Combined immunodeficiencies: An overview

INTRODUCTION — Variable defects of cell-mediated and humoral immunodeficiency lead to combined immunodeficiency (CID). Specific CIDs are rare disorders, but they are collectively increasing as a diagnostic category within inborn errors of immunity (IEI; primary immunodeficiency [PID]) as more monogenic disorders are genetically defined (table 1) [1,2]. CID can be diagnosed clinically based upon symptoms and laboratory features, but identification of a monogenic etiology may allow for targeted therapy.

This topic gives a broad overview of the CID that are not defined as "severe" and that do not have associated or syndromic features. Details of specific CID are reviewed separately, as are syndromic CID and severe combined immunodeficiencies (SCID). (See "Combined immunodeficiencies: Specific defects" and "Syndromic immunodeficiencies" and "Severe combined immunodeficiency (SCID): An overview" and "Severe combined immunodeficiency (SCID): Specific defects".)

An overview of the conditions and infections that should alert a clinician to the possibility of immunodeficiency in general is reviewed elsewhere. (See "Approach to the child with recurrent infections" and "Approach to the adult with recurrent infections" and "Gastrointestinal manifestations in primary immunodeficiency" and "Pulmonary complications of primary immunodeficiencies" and "Autoimmunity in patients with inborn errors of immunity/primary immunodeficiency" and "Malignancy in primary immunodeficiency".)

DEFINITIONS

●Severe combined immunodeficiencies (SCID) – SCID are combined immunodeficiencies that lead to early death from overwhelming infection in the first year or two of life. 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 "Severe combined immunodeficiency (SCID): An overview"):

•Typical SCID – These forms of CID have the most severe qualitative and quantitative T cell deficiency. Genetic defects in which the mutations primarily lead to a SCID phenotype are discussed separately. (See "Severe combined immunodeficiency (SCID): Specific defects" and "CD3/T cell receptor complex disorders causing immunodeficiency".)

•Atypical/leaky SCID – These forms of CID are 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 (NBS) 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.

●Combined immunodeficiencies (CID) – CID are distinguished from SCID in that they do not characteristically lead to death from overwhelming infection in the first year of life, and the degree of T cell deficiency is typically less profound. In addition, CID syndromes frequently have associated clinical features ranging from recurrent infections and autoimmunity presenting early in life to latent onset of symptoms in the second decade of life or even later.

GENOTYPES AND IMMUNOPHENOTYPE SEVERITY — For some involved genes, the clinical presentation can be variable, ranging in severity from typical severe combined immunodeficiency (SCID), to atypical/leaky SCID, to milder CID. Patients with SCID must be identified and treated with definitive therapies, such as hematopoietic cell transplantation (HCT) or gene therapy, very early in life to achieve a good chance for long-term survival. Thus, it is critical to evaluate for the severity of immunophenotype.

The most common gene defects associated with clinical presentation ranging from typical SCID to adult-onset CID are those associated with defects in the recombination-activating gene 1 (RAG1) and recombination-activating gene 2 (RAG2) genes. However, hypomorphic and CID phenotypes have been described for many of the genetic defects known to cause SCID.

Pathologic variants in RAG1 and RAG2 can cause both typical and leaky/atypical SCID. However, hypomorphic variants with partial protein function can also present with Omenn syndrome or have a relatively mild-appearing CID or common variable immunodeficiency (CVID). In particular, granulomatous lesions and autoimmune disease, especially autoimmune cytopenias, in addition to more typical infections associated with T cell lymphopenia but with a later age of onset have been described as part of the spectrum of disease symptoms observed in patients with pathologic variants in the RAG1/RAG2 genes [3-7]. (See "T-B-NK+ SCID: Pathogenesis, clinical manifestations, and diagnosis" and "Hyperimmunoglobulin M syndromes".)

IUIS CLASSIFICATION — The International Union of Immunological Societies (IUIS) Committee Report on Inborn Errors of Immunity includes a phenotype-based schema to describe the several subgroupings of monogenic disorders within the larger diagnostic category of CID (defects affecting both cellular and humoral immunity) in the 2022 IUIS classification scheme [2] (see "Inborn errors of immunity (primary immunodeficiencies): Classification"). These include:

●T-B+ SCID (see "Severe combined immunodeficiency (SCID): An overview" and "Severe combined immunodeficiency (SCID): Specific defects")

●T-B- SCID (see "Severe combined immunodeficiency (SCID): An overview" and "Severe combined immunodeficiency (SCID): Specific defects")

●CID, generally less profound than SCID (discussed in this topic review)

●CID with associated or syndromic features, including (see "Syndromic immunodeficiencies"):

•Immunodeficiency with congenital thrombocytopenia

•Deoxyribonucleic acid (DNA) repair defects

•Thymic defects with additional congenital anomalies

•Immuno-osseous dysplasias

•Hyperimmunoglobulin E syndromes (HIES)

•Defects of B12 and folate metabolism

•Anhidrotic ectodermal dysplasia with immunodeficiency

•Calcium channel defects

•Other defects

PRESENTATION

Age at presentation — Patients with CID often present in the first two years of life with recurrent infections and specific findings associated with the different syndromes (table 1). However, patients with milder defects may not present until later in childhood or even adulthood.

Presenting features in children — The diagnosis of CID should be suspected in children with any of the following:

●Chronic or recurrent respiratory tract infections (eg, more than eight upper respiratory tract infections or more than one lower respiratory tract infection yearly)

●Chronic viral disease (chronic warts, cytomegalovirus [CMV], Epstein-Barr virus [EBV])

●Opportunistic infections

●Failure to thrive

●Chronic diarrhea

●Autoimmunity (particularly autoimmune cytopenias) and other manifestations of immune dysregulation, such as granuloma formation or difficult-to-manage atopy

●EBV-driven lymphoproliferative disease/malignancy

●A family history of immunodeficiency

●Chronic lymphopenia (total lymphocyte count <1500 cells/microL in children over five years of age; <2500 cells/microL in younger children)

Presenting features in adults — Many of the presenting features are similar in adults with CID. Additional features that suggest a CID in adults are:

●Unexplained weight loss

●Development of lymphopenia either de novo or in a patient with a childhood history of an immunodeficiency

●Severe atopy or other evidence of immune dysregulation or autoimmunity, such as granulomas, new-onset inflammatory bowel disease (IBD), or evidence of otherwise unexplained lymphoproliferation

Late-onset combined immunodeficiency — In the French national study of adults with primary hypogammaglobulinemia, 28 of 313 patients (9 percent) with common variable immunodeficiency (CVID) had late-onset combined immunodeficiency (LOCID), with severe opportunistic infections and/or a CD4 count <200 cells/microL [8]. These patients had a higher incidence of gastrointestinal tract disease, splenomegaly, lymphomas, and granulomas than other patients with CVID. (See "Clinical manifestations, epidemiology, and diagnosis of common variable immunodeficiency in adults".)

Associated or syndromic features — Many of the CID syndromes have characteristic associated clinical and laboratory features that suggest a particular defect and help direct the diagnostic evaluation (table 2). These syndromic disorders are reviewed in detail separately. (See "Syndromic immunodeficiencies".)

REFERRAL — All patients suspected of having one of these disorders should be referred to an immunology specialist for evaluation and an attempt to determine a definitive diagnosis.

DIAGNOSIS

Diagnostic criteria — Diagnostic criteria for clinically suspected CID were published by the European Society for Immunodeficiencies (ESID) [9]. These criteria include both clinical and laboratory features as listed below. To make the diagnosis, patients should have both the clinical and laboratory criteria met, and human immunodeficiency virus (HIV) must be excluded.

These criteria are meant to be applied in the setting of a clinical suspicion. However, it is not necessary to have the clinical or laboratory features to start treatment if the patient has a known genetic defect associated with CID (eg, the patient is identified before onset of symptoms and/or laboratory testing due to a known diagnosis in the family).

T receptor excision circle (TREC) based newborn screening (NBS) for severe combined immunodeficiency (SCID) may sometimes detect patients with CID, but a normal test should not be interpreted to have excluded the potential for CID. (See "Newborn screening for inborn errors of immunity".)

An overview of the conditions and infections that should alert a clinician to the possibility of immunodeficiency in general is discussed separately. (See "Approach to the child with recurrent infections" and "Approach to the adult with recurrent infections".)

Clinical criteria — The clinical diagnostic criteria require one of the following to be present:

●At least one severe infection

●One manifestation of immune dysregulation (such as autoimmunity, inflammatory bowel disease [IBD], severe eczema, lymphoproliferation, or granuloma)

●Malignancy

●Similarly affected family member

Laboratory criteria — The laboratory feature criteria require two of the following four T cell-based criteria:

●Reduced CD3, CD4, or CD8 cells for age

●Reduced naïve T cells for age

●Expansion of gamma-delta T cell populations

●Reduced proliferation in response to mitogen or CD3 challenge

Initial evaluation — Strictly speaking, CID can be defined based upon T cell criteria. However, complete evaluation of both humoral and cellular immunity is recommended if there is suspicion for CID since T cell defects are commonly associated with defective B cell development and function and since the results can help guide therapeutic decisions. Algorithms for evaluation of patients with suspected immunodeficiency are published [10]. Specific tests are reviewed in detail separately (See "Laboratory evaluation of the immune system".)

The initial studies when CID is suspected should include absolute numbers and percentages of lymphocyte subsets (T, B, and natural killer [NK]) and assessment of T cell function, as well as the measurement of immunoglobulin levels (table 3) and specific antibody titers.

Further studies should include enumeration of naïve and memory T cells subsets and T cells expressing the gamma-delta T cell receptor (TCR) and assessment of T cell repertoire diversity through spectral flow cytometry when considering CID as a clinical diagnosis. Additional testing that also has diagnostic clinical utility but is not yet widely available outside of research-based settings includes assessment T cells expressing Va7.2, which are typically lower in patients with decreased recombinase activity, and enumeration of mucosa-associated invariant T (MAIT) cells [11].

Confirmation of the genetic defect — It is often useful to determine the genetic defect since it influences the clinical phenotype and may help to guide decisions for clinical management and aid in prognosis. Additionally, knowledge of the underlying genetic defect will allow for appropriate family genetic counseling. The form(s) of genetic testing performed depends upon the clinical features and family history. If there is a known family history of a specific gene defect, assessment for that same defect by directed sequencing is appropriate. There are commercially available next-generation sequencing panels that assess for genetic defects known to have association with CID and for syndromes with features of CID. Whole exome and, increasingly, whole genome sequencing may also be performed as part of the diagnostic evaluation. Clinical judgment should be used to determine which genetic testing approach is most appropriate for a given patient. (See "Genetic testing in patients with a suspected primary immunodeficiency or autoinflammatory syndrome".)

Identification through newborn screening — Combined immunodeficiencies are not a primary target of TREC-based SCID NBS programs. More severe forms of genetically defined immunodeficiencies that more commonly present as CID have been described to be detected by TREC-based NBS for SCID, but most CIDs are not [12,13]. (See "Newborn screening for inborn errors of immunity" and "Newborn screening for inborn errors of immunity", section on 'Diseases not identified by TREC testing'.)

MANAGEMENT — The choice of treatment depends upon the type and severity of the immune defect. Management should be tailored to the clinical presentation of the patient since phenotypes are variable. Treatments are noted here and discussed in greater detail separately.

●Immune globulin replacement therapy is given to almost all patients with CID since they typically manifest with deficiency of antibody quantity or quality. (See "Immune globulin therapy in primary immunodeficiency".)

●Palivizumab, a humanized monoclonal antibody against respiratory syncytial virus (RSV), is often also given to patients with severe immunodeficiency during RSV season [14]. (See "Respiratory syncytial virus infection: Prevention in infants and children", section on 'Palivizumab immunoprophylaxis'.)

●Patients with increased susceptibility to opportunistic bacterial or other infections are treated with prophylactic antimicrobial agents. (See "Inborn errors of immunity (primary immunodeficiencies): Overview of management", section on 'Prophylactic antimicrobial therapy'.)

●Live vaccines and nonirradiated blood transfusions should be avoided in patients with the most profound defects in T cell number and function. (See "Immunizations in patients with primary immunodeficiency" and "Inborn errors of immunity (primary immunodeficiencies): Overview of management", section on 'Caution with blood products'.)

●Some patients may require immunosuppressive or immunomodulatory therapies to manage autoimmune or autoinflammatory complications of the disease. (See "Autoimmunity in patients with inborn errors of immunity/primary immunodeficiency", section on 'Therapies'.)

●Hematopoietic cell transplantation (HCT) or, if available, gene therapy is indicated for defects that lead to more severe clinical phenotypes. (See "Hematopoietic cell transplantation for non-SCID inborn errors of immunity" and "Overview of gene therapy for inborn errors of immunity".)

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

●Definitions and classification – A myriad of genetic mutations lead to variable defects of humoral and cell-mediated immunity (table 1). Combined immunodeficiency (CID) syndromes are distinguished from severe combined immunodeficiency (SCID) in that they do not characteristically lead to death from overwhelming infection in the first year of life. In some cases, variants of a particular gene may lead to SCID or to milder CID, depending upon the extent of the gene defect. Some CID have associated or syndromic features (table 2). (See 'Definitions' above and 'Genotypes and immunophenotype severity' above and 'IUIS classification' above and "Syndromic immunodeficiencies".)

●Presentation – Patients with CID often present in the first two years of life with recurrent infections and specific findings associated with the different disorders (table 1). However, patients with milder defects may not present until later in childhood or even adulthood. Many of the CID syndromes have characteristic-associated clinical features that suggest a particular defect and help direct the diagnostic evaluation. (See 'Presentation' above.)

●When to refer – All patients suspected of having one of these disorders should be referred to an immunology specialist for evaluation and an attempt to determine a definitive diagnosis. (See 'Referral' above.)

●Diagnosis – To make the diagnosis in a patient with clinical features suggestive of a CID, the patient should meet both the clinical and laboratory criteria, and human immunodeficiency virus (HIV) must be excluded. However, it is not necessary to have the clinical or laboratory features to start treatment if the patient has a known genetic defect associated with CID (eg, the patient is identified before onset of symptoms and/or laboratory testing due to a known diagnosis in the family). An attempt should be made to confirm the specific genetic defect since it influences the clinical phenotype and may help to guide decisions for clinical management and aid in prognosis. Additionally, knowledge of the underlying genetic defect will allow for appropriate family genetic counseling. (See 'Diagnosis' above.)

●Management – The choice of treatment depends upon the type and severity of the immune defect. Treatment ranges from supportive therapies such as immune globulin replacement, antibiotic prophylaxis, and immune modulation/suppression to more definitive therapy with hematopoietic cell transplantation (HCT). (See 'Management' above and "Inborn errors of immunity (primary immunodeficiencies): Overview of management".)

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

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