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Immunodeficiency typically manifests as recurrent infections. However, more likely causes of recurrent infections in children are repeated exposures to infection at day care or school (infants and children may normally have up to 10 respiratory infections/yr), and more likely causes in children and adults are inadequate duration of antibiotic treatment, resistant organisms, and other disorders that predispose to infection (eg, congenital heart defects, allergic rhinitis, ureteral or urethral stenosis, immotile cilia syndrome, asthma, cystic fibrosis, severe dermatitis).
Immunodeficiency should be suspected when recurrent infections are the following:
Initially, infections due to immunodeficiency are typically upper and lower respiratory tract infections (eg, sinusitis, bronchitis, pneumonia) and gastroenteritis, but they may be serious bacterial infections (eg, meningitis, sepsis).
Immunodeficiency should also be suspected in infants or young children with chronic diarrhea and failure to thrive, especially when the diarrhea is caused by unusual viruses (eg, adenovirus) or fungi (eg, Cryptosporidium sp). Other signs include skin lesions (eg, eczema, warts, abscesses, pyoderma, alopecia), oral or esophageal thrush, oral ulcers, and periodontitis.
Less common manifestations include severe viral infection with herpes simplex or varicella zoster virus and CNS problems (eg, chronic encephalitis, delayed development, seizure disorder). Frequent use of antibiotics may mask many of the common symptoms and signs. Immunodeficiency should be considered particularly in patients with infections and an autoimmune disorder (eg, hemolytic anemia, thrombocytopenia).
Evaluation
History and physical examination are helpful but must be supplemented by immune function testing. Prenatal testing is available for many disorders and is indicated if there is a family history of immunodeficiency and the mutation has been identified in family members.
History
Clinicians should determine whether patients have a history of risk factors for infection or of symptoms and risk factors for secondary immunodeficiency disorders. Family history is very important.
Age when recurrent infections began is important. Onset of infections before age 12 mo suggests combined B- and T-cell defects or a B-cell defect, which becomes evident when maternal antibodies are disappearing (at about age 6 mo). In general, the earlier the age at onset in children, the more severe the immunodeficiency. Often, certain other primary immunodeficiencies (eg, common variable immunodeficiency [CVID]) do not manifest until adulthood.
Certain infections suggest certain immunodeficiency disorders (see Table 4: Immunodeficiency Disorders: Some Clues in Patient History to Type of Immunodeficiency ); however, no infection is specific to any one disorder, and certain common infections (eg, respiratory viral or bacterial infections) occur in many.
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Table 4
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| Some Clues in Patient History to Type of Immunodeficiency |
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Finding
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Immunodeficiency
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Recurrent Streptococcus pneumoniae and Haemophilus influenzae infections
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Ig, C2, or IRAK-4 deficiency
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Recurrent Giardia intestinalis (lamblia) infection
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Antibody deficiency syndromes
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Familial clustering of autoimmune disorders (eg, SLE, RA, pernicious anemia)
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Common variable immunodeficiency or IgA deficiency
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Pneumocystis infections, cryptosporidiosis, or toxoplasmosis
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T-cell disorders or occasionally Ig deficiency
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Viral, fungal, or mycobacterial (opportunistic) infections
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T-cell disorders
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Clinical infection due to live-attenuated vaccines (eg, varicella, polio, BCG)
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T-cell disorders
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Graft-vs-host disease due to blood transfusions
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T-cell disorders
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Staphylococcal infections, infections with gram-negative organisms (eg, Serratia or Klebsiella sp), or fungal infections (eg, aspergillosis)
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Phagocytic cell defects or hyper-IgE syndrome
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Skin infections
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Neutrophil defect or Ig deficiency
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Recurrent gingivitis
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Neutrophil defect
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Recurrent neisserial infections
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Certain complement deficiencies
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Recurrent sepsis
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Certain complement deficiencies or IgG deficiency
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Family history of childhood death or of infections in a maternal uncle that are similar to those in the patient
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X-linked disorders (eg, severe combined immunodeficiency, X-linked agammaglobulinemia, Wiskott-Aldrich syndrome, hyper-IgM syndrome)
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IRAK = IL-1R-associated kinase.
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Physical examination
Patients with immunodeficiency may or may not appear chronically ill. Macular rashes, vesicles, pyoderma, eczema, petechiae, alopecia, or telangiectasia may be evident.
Cervical lymph nodes and adenoid and tonsillar tissue are typically very small or absent in X-linked agammaglobulinemia, X-linked hyper-IgM syndrome, severe combined immunodeficiency (SCID), and other T-cell immunodeficiencies despite a history of recurrent infections. In certain other immunodeficiencies (eg, chronic granulomatous disease), lymph nodes of the head and neck may be enlarged and suppurative.
Tympanic membranes may be scarred or perforated. The nostrils may be crusted, indicating purulent nasal discharge. Chronic cough is common, as are lung crackles, especially in adults with CVID. The liver and spleen are often enlarged in patients with CVID or chronic granulomatous disease. Muscle mass and fat deposits of the buttocks are decreased. In infants, skin around the anus may break down because of chronic diarrhea. Neurologic examination may detect delayed developmental milestones or ataxia.
Other characteristic findings tentatively suggest a clinical diagnosis (see Table 5: Immunodeficiency Disorders: Characteristic Clinical Findings in Some Primary Immunodeficiency Disorders).
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Table 5
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| Characteristic Clinical Findings in Some Primary Immunodeficiency Disorders |
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Age Group
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Findings*
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Disorder
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< 6 mo
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Diarrhea, failure to thrive
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Severe combined immunodeficiency
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Maculopapular rash, splenomegaly
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Severe combined immunodeficiency when accompanied by graft-vs-host disease (eg, caused by transplacentally transferred T cells)
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Hypocalcemic tetany, a congenital heart disorder, unusual facies with low-set ears
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DiGeorge syndrome
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Recurrent pyogenic infections, sepsis
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C3 deficiency
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Oculocutaneous albinism, neurologic changes, lymphadenopathy
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Chédiak-Higashi syndrome
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Cyanosis, a congenital heart disorder, midline liver
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Congenital asplenia
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Delayed umbilical cord detachment, leukocytosis, periodontitis, poor wound healing
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Leukocyte adhesion deficiency
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Abscesses, lymphadenopathy, antral obstruction, pneumonia, osteomyelitis
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Chronic granulomatous disease
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Recurrent staphylococcal abscesses of the skin, lungs, joints, and viscera; pneumatoceles; coarse facial features; pruritic dermatitis
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Hyper-IgE syndrome
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Chronic gingivitis, recurrent aphthous ulcers and skin infections, severe neutropenia
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Severe congenital neutropenia
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GI bleeding (eg, bloody diarrhea), eczema
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Wiskott-Aldrich syndrome
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6 mo to 5 yr
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Paralysis after oral polio immunization
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X-linked agammaglobulinemia
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Severe progressive infectious mononucleosis
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X-linked lymphoproliferative syndrome
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Persistent oral candidiasis, nail dystrophy, endocrine disorders (eg, hypoparathyroidism, Addison's disease)
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Chronic mucocutaneous candidiasis
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> 5 yr (including adults)
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Ataxia, recurrent sinopulmonary infections, neurologic deterioration, telangiectasias
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Ataxia-telangiectasia
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Recurrent Neisseria meningitis
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C5, C6, C7, or C8 deficiency
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Recurrent sinopulmonary infections, malabsorption, splenomegaly, autoimmune disorders, nodular lymphoid hyperplasia of the GI tract, lymphoid interstitial pneumonia, bronchiectasis
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Common variable immunodeficiency
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Progressive dermatomyositis with chronic echovirus encephalitis
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X-linked agammaglobulinemia
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*In addition to infection.
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Adapted from Stiehm, ER, Conley ME: Immunodeficiency diseases: General considerations, in Immunodeficiency Disease in Infants and Children, ed 4, edited by ER Stiehm. Philadelphia, WB Saunders Company, 1996, p. 212.
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Initial testing
If a specific secondary immunodeficiency disorder is suspected clinically, testing should focus on that disorder (eg, diabetes, HIV infection, cystic fibrosis, primary ciliary dyskinesia).
Tests are needed to confirm a diagnosis of immunodeficiency (see Table 6: Immunodeficiency Disorders: Initial and Additional Laboratory Tests for Immunodeficiency). Initial screening tests should include
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Table 6
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| Initial and Additional Laboratory Tests for Immunodeficiency |
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Type
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Initial Tests
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Additional Tests
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B-cell deficiency
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IgG, IgM, IgA, and IgE levels
Isohemagglutinin titers
Antibody response to vaccine antigens (eg, Haemophilus influenzae type b, tetanus, diphtheria, conjugated and nonconjugated pneumococcal, and meningococcal antigens)
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B-cell phenotyping and count using flow cytometry and monoclonal antibodies to B cells
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T-cell deficiency
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Absolute lymphocyte count
Delayed hypersensitivity skin tests (eg, using Candida)
Chest x-ray for size of thymus in infants only
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T-cell phenotyping and count using flow cytometry and monoclonal antibodies to T cells and subsets
T-cell proliferative response to mitogens
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Phagocytic cell defects
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Phagocytic cell count and morphology
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Flow cytometric respiratory burst assay
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Complement deficiency
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C3 level
C4 level
CH50 activity
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Specific component assays
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C = complement; CH = hemolytic complement.
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If results are normal, immunodeficiency (especially Ig deficiency) can be excluded. If results are abnormal, further tests in specialized laboratories are needed to identify specific deficiencies. If chronic infections are objectively documented, initial and specific tests may be done simultaneously.
CBC can detect abnormalities in one or more cell types (eg, WBCs, platelets) characteristic of specific disorders. However, many abnormalities are transient manifestations of infection, drug use, or other factors; thus, abnormalities should be confirmed and followed.
 Clinical Calculator
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Peripheral blood smear should be examined for Howell-Jolly bodies and other unusual RBC forms, which suggest primary asplenia or impaired splenic function. Granulocytes may have morphologic abnormalities (eg, giant granules in Chédiak-Higashi syndrome).
Quantitative serum Ig levels are measured. Low serum levels of IgG, IgM, or IgA suggest antibody deficiency, but results must be compared with those of age-matched controls. An IgG level < 200 mg/dL usually indicates significant antibody deficiency, although such levels may occur in protein-losing enteropathies or nephrotic syndrome.
With skin testing,most immunocompetent adults, infants, and children react to 0.1 mL of Candida albicans extract (1:100 for infants and 1:1000 for older children and adults) injected intradermally. Positive reactivity, defined as erythema and induration > 5 mm at 24, 48, and 72 h, excludes a T-cell disorder. Lack of response does not confirm immunodeficiency in patients with no previous exposure to Candida.
Chest x-ray may be useful in some infants; an absent thymic shadow suggests a T-cell disorder, especially if the x-ray is obtained before onset of infection or other stresses that may shrink the thymus. Lateral pharyngeal x-ray may show absence of adenoidal tissue.
Additional testing
If clinical findings or initial tests suggest a specific disorder of immune cell or complement function, other tests are indicated.
If patients have recurrent infections and lymphopenia, lymphocyte phenotyping using flow cytometry and monoclonal antibodies to T, B, and natural killer (NK) cells is indicated to check for lymphocyte deficiency. If T cells are low or absent, invitro mitogen stimulation studies are done to assess T-cell function. If MHC antigen deficiency is suspected, serologic (not molecular) HLA typing is indicated.
If phagocytic cell defects are suspected, a flow cytometric respiratory burst assay can detect whether O2 radicals are produced during phagocytosis; no production is characteristic of chronic granulomatous disease.
If the type or pattern of infections suggests complement deficiency, the serum dilution required to lyse 50% of antibody-coated RBCs (CH50) is measured. This test detects complement component deficiencies in the classical or alternative complement activation pathway but does not indicate which component is abnormal.
If examination or screening tests detect abnormalities suggesting lymphocyte or phagocytic cell defects, other tests can more precisely characterize specific disorders (see Table 7: Immunodeficiency Disorders: Advanced Laboratory Tests for Immunodeficiency ).
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Table 7
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| Advanced Laboratory Tests for Immunodeficiency |
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Test
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Indications
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Interpretation
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B-cell deficiency*
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IgE level measurement
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Abscesses
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Levels are high in patients with abscesses and pneumatoceles (hyper-IgE syndrome), partial T-cell deficiencies, allergic disorders, or parasitic infections.
Levels may be high or low in patients with incomplete B-cell defects or deficiencies.
Isolated deficiency is not clinically significant.
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B-cell quantification via flow cytometry
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Low Ig levels
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< 1% B cells suggests X-linked agammaglobulinemia.
B cells are absent in Omenn's syndrome.
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Lymph node biopsy
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For some patients with lymphadenopathy, to determine whether germinal centers are normal and to exclude cancer and infection
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Interpretation varies by histology.
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Mutation analysis
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B cells < 1% (detected by flow cytometry)
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These tests can detect X-linked agammaglobulinemia and Omenn's syndrome.
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T-cell deficiency
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T-cell enumeration using flow cytometry and monoclonal antibodies†
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Lymphopenia, suspected SCID or complete DiGeorge syndrome
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Interpretation varies by molecular type of SCID.
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T-cell proliferation assays to mitogens, antigens, or irradiated allogeneic WBCs
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Low percentage of T cells, lymphopenia, suspected SCID or complete DiGeorge syndrome
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Low or absent uptake of radioactive thymidine during cell division indicates a T-cell or combined defect.
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Detection of antigens (eg, class II MHC molecules) using monoclonal antibodies or serologic HLA typing
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Suspected MHC deficiency, absence of MHC stimulation by cells
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Absence of class I or class II HLA antigens by serologic HLA typing is diagnostic for MHC antigen deficiency.
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RBC adenosine deaminase assay
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Severe lymphopenia
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Levels are low in a specific form of SCID.
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Purine nucleoside phosphorylase assay
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Severe persistent lymphopenia
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Levels are low in combined immunodeficiency with normal or elevated Ig levels.
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T-cell receptor and signal transduction assays
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Phenotypically normal T cells that do not proliferate normally in response to mitogen antigen
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Interpretation varies by test.
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Phagocytic cell defects
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Assays for oxidant products (hydrogen peroxide, superoxide) or proteins (CR3 [CD11] adhesive glycoproteins, NADPH oxidase components)
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History of staphylococcal abscesses or certain gram-negative or fungal infections (eg, Serratia marcescens aspergillosis)
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Abnormalities confirm phagocytic cell defects or deficiencies.
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Complement deficiency
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Measurement of levels of specific complement components
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CH50 level < 11%
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Interpretation varies by test.
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*Measuring IgG subclass levels is rarely helpful.
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†Test uses anti-CD3 for all T cells, anti-CD4 for helper T cells, anti-CD8 for cytotoxic T cells, anti-CD45RO or anti-CD45RA for activated and naive T cells, anti-CD25 for regulatory T cells, and anti-CD16 and anti-CD56 for natural killer cells.
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CH = hemolytic complement; MHC = major histocompatibility complex; NADPH = nicotinamide adenine dinucleotide phosphate; SCID = severe combined immunodeficiency.
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Prenatal diagnosis
An increasing number of primary immunodeficiency disorders can be diagnosed prenatally using chorionic villus sampling, cultured amniotic cells, or fetal blood sampling, but these tests are used only when a mutation in family members has already been identified (see Prenatal Genetic Counseling and Evaluation: Chorionic Villus Sampling). X-linked agammaglobulinemia, Wiskott-Aldrich syndrome, ataxia-telangiectasia, X-linked lymphoproliferative syndrome, all forms of SCID, and all forms of chronic granulomatous disease can be detected. Sex determination by ultrasonography can be used to exclude X-linked disorders.
Prognosis
Prognosis depends on the primary immunodeficiency disorder. Most patients with an Ig or a complement deficiency have a good prognosis with a near-normal life expectancy if they are diagnosed early, are treated appropriately, and have no coexisting chronic disorders (eg, pulmonary disorders such as bronchiectasis). Other immunodeficient patients (eg, those with a phagocytic cell defect or combined immunodeficiencies, such as Wiskott-Aldrich syndrome or ataxia-telangiectasia) have a guarded prognosis; most require intensive and frequent treatment. Some immunodeficient patients (eg, those with SCID) die during infancy unless immunity is provided through transplantation. All forms of SCID could be diagnosed at birth if a WBC count and manual differential of cord or peripheral blood were routinely done in neonates. Suspicion for SCID, a true pediatric emergency, must be high because prompt diagnosis is essential for survival. If done before patients reach age 3 mo, transplantation of bone marrow or stem cells from a matched or half-matched (haploidentical) relative is lifesaving in 95%.
Treatment
Treatment generally involves preventing infection, managing acute infection, and replacing missing immune components when possible.
Infection prevention
Infection can be prevented by advising patients to avoid environmental exposures and giving live-virus vaccines (varicella, rotavirus, measles, mumps, rubella). Patients at risk of serious infections (eg, those with SCID, chronic granulomatous disease, Wiskott-Aldrich syndrome, or asplenia) or a specific infection (eg, with Pneumocystis jirovecii in patients with T-cell disorders) can be given prophylactic antibiotics (eg, 5 mg/kg trimethoprim/sulfamethoxazole po bid).
To prevent graft-vs-host disease after transfusions, clinicians should use blood products from cytomegalovirus-negative donors; the products should be filtered to remove WBCs and irradiated (15 to 30 Gy).
Management of acute infection
After appropriate cultures are obtained, antibiotics that target likely causes should be given promptly. Sometimes surgery (eg, to drain abscesses) is needed. Usually, self-limited viral infections cause severe persistent disease in immunocompromised patients. Antivirals (eg, amantadine, rimantadine, oseltamivir, or zanamivir for influenza; acyclovir for herpes simplex and varicella-zoster infections; ribavirin for respiratory syncytial virus or parainfluenza 3 infections) may be lifesaving.
Replacement of missing immune components
Such replacement helps prevent infection. Therapies used in more than one primary immunodeficiency disorder include the following:
Retroviral vector gene therapy has been successful in a few patients with X-linked and ADA-deficient SCID, but this treatment is not widely used because some patients with X-linked SCID developed leukemia.
Last full review/revision September 2008 by Rebecca H. Buckley, MD
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