Chee K. Woo, MD, is Senior Fellow in Allergy and Immunology; and Sami L. Bahna, MD, DrPH, is Professor of Pediatrics and Medicine, and Chief, Allergy and Immunology Section, Department of Pediatrics, Louisiana State University Health Sciences Center, Shreveport, Louisiana.
Dr. Woo has disclosed no relevant financial relationships. Dr. Bahna has disclosed the following relevant financial relationships: CSL Behring and Shire: Contracted Research.
Address correspondence to Sami L. Bahna, MD, DrPH, Allergy/Immunology Section, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130-3932; fax: 318-675-8815; e-mail: firstname.lastname@example.org.
Immunodeficiency disorders (ID) constitute an important group of diseases, yet they are frequently misdiagnosed. The actual incidence of ID is not known but is probably higher than currently realized.1,2 The prevalence of primary ID is estimated at one in 10,000 in the general population. IgA deficiency, however, is the most common, at 1:300 to 1:700 of white people.2 It is estimated that approximately 50% of primary ID involves humoral immunity (B cell); 20% combined humoral and cell-mediated defects; 10% cell-mediated (T cell); 15% to 18% phagocytic dysfunction; and 1% to 2% complement system defects.2
Most primary ID manifest during early childhood. Their early diagnosis would improve quality of life, prevent fatalities, and provide appropriate family counseling. Currently, there are more than 150 recognized primary immunodeficiency disorders.3 With advances in diagnostic tests, this number is continuously increasing.
Suspicion of ID requires a thorough medical history and physical examination followed by appropriate laboratory screening tests, which often include special tests to confirm the specific defect.
A thorough medical history is the first and most important step in suspecting ID. A medical history of significance is one with infections that are chronic, frequent, severe, respond poorly to appropriate therapy, or caused by an unusual organism. It is worth noting in the differential diagnosis to consider certain conditions that may predispose to or prolong infections (see Sidebar 1, page 207).
Anatomic abnormalities of the respiratory or urogenital tractsAllergic diseases of respiratory tract or skinChronic airway inflammationCystic fibrosisForeign bodyGastroesophageal refluxImmotile cilia syndromeIncreased exposure to: crowded home environment; day care; school-aged siblings; other household members who are sickTobacco smoke
The frequency of infection should be interpreted cautiously, taking into consideration the site, causative organism and risk of exposure. A child with multiple siblings or who attends a day care facility may get more respiratory and ear infections than an only child who stays at home. In general, a child who within 12 months has more than eight episodes of otitis media and/or more than two serious episodes of sinusitis, pneumonia, or deep-seated infections should alert a physician the practitioner to possible immunodeficiency (see Sidebar 1, page 207).4
Age of Onset
In general, the earlier the age at onset of frequent infections, the more likely ID exists. Most infants born with severe combined immunodeficiency suffer major infections during the first weeks or months of age, and unless immune reconstituted, they will not survive beyond 1 to 2 years.5,6 Patients with congenital hypogammaglobulinemia typically present during the second 6 months of life when maternally transferred antibodies wane.
Later in life, common variable immunodeficiency, selective IgA deficiency, IgG subclass deficiency, and certain complement deficiencies become manifest.
Transfusion or Vaccine Reactions
Immediate reactions or anaphylaxis after administration of blood products (plasma or immunoglobulins) or of properly matched blood can be due to IgE antibodies to IgA in the recipient’s circulation.7 A graft-versus-host reaction after blood transfusion raises the suspicion of T-cell defect.8 Therefore, whenever ID diagnosis is being considered, blood transfusion should be with packed red blood cells that have been irradiated to render any of the donors’ T cells immune incompetent.
Children with ID have a high risk of developing infection to live vaccines. Paralytic polio has been reported in patients with ID who received live-attenuated oral polio vaccine.9,10 BCG immunization can lead to disseminated mycobacterial disease in severe combined immunodeficiency or in patients with interferon gamma- or IL-12-related deficiencies.11,12 Therefore, live vaccines should be avoided while ID is being suspected, particularly for T-cell defects.
Type and Location of Infection
The type and location of infection may suggest the defective immunologic component (see Sidebar 2, see page 209). HIV infection remains the most common cause of secondary immunodeficiency worldwide and should be considered early in the evaluation. Recurrent sinopulmonary or enteroviral infection suggests humoral or complement defects. Viral, fungal, and opportunistic infections are more common in T-cell defects. Herpes simplex virus encephalitis may be related to an innate immune defect involving Toll-like-receptor signaling pathways.13
Sidebar 2.Suspect B-Cell (humoral) Defect
Suspect T-Cell (cell-mediated) Defect (alone 10%; both B- and T-cell defect 20%)
- Onset of infections is usually delayed until 6–9 months of age, mostly with bacterial pathogens
- Very hypoplastic lymphoid tissue (tonsils, lymph nodes)
- Sinopulmonary infections, meningitis, sepsis, abscess, osteomyelitis, otitis media
- Few problems with fungal or viral infections (except enteroviruses)
Suspect Phagocytic Defect (15% to 18%)
- Onset of infections is usually by 3 months
- Oral and cutaneous candidiasis
- Opportunistic infections (Pneumocystis carinii)
- Systemic viral infections (cytomegalovirus, varicella, adenovirus)
- Chronic diarrhea, malabsorption
- Failure to thrive or features suggestive of specific syndromes
Suspect Complement Defects (2% to 5%)
- Delayed separation of umbilical cord
- Cutaneous abscesses
- Deep-seated abscesses
- Poor wound healing
- Oral ulcers
- Organisms: Staphylococcus, Klebsiella, Serratia, Salmonella, fungal
- C1 esterase inhibitor: Angioedema (hereditary or acquired)
- C2: Synovitis, purpura, polymyositis, vasculitis
- C1q, C2, C4, C5: Lupus-like syndrome
- C2, C3: Rec bacterial infections, glomerulonephritis
- C6, C7, C8: Recurrent Neisseria
- C8: Xeroderma pigmentosa
Gram-positive bacterial infection is occasionally due to a deficiency of “early” complement components, especially C3, whereas recurrent or Neisseria infections are associated with deficiency of one of the “late” complement components (C5 to C9). Patients with phagocytic dysfunction usually present with recurrent skin abscesses, liver abscesses, or lymphadenitis.
In chronic granulomatous disease patients, defective intracellular killing predisposes to infections with catalase-positive organisms, such as Staphylococcus aureus, Serratia marcescens, Pseudomonas, and Salmonella. However, catalase-negative organisms (eg, Streptococcus, Pneumococcus, and Haemophilus) do not impose a major problem because they can be killed by their self-generated peroxide and other oxygen radicals.
Family Medical History
Inquiry should be made about parental consanguinity, history of similar illnesses or early childhood deaths in the family and the age and sex of affected members. Many of the immunodeficiency diseases are inherited either as an autosomal recessive or an X-linked disorder.
Immune deficiency patients, as well as their families, have an increased incidence of autoimmune diseases, hematologic disorders, and neoplasms.14 Patients with a deficiency of an early complement system component may present with features of systemic lupus erythematosus.15 Patients with autoimmune lymphoproliferative syndrome present with autoimmune hemolytic anemia, thrombocytopenia, massive splenomegaly and lymphadenopathy.16
Approximately 20% of patients with common variable ID have rheumatic disease or autoimmune endocrinopathies.17 Other primary immunodeficiency with autoimmune endocrinopathy syndromes include autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy and immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX).18
Growth and Development
Evaluation of growth and development may reveal signs of malnutrition (as either a cause or a sequela of immunodeficiency); disproportionate growth (short-limbed dwarfism); or short stature (X-linked hypogammaglobulinemia with growth hormone deficiency).
Children with ID, particularly with a T-cell defect, often suffer from failure to thrive. However, physicians should not be deterred from suspecting ID in children with normal development.
Several dysmorphic disorders have been reported to be associated with various degrees of immune defects.19,20 A characteristic facies (hypertelorism, malformed or low-set ears, small mandible, short philtrum), neonatal tetany, absent thymus and congenital heart disease suggest DiGeorge syndrome, which involves T-cell defect.21 Conical teeth, fine sparse hair, frontal bossing, and poor sweat gland development are features of ectodermal dysplasia, which is a defect in the NF-kappa B essential modulator.22
A combination of hypertelorism, epicanthal folds, a flat nasal bridge, and growth retardation are features of immunodeficiency centromere instability and facial anomalies syndrome.23 In addition to excessive upper respiratory tract secretions, Down syndrome patients are prone to respiratory or other infections due to immunologic abnormalities, such as lymphopenia, impaired antibody response, or phagocytic dysfunction.24
Skin and Mucous Membranes
Skin lesions suggestive of primary immunodeficiency include Candida infection (T-cell defect); severe eczema (hyper-IgE and Wiskott-Aldrich syndromes); furuncles or abscesses (phagocytic defects); generalized seborrhea (Leiner’s disease and Omenn’s syndrome); bruises (Wiskott-Aldrich syndrome); and Kaposi’s sarcoma (AIDS). An infant with generalized erythroderma, congenital ichthyosis, and sparse malformed hair are features of Comèl-Netherton syndrome, which has humoral and NK-cell deficiency.25
Periodontitis and skin or deep tissue abscesses suggest a phagocytic defect (chronic granulomatous disease). Recurrent skin infections with absence of pus, delayed umbilical cord separation beyond 4 weeks, omphalitis, and impaired wound healing would suggest leukocyte adhesion defect. Telangiectasia should suggest ataxia-telangiectasia syndrome, but telangiectasias may not appear until after the development of ataxia in late childhood.26 There are several immunodeficiency syndromes with pigment disorders, such as Chediak-Higashi syndrome with silvery hair, pale skin, and photophobia.1
Recurrent lower respiratory infections, chronic sinusitis, and to a lesser degree, otitis media are common presenting symptoms in children with antibody deficiency. Pharyngitis, however, is not a significant feature unless caused by persistent candidiasis.
Hypoplastic lymph nodes and tonsils should strongly suggest a defect of humoral immunity or severe combined immunodeficiency. On the other hand, lymphadenopathy and splenomegaly may suggest acquired immunodeficiency syndrome, chronic granulomatous disease, common variable immunodeficiency, a lymphoproliferative disorder, mononucleosis, or lymphoreticular malignancy. X-linked lymphoproliferative disease manifests as an unusual susceptibility to Epstein-Barr viral infections and presents as fulminant infectious mononucleosis, hemophagocytic lymphohistiocytis and a lymphoproliferative disease often resulting in lymphoma and hypogammaglobulinemia.27
Increased incidence of septic arthritis is seen in patients with antibody or complement deficiency.
Defects in the early classic complement pathway may manifest as lupus-like syndrome. Osteomyelitis due to an unusual organism should raise the suspicion of chronic granulomatous disease.
Basic Laboratory Tests
A complete blood count (CBC) may reveal lymphopenia, anemia, thrombocytopenia, or neutropenia. Persistent lymphopenia should be investigated further for quantitative T-cell and/or B-cell defects. It is important to note that the normal lymphocyte count is much higher in infants than in older children. Lymphopenia should be considered at the level of less than 3,000/mm3 in the infant and at less than 1,500/mm3 in older children.
Large cytoplasmic inclusion bodies in a person with oculocutaneous albinism are compatible with Chediak-Higashi syndrome. Leukocytosis without evidence of infection may suggest leukocyte adhesion defect. Thrombocytopenia is particularly present in Wiskott-Aldrich syndrome (with small platelets) and often in hyper-IgM syndrome.28
Howell-Jolly bodies in red blood cells suggest splenic dysfunction or asplenia. The erythrocyte sedimentation rate may be used as a non-specific indicator of active infection, but it may not be elevated in cases of hypogammaglobulinemia. In blood chemistry profiles, decreased globulin level suggests hypogammaglobulinemia, malnutrition, or protein loss. However, elevated globulin level is a common finding in chronic infections.
Radiologic studies may be needed to evaluate the site of infection, the cardiac configuration, the presence of a thymic shadow in infants, or the size of adenoidal lymphoid tissue. In patients with chronic lung disease, a baseline high-resolution chest computerized tomography (CT) scan may detect bronchiectasis or other lesions that may not be revealed in a chest X-ray film.
Whenever applicable, microbiologic and/or serologic tests should be requested to identify the infecting organism and its antibiotic sensitivity. Sweat electrolyte test or molecular genetic testing is indicated in children with chronic pulmonary illness and/or malabsorption. Electron microscopic examination of the respiratory tract cilia is indicated in patients with situs inversus or chronic sinopulmonary disease with normal routine evaluation.
Assessing B-Cell Function
The first step in evaluating the humoral immunity is measurement of serum IgG, IgA, IgM, and IgE levels. The result should always be compared with normal values for age. Because the transplacental transfer of maternal IgG occurs mainly during the last trimester, premature infants have low levels, depending on their degree of prematurity. Maternally transmitted IgG slowly decreases to negligible levels at about 6 months, while the infant’s production is gradually increasing, although it may be suboptimal.29 In full-term infants, IgG concentration reaches a low point of 300 to 400 mg/dL at 3 to 6 months, reaches 60% of adult levels by 12 months, and attains adult levels by about 6 years. In some infants, IgG production does not reach age-appropriate levels for as long as 36 months;1 this passes uneventfully in most cases, and is termed “transient hypogammaglobulinemia of infancy.” However, IgG levels below the fifth percentile for age may predispose to infections.
IgM is the first line of defense in humoral immunity; its concentration rises rapidly from the first month of life and reaches approximately 60% of the adult level by 1 year of age. It is the first immunoglobulin isotype produced by the B-cell, which through subsequent class switching produces other isotypes. If the latter does not happen, IgM levels can be high or normal, whereas other immunoglobulins levels are low (hyper IgM syndrome).30
IgA, although it has the highest rate of production, has serum levels much lower than those of IgG because of its shorter half life (approximately 6 days compared with 28 days). It is the slowest to develop and approaches adult levels by preadolescence. Therefore, a normal IgA level for age usually excludes major B-cell defects. Selective IgA deficiency is generally considered at a level of less than 10 mg/dL in the absence of chronic intake of medications that can suppress IgA production, such as phenytoin, carbamazepine, valproic acid, zonisamide, sulfasalazine, gold, penicillamine, hydroxychloroquine, and nonsteroidal anti-inflammatory drugs.31
An elevated IgE level may indicate allergy as the underlying cause of symptoms but an extremely elevated IgE level (> 1,000 IU/mL) together with eczema and recurrent skin abscesses should suggest hyper-IgE syndrome. In certain subjects, serum immunoglobulin levels may be within normal range, yet a deficiency may exist in certain IgG subclasses that can be of clinical significance, particularly when associated with of certain specific antibodies deficiency. B cells constitute 15% to 35% of circulating lymphocytes and can be quantitated by flow cytometry as CD19 or CD20.
Specific Antibody Titers
Functional antibody testing generally involves measurement of antibody titers to diphtheria, and tetanus, and pneumococcus. If the level is non-protective, a vaccine booster dose is given, and the titer is measured 4 to 6 weeks later. Regarding pneumococcal antibodies, if the response was inadequate to a booster with the conjugate vaccine, some subjects may respond to the polysaccharide pneumococcal vaccine. An adequate response would be an antibody concentration of at least 1.3 mcg/mL or a fourfold rise of titer compared with prevaccination level.1
Patients aged 2 to 5 years should respond to approximately at least half of the pneumococcal serotypes tested, and patients older than 5 years should respond to at least 70% of the serotypes.1 The ability to produce antibodies to unconjugated polysaccharide antigens is not fully developed until about 2 years. For younger children, measurement of antibodies to the ABO red blood cell antigens (isohemagglutinins of the IgM class) is sometimes helpful.
Assessing T-Cell Immunity
Because T cells constitute 55% to 80% of peripheral blood lymphocytes, a T-cell defect can be suspected early whenever lymphopenia is detected. Simplified testing for T-cell development by real-time quantitative PCR assay has been recently developed and is being recommended for generalized newborn screening for severe combined immunodeficiency.32 The test measures the number of T-cell receptor excision circles (TRECs), which are stable circular DNA molecules generated during T-cell development. Low or absent TRECs indicate the possibility of a primary immune defect that prevents a newborn from generating T lymphocytes. TRECs below the cutoff value are considered as positive for a T-cell deficiency disease, including severe combined immunodeficiency.33
On May 21, 2010, Kathleen Sebelius, Secretary of Health and Human Services (HHS), announced the addition of severe combined immunodeficiency (SCID) to the core panel of 29 genetic disorders for neonatal screening. Wisconsin and Massachusetts were the first to implement the screening program. Several other states, including California, New York, Louisiana, and the territory of Puerto Rico, have adopted such screening programs.
The function of T cells is a balance between its various subsets that can be enumerated by flow-cytometry which can provide the total lymphocyte (CD3+), T helper (CD4+) and T suppressor (CD8+) numbers. In addition to the numbers, the ratio of CD4+: CD8+ T cells (normal 1.5 – 2) is of importance. A reversed ratio CD4: CD8 can result from various causes and should prompt further evaluation, particularly for HIV infection.
T-Cell Function Assessment
Delayed hypersensitivity skin testing is the simplest screening test in clinical practice; this uses selected T-cell-dependent antigens to which the patient most likely has been previously exposed. Currently available antigens include Candida albicans, 1:100 (Candin Allermed Laboratories, San Diego; CASTA Greer Laboratories, Lenoir, NC); tetanus toxoid 1:100 (or 0.2 Loeffler units/0.1 mL) (Aventis-Pasteur, Swiftwater, PA); and trichophytin, 1:30 (Allermed Laboratories; Greer Laboratories).
A good response (more than or equal to 5-mm in duration) usually indicates adequate cell-mediated immunity. Because these three antigens have not been compared in a large panel of immunocompetent volunteers, anergy may only be inferred if all three antigens are negative. In a study of immunocompetent children aged 6 weeks to 12 years, 73% of subjects tested with two recall antigens (C. albicans and tetanus toxoid) had at least one positive response.34
T-cell function can also be evaluated in a more sensitive way by in vitro stimulation assays, such as lymphocyte proliferation to mitogens (pokeweed mitogen, phytohemaglutinin) and specific antigens (Candida, tetanus, trichophyton). It is worth noting that cell-mediated immunity may be suppressed for several weeks after viral diseases (particularly measles and infectious mononucleosis), severe infections, immunization with viral vaccines, or immunosuppressant therapy.
Assessing Phagocytic Function
Phagocytosis encompasses several functions of the phagocytic cells (neutrophils, monocytes, and macrophages) in dealing with a microorganism. Steps involved in sequence are recognition, chemotaxis, ingestion, phagosome formation, generation of enzymes, generation of oxygen radicals, and killing of ingested microorganisms.35 Detailed evaluation of all steps of phagocyte function requires certain complex assays that may be available only at certain academic laboratories.
A CBC may reveal a quantitative deficiency of phagocytes, such as neutropenia (more than 1,500/mm3) with the risk of infection beginning to increase at less than an absolute nuetrophil count (ANC) of 1,000/mm3. Hematologic and immunologic evaluation would be necessary in defining the underlying cause and further management. In cyclic neutropenia, the neutrophil count drops at about 2- to 3-week intervals and can be identified by checking the neutrophil count 2 to 3 times a week for at least 6 weeks. It can be strongly suspected by a molecular genetic testing for neutrophil elastase. The evaluation often requires a bone marrow biopsy to rule out myeloid hypoplasia. The neutrophil pre-and postepinephrine test can be useful in assessing neutrophil vascular margination, whereas mobilization from the bone marrow can be tested by hydrocortisone stimulation.
Patients with CED have a qualitative defect in neurtrophils. Assessing the oxidative metabolism of neutrophils by the nitroblue tetrazolium test or chemiluminescence has been replaced by a more sensitive method — the dihydrorhodamine flow-cytometric assay. These tests require viable cells; therefore, the collection and transportation of blood sample should be coordinated with the specialized laboratory. Leukocyte adhesion defect can be detected by flow cytometry assay for CD11/CD18 and CD15.
Assessing Complement Function
Defects in the complement system are very rare, but should particularly be suspected in patients with recurrent Neisseria infections. The function of the complement system is generally screened by the complement hemolytic assay; the CH50 for the classic pathway and the individual components C3 and C4. In patients with homozygous deficiencies of any single component of the classic pathway, CH50 level is usually zero or very low, except in C9 deficiency, in which CH50 level can be up to 50% of the normal value.36
Because complement is heat-labile, blood samples should be collected and transported on ice. Low complement levels can also be secondary to infection, or immune complex disease, which can be verified by demonstrating that one or more individual components is decreased, or that complement split products are elevated.37 Testing for the alternative pathway, the lectin activation pathway, and individual complement components or fractions can be done in certain specialized laboratories.
Immunodeficiency disorders are under-diagnosed. An increasing knowledge about their manifestations and diagnosis would prevent morbidity and mortality (see Sidebar 2, see page 209). It cannot be overemphasized that live viral vaccines and transfusion of nonirradiated blood cells should be avoided if immunodeficiency is suspected. The selection of laboratory tests (see Sidebar 3) should be guided by the history and clinical findings.
Sidebar 3.Basic Screening Laboratories:
Screening Tests for B-cell Immunity:
- Complete blood count with differential
- Chest X-ray
- Culture for identification of the infection
- Erythrocyte sedimentation rate
- Serum total protein and albumin
Screening Tests for T-cell Immunity:
- Quantitative serum immunoglobulins (IgG, IgA, IgM, IgE)
- Specific antibodies to vaccination (Pneumococcus, diphtheria, and tetanus)
- Isohemaglutinins to ABO antigens
- B cell quantitative by flow cytometry
Screening tests for Phagocyte Function:
- Absolute lymphocyte count
- Delayed hypersensitivity skin testing
- T-cell subset quantification by flow cytometry
Screening Tests for Complement:
- Dihydrorhodamine test
- Leukocyte adhesion molecules (CD11/CD18 and CD15 by flow cytometry)
- CH50 for classic pathway
- C3, C4
More specific tests are available at the discretion of the immunologist
A referral to a specialist, particularly at an academic center, will help in detailed evaluation to reach definitive diagnosis and an appropriate management plan.
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