients must have a total T cell (CD3) count of <50 autologous (not maternally derived) cells/microL and one of the following:

●Pathologic variant(s) in an X-linked (or autosomal recessive) SCID-associated gene

●Low or absent T cell receptor excision circles (TRECs), as found on newborn screen

●Less than 20 percent of CD4 T cells of naïve phenotype

●Documented engraftment of maternal T cells, in which case total T cell count may exceed 50 cells/microL

Diagnostic criteria for leaky (atypical) SCID — Leaky (atypical) SCID is caused by hypomorphic mutations in any defined SCID gene, allowing development of some T cells, generally with poor function and limited diversity. Individuals with leaky SCID may present via newborn screening or have somewhat milder symptoms and/or a later presentation compared with those who have full loss of function of the gene product. The diagnosis of leaky SCID requires extensive evaluation of potential genotype, T cell number, diversity, and function.

All patients with leaky or atypical SCID must have two of the following:

●Low T cell count compared with age-adjusted reference range (usually a total T cell [CD3] count between 50 to 1000 cells/microL)

●Oligoclonal T cells with limited diversity

●Low TRECs or <20 percent of CD4 T cells that are naïve

Patients must also demonstrate either pathologic variant(s) in a SCID-associated gene or reduced in vitro proliferation to a stimulus such as PHA.

In addition, all patients with leaky or atypical SCID must not have:

●Another SCID subtype

●Combined immunodeficiency with a known genotype in which null mutations do not ablate T cell development

●A primary disorder of thymic function

●A recognized non-SCID disorder in which T cell numbers are known to be low

●Evidence of maternal T cell engraftment

Diagnostic criteria for Omenn syndrome in patients with leaky SCID — Some patients with hypomorphic mutations in known SCID genes develop Omenn syndrome, in which oligoclonal, dysregulated, autologous T cells cause skin rashes, adenopathy, hepatosplenomegaly, and elevations in eosinophil numbers and immunoglobulin E (IgE). (See "T-B-NK+ SCID: Pathogenesis, clinical manifestations, and diagnosis", section on 'Omenn syndrome phenotype' and "T-B-NK+ SCID: Pathogenesis, clinical manifestations, and diagnosis", section on 'T-B-NK+ SCID without radiation sensitivity due to RAG defects (includes most cases of Omenn syndrome)'.)

The diagnostic criteria for Omenn syndrome include the following:

●At least 80 percent of CD4 T cells have a CD45RO+ memory phenotype

●Presence of a pathologic gene variant in a known SCID gene

●Generalized, typically erythematous rash without maternally engrafted T cells

●And at least two of the following:

•Absolute eosinophil count >800 cells/microL

•Elevated IgE

•Low TREC numbers, such as by newborn screen

•Lymphadenopathy

•Liver or spleen enlargement

•Oligoclonal T cells

Detection of maternal T cell engraftment — Infants with SCID are unable to eliminate maternal T cells, which cross the placenta and enter the fetal circulation or are transferred to the infant during delivery. All infants with a potential diagnosis of SCID should be evaluated for the presence of maternal T cells, which may react against the infant's HLA antigens and expand to levels >8000 cells/microL [34,35]. Maternal T cells may cause the total T cell count to appear "normal." One indicator of maternal T cell engraftment is a strong predominance of either CD4+ or CD8+ T cells, since maternally engrafted cells are oligoclonal. A majority of the maternally engrafted T cells have an activated or memory phenotype (expressing CD45RO). Normal infant T cells are predominantly naïve T cells (expressing CD45RA). These cell surface markers can be measured by flow cytometry. Molecular testing for maternal chimerism should be performed. (See "The adaptive cellular immune response: T cells and cytokines", section on 'Memory T cells' and "Flow cytometry for the diagnosis of inborn errors of immunity".)

Preimplantation and prenatal diagnosis — The use of in vitro fertilization combined with genetic testing of an embryo prior to implantation is an option when there is a history of a prior relative affected with SCID, the specific molecular defect is known, and parent(s) are known mutation carriers. In the case of natural conception, a prenatal diagnosis can be made by genetic tests performed on amniotic fluid or chorionic villus cells [36]. However, there is a small risk of fetal loss in both amniocentesis and chorionic villus cell sampling. Noninvasive prenatal testing of maternal cell-free DNA is now performed for certain disorders such as trisomy 21 but is not generally available for rare single-gene disorders such as those that cause SCID. In any instance, postnatal lymphocyte phenotype testing is necessary to confirm prenatal findings, whether affected or unaffected. (See "Cell-free DNA screening for fetal conditions other than the common aneuploidies".)

Newborn screening — A cost-effective method for screening newborns for T cell lymphopenia uses dried blood spots (DBS) to measure TRECs as a biomarker of naïve T cells. This method of screening for SCID and other disorders with T cell deficiency was added to the recommended uniform newborn screening panel in the United States in 2010. All states in the US perform universal SCID newborn screening, and several other countries and regions have instituted SCID screening or have initiated pilot projects [32,37-39]. Newborn screening for SCID and other inborn errors of immunity is discussed in greater detail separately. (See "Newborn screening for inborn errors of immunity".)

DIFFERENTIAL DIAGNOSIS — 

Three conditions that have similar presentations to SCID in persons who have not been identified by newborn screening are extreme malnutrition, other forms of combined immunodeficiency, and human immunodeficiency virus (HIV) infection/acquired immunodeficiency syndrome (AIDS):

●Extreme malnutrition – Extreme malnutrition can have a SCID-like presentation, including opportunistic infection. T cell function normalizes once adequate nutrition is established. Infants with intestinal lymphangiectasia often present with profound lymphopenia and hypogammaglobulinemia and have been mistakenly diagnosed as having SCID. In these patients, there is usually evidence of intestinal protein loss (hypoalbuminemia, elevated stool alpha-1-antitrypsin). Hereditary folate malabsorption due to mutations in the proton-coupled folate transporter (PCFT) gene can also mimic SCID [40]. These patients will have an associated anemia that is not usually seen in SCID, and their anemia and immune function respond to leucovorin (folinic acid) supplementation. (See "Malnutrition in children in resource-limited settings: Clinical assessment" and "Causes and pathophysiology of vitamin B12 and folate deficiencies", section on 'Genetic disorders (folate)'.)

●Other combined immunodeficiencies – Other forms of combined immunodeficiency may have many of the elements of the clinical presentation of SCID, including opportunistic infections. Some patients with DiGeorge (22q11.2 deletion) syndrome (DGS) or CHARGE (coloboma of the eye, heart anomalies, choanal atresia, retardation, genital and ear anomalies) syndrome have thymic agenesis or partial T cell deficiency, and their syndromic features may be absent, subtle, or not recognized in the newborn period. Partial DGS is the most common non-SCID genetic cause of T cell lymphopenia [32,41]. Genetic testing for these diagnoses should be completed prior to hematopoietic cell transplantation (HCT) since thymic agenesis will not improve without a thymic implant procedure. (See "DiGeorge (22q11.2 deletion) syndrome: Clinical features and diagnosis".)

Other examples of combined immunodeficiencies that have aspects similar to SCID include [1]:

•X-linked hyperimmunoglobulin M syndrome (CD40 ligand deficiency and CD40 deficiency) (see "Hyperimmunoglobulin M syndromes")

•Wiskott-Aldrich syndrome (see "Wiskott-Aldrich syndrome")

•Nuclear factor (NF) kappa-B essential modifier (NEMO) deficiency (see "Syndromic immunodeficiencies")

•Zeta-chain-associated protein 70 (ZAP-70) deficiency (see "ZAP-70 deficiency")

•Calcium channel deficiencies (see "Syndromic immunodeficiencies")

•Purine nucleoside phosphorylase deficiency (see "Purine nucleoside phosphorylase deficiency")

These forms of combined immunodeficiency are usually distinguished by distinctive laboratory features and other elements of the clinical presentation. However, in some cases, the distinction between SCID and a non-SCID combined immunodeficiency is made only by molecular testing. (See "Combined immunodeficiencies: An overview" and "Combined immunodeficiencies: Specific defects" and "Syndromic immunodeficiencies".)

●HIV/AIDS – Infants and young children with HIV/AIDS can present with the SCID symptoms of recurrent severe infections, chronic diarrhea, and failure to thrive (FTT) [42]. Findings that can differentiate HIV/AIDS from SCID, particularly early in the disease course, include a normal T cell receptor excision circle (TREC) count on newborn screening, presence of a thymic shadow on a chest radiograph, normal lymphocyte count with an elevated proportion of CD8+ T cells, normal lymphocyte proliferation to mitogens and antigens, and elevated serum immunoglobulin levels. In young infants, maternal HIV antibodies are often found, and HIV DNA is detected by polymerase chain reaction (PCR). (See "Pediatric HIV infection: Epidemiology, clinical manifestations, and outcome" and "Pediatric HIV infection: Diagnostic testing in children younger than 18 months".)

INITIAL MANAGEMENT

Measures to prevent initial infections — Prevention of infection is imperative for the survival of infants with suspected or confirmed SCID until they are able to undergo definitive therapy for immune reconstitution. In addition, lack of infection at the time of definitive therapy is associated with improved outcomes (see 'Prognosis' below). Thus, several measures to prevent initial infections are commonly undertaken as soon as there is clinical or laboratory suspicion of SCID [11,43], although exact practices may vary by center.

Population-based screening — Population-based newborn screening for SCID has been directly shown to lead to fewer infections and improved survival [24]. (See "Newborn screening for inborn errors of immunity", section on 'Screening for SCID and other T cell defects'.)

Protective isolation — Protective isolation to limit exposure to infection is warranted for all infants with suspected SCID until immune reconstitution has taken place. Isolation can either occur at home or in the hospital. The choice is situationally dependent and can change over time (eg, balance in favor of isolation at home if there are no older siblings who are in daycare/school, a caregiver that is able to stay home to care for the infant, and higher risk of nosocomial infection in the hospital versus balance in favor of hospital isolation if there are several older siblings at home, caregivers that work full time, and greater distance to a tertiary care center if the infant develops an infection) [43,44]. The clinician must weigh the risks and benefits of each option and discuss these options, including specific precautions taken in each setting, with the parent(s)/caregiver(s). Isolation measures and caregiver counseling are discussed in greater detail separately. (See "Inborn errors of immunity (primary immunodeficiencies): Overview of management", section on 'Isolation measures for infants' and "Inborn errors of immunity (primary immunodeficiencies): Overview of management", section on 'Caregiver counseling'.)

Avoidance of live vaccines — Live-attenuated vaccines (table 2) are contraindicated in patients with suspected SCID because immunization with live-attenuated viruses or bacteria can cause disseminated disease in patients with combined immunodeficiencies. Other routine childhood immunizations are typically delayed until immune reconstitution or exclusion of the diagnosis of SCID because they are unlikely to be effective; there are not any SCID-specific concerns about harm for these vaccines. Immunizations in patients with SCID and other inborn errors of immunity are discussed in greater detail separately. (See "Immunizations in patients with inborn errors of immunity", section on 'Live vaccines' and "Immunizations in patients with inborn errors of immunity", section on 'Combined immunodeficiencies'.)

Vaccination of healthy close contacts — All inactivated vaccines should be offered according to schedule to healthy household contacts and other close contacts of infants with suspected SCID in order to provide secondary protection to the patient with SCID. Live influenza, oral polio, and smallpox vaccine are avoided in close contacts [45]. Other live vaccines are permitted. Immunization in close contacts and standard immunizations in children, adolescents, and adults are discussed in greater detail separately. (See "Immunizations in patients with inborn errors of immunity", section on 'Healthy household contacts of immunodeficient patients' and "Standard immunizations for children and adolescents: Overview" and "Standard immunizations for nonpregnant adults" and "Immunizations during pregnancy".)

Caution with blood products — Patients with suspected or known T cell immunodeficiencies such as SCID should not be given blood or blood components that may contain viable lymphocytes because of the high risk of fatal transfusion-associated graft-versus-host disease (GVHD) [46,47]. Any cellular blood products given to these patients must be irradiated to inactivate viable T cells [21]. Leukocyte reduction is also required in order to minimize chances of transmission of cytomegalovirus (CMV), which can cause significant disease in persons who have an underlying T cell defect or have undergone hematopoietic cell transplantation (HCT); in addition, CMV-negative blood products are preferred [48-50]. These approaches are reviewed in greater detail separately. (See "Inborn errors of immunity (primary immunodeficiencies): Overview of management", section on 'Caution with blood products' and "Transfusion-associated graft-versus-host disease", section on 'Immunodeficiency' and "Transfusion-associated graft-versus-host disease", section on 'Prevention' and "Red blood cell transfusion in infants and children: Selection of blood products", section on 'Red blood cell products' and "Overview of cytomegalovirus (CMV) infections in children", section on 'Prevention of neonatal transmission' and "Overview of cytomegalovirus (CMV) infections in children", section on 'CMV-safe blood products'.)

Breast milk precautions — For infants with suspected or confirmed SCID, we recommend avoidance of breast milk from CMV-seropositive females. If the current CMV status of the lactating parent or donor is not known, the infant should be fed sterile formula rather than breast milk until CMV seronegativity can be confirmed.

Observational data from cohorts of patients with SCID who have undergone HCT demonstrate that CMV remains one of the most common causes of death for infants with SCID and has occurred despite newborn screening when infants received breast milk prior to SCID diagnosis [11,43,51-54]. CMV infection is also associated with worse neurologic outcomes and autoimmune cytopenias in these patients. CMV infections most commonly occur in infants who receive breast milk from seropositive mothers, who can continue to shed CMV in breast milk years after initial infection, although CMV transmission may still occur in the absence of breastfeeding [52]. (See "Overview of cytomegalovirus (CMV) infections in children", section on 'Prevention of neonatal transmission' and "Infant benefits of breastfeeding".)

A retrospective analysis of patients in the United Kingdom reported that CMV infection was exclusively seen in breastfed SCID infants [51]. However, other studies have shown a lower than expected maternal-to-infant transmission in infants with SCID (6 percent) [31,52] compared with transmission in preterm infants (40 percent) [55]. Methods to eliminate CMV from breast milk have not been proven completely effective and are therefore not advised [56].

Immune globulin replacement therapy — For all infants with confirmed SCID, we recommend initiation of antibody replacement therapy with immune globulin (either intravenously or subcutaneously). Immune globulin replacement is typically started at standard replacement dosing used for patients with other forms of antibody deficiency and combined immunodeficiencies and is typically continued through immune reconstitution with either HCT or gene therapy. It is stopped once there is evidence of functional B cell recovery. The purpose of immune globulin replacement therapy in patients with SCID is to prevent severe, life-threatening bacterial infections, both before undergoing HCT and until B cell reconstitution is demonstrated [31,43,57]. Observational data from HCT cohorts indicate survival is significantly higher in patients who undergo HCT before they developed serious infections (approximately 90 to 96 versus 70 to 76 percent) [13,58-62]. Details on dosing and administration are reviewed in detail separately, as are outcomes and factors associated with improved survival. (See "Immune globulin therapy in inborn errors of immunity" and "Hematopoietic cell transplantation for severe combined immunodeficiencies", section on 'Early identification'.)

Antimicrobial prophylaxis — Antimicrobial prophylaxis may be given for the following indications (example regimens are listed in the table (table 3) (see "Inborn errors of immunity (primary immunodeficiencies): Overview of management", section on 'Prophylactic antimicrobial therapy'):

●P. jirovecii pneumonia (PJP) – All infants with SCID should receive PJP prophylaxis. The standard approach is followed. PJP prophylaxis is discussed in greater detail separately. (See "Treatment and prevention of Pneumocystis pneumonia in patients without HIV", section on 'Prophylaxis'.)

●Mucocutaneous candidiasis – Mucocutaneous candidiasis is a common finding in patients with T cell deficiencies, including SCID [5]. It is seen even in infants diagnosed with SCID via newborn screening, although incidence is lower, which may be attributable to early intervention with antifungal prophylaxis directed towards this infection [15,43]. For infants with SCID, we suggest antifungal prophylaxis with fluconazole. Oral or topical nystatin is a reasonable alternative. Dosing is similar to that used in other neonates and is reviewed in detail separately. (See "Candida infections in neonates: Treatment and prevention".)

●Respiratory syncytial virus (RSV) – All infants with SCID who are born during the RSV season or entering their first RSV season should be given RSV immunoprophylaxis. The standard approach to RSV immunoprophylaxis is followed. This approach is reviewed in greater detail separately. (See "Respiratory syncytial virus infection in infants and children: Prevention", section on 'Immunoprophylaxis'.)

●Herpesviruses – Prophylaxis against viruses in the herpesvirus family (eg, herpes simplex virus [HSV]) is indicated if the birthing parent had active HSV lesions at the time of delivery or if the infant has been exposed to a person with cold sores. The approach in infants with SCID is the same as for other neonates and is reviewed in detail separately. (See "Neonatal herpes simplex virus (HSV) infection: Management and prevention".)

Surveillance for viral infections — Screening for congenital or postnatally acquired CMV infection, Epstein-Barr virus (EBV), human immunodeficiency virus (HIV), and other respiratory viruses, by molecular rather than serologic testing because of the lack of immunologic response to infection, is indicated after confirmation of the diagnosis of SCID. (See "Congenital cytomegalovirus (cCMV) infection: Clinical features and diagnosis", section on 'Clinical suspicion'.)

Monitoring for autoinflammatory complications — Some patients with SCID, particularly those with leaky SCID due to hypomorphic mutations in known SCID-causing genes, are able to make small number of T cells. However, these T cells do not go through typical development and commonly have a restricted diversity with a propensity towards autoreactivity and resulting inflammatory complications that include the Omenn syndrome phenotype. Thus, serial monitoring of the complete blood count with differential for development of rising absolute lymphocyte count or absolute eosinophil count can aid in monitoring for development of this population of T cells. If present, treatment with immunosuppression, such as prednisone and other systemic immunosuppression, is indicated to control the autoreactive T cells and limit their ability to infiltrate and damage peripheral tissues such as the liver, lung, gut, and others.

DEFINITIVE THERAPY — 

Definitive therapy should be pursued once a diagnosis of typical SCID, leaky/atypical SCID, or Omenn syndrome is made, since early treatment improves outcomes and SCID is uniformly fatal in the first year or two of life without such treatment. A genetic diagnosis is helpful to direct therapy, but it is not necessary for patients treated with hematopoietic cell transplantation (HCT). (See 'Prognosis' below.)

The most common definitive therapy for all forms of SCID is HCT from a tissue-matched healthy donor, ideally a sibling. In addition to HCT for definitive therapy, gene therapy has also demonstrated efficacy in the definitive management of certain genetic forms of SCID, including adenosine deaminase deficiency (ADA), common gamma chain deficiency (IL-2RG, X-linked SCID), and Artemis (DCLRE1C) deficiency, and is in development for other forms of SCID. Gene therapy is advantageous compared with HCT because there is no risk of graft-versus-host disease (GVHD), and it is typically associated with only low-dose chemotherapy-based conditioning with attendant late effect risk. However, access to gene therapy outside of clinical trials is limited. Enzyme replacement therapy (ERT) is also available for ADA deficiency with injections of polyethylene glycol-conjugated recombinant adenosine deaminase [PEG-ADA]). Definitive therapies are discussed in greater detail separately in general and disease-specific topics. (See "Hematopoietic cell transplantation for severe combined immunodeficiencies" and "Overview of gene therapy for inborn errors of immunity", section on 'Gene therapy for specific disorders' and "Adenosine deaminase deficiency: Treatment and prognosis".)

PROGNOSIS — 

SCID is fatal, usually within the first year of life, unless the lack of T cell immunity is corrected. Overall survival rates for patients with SCID are as high as 90 percent following hematopoietic cell transplantation (HCT), with noninfected patients having survival rates of approximately 95 percent, although certain SCID genotypes may continue to have worse outcomes [5]. Survival rates for gene therapy are excellent and may exceed those for HCT for some forms of SCID, but access is limited. These outcomes are discussed in greater detail separately. (See "Hematopoietic cell transplantation for severe combined immunodeficiencies" and "Overview of gene therapy for inborn errors of immunity".)

Viral infections are a leading cause of death in patients with SCID, both before and in the first several months after HCT before T cell reconstitution has occurred. The most commonly implicated viruses are cytomegalovirus (CMV), Epstein-Barr virus (EBV), and adenovirus. Adoptive immunotherapy with virus-specific cytotoxic T cells can be used along with antiviral agents to treat these life-threatening viral infections [63]. Management of these and other posttransplant infections are discussed in greater detail separately. (See "Evaluation for infection before hematopoietic cell transplantation" and "Prevention of viral infections in hematopoietic cell transplant recipients" and "Overview of infections following hematopoietic cell transplantation" and "Clinical manifestations and treatment of Epstein-Barr virus infection", section on 'Treatment' and "Diagnosis, treatment, and prevention of adenovirus infection", section on 'Treatment'.)

While most patients survive transplant for SCID, many need continued medical therapy and immune support. Patients who are successfully treated with definitive therapy for SCID require lifelong monitoring of the quality of their immune reconstitution [64,65]. Up to 50 percent of patients have continued need for immune globulin replacement therapy after HCT, particularly those who receive HCT without conditioning and those with the interleukin 2 receptor gamma chain (IL2RG) or Janus kinase 3 (JAK3) genotypes [58,66].

In patients who receive pretreatment chemotherapy-based conditioning regimens, lifelong monitoring for nonimmune system late effects is typically managed through posttransplant survivorship programs [64-67].

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Inborn errors of immunity (previously called primary immunodeficiencies)".)

SUMMARY AND RECOMMENDATIONS

●Overview – Severe combined immunodeficiency (SCID) diseases result from a severe disturbance in the development and function T cells that leads to defects in cellular and humoral immunity and may also involve natural killer (NK) cells (table 1). SCID disorders typically lead to death in the first year of life from overwhelming infection without definitive treatment. (See 'Introduction' above and 'Pathogenesis' above and 'Genetics' above and 'SCID classification' above and 'Prognosis' above.)

●Clinical manifestations – Infants with SCID diagnosed at birth by newborn screening or family history appear normal at birth and in early infancy. The symptoms of SCID in patients who are not diagnosed in the neonatal period are recurrent, severe, and opportunistic infections; chronic diarrhea; and failure to thrive (FTT). In the absence of population-based newborn screening for SCID, a diagnosis is often not made until the infant develops one or more severe infections. (See 'Clinical features' above.)

●Diagnosis:

•Typical SCID – Typical SCID is defined as an autologous T cell count <50/microL together with either low T cell receptor excision circles (TRECs) and low naïve T cells or a pathologic variant or compound heterozygous variants in an X-linked or autosomal gene known to cause SCID. In the absence of these features, presence of maternal T cells in the circulation is strong evidence for SCID. (See 'Diagnostic criteria for typical SCID' above.)

•Leaky (atypical) SCID – Leaky/atypical SCID is defined as low T cell counts for age and/or oligoclonal T cells and/or low TRECs/low naïve T cells together with either gene defects known to cause SCID or reduced lymphocyte proliferation to phytohemagglutinin (PHA). In addition, patients with leaky/atypical SCID must be evaluated to exclude a thymic disorder and other known genotypes of combined immunodeficiency or other disorders known to have low T cells. (See 'Diagnostic criteria for leaky (atypical) SCID' above.)

•Omenn syndrome – Omenn syndrome is due to hypomorphic mutations in known SCID genes that result in oligoclonal, dysregulated, autologous T cells that cause skin rashes, adenopathy, hepatosplenomegaly, and elevations in eosinophil numbers and immunoglobulin E (IgE). (See 'Diagnostic criteria for Omenn syndrome in patients with leaky SCID' above.)

●Protective measures to prevent infection before definitive therapy (see 'Measures to prevent initial infections' above):

•Isolation from potential sick contacts – Protective isolation to limit exposure to infection is warranted for all infants with suspected SCID until immune reconstitution has taken place. Isolation can either occur at home or in the hospital. The choice is situationally dependent and can change over time. (See 'Protective isolation' above.)

•Avoidance of live-virus vaccines – Live-attenuated vaccines (table 2) are contraindicated in patients with suspected SCID because immunization with live-attenuated viruses or bacteria can cause disseminated disease in patients with combined immunodeficiencies. (See 'Avoidance of live vaccines' above.)

•Vaccination of healthy close contacts – All inactivated vaccines should be offered according to schedule to healthy household contacts and other close contacts of infants with suspected SCID in order to provide secondary protection to the patient with SCID. Live influenza, oral polio, and smallpox vaccines are avoided in close contacts. Other live vaccines are permitted. (See 'Vaccination of healthy close contacts' above.)

•Caution with blood products – Patients with suspected or known T cell immunodeficiencies such as SCID should not be given blood or blood components that may contain viable lymphocytes because of the high risk of fatal transfusion-associated graft-versus-host disease (GVHD). Any cellular blood products given to these patients must be irradiated to inactivate viable T cells. Leukocyte reduction is also required to minimize chances of transmission of cytomegalovirus (CMV). (See 'Caution with blood products' above.)

•Breast milk precautions – For infants with suspected or confirmed SCID, we recommend avoidance of breast milk from CMV-seropositive females (Grade 1B). If the current CMV status of the lactating parent or donor is not known, the infant should be fed sterile formula rather than breast milk until CMV seronegativity can be confirmed. (See 'Breast milk precautions' above.)

•Immune globulin replacement therapy – For all infants with confirmed SCID, we recommend initiation of antibody replacement therapy with immune globulin (either intravenously or subcutaneously) (Grade 1B). (See 'Immune globulin replacement therapy' above.)

•Antimicrobial prophylaxis – For infants with SCID, we suggest antifungal prophylaxis with fluconazole (Grade 2C). Oral or topical nystatin is a reasonable alternative. Standard prophylaxis should also be given for P. jirovecii pneumonia (PJP) and respiratory syncytial virus (RSV), as well as for herpesviruses in infants with a history of exposure (table 3). (See 'Antimicrobial prophylaxis' above.)

●Surveillance and monitoring – Screening for congenital or postnatally acquired CMV infection, Epstein-Barr virus (EBV), human immunodeficiency virus (HIV), and other respiratory viruses, by molecular rather than serologic testing because of the lack of immunologic response to infection, is indicated after confirmation of the diagnosis of SCID. Patients should also be monitored for autoinflammatory complications. (See 'Surveillance for viral infections' above and 'Monitoring for autoinflammatory complications' above.)

●Definitive therapy – The most common, widely available, definitive therapy for most forms of SCID is hematopoietic cell transplantation (HCT) from a well-matched, healthy allogeneic donor. This treatment has excellent overall survival, reconstitution of T cell immunity, and, in many cases, B cell immunity. Gene therapy is a viable alternative for some forms of SCID. Enzyme replacement therapy (ERT) is available for adenosine deaminase (ADA) deficiency. These treatments are all reviewed in detail separately in treatment and disease-specific topics. (See 'Definitive therapy' above and "Hematopoietic cell transplantation for severe combined immunodeficiencies" and "Overview of gene therapy for inborn errors of immunity" and "Adenosine deaminase deficiency: Treatment and prognosis".)

●Outcomes – SCID is fatal, usually within the first year of life, unless the lack of T cell immunity is corrected. Overall survival rates for patients with SCID are high following HCT, although certain SCID genotypes may continue to have worse outcomes. Survival rates for gene therapy are excellent and may exceed those for HCT for some forms of SCID. These outcomes are discussed in greater detail separately. (See 'Prognosis' above and "Hematopoietic cell transplantation for severe combined immunodeficiencies" and "Overview of gene therapy for inborn errors of immunity".)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges Francisco A Bonilla, MD, PhD, who contributed to earlier versions of this topic review.