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Overview of Immunodeficiency Disorders

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Immunodeficiency disorders are associated with or predispose affected patients to various complications, including infections, autoimmune disorders, and lymphomas and other cancers. Primary immunodeficiencies are hereditary; secondary immunodeficiencies are acquired. Secondary immunodeficiencies are much more common.

Evaluation of immunodeficiency includes history, physical examination, and immune function testing. Testing varies based on the following:

  • Whether a primary or secondary immunodeficiency is suspected

  • For primary immunodeficiency, which component of the immune system is thought to be deficient

Secondary Immunodeficiencies

Causes (see Table: Causes of Secondary Immunodeficiency) include

  • Systemic disorders (eg, diabetes, undernutrition, HIV infection)

  • Immunosuppressive treatments (eg, cytotoxic chemotherapy, bone marrow ablation before transplantation, radiation therapy)

  • Prolonged serious illness

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.

Causes of Secondary Immunodeficiency

Category

Examples

Endocrine

GI

Hematologic

Iatrogenic

Certain drugs, such as chemotherapeutic drugs, immunosuppressants, corticosteroids; radiation therapy; splenectomy

Infectious

Viral infections (eg, cytomegalovirus, Epstein-Barr virus, HIV, measles virus, varicella-zoster virus), bacterial infections, rare bacterial infections with superantigens (antigens that can activate large numbers of T cells, resulting in massive cytokine production, most notably from Staphylococcus aureus), mycobacterial infections

Nutritional

Physiologic

Physiologic immunodeficiency in infants due to immaturity of the immune system, pregnancy

Renal

Nephrotic syndrome, renal insufficiency, uremia

Rheumatologic

SLE

Other

Burns, cancers, chromosomal abnormalities (eg, Down syndrome), congenital asplenia, critical and chronic illness, histiocytosis, sarcoidosis

Some Drugs That Cause Immunosuppression

Class

Examples

Anticonvulsants

Lamotrigine, phenytoin, valproate

Disease-modifying anti-rheumatic drugs (DMARDs)

IL-1 inhibitors (eg, anakinra)

IL-6 inhibitors (eg, tocilizumab)

IL-17 inhibitors (eg, brodalumab)

TNF inhibitors (eg, adalimumab, etanercept, infliximab)

T-cell activation inhibitors (eg, abatacept, basiliximab)

CD20 inhibitors (eg, rituximab)

CD3 inhibitors (eg, muromonab-CD3)

Janus kinase (JAK) inhibitors (eg, ruxolitinib)

Calcineurin inhibitors

Cyclosporine, tacrolimus

Corticosteroids

Methylprednisolone, prednisone

Cytotoxic chemotherapy drugs

Multiple (see Table: Commonly Used Antineoplastic Drugs)

Purine metabolism inhibitors

Azathioprine, mycophenolate mofetil

Rapamycins

Everolimus, sirolimus

Immunosuppressive immunoglobulins

Antilymphocyte globulin, antithymocyte globulin

Immunodeficiency can result from loss of serum proteins (particularly IgG and albumin) through the following:

  • The kidneys in nephrotic syndrome

  • The skin in severe burns or dermatitis

  • The GI tract in enteropathy

Enteropathy may also lead to lymphocyte loss, resulting in lymphopenia. All of 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 immunoglobulins (Igs) and lymphocytes from the GI tract and be remarkably beneficial.

If a specific secondary immunodeficiency disorder is suspected clinically, testing should focus on that disorder (eg, diabetes, HIV infection, cystic fibrosis, primary ciliary dyskinesia).

Primary Immunodeficiencies

These disorders are genetically determined; they may occur alone or as part of a syndrome. More than 100 of these disorders 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:

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

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.

Immunodeficiency typically manifests as recurrent infections. The age at which recurrent infections began provides a clue as to which component of the immune system is affected. Other characteristic findings tentatively suggest a clinical diagnosis (see Table: Characteristic Clinical Findings in Some Primary Immunodeficiency Disorders). However, tests are needed to confirm a diagnosis of immunodeficiency (see Table: Initial and Additional Laboratory Tests for Immunodeficiency). If clinical findings or initial tests suggest a specific disorder of immune cell or complement function, additional tests are indicated (see Table: Specific and Advanced Laboratory Tests for Immunodeficiency*).

The prognosis in primary immunodeficiency disorders depends on the specific disorder.

Humoral immunity deficiencies

Humoral immunity deficiencies (B-cell defects) that cause antibody deficiencies account for 50 to 60% of primary immunodeficiencies (see Table: Humoral Immunity Deficiencies). Serum antibody titers decrease, predisposing to bacterial infections.

The most common B-cell disorder is

Humoral Immunity Deficiencies

Disorder

Inheritance

Gene Affected

Clinical Findings

Variable

TACI , ICOS , BAFFR

Recurrent sinopulmonary infections, autoimmune disorders (eg, immune thrombocytopenia, autoimmune hemolytic anemia), malabsorption, giardiasis, granulomatous interstitial lung disease, nodular lymphoid hyperplasia of GI tract, bronchiectasis, lymphoid interstitial pneumonia, splenomegaly; in 10%, gastric carcinoma and lymphoma

Usually diagnosed in patients aged 20–40 yr

Autosomal recessive

AID , UNG

Similar to X-linked hyper-IgM syndrome but with lymphoid hyperplasia

No leukopenia

Autosomal recessive

CD40

Similar to X-linked hyper-IgM syndrome

Lymphoid hypoplasia, neutropenia

X-linked

CD40 ligand (CD40L)

Similar to X-linked agammaglobulinemia (eg, recurrent pyogenic bacterial sinopulmonary infections) but greater frequency of Pneumocystis jirovecii pneumonia, cryptosporidiosis, severe neutropenia, and lymphoid hypoplasia

Unknown

Recurrent sinopulmonary infections

Sometimes atopic manifestations (eg, atopic dermatitis, asthma, chronic rhinitis)

Can occur in mild, moderate, severe, and memory phenotypes

Unknown

In some cases, TACI

Most often asymptomatic

Recurrent sinopulmonary infections, diarrhea, allergies (including anaphylactic transfusion reactions [rare]), autoimmune disorders (eg, celiac disease, inflammatory bowel disease, SLE, chronic active hepatitis)

Unknown

Usually asymptomatic

Sometimes recurrent sinopulmonary or GI infections, candidiasis, meningitis

X-linked

BTK

Recurrent sinopulmonary and skin infections during infancy, transient neutropenia, lymphoid hypoplasia

Persistent CNS infections resulting from live-attenuated oral polio vaccine, echoviruses, or coxsackieviruses

Increased risk of infectious arthritis, bronchiectasis, and certain cancers

AID = activation-dependent (induced) cytidine deaminase; BAFFR = B-cell activating factor receptor; BTK = Bruton tyrosine kinase; C = complement; CAML = calcium-modulator and cyclophilin ligand; CD = clusters of differentiation; ICOS = inducible T-cell co-stimulator; TACI = transmembrane activator and CAML interactor; UNG = uracil DNA glycosylase.

Cellular immunity deficiencies

Cellular immunity deficiencies (T-cell defects) 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 (see Table: Cellular Immunity Deficiencies). T-cell disorders also cause Ig deficiencies because the B- and T-cell immune systems are interdependent.

The most common T-cell disorders are

Primary natural killer cell defects, which are very rare, may predispose to viral infections and tumors. Secondary natural killer cell defects can occur in patients who have various other primary or secondary immunodeficiencies.

For diagnostic evaluation of cellular immunity deficiencies, see Table: Initial and Additional Laboratory Tests for Immunodeficiency and Specific and Advanced Laboratory Tests for Immunodeficiency*.

Cellular Immunity Deficiencies

Disorder

Inheritance

Gene Affected

Clinical Findings

Autosomal dominant or recessive

STAT1 (dominant)

AIRE (recessive)

Persistent or recurrent candidal infections, onychomycosis, autosomal recessive autoimmune polyendocrinopathy–candidosis-ectodermal dystrophy (with hypoparathyroidism and adrenal insufficiency)

Autosomal

Genes at chromosomal region 22q11.2

Genes at chromosome 10p13

Unusual facies with low-set ears, a congenital heart disorder (eg, aortic arch abnormalities), thymic hypoplasia or aplasia, hypoparathyroidism with hypocalcemic tetany, recurrent infections, developmental delay

X-linked

SH2D1A (type 1)

XIAP (type 2)

Asymptomatic until onset of Epstein-Barr virus infection, then fulminant or fatal infectious mononucleosis with liver failure, B-cell lymphomas, splenomegaly, aplastic anemia

Autosomal recessive

Common and opportunistic infections

No CD8 cells

AIRE = autoimmune regulator; CD = clusters of differentiation; SH2D1A = SH2 domain containing 1A; STAT = signal transducer and activator of transcription; TYK = tyrosine kinase; UNG = uracil DNA glycosylase; WASP = Wiskott-Aldrich syndrome protein; XIAP = X-linked inhibitor of apoptosis.

Combined humoral and cellular immunity deficiencies

Combined humoral and cellular immunity deficiencies (B- and T-cell defects) account for about 20% of primary immunodeficiencies (see Table: Combined Humoral and Cellular Immunity Deficiencies).

The most important form is

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.

For diagnostic evaluation of combined humoral and cellular immunodeficiencies, see Table: Specific and Advanced Laboratory Tests for Immunodeficiency*.

Combined Humoral and Cellular Immunity Deficiencies

Disorder

Inheritance

Gene Affected

Clinical Findings

Autosomal recessive

ATM

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 immunoglobulins

Autosomal recessive or X-linked

NEMO

Common and opportunistic infections, lymphopenia, lymphadenopathy, hepatosplenomegaly, skin lesions resembling those of Langerhans cell histiocytosis in some patients

Autosomal dominant or recessive

STAT3 (dominant)

TYK2 , DOCK8 (recessive)

Sinopulmonary infections; 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

Autosomal recessive or X-linked

JAK3 , PTPRC ( CD45 ), RAG1 , RAG2 (autosomal recessive)

IL-2RG (X-linked)

Oral candidiasis, P. 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 syndrome

X-linked recessive

WASP

Typically, pyogenic and opportunistic infections, eczema, thrombocytopenia

Possibly GI bleeding (eg, bloody diarrhea), recurrent respiratory infections, cancer (in 10% of patients > 10 yr), varicella-zoster virus infection, herpesvirus infection

ADA = adenosine deaminase; ATM = ataxia telangiectasia–mutated; DOCK = dedicator of cytokinesis; IL-2RG = IL-2 receptor gamma; ITGB2 = integrin beta-2; JAK = Janus kinase; MHC = major histocompatibility complex; NEMO = nuclear factor–kappa-B essential modulator; PTPRC = protein tyrosine phosphatase, receptor type, C; RAG = recombination activating gene; STAT = signal transducer and activator of transcription; TYK = tyrosine kinase; WASP = Wiskott-Aldrich syndrome protein.

Phagocytic cell defects

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 (see Table: Phagocytic Cell Defects). Cutaneous staphylococcal and gram-negative infections are characteristic.

The most common (although still rare) phagocytic cell defects are

Phagocytic Cell Defects

Disorder

Inheritance

Gene Affected

Clinical Findings

Autosomal recessive

LYST (CHS1)

Oculocutaneous albinism, recurrent infections, fever, jaundice, hepatosplenomegaly, lymphadenopathy, neuropathy, pancytopenia, bleeding diathesis

X-linked or autosomal recessive

gp91phox ( CYBB ; X-linked)

p22phox, p47phox, p67phox (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

Autosomal recessive

ITGB2 gene, encoding CD18 of beta-2 integrins (type 1)

GDP-fucose transporter gene (type 2)

Soft-tissue infections, periodontitis, poor wound healing, delayed umbilical cord detachment, leukocytosis, no formation of pus

Developmental delay (type 2).

Mendelian susceptibility to mycobacterial disease (MSMD)

Autosomal dominant or recessive

Defects in genes encoding the IFN-gamma receptor, IL-12, or the IL-12 receptor

Mycobacterial infections

Varying clinical severity based on genetic defect

Cyclic neutropenia

Autosomal dominant

ELA2

Pyogenic bacterial infections during recurrent episodes of neutropenia (eg, every 14 to 35 days)

CD = clusters of differentiation; CHS = Chédiak-Higashi syndrome; CYBB = cytochrome b-245, beta polypeptide; DOCK = dedicator of cytokinesis; ELA = elastase; GDP = glucose diphosphate; gp = glycoprotein; IFN =interferon; ITGB2 = integrin beta-2; JAK = Janus kinase; LYST = lysosomal transporter; .

Complement deficiencies

Complement deficiencies are rare ( 2%); they include isolated deficiencies of complement components or inhibitors and may be hereditary or acquired (see Table: Complement Deficiencies). 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.

The most serious consequences are

  • Recurrent infection, which is due to defective opsonization

  • Autoimmune disorders (eg, SLE, glomerulonephritis), which is due to defective clearance of antigen-antibody complexes

A deficiency in a complement regulatory protein causes hereditary angioedema.

Complement deficiencies can affect the classical and/or alternate pathways (see Complement System ). The alternate pathway shares C3 and C5 through C9 with the classical pathway but has additional components: factor D, factor B, properdin (P), and regulatory factors H and I.

Complement Deficiencies

Disorder

Inheritance

Clinical Findings

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. gonorrhoeaeinfections

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)

C = complement; MASP = mannose-binding lectin-associated serine protease; MBL = mannose-binding lectin.

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

Certain disorders (eg, diabetes, chronic kidney disease, undernutrition), which are more common among the elderly, and certain therapies (eg, immunosuppressants, immunomodulatory drugs and treatments), which the elderly are more likely to use, can also impair immunity.

Key Points

  • Secondary (acquired) immunodeficiencies are much more common than primary (hereditary) immunodeficiencies.

  • Primary immunodeficiencies can affect humoral immunity (most commonly), cellular immunity, both humoral and cellular immunity, phagocytic cells, or the complement system.

  • Patients who have primary immunodeficiencies may have nonimmune manifestations that can be recognized more easily than the immunodeficiencies.

  • Immunity tends to decrease with aging partly because of age-related changes; also, conditions that impair immunity (eg, certain disorders, use of certain drugs) are more common among the elderly.

Resources In This Article

Drugs Mentioned In This Article

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  • LAMICTAL
  • SIMULECT
  • NEORAL, SANDIMMUNE
  • ADENOCARD
  • ENBREL
  • REMICADE
  • HUMIRA
  • IMURAN
  • AFINITOR
  • DILANTIN
  • RAYOS
  • KINERET
  • RAPAMUNE
  • RITUXAN
  • ACTEMRA
  • PROGRAF
  • ORENCIA
  • MEDROL

* This is the Professional Version. *