Immunodeficiency disorders increase susceptibility to infection. They may be secondary or primary; secondary is more common.

Secondary immunodeficiencies

Causes include systemic disorders (eg, diabetes, undernutrition, HIV infection) and immunosuppressive treatments (eg, chemotherapy, radiation therapy—see Table 1: Immunodeficiency Disorders: Causes of Secondary Immunodeficiency). Secondary immunodeficiency also occurs among critically ill, older, or hospitalized patients. Prolonged serious illness may impair immune responses; impairment is often reversible if the underlying illness resolves.

Table 1
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Causes of Secondary Immunodeficiency Category Examples Endocrine Diabetes mellitus GI Hepatic insufficiency, hepatitis, intestinal lymphangiectasia, protein-losing enteropathy Hematologic Aplastic anemia, cancer, graft-vs-host disease, sickle cell disease Iatrogenic Certain drugs, such as chemotherapeutic drugs, immunosuppressants, corticosteroids (see Table 2: Immunodeficiency Disorders: Some Drugs That Cause Immunosuppression); radiation therapy; splenectomy Infectious Cytomegalovirus, Epstein-Barr virus, HIV, measles virus, varicella-zoster virus Nutritional Alcoholism, undernutrition Physiologic Physiologic immunodeficiency in infants due to immaturity of the immune system, pregnancy Renal Nephrotic syndrome, renal insufficiency, uremia Rheumatologic RA, SLE Other Burns, chromosomal abnormalities (eg, Down syndrome), congenital asplenia, critical and chronic illness, histiocytosis, sarcoidosis

Table 2
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Some Drugs That Cause Immunosuppression Class Examples Anticonvulsants Carbamazepine, diphenylhydantoin, lamotrigine, valproate Calcineurin inhibitors Cyclosporine, tacrolimus Corticosteroids Methylprednisolone, prednisone Cytotoxic chemotherapy drugs Multiple (see Table 3: Principles of Cancer Therapy: Commonly Used Antineoplastic Drugs) Purine metabolism inhibitors Azathioprine, mycophenolate mofetil Rapamycins Everolimus, sirolimus Immunosuppressive immunoglobulins Antilymphocyte globulin, antithymocyte globulin Monoclonal antibodies OKT3, basiliximab, daclizumab

Immunodeficiency can result from loss of serum proteins (particularly IgG and albumin) through the kidneys in nephrotic syndrome, through skin in severe burns or dermatitis, or through the GI tract in enteropathy. Enteropathy may also lead to lymphocyte loss, resulting in lymphopenia. These disorders can mimic B- and T-cell defects. Treatment focuses on the underlying disorder; a diet high in medium-chain triglycerides may decrease loss of Igs and lymphocytes from the GI tract and be remarkably beneficial.

Primary immunodeficiencies

These disorders are genetically determined; they may occur alone or as part of a syndrome. More than 200 have been described, and heterogeneity within each disorder may be considerable. The molecular basis for about 80% is known. Primary immunodeficiencies typically manifest during infancy and childhood as abnormally frequent (recurrent) or unusual infections. About 70% of patients are < 20 yr at onset; because transmission is often X-linked, 60% are male. Overall incidence of symptomatic disease is about 1/280 people.

Primary immunodeficiencies are classified by the main component of the immune system that is deficient, absent, or defective (see Table 3: Immunodeficiency Disorders: Primary Immunodeficiency Disorders ):

• B cells (or Ig)
• T cells
• Natural killer cells (very rare)
• Phagocytic cells
• Complement proteins

As more molecular defects are defined, classifying immunodeficiencies by their molecular defects will be more appropriate.

B-cell defects causing Ig and antibody deficiencies account for 50 to 60% of primary immunodeficiencies. Serum Ig and antibody titers decrease, predisposing to infections with encapsulated gram-positive bacteria. The most common B-cell disorder is selective IgA deficiency.

T-cell disorders account for about 5 to 10% of primary immunodeficiencies and predispose to infection by viruses, Pneumocystis jirovecii, fungi, other opportunistic organisms, and many common pathogens. T-cell disorders also cause Ig deficiencies because the B- and T-cell immune systems are interdependent. The most common T-cell disorders are DiGeorge syndrome, ZAP-70 deficiency, X-linked lymphoproliferative syndrome, and chronic mucocutaneous candidiasis (see Immunodeficiency Disorders: Chronic Mucocutaneous Candidiasis).

Combined B- and T-cell defects account for about 20% of primary immunodeficiencies. The most important form is severe combined immunodeficiency (SCID). In some forms of combined immunodeficiency (eg, purine nucleoside phosphorylase deficiency), Ig levels are normal or elevated, but because of inadequate T-cell function, antibody formation is impaired.

Natural killer cell defects are very rare and may predispose to viral infections and tumors.

Phagocytic cell defects account for 10 to 15% of primary immunodeficiencies; the ability of phagocytic cells (eg, monocytes, macrophages, granulocytes such as neutrophils and eosinophils) to kill pathogens is impaired. Cutaneous staphylococcal and gram-negative infections are characteristic. The most common phagocytic cell defects are chronic granulomatous disease, leukocyte adhesion deficiency, and Chédiak-Higashi syndrome.

Complement deficiencies are rare (≤ 2%); they include isolated deficiencies of complement components or inhibitors and may be hereditary or acquired. Hereditary deficiencies are autosomal recessive except for deficiencies of C1 inhibitor, which is autosomal dominant, and properdin, which is X-linked. The deficiencies result in defective opsonization, phagocytosis, and lysis of pathogens and in defective clearance of antigen-antibody complexes. Recurrent infection, due to defective opsonization, and autoimmune disorders (eg, SLE, glomerulonephritis), due to defective clearance of antigen-antibody complexes (see Table 3: Immunodeficiency Disorders: Primary Immunodeficiency Disorders ), are the most serious consequences. One of these deficiencies causes hereditary angioedema.

Table 3
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Primary Immunodeficiency Disorders  Disorder Inheritance Clinical Findings Ig (B-cell) deficiencies Common variable immunodeficiency Autosomal dominant Similar to X-linked agammaglobulinemia but with later manifestation and presence of B cells Autoimmune disorders, malabsorption, nodular lymphoid hyperplasia of GI tract, bronchiectasis, lymphoid interstitial pneumonia, lymphoma (in 10%) Hyper-IgM syndrome with AID or UNG deficiencies Autosomal recessive Similar to X-linked hyper-IgM syndrome but with lymphoid hyperplasia No leukopenia Hyper-IgM syndrome with CD40 deficiency Autosomal recessive Similar to X-linked hyper-IgM syndrome Lymphoid hypoplasia, neutropenia Hyper-IgM syndrome with CD40 ligand deficiency X-linked Similar to X-linked agammaglobulinemia but greater frequency of Pneumocystis jirovecii pneumonia, cryptosporidiosis, severe neutropenia, and lymphoid hypoplasia IgA deficiency Autosomal dominant Sometimes asymptomatic Recurrent sinopulmonary infections, diarrhea, allergies (including anaphylactic transfusion reactions), autoimmune disorders (eg, celiac disease, inflammatory bowel disease, SLE, chronic active hepatitis) Transient hypogammaglobulinemia of infancy — Low Ig but normal antibody levels X-linked agammaglobulinemia X-linked Recurrent sinopulmonary and skin infections during infancy, neutropenia, lymphoid hypoplasia T-cell disorders Chronic mucocutaneous candidiasis Autosomal dominant or recessive Persistent or recurrent candidal infections, onychomycosis, autosomal recessive autoimmune polyendocrinopathy syndrome (eg, hypoparathyroidism, Addison's disease) DiGeorge syndrome Autosomal Unusual facies with low-set ears, a congenital heart disorder (eg, aortic arch abnormalities), thymic hypoplasia or aplasia, hypoparathyroidism with hypocalcemic tetany, recurrent infections X-linked lymphoproliferative syndrome X-linked Asymptomatic until onset of Epstein-Barr virus infection, then fulminant or fatal infectious mononucleosis with liver failure and, in survivors, B-cell lymphomas, aplastic anemia, hypogammaglobulinemia, or a combination ζ-Associated protein 70 (ZAP-70) deficiency Autosomal recessive Common and opportunistic infections No CD8 cells Combined B- and T-cell defects Ataxia-telangiectasia Autosomal recessive Ataxia, telangiectasias, recurrent sinopulmonary infections, endocrine abnormalities (eg, gonadal dysgenesis, testicular atrophy, diabetes mellitus), increased risk of cancer Cartilage-hair hypoplasia Autosomal recessive Short-limbed dwarfism, common and opportunistic infections Combined immunodeficiency with inadequate but not absent T-cell function and normal or elevated Igs Autosomal recessive or X-linked Common and opportunistic infections, lymphopenia, lymphadenopathy, hepatosplenomegaly, skin lesions resembling those of Langerhans cell histiocytosis in some patients Hyper-IgE syndrome Autosomal dominant Staphylococcal abscesses of skin, lungs, joints, and viscera; pulmonary pneumatoceles; pruritic dermatitis; coarse facial features; delayed shedding of baby teeth; osteopenia; recurrent fractures; tissue and blood eosinophilia MHC antigen deficiencies Autosomal recessive Common and opportunistic infections Severe combined immunodeficiency Autosomal recessive or X-linked Oral candidiasis, Pneumocystis jirovecii pneumonia, diarrhea before 6 mo, failure to thrive, graft vs host disease, absent thymic shadow, lymphopenia, bone abnormalities (in ADA deficiency), exfoliative dermatitis as part of Omenn's syndrome Wiskott-Aldrich syndrome X-linked recessive GI bleeding (eg, bloody diarrhea), recurrent respiratory infections, opportunistic infections, eczema, thrombocytopenia, cancer (in 10% of patients > 10 yr), varicella-zoster virus infection, herpesvirus infection Phagocytic cell defects Chédiak-Higashi syndrome Autosomal recessive Recurrent infections, albinism, fever, jaundice, hepatosplenomegaly, lymphadenopathy, neurologic changes, pancytopenia, bleeding diathesis Chronic granulomatous disease X-linked or autosomal recessive Granulomatous lesions in the lungs, liver, lymph nodes, and GI and GU tract (causing obstruction); lymphadenitis; hepatosplenomegaly; skin, lymph node, lung, liver, and perianal abscesses; osteomyelitis; pneumonia; staphylococcal, gram-negative, and aspergillus infections Leukocyte adhesion deficiency Autosomal recessive Soft-tissue infections, periodontitis, poor wound healing, delayed umbilical cord detachment, leukocytosis IFN-γ receptor defects Autosomal dominant or recessive Mycobacterial infections IL-12 deficiency and IL-12 receptor β1 defect Autosomal recessive Salmonellal and mycobacterial infections Complement deficiencies in the classical pathway C1 Autosomal recessive SLE C2 Autosomal recessive SLE, recurrent pyogenic infections with encapsulated bacteria (especially pneumococcal) that start in early childhood, other autoimmune disorders (eg, glomerulonephritis, polymyositis, vasculitis, Henoch-Schönlein purpura, Hodgkin lymphoma) C3 Autosomal recessive Recurrent pyogenic infections with encapsulated bacteria that start at birth, glomerulonephritis, other antigen-antibody complex disorders, sepsis C4 Autosomal recessive SLE, other autoimmune disorders (eg, IgA nephropathy, progressive systemic sclerosis, Henoch-Schönlein purpura, type 1 diabetes mellitus, autoimmune hepatitis) C5, C6, C7, C8, C9 (membrane attack complex) Autosomal recessive Recurrent Neisseria meningitidis and disseminated N. gonorrhoeae infections Complement deficiencies in the MBL pathway MBL Autosomal recessive Recurrent pyogenic infections with encapsulated bacteria that start at birth; unexplained sepsis; increased severity of infection in secondary immunodeficiencies due to corticosteroid use, cystic fibrosis, or chronic lung disorders MASP-2 Unknown Autoimmune disorders (eg, inflammatory bowel disease, erythema multiforme), recurrent pyogenic infections with encapsulated bacteria (eg, Streptococcus pneumoniae) Complement deficiencies in the alternative pathway Factor B Autosomal recessive Pyogenic infections Factor D Autosomal Pyogenic infections Properdin X-linked Increased risk of fulminant neisserial infection Complement regulatory protein deficiencies C1 inhibitor Autosomal dominant Angioedema Factor I Autosomal codominant Same as C3 deficiency Factor H Autosomal codominant Same as C3 deficiency Hemolytic-uremic syndrome Decay accelerating factor Autosomal recessive Paroxysmal nocturnal hemoglobinuria Complement receptor (CR) deficiencies CR1 Acquired Secondary finding in immune (antigen-antibody) complex–mediated disease CR3 Autosomal recessive Leukocyte adhesion deficiency syndrome (recurrent Staphylococcus aureus and Pseudomonas aeruginosa infections) ADA = adenosine deaminase; AID = activation-dependent (induced) cytidine deaminase; C = complement; CD = clusters of differentiation; IFN = interferon; MASP = mannose-binding lectin-associated serine protease; MBL = mannose-binding lectin; MHC = major histocompatibility complex; UNG = uracil DNA glycosylase. Primary Immunodeficiency Disorders  Disorder Inheritance Clinical Findings Ig (B-cell) deficiencies Common variable immunodeficiency Autosomal dominant Similar to X-linked agammaglobulinemia but with later manifestation and presence of B cells Autoimmune disorders, malabsorption, nodular lymphoid hyperplasia of GI tract, bronchiectasis, lymphoid interstitial pneumonia, lymphoma (in 10%) Hyper-IgM syndrome with AID or UNG deficiencies Autosomal recessive Similar to X-linked hyper-IgM syndrome but with lymphoid hyperplasia No leukopenia Hyper-IgM syndrome with CD40 deficiency Autosomal recessive Similar to X-linked hyper-IgM syndrome Lymphoid hypoplasia, neutropenia Hyper-IgM syndrome with CD40 ligand deficiency X-linked Similar to X-linked agammaglobulinemia but greater frequency of Pneumocystis jirovecii pneumonia, cryptosporidiosis, severe neutropenia, and lymphoid hypoplasia IgA deficiency Autosomal dominant Sometimes asymptomatic Recurrent sinopulmonary infections, diarrhea, allergies (including anaphylactic transfusion reactions), autoimmune disorders (eg, celiac disease, inflammatory bowel disease, SLE, chronic active hepatitis) Transient hypogammaglobulinemia of infancy — Low Ig but normal antibody levels X-linked agammaglobulinemia X-linked Recurrent sinopulmonary and skin infections during infancy, neutropenia, lymphoid hypoplasia T-cell disorders Chronic mucocutaneous candidiasis Autosomal dominant or recessive Persistent or recurrent candidal infections, onychomycosis, autosomal recessive autoimmune polyendocrinopathy syndrome (eg, hypoparathyroidism, Addison's disease) DiGeorge syndrome Autosomal Unusual facies with low-set ears, a congenital heart disorder (eg, aortic arch abnormalities), thymic hypoplasia or aplasia, hypoparathyroidism with hypocalcemic tetany, recurrent infections X-linked lymphoproliferative syndrome X-linked Asymptomatic until onset of Epstein-Barr virus infection, then fulminant or fatal infectious mononucleosis with liver failure and, in survivors, B-cell lymphomas, aplastic anemia, hypogammaglobulinemia, or a combination ζ-Associated protein 70 (ZAP-70) deficiency Autosomal recessive Common and opportunistic infections No CD8 cells Combined B- and T-cell defects Ataxia-telangiectasia Autosomal recessive Ataxia, telangiectasias, recurrent sinopulmonary infections, endocrine abnormalities (eg, gonadal dysgenesis, testicular atrophy, diabetes mellitus), increased risk of cancer Cartilage-hair hypoplasia Autosomal recessive Short-limbed dwarfism, common and opportunistic infections Combined immunodeficiency with inadequate but not absent T-cell function and normal or elevated Igs Autosomal recessive or X-linked Common and opportunistic infections, lymphopenia, lymphadenopathy, hepatosplenomegaly, skin lesions resembling those of Langerhans cell histiocytosis in some patients Hyper-IgE syndrome Autosomal dominant Staphylococcal abscesses of skin, lungs, joints, and viscera; pulmonary pneumatoceles; pruritic dermatitis; coarse facial features; delayed shedding of baby teeth; osteopenia; recurrent fractures; tissue and blood eosinophilia MHC antigen deficiencies Autosomal recessive Common and opportunistic infections Severe combined immunodeficiency Autosomal recessive or X-linked Oral candidiasis, Pneumocystis jirovecii pneumonia, diarrhea before 6 mo, failure to thrive, graft vs host disease, absent thymic shadow, lymphopenia, bone abnormalities (in ADA deficiency), exfoliative dermatitis as part of Omenn's syndrome Wiskott-Aldrich syndrome X-linked recessive GI bleeding (eg, bloody diarrhea), recurrent respiratory infections, opportunistic infections, eczema, thrombocytopenia, cancer (in 10% of patients > 10 yr), varicella-zoster virus infection, herpesvirus infection Phagocytic cell defects Chédiak-Higashi syndrome Autosomal recessive Recurrent infections, albinism, fever, jaundice, hepatosplenomegaly, lymphadenopathy, neurologic changes, pancytopenia, bleeding diathesis Chronic granulomatous disease X-linked or autosomal recessive Granulomatous lesions in the lungs, liver, lymph nodes, and GI and GU tract (causing obstruction); lymphadenitis; hepatosplenomegaly; skin, lymph node, lung, liver, and perianal abscesses; osteomyelitis; pneumonia; staphylococcal, gram-negative, and aspergillus infections Leukocyte adhesion deficiency Autosomal recessive Soft-tissue infections, periodontitis, poor wound healing, delayed umbilical cord detachment, leukocytosis IFN-γ receptor defects Autosomal dominant or recessive Mycobacterial infections IL-12 deficiency and IL-12 receptor β1 defect Autosomal recessive Salmonellal and mycobacterial infections Complement deficiencies in the classical pathway C1 Autosomal recessive SLE C2 Autosomal recessive SLE, recurrent pyogenic infections with encapsulated bacteria (especially pneumococcal) that start in early childhood, other autoimmune disorders (eg, glomerulonephritis, polymyositis, vasculitis, Henoch-Schönlein purpura, Hodgkin lymphoma) C3 Autosomal recessive Recurrent pyogenic infections with encapsulated bacteria that start at birth, glomerulonephritis, other antigen-antibody complex disorders, sepsis C4 Autosomal recessive SLE, other autoimmune disorders (eg, IgA nephropathy, progressive systemic sclerosis, Henoch-Schönlein purpura, type 1 diabetes mellitus, autoimmune hepatitis) C5, C6, C7, C8, C9 (membrane attack complex) Autosomal recessive Recurrent Neisseria meningitidis and disseminated N. gonorrhoeae infections Complement deficiencies in the MBL pathway MBL Autosomal recessive Recurrent pyogenic infections with encapsulated bacteria that start at birth; unexplained sepsis; increased severity of infection in secondary immunodeficiencies due to corticosteroid use, cystic fibrosis, or chronic lung disorders MASP-2 Unknown Autoimmune disorders (eg, inflammatory bowel disease, erythema multiforme), recurrent pyogenic infections with encapsulated bacteria (eg, Streptococcus pneumoniae) Complement deficiencies in the alternative pathway Factor B Autosomal recessive Pyogenic infections Factor D Autosomal Pyogenic infections Properdin X-linked Increased risk of fulminant neisserial infection Complement regulatory protein deficiencies C1 inhibitor Autosomal dominant Angioedema Factor I Autosomal codominant Same as C3 deficiency Factor H Autosomal codominant Same as C3 deficiency Hemolytic-uremic syndrome Decay accelerating factor Autosomal recessive Paroxysmal nocturnal hemoglobinuria Complement receptor (CR) deficiencies CR1 Acquired Secondary finding in immune (antigen-antibody) complex–mediated disease CR3 Autosomal recessive Leukocyte adhesion deficiency syndrome (recurrent Staphylococcus aureus and Pseudomonas aeruginosa infections) ADA = adenosine deaminase; AID = activation-dependent (induced) cytidine deaminase; C = complement; CD = clusters of differentiation; IFN = interferon; MASP = mannose-binding lectin-associated serine protease; MBL = mannose-binding lectin; MHC = major histocompatibility complex; UNG = uracil DNA glycosylase.

Primary immunodeficiency syndromes are genetically determined immunodeficiencies with immune and nonimmune defects. Nonimmune manifestations are often more easily recognized than those of the immunodeficiency. Examples are ataxia-telangiectasia, cartilage-hair hypoplasia, DiGeorge syndrome, hyper-IgE syndrome, and Wiskott-Aldrich syndrome.

Geriatrics Essentials

Some decrease in immunity occurs with aging. For example, in the elderly, the thymus tends to produce fewer naive T cells; thus, fewer T cells are available to respond to new antigens. The number of T cells does not decrease (because of oligoclonality), but these cells can recognize only a limited number of antigens.

Signal transduction (transmission of antigen-binding signal across the cell membrane into the cell) is impaired, making T cells less likely to respond to antigens. Also, helper T cells may be less likely to signal B cells to produce antibodies.

The number of neutrophils does not decrease, but these cells become less effective in phagocytosis and microbicidal action.

Undernutrition, common among the elderly, impairs immune responses. Ca, zinc, and vitamin E are particularly important to immunity. Risk of Ca deficiency is increased in the elderly, partly because with aging, the intestine becomes less able to absorb Ca. Also, the elderly may not ingest enough Ca in their diet. Zinc deficiency is very common among the institutionalized elderly and homebound patients.

Last full review/revision September 2008 by Rebecca H. Buckley, MD