Immunodeficiency Disorders (Primary and Secondary)

Etiology

Primary immunodeficiencies are also known as inborn errors of immunity (IEI). The International Union of Immunological Societies classifies IEI into several major categories, including combined immunodeficiencies, predominantly antibody deficiencies, disorders of immune dysregulation, congenital phagocyte disorders, defects of innate immunity, autoinflammatory diseases, complement deficiencies, bone marrow failure syndromes, and phenocopies of IEI. Although recurrent infections remain a defining feature, many IEI also present with autoimmunity, immune dysregulation, allergy, inflammation, lymphoproliferation, or malignant neoplasms. Table 1 summarizes the most common forms of IEI and their phenotypic features.[1]

Combined immunodeficiencies affect both cellular and humoral immunity and range in severity from severe combined immunodeficiency (SCID) to less severe combined immunodeficiency (CID) syndromes. SCID is the most profound form of T-cell immunodeficiency, characterized by severe defects in T-cell development, often accompanied by impaired B-cell and natural killer cell function.[3] The most common form is X-linked SCID, caused by pathogenic variants in the interleukin-2 receptor subunit γ (IL2RG) gene, which encodes the common γ chain shared by several cytokine receptors. Other important causes include defects in the Janus kinase 3 (JAK3) gene, interleukin 7 receptor (IL7R) gene, recombination activating genes 1 and 2 (RAG1 and RAG2), DNA cross-link repair 1C (DCLRE1C) gene, and adenosine deaminase (ADA) gene. Infants typically present with failure to thrive, persistent candidiasis, chronic diarrhea, severe or opportunistic infections, and absent lymphoid tissue. Newborn screening programs have significantly improved early detection and outcomes.

Combined immunodeficiency syndromes generally present with less severe immune dysfunction than SCID and are frequently associated with characteristic syndromic features. Major groups include disorders of thymic development, such as 22q11.2 deletion syndrome (DiGeorge syndrome); defects in nuclear factor κB signaling and ectodermal development; hyper-IgE syndromes; DNA repair disorders, such as ataxia-telangiectasia and Nijmegen breakage syndrome; skeletal dysplasia syndromes; bone marrow failure syndromes; and disorders associated with intestinal atresia or developmental abnormalities.[1] Recognition of associated noninfectious manifestations often provides important diagnostic clues. 

The most common forms of IEI are composed predominantly of antibody deficiencies.[4] These disorders range from a complete absence of B cells to selective defects in immunoglobulin production or antibody function. X-linked agammaglobulinemia, caused by pathogenic variants in the Bruton tyrosine kinase (BTK) gene, results in arrested B-cell maturation and profound hypogammaglobulinemia. Common variable immunodeficiency (CVID) is a heterogeneous disorder characterized by impaired antibody production, recurrent sinopulmonary infections, autoimmunity, lymphoproliferation, and variable genetic associations. Other important antibody deficiencies include selective IgA deficiency, specific antibody deficiency, IgG subclass deficiency, hyper-IgM syndromes, and activated phosphoinositide 3-kinase δ syndromes.

Congenital phagocyte disorders result from abnormalities in phagocyte number, migration, or function. Major examples include severe congenital neutropenia, leukocyte adhesion deficiency, chronic granulomatous disease (CGD), and GATA-binding protein 2 (GATA2) gene deficiency. These disorders typically present with recurrent bacterial and fungal infections, poor wound healing, deep-seated abscesses, granulomatous inflammation, or unusual susceptibility to opportunistic pathogens.

Defects of innate immunity are characterized by increased susceptibility to specific pathogens due to impaired pathogen recognition or cytokine signaling pathways.[1] Examples include Toll-like receptor 3 pathway defects associated with herpes simplex encephalitis, IL-17 pathway defects causing chronic mucocutaneous candidiasis, caspase recruitment domain–containing protein 9 deficiency (CARD9) predisposing to invasive fungal infections, and defects in the IL-12/interferon γ axis leading to Mendelian susceptibility to mycobacterial disease. Recognition of recurrent infections caused by a particular pathogen often provides a clue to the underlying immune defect.

Several IEIs have characteristic clinical presentations that facilitate diagnosis. SCID typically presents with severe infections and failure to thrive during infancy. X-linked agammaglobulinemia manifests after maternal antibodies wane, with recurrent bacterial infections and absent tonsils. CVID commonly presents with recurrent sinopulmonary infections, lymphadenopathy, splenomegaly, or bronchiectasis. Hyper-IgM syndromes are characterized by impaired immunoglobulin class switching, whereas chronic granulomatous disease presents with recurrent abscesses and granulomatous inflammation. Complement deficiencies predispose to recurrent Neisseria spp infection, and leukocyte adhesion deficiency presents with delayed umbilical cord separation, recurrent infections without pus formation, poor wound healing, and omphalitis.

Table 1. Most Common Inborn Errors Of Immunity and Their Defining Phenotype

Secondary immunodeficiencies result from acquired conditions that impair normal immune function.[2] Common causes include immunosuppressive medications, chronic infections, malignant neoplasms, malnutrition, protein-losing states, and surgical removal of immunologically active organs. Medications associated with secondary immunodeficiency include corticosteroids, cyclophosphamide, azathioprine, mycophenolate mofetil, methotrexate, calcineurin inhibitors, mammalian target of rapamycin inhibitors, and other immunomodulatory therapies that impair T-cell and B-cell function.

Among chronic infections, HIV directly invades T lymphocytes, resulting in profound immunosuppression called AIDS and characterized by quantitative impairment of CD4+ lymphocytes, impaired cellular immunity, and other immunologic disruptions. Other chronic infections, including hepatitis B virus, Epstein-Barr virus, and cytomegalovirus, can also disrupt immune regulation. Acute illnesses, including severe bacterial sepsis and malaria, may cause transient immunosuppression. 

Malnutrition is another important cause of secondary immunodeficiency. Protein-energy malnutrition impairs cell-mediated immunity, cytokine production, and phagocyte function, particularly intracellular microbial killing. Micronutrient deficiencies, including deficiencies of zinc, iron, selenium, copper, and vitamins B₆ and B₁₂, can adversely affect immune function and host defense mechanisms. Nutritional deficiencies may occur in the setting of malignant neoplasms, burns, chronic kidney disease, trauma, or chronic infections. Additional causes of secondary immunodeficiency include hematologic neoplasms, such as chronic lymphocytic leukemia, multiple myeloma, and non–Hodgkin lymphoma; protein-losing conditions, such as nephrotic syndrome and protein-losing enteropathy; and surgical procedures, including splenectomy or thymectomy.

Epidemiology

Underdiagnosis remains a major challenge for IEI worldwide, particularly in resource-limited countries where access to specialized diagnostic testing and registries is limited. Current registries likely capture only a small proportion of affected individuals. Predominantly, antibody deficiencies are the most common category of IEI, accounting for nearly half of all cases.[5] CVID is among the most frequently diagnosed clinically significant syndromes, whereas selective IgA deficiency is the most common primary immunodeficiency overall, with an estimated prevalence of approximately 1 in 300 to 700 individuals of European ancestry. Results from epidemiologic studies in the US demonstrated a higher reported prevalence of primary immunodeficiency among White individuals than among Black or Hispanic populations, although disparities in recognition and access to care likely contribute to these differences. Certain complement deficiencies also demonstrate geographic variation, including increased prevalence of C6 deficiency in African populations and C9 deficiency in East Asian populations. Phagocytic disorders represent the next most common group of IEI.

Severe combined immunodeficiency is rare but life-threatening, occurring in approximately 1 in 58,000 live births in the United States based on newborn screening data. Many causes of SCID are incompatible with life. Affected infants who survive typically present early in life with severe or opportunistic infections, failure to thrive, and impaired lymphocyte development.[3] 

Secondary immunodeficiencies are substantially more common than primary immunodeficiencies, and the immunocompromised population in the United States has increased significantly over the past decade.[6] Malnutrition remains the leading cause of secondary immunodeficiency worldwide and disproportionately affects resource-limited countries. HIV infection is the most extensively studied infectious cause of secondary immunodeficiency and results in AIDS. The widespread implementation of antiretroviral therapy has significantly reduced HIV-related mortality worldwide, although the global burden of disease remains substantial. Medication-induced immunodeficiency is one of the fastest-growing categories of secondary immunodeficiency due to the expanding use of corticosteroids, biologic therapies, chemotherapy, transplant-related immunosuppression, and other immunomodulatory agents. 

Pathophysiology

The pathophysiology of immunodeficiency disorders is best understood according to the immune compartment affected, including humoral immunity, cellular immunity, innate immunity, and combined immune defects.[7] These are summarized in Table 2. Humoral immunity is mediated by B lymphocytes and plasma cells, which produce immunoglobulins that protect against extracellular pathogens. Disorders affecting B-cell development or antibody production result in increased susceptibility to recurrent sinopulmonary infections, particularly those caused by encapsulated bacteria. X-linked agammaglobulinemia is a classic example of a humoral immunodeficiency characterized by the absence or marked reduction of mature B cells and profound hypogammaglobulinemia.[4]

Cellular immunity is mediated primarily by T lymphocytes, including helper, cytotoxic, and regulatory T cells. T cells play a central role in defense against intracellular pathogens such as viruses, fungi, and certain opportunistic organisms, while also supporting B-cell activation and antibody production. Defects in T-cell development or function predispose patients to severe viral, fungal, and opportunistic infections. SCID is the most profound form of cellular immunodeficiency and may result from defects in genes involved in lymphocyte development, including RAG1 and RAG2, which are required for variable, diversity, and joining (V[D]J) recombination during antigen receptor gene rearrangement. Some patients with hypomorphic RAG mutations develop Omenn syndrome, characterized by erythroderma, eosinophilia, lymphadenopathy, and immune dysregulation. Other T-cell disorders, such as DiGeorge syndrome, result from abnormal thymic development and variable T-cell deficiency.

Innate immunity provides the first line of host defense and includes phagocytic cells, the complement cascade, cytokines, and pattern-recognition receptors. Defects in innate immunity impair early pathogen recognition and clearance, resulting in recurrent bacterial, fungal, or opportunistic infections. Complement deficiencies may also predispose to autoimmune disease. For example, early-classical complement pathway defects, such as C4 deficiency, are associated with lupus-like syndromes.

Most primary immunodeficiencies are congenital and follow X-linked or autosomal recessive inheritance patterns. Some disorders involve defects in DNA repair pathways, such as ataxia-telangiectasia, an autosomal recessive condition caused by mutations affecting DNA damage repair and lymphocyte maturation. Conversely, the pathophysiology of secondary immunodeficiencies depends on the affected immune compartment and underlying condition.[2] Humoral immune defects commonly result from hypogammaglobulinemia caused by decreased antibody production or increased immunoglobulin loss. Reduced antibody production may occur following B-cell depletion with rituximab or chimeric antigen receptor T-cell therapy, plasma cell suppression with agents such as daratumumab or bortezomib, bone marrow infiltration by hematologic neoplasm, or corticosteroid-induced suppression of immunoglobulin synthesis.

Secondary T-cell dysfunction is most commonly associated with HIV infection, which causes progressive CD4⁺ T-cell depletion and impaired cellular immunity. Aging also contributes to immune dysfunction through immunosenescence, resulting in reduced responses to novel antigens and vaccines. Certain immunosuppressive therapies, including alemtuzumab, produce profound lymphocyte depletion affecting both T and B cells. Additional mechanisms of secondary immunodeficiency include impaired phagocyte function in cirrhosis, loss of splenic immune function following splenectomy with reduced clearance of encapsulated organisms, and neutropenia-associated defects in phagocytosis, mucosal barrier integrity, and cytokine signaling. In many patients, multiple mechanisms of immune dysfunction coexist simultaneously.

Table 2. Pathophysiology of Immunodeficiency Disorders Classified by the Immune Compartment Affected

Histopathology

Histopathologic findings in IEI vary according to the affected immune compartment and may provide important diagnostic clues. In SCID, the thymus typically shows severe lymphoid depletion, with absent corticomedullary differentiation and a lack of Hassall corpuscles, reflecting defective thymic epithelial maturation and impaired T-cell development.[8] Conversely, DiGeorge syndrome is characterized by thymic hypoplasia or aplasia, although residual thymic tissue may preserve corticomedullary architecture. 

Lymph node histopathology may help distinguish different antibody deficiencies. In CVID, lymph nodes often show poorly formed germinal centers with markedly reduced or absent class-switched plasma cells. Reactive lymphoid hyperplasia is common, and noncaseating granulomatous inflammation may occur. In X-linked agammaglobulinemia (XLA), lymphoid tissue demonstrates absent or markedly hypoplastic germinal centers due to failure of B-cell maturation. Bone marrow findings also reflect the underlying immunologic defect.[9] Patients with CVID may demonstrate reduced or absent plasma cells and prominent CD3⁺ T-cell infiltrates, particularly in association with autoimmune cytopenias. In some forms of SCID, bone marrow examination reveals severe depletion or absence of lymphoid precursors.

Hyper-IgM syndromes are characterized by impaired immunoglobulin class switching, resulting in markedly reduced IgG and IgA levels with preserved or elevated IgM production. Tissue biopsies may demonstrate plasma cells containing abundant eosinophilic cytoplasm consistent with active IgM secretion. Additionally, granulomatous inflammation is a hallmark of chronic granulomatous disease, in which defective phagocyte oxidative burst leads to persistent inflammation and formation of noncaseating granulomas with multinucleated giant cells.[10] 

Histopathologic findings in secondary immunodeficiencies generally reflect acquired immune depletion or tissue injury rather than congenital developmental abnormalities. In advanced HIV infection, opportunistic infections produce characteristic tissue findings. Small bowel biopsies in cryptosporidiosis demonstrate organisms attached to the intestinal epithelium, while Pneumocystis jirovecii pneumonia shows cystic organisms highlighted by Gomori methenamine silver stain. Cytomegalovirus infection produces enlarged cells with basophilic intranuclear inclusions surrounded by a clear halo. Furthermore, malnutrition-associated immunodeficiency is characterized by lymphoid atrophy involving the thymus, spleen, and lymph nodes. Histologic findings include loss of corticomedullary differentiation, depletion of lymphoid cells, and enlarged or degenerating Hassall corpuscles, reflecting impaired cellular immunity.

History and Physical

Given the broad clinical spectrum of immunodeficiency disorders, a systematic history and physical examination are essential for early recognition. The 10 Warning Signs proposed by the Jeffrey Modell Foundation remain a useful screening tool for identifying patients who warrant further evaluation for IEI.[11] The most important historical feature is recurrent or unusually severe infection. Red flag findings include 4 or more episodes of otitis media within 1 year, 2 or more serious sinus infections, recurrent pneumonias, deep-seated abscesses, persistent mucocutaneous candidiasis, or infections caused by opportunistic or uncommon organisms.[12] The type of pathogen often suggests the affected immune compartment (Table 3). Recurrent infections with encapsulated bacteria such as Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis suggest an opsonization defect, whereas infections caused by Pneumocystis jirovecii, Candida species, nontuberculous mycobacteria, or Aspergillus species suggest T-cell or phagocytic defects. Recurrent infections with catalase-positive organisms, including Staphylococcus aureus, Serratia marcescens, and Aspergillus species, are characteristic of chronic granulomatous disease. Recurrent mycobacterial infections may indicate defects in the IL-12/interferon-γ axis.

A detailed family history is essential and should include consanguinity, early childhood deaths from infection, recurrent severe infections among relatives, or known diagnoses of immunodeficiency. Although many IEIs are X-linked and therefore more common in boys and men, both sexes may be affected depending on the inheritance pattern.[13] Moreover, noninfectious manifestations are increasingly recognized as major clues to IEI and may precede recurrent infections. Important historical findings include failure to thrive, chronic diarrhea, autoimmune cytopenias, inflammatory bowel disease-like symptoms, endocrinopathies, severe atopy, unexplained lymphoproliferation, granulomatous disease, and malignant neoplasms. 

Physical examination should assess for evidence of recurrent infection, chronic inflammation, immune dysregulation, and syndromic features. Common findings include recurrent otitis media, sinusitis, pneumonia, oral candidiasis, bronchiectasis, chronic diarrhea, lymphadenopathy, hepatosplenomegaly, eczema, recurrent skin abscesses, poor wound healing, and severe atopic disease. Absent or markedly hypoplastic tonsils and lymph nodes suggest X-linked agammaglobulinemia, while petechiae with thrombocytopenia and eczema are characteristic of Wiskott-Aldrich syndrome. Delayed umbilical cord separation and recurrent infections without purulence suggest leukocyte adhesion deficiency.

Syndromic findings may provide important diagnostic clues.[14] Facial dysmorphism, cleft palate, hypocalcemia, and congenital cardiac defects suggest DiGeorge syndrome. Ataxia and telangiectasias are characteristic of ataxia-telangiectasia. Partial albinism may occur in Chédiak-Higashi syndrome, while retained primary teeth, fractures, and coarse facial features suggest hyper-IgE syndrome. Short stature, skeletal abnormalities, café au lait spots, hearing impairment, alopecia, erythroderma, or neurodevelopmental delay may indicate a specific syndromic IEI.

Evaluation of suspected secondary immunodeficiency should similarly focus on infection history and immune-related complications, but careful review of medications and underlying medical conditions is critical. The temporal relationship between the onset of infections and the initiation of immunosuppressive therapy may help distinguish secondary from primary immune dysfunction. Common causes include corticosteroids, biologic therapies, chemotherapy, hematologic malignant neoplasms, HIV infection, protein-losing states, malnutrition, and transplant. Opportunistic infections such as Pneumocystis jirovecii, cytomegalovirus, invasive mold infections, or herpesvirus reactivation suggest significant T-cell dysfunction or combined immunodeficiency.

Table 3. Pathogens Associated with Immunodeficiencies

Evaluation

The evaluation of suspected IEI follows a structured, stepwise approach guided by clinical presentation, infection pattern, and severity. International and national recommendations emphasize an initial screening phase, followed by targeted immunologic assessment and, when indicated, molecular confirmation.[7]

Step 1: Initial Screening Tests

All patients with a suspected IEI should undergo the following baseline studies:

• Complete blood count (CBC) with manual differential: CBC with manual differential provides early clues to lineage-specific immune defects. Lymphocytopenia suggests a T-cell defect (an absolute lymphocyte count < 2500/μL in infants is abnormal). Neutropenia suggests phagocyte dysfunction, whereas thrombocytopenia with small platelets is characteristic of Wiskott–Aldrich syndrome.
• Quantitative serum immunoglobulins (IgG, IgA, IgM, IgE, including IgG subclasses): Reduced levels of IgG, IgA, and IgM suggest humoral immunodeficiency (eg, X-linked agammaglobulinemia or common variable immunodeficiency). Elevated IgE levels may be seen in hyper-IgE syndromes or Omenn syndrome. A pattern of low IgG and elevated IgM is suggestive of hyper-IgM syndromes. Interpretation must always consider age-adjusted reference ranges.
• Specific antibody titers: Specific antibody titers measure responses to both protein antigens (tetanus and diphtheria) and polysaccharide antigens (pneumococcal serotypes). Failure to mount protective titers after vaccination is a hallmark of antibody deficiency.
• Complement studies:  An undetectable total hemolytic complement activity suggests a classic pathway component deficiency; an undetectable alternative complement pathway activity suggests an alternative pathway defect. Undetectable results in both studies suggest a shared deficiency in the terminal pathway (C3 through C9).

Step 2: Advanced Immunologic Testing

Advanced immunologic testing is indicated when screening tests are abnormal or when clinical suspicion remains high despite normal screening results.

• Flow cytometry for lymphocyte subsets: Flow cytometry evaluates T-lymphocyte subsets (CD3+, CD4+, and CD8+), B-lymphocyte count (CD19+ or CD20+), and CD16+/CD56+ natural killer cells. Further characterization includes naive (CD45RA+) and memory (CD45RO+) T cells, as well as switched memory B cells (CD27+ IgD−).
• Lymphocyte proliferation assays: Lymphocyte proliferation assays assess T-cell function by measuring responses to mitogens (phytohemagglutinin and concanavalin A), antigens (Candida spp and tetanus), and anti-CD3.
• Neutrophil oxidative burst testing: Dihydrorhodamine flow cytometry or nitroblue tetrazolium testing evaluates neutrophil oxidative burst function. Dihydrorhodamine flow cytometry is preferred due to its ability to detect X-linked carrier status and distinguish residual oxidase activity. An abnormal result is diagnostic of chronic granulomatous disease.
• Leukocyte adhesion testing: Flow cytometry for detection of CD18 and CD11 expression to evaluate for leukocyte adhesion deficiency.

Step 3: Genetic Testing

Genetic evaluation is increasingly considered the standard of care for definitive diagnosis, prognostication, and therapeutic planning.[15]  Targeted gene panels are appropriate when clinical phenotypes are highly suggestive (eg, BTK in X-linked agammaglobulinemia or cytochrome b-245 β chain [CYBB] gene in chronic granulomatous disease). Whole exome sequencing or whole genome sequencing is recommended for atypical presentations, negative targeted testing results, or novel disease discovery, with diagnostic yields of approximately 25% to 40% in previously undiagnosed cases. Chromosomal microarray remains first-line when syndromic chromosomal abnormalities are suspected, such as 22q11.2 deletion syndrome.

Additional systemic investigations: Further evaluation may include coagulation studies (factor V activity, fibrinogen level, prothrombin time, thrombin time, and bleeding time), general laboratory testing (liver function testing, metabolic panels, and cytokine levels), imaging (chest radiography, ultrasonography, and CT), histopathology, bone marrow biopsy, tumor markers when relevant, and cytogenetic or molecular studies, including fluorescence in situ hybridization. Given the association of some IEI with autoimmune disorders, screening for autoimmunity is often indicated. Autoimmune screening includes antinuclear antibodies; disease-specific autoantibodies (anti–double-stranded DNA, rheumatoid factor, anti-Smith, anti-histone, and anti-SSA/SSB); cytopenia-associated antibodies (anti-erythrocyte, anti-platelet, and anti-neutrophil); and organ-specific autoimmune markers.

Newborn screening for severe combined immunodeficiency: The T-cell receptor excision circle (TREC) assay is now implemented internationally. TRECs are byproducts of T-cell receptor rearrangement in the thymus and are absent or markedly reduced in neonates with T-cell lymphopenia, including all forms of SCID. Newborn screening has dramatically improved outcomes by enabling presymptomatic diagnosis and early definitive therapy.[16]

Evaluation of suspected secondary immunodeficiency similarly follows structured guidance, emphasizing sequential screening, longitudinal monitoring, and functional immune assessment. Initial evaluation requires careful review of medications and identification of secondary causes, including hematologic malignant neoplasms, HIV infection, protein-losing states, and malnutrition. A central objective is to distinguish reversible secondary causes from underlying primary immune defects.

In selected cases, immune abnormalities may precede immunosuppressive therapy, raising the possibility of an underlying inborn error of immunity. Clinical features suggesting a primary etiology include pretreatment hypogammaglobulinemia, persistent immune dysfunction after cessation of immunosuppressive therapy, or disproportionate immune impairment relative to the degree of iatrogenic exposure. In such scenarios, genetic testing should be considered to clarify diagnosis and guide treatment.

Treatment / Management

Treatment of immunodeficiency syndromes requires an interdisciplinary, individualized approach based on the underlying immune defect, the severity of infections, the degree of immune dysfunction, and the presence of immune dysregulation or malignant neoplasms. Treatment strategies broadly include supportive care, infection prevention, immune replacement, immune reconstitution, targeted therapies, and treatment of secondary causes.[17]

Management strategies are tailored according to:

• The immune compartment affected (humoral, cellular, phagocytic, complement, or combined defects)
• Severity and frequency of infections
• Presence of autoimmunity, inflammation, or malignant neoplasm
• Availability of curative therapies
• Reversibility of secondary immune defects

Supportive and Preventive Measures

• Infection prophylaxis: Antimicrobial prophylaxis is tailored to the specific immune defect. Trimethoprim-sulfamethoxazole is used for Pneumocystis jirovecii prophylaxis in T-cell defects and chronic granulomatous disease. Itraconazole or posaconazole is recommended for antifungal prophylaxis in chronic granulomatous disease because studies have shown reduced rates of invasive fungal infections.  
• Vaccination considerations: Vaccination remains a cornerstone of infection prevention. Inactivated vaccines should be administered whenever feasible. Live attenuated vaccines are contraindicated in severe T-cell defects, including SCID, DiGeorge, and combined cellular immunodeficiencies. Live attenuated vaccines include measles, mumps, and rubella; varicella; rotavirus; bacille Calmette-Guérin; live attenuated influenza; and oral polio vaccines.
• Interferon-γ: Subcutaneous interferon-γ is used as adjunctive prophylaxis in CGD, where it reduces the frequency of serious infections, though the mechanism is not fully understood, as it does not correct the oxidative burst defect.

Immunoglobulin Replacement Therapy

Immunoglobulin replacement therapy is the mainstay of treatment for antibody deficiencies (X-linked agammaglobulinemia, common variable immunodeficiency, hyper-IgM syndromes, and other conditions with impaired antibody production). Immunoglobulin replacement therapy is administered as intravenous immunoglobulin or subcutaneous immunoglobulin. The goal is to maintain trough IgG levels sufficient to prevent infections, generally 500 mg/dL or greater, though individualized targets may be higher. Immunoglobulin replacement therapy reduces sinopulmonary infections but does not completely prevent chronic lung disease or systemic enteroviral infections. Patients who do not undergo curative therapy require lifelong immunoglobulin replacement therapy.

Treatments With Curative Intent

Hematopoietic stem cell transplant (HSCT) is the definitive curative therapy for many IEI, including SCID, CGD, Wiskott-Aldrich syndrome, hyper-IgM syndrome, leukocyte adhesion deficiency, and other severe combined or phagocyte defects. Important determinants of the clinical outcome after HSCT for SCID include younger age at transplant, absence of active infection, matched sibling donors, and early diagnosis.[18](B2)

Gene therapy has become an increasingly important curative strategy for selected monogenic IEIs.[19] Modern lentiviral approaches have substantially improved safety compared with earlier γ-retroviral vectors, which were associated with insertional oncogenesis and leukemia. SCID due to adenosine deaminase deficiency and X-linked SCID have established lentiviral approaches available. [20] 

Cultured thymus tissue transplant is the treatment of choice for complete DiGeorge syndrome. Targeted immunotherapy includes Janus kinase inhibitors (eg, ruxolitinib) for gain-of-function STAT1 or STAT3 variants; mammalian target of rapamycin inhibitors (mTOR) (eg, sirolimus) for activated phosphoinositide 3-kinase δ syndrome (APDS) and autoimmune lymphoproliferative syndrome; abatacept, a cytotoxic T-lymphocyte antigen 4 immunoglobulin fusion protein (CTLA-4-Ig), for cytotoxic T-lymphocyte antigen 4 (CTLA-4) haploinsufficiency and LRBA deficiency; and leniolisib, a selective phosphoinositide 3-kinase δ inhibitor, for activated phosphoinositide 3-kinase δ (PI3Kδ) syndrome. Treatment of secondary immunodeficiencies centers on 3 major principles: correction of the underlying cause, prevention of infections, and replacement of deficient immune components when clinically indicated.[21] Identification and reversal of the precipitating condition are critical and include, when feasible, discontinuation or reduction of immunosuppressive therapies; correction of nutritional deficiencies; treatment of chronic infections, such as HIV, with antiretroviral therapy;[6] and treatment of underlying hematologic malignant neoplasms or protein-losing conditions.(B3)

Differential Diagnosis

The differential diagnosis of immunodeficiency syndromes is broad and requires careful distinction between primary IEI and secondary (acquired) causes of immune dysfunction. Secondary immunodeficiencies are considerably more common in adults and should be systematically excluded during the initial evaluation. [22] The distinction is clinically important because management, prognosis, and the need for genetic counseling differ substantially between inherited and acquired disorders.

Secondary Immunodeficiencies to Exclude

Secondary immunodeficiencies frequently mimic primary antibody or cellular immune defects and may present with recurrent, severe, or opportunistic infections.

• HIV infection: HIV remains one of the most important causes of acquired T-cell immunodeficiency and must be excluded in any patient presenting with opportunistic infections, chronic mucocutaneous candidiasis, unexplained lymphopenia, weight loss, or recurrent pneumonias. HIV testing should be performed early in the evaluation of suspected immunodeficiency.
• Medication-induced immunodeficiency: Immunosuppressive therapies are an increasingly common cause of secondary immune dysfunction.
• Hematologic malignant neoplasms: Chronic lymphocytic leukemia, multiple myeloma, and lymphomas commonly produce secondary antibody deficiency due to impaired B-cell or plasma cell function.
• Protein-losing conditions: Nephrotic syndrome and protein-losing enteropathy may result in substantial immunoglobulin loss and clinically mimic humoral immunodeficiency syndromes.
• Malnutrition: Protein-energy malnutrition is the most common cause of secondary immunodeficiency worldwide and disproportionately affects low- and middle-income countries. Micronutrient deficiencies involving zinc, selenium, copper, and iron can further impair immune responses.
• Iatrogenic causes: Splenectomy increases susceptibility to infections caused by encapsulated organisms, while thymectomy may impair T-cell immunity depending on timing and patient age.

Several nonimmunologic disorders can present with recurrent infections and should be distinguished from true immune defects.

• Cystic fibrosis: Recurrent sinopulmonary infections, chronic sinus disease, and bronchiectasis may resemble antibody deficiency syndromes.
• Primary ciliary dyskinesia: Defective mucociliary clearance causes recurrent respiratory infections despite otherwise normal immune function.
• Allergic disorders: Allergic rhinitis, asthma, and chronic sinusitis may mimic recurrent infectious disease but generally occur without opportunistic infections or abnormal immunologic testing.
• Structural or anatomic abnormalities: Cleft palate, tracheoesophageal fistula, eustachian tube dysfunction, or airway abnormalities may predispose to recurrent localized infections independent of immune dysfunction.
• Physiologic hypogammaglobulinemia of infancy: Infants normally experience a transient decline in IgG levels between approximately 3 and 6 months of age as maternally derived antibodies wane. This physiologic process usually resolves spontaneously by 24 months and must be distinguished from persistent antibody deficiency syndromes.

Prognosis

The prognosis of immunodeficiency syndromes varies widely according to the specific disorder, severity of immune dysfunction, timing of diagnosis, infectious burden, associated immune dysregulation or malignant neoplasms, and availability of definitive therapies. Early recognition and advances in immunoglobulin replacement, antimicrobial prophylaxis, hematopoietic stem cell transplant, gene therapy, and targeted immunomodulatory therapies have significantly improved survival and quality of life in many patients with both primary and secondary immunodeficiencies.[23][24]

CVID is associated with reduced life expectancy compared with the general population, although prognosis varies considerably according to the clinical phenotype. Patients with predominantly infectious complications generally have favorable long-term survival with immunoglobulin replacement therapy. Lower baseline IgG levels, reduced peripheral B-cell numbers, and persistent immune dysregulation correlate with poorer outcomes. The prognosis of secondary immunodeficiencies depends primarily on the reversibility of the underlying condition and the degree of immune suppression:

• HIV/AIDS: Prognosis has improved dramatically with effective antiretroviral therapy, transforming HIV infection into a chronic, manageable disease in many patients. Treatment adherence, opportunistic infections, and timing of diagnosis strongly influence survival.
• Malnutrition-associated immunodeficiency: Nutritional rehabilitation and correction of micronutrient deficiencies can significantly improve immune function and clinical outcomes.
• Drug-induced immunodeficiency: Prognosis depends on the underlying disease requiring immunosuppression, cumulative immune injury, and the ability to discontinue or reduce immunosuppressive therapies.
• Malignancy-associated immunodeficiency: Outcomes vary by cancer type, stage, therapy response, and treatment-related immunosuppression.

Complications

Complications of immunodeficiency syndromes extend far beyond recurrent infections and increasingly represent the major determinants of long-term morbidity and mortality, particularly in patients with chronic primary immunodeficiencies such as CVID.[25][26] Noninfectious complications are especially important in CVID, where they occur in most patients and are associated with substantially reduced survival. Recurrent, severe, and opportunistic infections remain the hallmark complication of immunodeficiency syndromes. Infections may involve virtually any organ system and are caused by bacteria, viruses, fungi, or parasites, depending on the underlying immune defect.

Common infectious complications include:

• Recurrent sinopulmonary infections
• Chronic otitis media and sinusitis
• Bronchiectasis
• Invasive fungal infections
• Opportunistic viral infections
• Septicemia and septic shock
• Chronic mucocutaneous candidiasis
• Recurrent abscess formation
• Meningitis and encephalitis
• Multiorgan failure secondary to overwhelming infection

Autoimmune disease is increasingly recognized as a major manifestation of IEI and may even precede recurrent infections. Chronic pulmonary disease is one of the leading causes of long-term morbidity in antibody deficiencies. Major pulmonary complications include bronchiectasis, granulomatous-lymphocytic interstitial lung disease, pneumatoceles, chronic respiratory insufficiency, and pulmonary fibrosis in advanced disease.[27] Pulmonary complications may progress despite adequate immunoglobulin replacement therapy. Gastrointestinal tract involvement is common in several immunodeficiency syndromes. Manifestations include chronic diarrhea, malabsorption, villous atrophy or villous blunting, nodular lymphoid hyperplasia, inflammatory bowel disease-like colitis, protein-losing enteropathy, chronic liver disease, and portal hypertension. Liver disease may result from chronic inflammation, granulomatous disease, infection, or immune dysregulation.

Patients with primary immunodeficiencies have a significantly increased risk of malignant neoplasms due to impaired immune surveillance, chronic inflammation, oncogenic viral infections, and defects in DNA repair.[28] The most strongly associated malignancies include non-Hodgkin lymphoma, leukemia, gastric carcinoma, colorectal carcinoma, and virus-associated malignancies such as Kaposi sarcoma and Epstein-Barr virus–driven lymphoproliferative disorders. The highest malignancy risks are observed in CVID, Wiskott-Aldrich syndrome, ataxia-telangiectasia, and Nijmegen breakage syndrome.