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

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). In contrast, autosomal recessive recombination-activating gene 1 (RAG1) and recombination-activating gene 2 (RAG2) mutations more commonly cause leaky SCID.

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), TCR and immunoglobulin V(D)J recombination (recombination of the variable, joining and diversity regions of the T cell receptor and immunoglobulin genes), and various cellular metabolic pathways. Other commonly identified autosomal recessive genetic defects causing SCID occur in the interleukin 7 receptor alpha chain (IL7R) gene, Janus kinase 3 (JAK3) gene, deoxyribonucleic acid (DNA) cross-link repair protein 1C gene or Artemis (DCLRE1C), and adenosine deaminase (ADA) gene.

In a report by the Primary Immune Deficiency Treatment Consortium 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 upon lymphocyte subset profiles. Most patients with SCID have low to absent autologous T cell numbers, while numbers of B and natural killer (NK) cell numbers, regardless of the functional status of these cells, generally fall into the above categories (table 1). However, some patients with leaky or atypical SCID, as well as patients with Omenn syndrome, may have normal or even higher than expected overall numbers of T cells, but these cells will predominantly have a memory phenotype (CD45RO+).

The mutated gene responsible for a majority of cases of SCID can be determined since genetic sequence-based diagnosis is readily available [6]. Thus, it is more 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.

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.

The classic symptoms of typical SCID not diagnosed at birth are recurrent, increasingly severe infections, chronic diarrhea, and failure to thrive (FTT) [7]. Increased resting energy expenditure (hypermetabolism) is more common in SCID patients with FTT and may contribute to its development [8]. SCID, by definition, is universally fatal in the first year or two of life if not treated with definitive therapy. (See 'Treatment' below.)

Physical examination of infants with SCID may reveal a focus of infection, such as thrush. In addition, discernible peripheral lymphoid tissue (tonsils, adenoids, axillary/inguinal nodes) is usually 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:

●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 frequently fatal.

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

●Live-attenuated vaccine organisms, such as oral polio vaccine virus, rotavirus, varicella, measles/mumps/rubella (MMR), and Bacillus Calmette-Guérin (BCG), may cause severe, disseminated, or fatal infection [9]. (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. 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) [10]. Moreover, infants who do not have SCID, but who have severe metabolic stress due to serious or overwhelming infection, severe malnutrition, or other severe illness, may have rapid 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:

●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 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. In the United States and other countries and regions that include testing for SCID on newborn screening, the most common initial sign of SCID is a low TREC count detected on SCID newborn screening. The laboratory abnormalities observed in typical SCID include low to absent T cell numbers, as measured by T cell enumeration by flow cytometry; low proportions of naïve T cells, such as T cells bearing the cell surface marker CD45RA; and abnormalities in known SCID genes. Maternal T cells may be present. 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 that may be 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. (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 that have association with SCID and radiosensitivity. The presence of radiosensitivity can have implications for safety of imaging modalities as well as choice of conditioning regimen 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. 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 may range from nearly absent to markedly elevated in the case of 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. 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. This is also true if the infant has already 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. In vitro tests of T cell antigen response may be used 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 upon clinical symptoms of infection or family history. The diagnosis of SCID should be suspected in children with any of the following (see "Approach to the child with recurrent infections", section on 'Clinical features suggestive of a primary immunodeficiency'):

●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

●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

●Adverse reactions (infectious complications) caused by live vaccines, such as Bacillus Calmette-Guérin (BCG), rotavirus vaccine, or varicella vaccine

●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) [11] 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. The T cell count may be normal or high in some cases due to the presence of maternal T cells in the peripheral circulation (typical SCID) or abnormal expansion of a few clones (eg, Omenn syndrome). In these cases, there is a predominance of memory (CD45RO+) T cells rather than naïve (CD45RA+) T cells. (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. (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. This is most commonly accomplished via commercially available panel-based testing. In cases where panel-based testing is not diagnostic, an unbiased approach using whole exome or whole genome testing 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 with a stem cell/human leukocyte antigen (HLA) typing lab at centers that perform hematopoietic cell transplant (HCT). Clinically, the presence of maternal engraftment may lead to need for immunosuppression to treat symptoms from the alloreactive maternal T cells and/or use of more aggressive conditioning regimen prior to transplant 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 flow cytometry-based assessment of the diversity of TCRVb segment is used as a proxy for overall TCR diversity. (See "CD3/T cell receptor complex disorders causing immunodeficiency", section on 'Overview of T cell receptor biology'.)

●T cell mitogen or CD3 proliferative responses – T cell proliferative responses may be low, and this is one of the criteria that can be used in confirming a diagnosis of leaky/atypical SCID [2,12-14]. (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 developed updated diagnostic parameters in 2022 based upon the prospective assessment of infants with SCID [15-17].

To diagnose typical SCID, patients must have a total T cell (CD3) count of <50 cells/microL, and one of the following:

●A known pathologic variant in a SCID-associated gene

●Low or absent T cell receptor excision circle (TREC)

●Less than 20 percent naïve CD4 T cells

Typical SCID can also be diagnosed in any patient with TME of T cells, irrespective of T cell counts.

Diagnosis of leaky or atypical SCID — Leaky or atypical SCID is caused by a hypomorphic mutation in a defined SCID gene that allows development of some T cells, generally with poor function and limited diversity. They 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 or atypical SCID requires extensive evaluation of potential genotype, T cell number, diversity, and function.

Diagnostic criteria for leaky or atypical SCID — All patients with leaky or atypical SCID must meet two of the following three T cell parameters:

●Low T cell count for age (a total T cell [CD3] count between 50 to 1000 cells/microL)

●Oligoclonal T cells

●Abnormal TREC or <20 percent of CD4 T cells are naïve

Patients must also demonstrate either a pathologic gene variant or reduced proliferation.

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

●Another SCID subtype

●Combined immunodeficiency with a known genotype

●A thymic disorder

●Another disorder with low T cells

●Evidence of TME

Diagnostic criteria for Omenn syndrome — Some patients with hypomorphic mutations in known SCID genes will develop symptoms of Omenn syndrome, in which oligoclonal T cells cause skin rashes, adenopathy, hepatosplenomegaly, and elevations in eosinophil numbers and immunoglobulin E (IgE). 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 TME.

●At least two of the following:

•Absolute eosinophil count >800 cells/microL

•Elevated IgE

•Abnormal TREC

•Lymphadenopathy

•Liver or spleen enlargement

•Oligoclonal T cells

Detection of maternal T cell engraftment — All infants with a potential diagnosis of SCID should be evaluated for TME of T cells. In some infants with SCID, maternal T cells that cross the placenta and enter the circulation of a fetus and may expand to levels >8000 cells/microL [18,19]. This may cause the total T cell count to appear "normal." One indicator that TME has occurred is a greater predominance of either CD4+ or CD8+ T cells since maternally engrafted cells are oligoclonal. However, this phenotype is not always evident. A majority of the maternally engrafted T cells have an activated or memory phenotype (they express CD45RO). Normal infant T cells are predominantly naïve (ie, they express 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 genetic testing of an embryo prior to implantation combined with in vitro fertilization is an option when there is a history of a prior relative affected with SCID and the specific molecular defect is known. In the case of natural conception, a prenatal diagnosis can be made by genetic tests performed on amniotic fluid or chorionic villus cells [20]. However, there is a small risk of fetal loss in both amniocentesis and chorionic villus cell sampling. In these instances, postnatal testing is necessary to confirm prenatal findings, even for infants thought to be unaffected.

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 have instituted SCID screening or have initiated pilot projects [14,21-23]. 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 — The three most common 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 quickly 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 [24]. 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. Partial DGS is the most common non-SCID genetic cause of T cell lymphopenia [14,25]. Genetic testing to rule out these diagnoses should be completed prior to hematopoietic cell transplantation (HCT) since thymic agenesis will not improve without thymic transplant. (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)

•Wiskott-Aldrich syndrome

•NF-kappa-B essential modifier (NEMO) deficiency

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

•Calcium channel deficiencies

•Cernunnos deficiency

•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 only made by molecular testing. (See "Combined immunodeficiencies: An overview" and "Combined immunodeficiencies: Specific defects" and "Hyperimmunoglobulin M syndromes" and "Wiskott-Aldrich syndrome" and "ZAP-70 deficiency" and "Adenosine deaminase deficiency: Pathogenesis, clinical manifestations, and diagnosis" and "Purine nucleoside phosphorylase deficiency" and "T-B-NK+ SCID: Pathogenesis, clinical manifestations, and diagnosis", section on 'Omenn syndrome phenotype'.)

●HIV/AIDS – Infants and young children with HIV/AIDS can also present with the classic SCID symptoms of recurrent severe infections, chronic diarrhea, and failure to thrive (FTT) [26]. 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 elevated numbers 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: Classification, clinical manifestations, and outcome" and "Diagnostic testing for HIV infection in infants and children younger than 18 months".)

INITIAL MANAGEMENT

Overview — The patient suspected of having SCID requires protective measures to prevent infection and evaluation of humoral and cellular immunity as quickly as possible. Once the diagnosis of probable SCID is made, plans for definitive therapy should be made immediately. Medical management of patients with known or suspected inborn errors of immunity includes isolation measures and precautions related to blood products, avoidance of live vaccinations, and antiinfective treatment prior to definitive diagnosis and treatment by transplantation or gene therapy. These measures are discussed in greater detail separately. (See "Inborn errors of immunity (primary immunodeficiencies): Overview of management" and "Immune globulin therapy in inborn errors of immunity" and "Immunizations in patients with inborn errors of immunity".)

Measures to prevent initial infections — Several measures to prevent initial infections are commonly undertaken prior to exact diagnosis or therapy if there is clinical or laboratory suspicion of SCID [7,27], although exact practices vary significantly by center. The precautions, which are primarily discussed in detail separately, include:

●Protective isolation to limit exposure to infection. (See "Inborn errors of immunity (primary immunodeficiencies): Overview of management", section on 'Isolation measures' and "Inborn errors of immunity (primary immunodeficiencies): Overview of management", section on 'Caregiver counseling'.)

●Avoidance of live vaccines (eg, measles, mumps, and rubella [MMR]; intranasal influenza; Bacillus Calmette-Guérin [BCG]; varicella; oral rotavirus and oral polio virus [OPV] vaccines) in the patient. (See "Immunizations in patients with inborn errors of immunity", section on 'Live vaccines'.)

●Vaccination of expectant females with recommended booster vaccines prior to delivery to provide transplacental antibodies to the fetus when there is a history of a prior affected child with SCID and vaccination of parents/caregivers and other close contacts with inactivated vaccines after the birth of an infant with suspected SCID. (See "Inborn errors of immunity (primary immunodeficiencies): Overview of management", section on 'Vaccination of patients, family members, caregivers'.)

●Caution with blood products. (See "Inborn errors of immunity (primary immunodeficiencies): Overview of management", section on 'Caution with blood products' and "Red blood cell transfusion in infants and children: Selection of blood products", section on 'Red blood cell products'.)

●Feeding precautions. Most providers recommend against breastfeeding if the mother has cytomegalovirus (CMV) IgG or IgM seropositivity to avoid risk of CMV transmission to an infant with SCID. Viral infections, and CMV in particular, remain the most common cause of death for infants with SCID and have occurred despite newborn screening when infants received breastmilk prior to SCID diagnosis [27]. A prior retrospective analysis of patients in the UK reported that CMV infection was exclusively seen in breastfed SCID infants [28]. However, studies have shown a lower than expected maternal-to-infant transmission in infants with SCID (6 percent) [13,29] compared with transmission in preterm infants (40 percent) [30]. In one case series of 31 infants born with SCID who had available data on breastfeeding habits and whose mothers were CMV seropositive, no difference in the rate of CMV transmission was seen between those infants with any reported breastfeeding (1 of 19; 5 percent) versus no breastfeeding (1 of 12; 8 percent) [29]. Clinical outcomes after hematopoietic cell transplantation (HCT) also did not differ significantly between the two groups. Further data are needed to determine if the benefits of breastfeeding outweigh the risks of CMV transmission for infants with SCID.

Typical prophylaxis against infection is reviewed in greater detail separately (example regimens are listed in the table (table 2)), and often includes (see "Inborn errors of immunity (primary immunodeficiencies): Overview of management", section on 'Prophylactic antimicrobial therapy'):

●Antibody replacement therapy with immune globulin (either intravenously or subcutaneously) (see "Immune globulin therapy in inborn errors of immunity")

●Prophylaxis for P. jirovecii pneumonia (typically with trimethoprim-sulfamethoxazole, pentamidine, or atovaquone) (see "Treatment and prevention of Pneumocystis pneumonia in patients without HIV", section on 'Prophylaxis')

●Antifungal prophylaxis (see "Candida infections in neonates: Treatment and prevention")

●Respiratory syncytial virus (RSV) immunoprophylaxis (see "Respiratory syncytial virus infection: Prevention in infants and children")

●Prophylaxis against viruses in the herpesvirus family (eg, herpes simplex virus [HSV]); this is especially important if the mother had active HSV lesions at the time of delivery or if the infant has been exposed to a person with cold sores (see "Neonatal herpes simplex virus infection: Management and prevention")

Evaluation and monitoring for complications once a diagnosis is confirmed — Screening for congenital or postnatally acquired CMV infection, Epstein-Barr virus (EBV), human immunodeficiency virus (HIV), and other respiratory viruses by molecular, not serologic, testing is indicated after confirmation of the diagnosis of SCID.

In addition, serial monitoring of the complete blood count with differential for development of rising absolute lymphocyte count or absolute eosinophil count can aid in the management of patients with leaky/atypical SCID. (See "Congenital cytomegalovirus infection: Clinical features and diagnosis", section on 'Clinical suspicion'.)

Treatment — Definitive therapy should be pursued once a clinical diagnosis of either typical or leaky/atypical SCID is made since early treatment improves outcomes. A genetic diagnosis is helpful to direct therapy, but it is not necessary to pursue definitive therapy.

The most common definitive therapy for all forms of SCID is HCT from a tissue-matched healthy donor. In addition to HCT for definitive therapy, gene therapy has also demonstrated efficacy in the definitive management for certain genetic forms of SCID, including adenosine deaminase deficiency (ADA), common gamma chain deficiency (IL-2RG, X-linked SCID), and DCLRE1C (Artemis) 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 a lower need for chemotherapy-based conditioning with attendant late effect risk. However, access to gene therapy outside of clinical trials is limited. Enzyme replacement therapy (ERT; polyethylene glycol-adenosine deaminase [PEG-ADA]) is also available for ADA deficiency. HCT, gene therapy, and ERT for ADA deficiency are discussed in greater detail separately in general and disease-specific topics.

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 improving and approach to exceed those for HCT for some forms of SCID. 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 engraftment has occurred. The most commonly implicated viruses are cytomegalovirus (CMV), Epstein-Barr virus (EBV), and adenovirus. Adoptive immunotherapy with virus-specific T cells can be used along with antiviral agents to treat these life-threatening viral infections [31]. 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 for quality of their immune reconstitution [32,33]. 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 [34,35].

In patients who receive pretreatment chemotherapy-based conditioning regiments, lifelong monitoring for nonimmune system late effects is typically managed through posttransplant survivorship programs [32-34,36].

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 are a heterogeneous group of disorders arising from a disturbance in the development and function T cells, which functionally leads to defects in cellular and humoral immunity and can also involve natural killer (NK) cells. These disorders are termed "severe" (ie, SCID) when T cell numbers are severely decreased. SCID disorders often lead to early death from overwhelming infection, typically in the first year of life for patients who do not receive definitive treatment. (See 'Introduction' above and 'Pathogenesis' above and 'Prognosis' above.)

●Classification and genetics – In the past, when genetic diagnosis was more difficult to establish, SCID syndromes were classified as T-B+NK+, T-B+NK-, T-B-NK+, or T-B-NK- based upon the presence of defects affecting T cell numbers and presence or absence of defects affecting B and/or NK cell numbers, regardless of the functional status of these cells (table 1). However, the mutated genes responsible for a majority of cases of SCID are now known and can be readily determined. Thus, it is more appropriate to refer to SCID according to the specific molecular defect once it is identified. (See 'SCID classification' above and 'Genetics' above.)

●Clinical manifestations – Infants with SCID diagnosed at birth by newborn screening or family history appear normal at birth and in early infancy. The classic symptoms of SCID in patients who are not diagnosed in the neonatal period are recurrent severe 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 is defined as an autologous T cell count <50/microL together with either low T cell receptor excision circle (TREC)/naïve T cells or a pathologic variant in a gene known to cause SCID or, absent these features, any presence of maternal T cells in the circulation. Leaky/atypical SCID is defined as low T cell counts for age and/or oligoclonal T cells and/or low TREC/naïve T cells together with either a pathologic variant in a gene known to cause SCID or reduced phytohemagglutinin (PHA) proliferation. In addition, patients with leaky/atypical SCID must be evaluated to exclude thymic disorder and other known genotypes of combined immunodeficiency or other disorders known to have low T cells. (See 'Diagnosis' above.)

●Initial protective measures to prevent infection – Initial management includes several protective measures to prevent infection, including isolation from potential sick contacts, immune globulin replacement therapy, initiation of antimicrobial prophylaxis, and avoidance of live-virus vaccines. (See 'Measures to prevent initial infections' above.)

●Definitive therapy – The most common, widely available, curative 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; eg, polyethylene glycol-adenosine deaminase [PEG-ADA]) is available for adenosine deaminase (ADA) deficiency. These treatments are all reviewed in detail separately. (See 'Treatment' 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 improving and approach to 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 as an author to earlier versions of this topic review.