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Severe combined immunodeficiency (SCID): An overview

Severe combined immunodeficiency (SCID): An overview
Author:
Jennifer Heimall, MD
Section Editor:
Jennifer M Puck, MD
Deputy Editor:
Elizabeth TePas, MD, MS
Literature review current through: Nov 2022. | This topic last updated: Dec 12, 2019.

INTRODUCTION — The term "primary immunodeficiency" denotes diseases resulting from inherited defects of the immune system. Many distinct disorders have been described [1,2]. 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.

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" and "X-linked severe combined immunodeficiency (X-SCID)" and "Adenosine deaminase deficiency: Pathogenesis, clinical manifestations, and diagnosis" and "T-B-NK+ SCID: Pathogenesis, clinical manifestations, and diagnosis" and "Severe combined immunodeficiency (SCID) with JAK3 deficiency" and "ZAP-70 deficiency" and "Combined immunodeficiencies" and "CD3/T cell receptor complex disorders causing immunodeficiency".)

The humoral immunodeficiencies and disorders involving phagocytic and complement defects are presented separately. (See "Primary humoral immunodeficiencies: An overview" and "Primary disorders of phagocyte number and/or function: An overview" and "Inherited disorders of the complement system".)

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 [3]. The incidence of autosomal-recessive SCID is higher in cultures in which consanguineous marriage is common [4,5]. (See 'SCID classification' below and "Newborn screening for primary immunodeficiencies".)

PATHOGENESIS — SCID is a syndrome caused by mutations in any of several genes whose products are crucial for the development and function of both T and B cells and may also affect natural killer (NK) cells. In some cases, the molecular defect results in only T cell deficiency, while B cells are intrinsically normal. 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 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, 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 [6].

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. All 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, now that genetic sequence-based diagnosis is readily available, the mutated gene responsible for a majority of cases of SCID can be determined. 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.

Typical SCID patients have a total T cell (CD3) count of <300 cells/microL, and response to phytohemagglutinin (PHA) mitogen stimulation is <10 percent of the lower limit of the range found in healthy persons [7]. Leaky SCID refers to combined immunodeficiencies caused by a hypomorphic mutation in a defined SCID gene that allows development of some T cells, generally with poor function and limited diversity. Patients with leaky SCID may have 300 to 1500 or even more T cells/microL, with responses to PHA mitogen stimulation between 10 and 50 percent of that found in normal controls. 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. They may also have Omenn syndrome, in which oligoclonal T cells cause skin rashes, adenopathy, hepatosplenomegaly, and elevations in eosinophil numbers and immunoglobulin E (IgE). (See 'Diagnosis' below.)

CLINICAL MANIFESTATIONS — 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 classic symptoms of typical SCID not diagnosed at birth are recurrent, increasingly severe infections; opportunistic infections such as pneumonia due to Pneumocystis jirovecii; chronic diarrhea; and failure to thrive (FTT) [8]. Increased resting energy expenditure (hypermetabolism) is more common in SCID patients with FTT and may contribute to its development [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. 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".)

The absence of a thymic shadow on chest radiography is a typical finding in infants with SCID. Thus, a chest radiograph may be useful in the newborn suspected of SCID (image 1). However, 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.

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 [11]. (See "Immunizations in patients with primary immunodeficiency", section on 'Live vaccines'.)

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 — 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. The typical laboratory abnormalities observed in SCID include low to absent T cell numbers and function, 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 poor T cell proliferation to mitogens such as phytohemagglutinin (PHA) and concanavalin A (ConA). Maternal T cells may be present. Other immunologic abnormalities are seen but are not critical to the initial evaluation. (See "Laboratory evaluation of the immune system" and 'Diagnosis' below and "Flow cytometry for the diagnosis of primary immunodeficiencies".)

Laboratory studies necessary to confirm the diagnosis include the following (see 'Diagnosis' below):

Absolute lymphocyte count (compared with age-adjusted reference range) [12]. There is usually a low absolute lymphocyte count (<2500 cells/microL). 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.

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 <300 cells/microL in typical SCID and between 300 to <1500 cells/microL in leaky 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 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.

T cell mitogen responses. T cell proliferative responses to mitogens are absent or extremely low, and this is one of the most important tests to perform early. Absence of T cell mitogen response is a crucial element in the diagnosis of SCID, distinguishing the functionally abnormal T cell responses in SCID from responses that are normal in infants with transient low T cell numbers secondary to maternal medication during pregnancy or other newborn conditions [3,13-15].

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.

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, but the diagnosis of SCID rests largely upon the absence of a T cell mitogen response and/or a mixed lymphocyte culture response. Thus, testing for antigen response is not usually required in the context of evaluation for SCID.

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. 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.

Specific antibody responses to antigens. Specific antibody responses are severely impaired. However, it is not useful to test these 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.

DIAGNOSIS — 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

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)

The diagnostic criteria for typical SCID are reviewed in the table (table 2) [16]. Laboratory findings used for these criteria include an absolute CD3+ T cell count of <300 cells/microL, lack of naïve T cells, or maternal T cells present in the infant's circulation. (See 'Laboratory abnormalities' above and 'Detection of maternal T cell engraftment' below.)

Leaky SCID, which is less severe and/or delayed in onset compared with typical SCID, is defined as age-adjusted relative CD3+ T cell lymphopenia (under age two years, <1000 cells/microL; age two to four years, <800 cells/microL; age greater than four years, <600 cells/microL) and proliferation to mitogens <30 percent of normal [7]. Patients with leaky SCID may have up to 1500 T cells/microL at birth, but these T cells are usually CD45RO+ memory T cells and/or oligoclonal T cells.

Detection of maternal T cell engraftment — An infant with any of the above features suggestive of an immunodeficiency, but who has a normal lymphocyte count, should be evaluated for maternal T cell engraftment. 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 [17,18]. This may cause the total T cell count to appear "normal." One indicator that maternal T cell engraftment 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 primary immunodeficiencies".)

Preimplantation and prenatal diagnosis — In the case of a family where there is a history of a prior relative affected with SCID for which the specific molecular defect is known, the use of genetic testing of the embryo prior to implantation combined with in vitro fertilization is now an option. In the case of natural conception, a prenatal diagnosis can be made by genetic tests performed on amniotic fluid or chorionic villus cells [19]. 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 — Early treatment of SCID with hematopoietic cell transplantation (HCT) improves outcomes [13,15,20-22], suggesting that identification of patients through newborn screening will decrease the morbidity and mortality of the disease. A cost-effective method for screening newborns for T cell lymphopenia uses dried blood spots (DBS) to measure T cell receptor excision circles (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 [15,23-25]. Newborn screening for primary immunodeficiencies is discussed in greater detail separately. (See "Newborn screening for primary immunodeficiencies".)

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 (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 [26]. 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 countries: 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 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 [15,27]. Genetic testing to rule out these diagnoses should be completed prior to 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 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, and purine nucleoside phosphorylase deficiency [2]. 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" 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) [28]. 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 — 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 primary immunodeficiencies, discussed in detail separately, 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. (See "Primary immunodeficiency: Overview of management" and "Immune globulin therapy in primary immunodeficiency" and "Immunizations in patients with primary immunodeficiency".)

Protective measures — Several precautions are commonly undertaken prior to exact diagnosis or therapy if there is clinical or laboratory suspicion of SCID [8], although exact practices vary significantly by center:

Protective measures can start before birth when there is a history of a prior affected child with SCID. These expectant mothers should receive recommended booster vaccines prior to delivery to provide transplacental antibodies to the fetus.

Infants with suspected SCID should be kept in protective isolation until they have received definitive treatment and recovered T cell function. This may be done in the hospital, but some immunologists consider the risk of the infant acquiring a nosocomial hospital infection to be greater than the risk of isolation within the home, as long as exposure to young children and any potentially contagious contacts at home can be avoided. The clinician determining how to manage a SCID infant must weigh the risks and benefits of hospital versus home settings, including the social situation of the family and ease of access to the hospital in case symptoms of infection develop.

Live vaccines (eg, measles, mumps, and rubella [MMR]; intranasal influenza; Bacillus Calmette-Guérin [BCG]; varicella; oral rotavirus and oral polio virus [OPV] vaccines), should NOT be administered to the patient. Possible vaccine-induced infection should be considered in the event that one or more live vaccines have already been given. Inactivated vaccines should be given to the parents and other close contacts.

All blood products must be irradiated, leukodepleted, and cytomegalovirus (CMV) negative.

Most providers recommend against breastfeeding if the mother has CMV IgG or IgM seropositivity to avoid risk of CMV transmission to a SCID infant. 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. A prior retrospective analysis of patients in the UK reported that CMV infection was exclusively seen in breastfed SCID infants [29]. However, studies have shown a lower than expected maternal-to-infant transmission in infants with SCID (6 percent) [14,30] compared with transmission in preterm infants (40 percent) [31]. 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) [30]. 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 often includes:

Antibody replacement therapy with immune globulin (either intravenously or subcutaneously). (See "Immune globulin therapy in primary immunodeficiency".)

Prophylaxis for P. jirovecii pneumonia (typically with trimethoprim-sulfamethoxazole).

Fluconazole for antifungal prophylaxis.

Palivizumab, a monoclonal antibody against respiratory syncytial virus (RSV), which is given only during RSV season [32].

Acyclovir or another antiviral agent for 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 an individual with cold sores.

Evaluation — Studies to evaluate humoral and cellular immunity include the measurement of immunoglobulin levels (particularly IgA and IgM since passive maternal IgG is present in infants early in life), absolute numbers and percentages of lymphocyte subsets (T [CD3, CD4, CD8, CD3/CD4/CD45RA, CD3/CD4/CD45RO, CD3/CD8/CD45RA, CD3/CD8/CD45RO], B, and natural killer [NK]), and assessment of T cell function. In newborns, T cell function is best determined by measurement of in vitro proliferation to a mitogen such as phytohemagglutinin (PHA). (See 'Laboratory abnormalities' above and "Laboratory evaluation of the immune system" and "Flow cytometry for the diagnosis of primary immunodeficiencies".)

An attempt should be made to establish a molecular diagnosis by ordering a SCID gene sequencing panel or single gene sequencing if one genotype is suspected based upon the patient's gender, family history, and lymphocyte profile. Specific SCID gene defects are increasingly treated with individualized transplant protocols or gene therapy, which requires identification of the disease gene. However, in the absence of a molecular diagnosis, definitive therapy with an allogeneic transplant should not be withheld. Identifying the specific gene defect aids in genetic counseling (eg, autosomal versus X-linked defects and inherited versus spontaneous defects) (table 1). (See "Severe combined immunodeficiency (SCID): Specific defects".)

Screening for congenital or postnatally acquired CMV infection, Epstein-Barr virus (EBV), human immunodeficiency virus (HIV), and other respiratory viruses by molecular testing is indicated. (See "Congenital cytomegalovirus infection: Clinical features and diagnosis", section on 'Clinical suspicion'.)

Treatment — The most common curative therapy for all forms of SCID is HCT from a tissue-matched healthy donor [18,33,34]. Most patients with adenosine deaminase deficiency (ADA) have historically received HCT; some have been treated initially with enzyme replacement therapy (polyethylene glycol-adenosine deaminase [PEG-ADA]), and a growing number have received gene therapy. The latter treatment is now licensed in Europe and available in clinical trials in the US. Gene therapy is also becoming a successful alternative for X-linked SCID (common gamma-chain deficiency) and is being explored as a form of treatment for other genetic types of SCID. Gene therapy should be explored if a human leukocyte antigen (HLA)-identical sibling or in some cases matched unrelated donor is unavailable. (See "Hematopoietic cell transplantation for severe combined immunodeficiencies" and "Adenosine deaminase deficiency: Treatment and prognosis" and "Overview of gene therapy for primary immunodeficiency".)

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 CMV, EBV, and adenovirus (ADV). Adoptive immunotherapy with virus-specific T cells (VST) can be used along with antiviral agents to treat these life-threatening viral infections.

One retrospective series examined 26 patients with a primary immunodeficiency who required treatment with HCT and who had at least one documented serious viral infection and were treated with VST either before (n = 2) or after (n = 24) HCT [35]. Complete or partial antiviral response was seen in 76 to 100 percent of patients, depending upon the particular virus. Six of the 26 patients had reactivation infections after VST that resolved in one to two months. VST was effective despite the use of immunosuppressive medications in many patients. An additional 10 patients were treated preventively with VST prior to HCT. Of these, eight remained free of EBV, CMV, and ADV infection. Two patients developed viral infections after VST (one with CMV and the other with EBV). Both had complete response to subsequent therapy. Reported adverse reactions to VST were mild. Four cases of graft-versus-host disease were felt to be transplant associated rather than due to VST.

PROGNOSIS — SCID is fatal, usually within the first year of life, unless the lack of T and B cell immunity is corrected. However, in patients transplanted under 3.5 months of age without infection, survival posttransplantation was 96 percent, and overall survival 90 percent in one study [6]. (See "Hematopoietic cell transplantation for severe combined immunodeficiencies".)

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

Combined immunodeficiency diseases 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 can also involve natural killer (NK) cells. These disorders are termed "severe" (eg, severe combined immunodeficiency [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 with SCID who do not receive definitive treatment. (See 'Introduction' above and 'Pathogenesis' above and 'Prognosis' above.)

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.)

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. The thymic shadow is absent on chest radiography in most infants with SCID, and the absolute lymphocyte count is usually very low. (See 'Clinical manifestations' above.)

Typical SCID is defined as an autologous T cell count <300/microL together with an in vitro phytohemagglutinin (PHA) response <10 percent of normal or the presence of maternal T cells in the circulation. Leaky SCID is defined as lymphopenia (an autologous T cell count <1000 cells/microL under age two years, <800 cells/microL age two to four years, or <600 cells/microL age greater than four years) together with a PHA response <30 percent of normal. (See 'Diagnosis' above.)

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 'Protective measures' above.)

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. Adenosine deaminase (ADA) deficiency may be treated with enzyme replacement therapy (eg, polyethylene glycol-adenosine deaminase [PEG-ADA]) instead. Gene therapy is an increasingly available and successful alternative in some forms of SCID if a human leukocyte antigen (HLA)-identical donor is unavailable. (See 'Treatment' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Francisco A Bonilla, MD, PhD, who contributed as an author to an earlier version of this topic review.

The UpToDate editorial staff also acknowledges E Richard Stiehm, MD, who contributed as a Section Editor to an earlier version of this topic review.

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Topic 3955 Version 36.0

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