immunology allergic disorders
Approach to the Patient With Suspected Immunodeficiency
Evaluation of Suspected Immunodeficiency
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. Clinicians should determine whether patients have risk factors for infection or a history of symptoms of secondary immunodeficiency disorders and/or risk factors for them. Family history is very important. Age when recurrent infections began is important: Onset before age 6 months suggests a T-cell defect because maternal antibodies are usually protective for the first 6 to 9 months. Onset between the age of 6 and 12 months may suggest combined B- and T-cell defects or a B-cell defect, which becomes evident when maternal antibodies are disappearing (at about age 6 months). Onset much later than 12 months usually suggests a B-cell defect or secondary immunodeficiency. 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) [CVID]) do not manifest until adulthood. Certain infections suggest certain immunodeficiency disorders (see table 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. 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 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. Delayed umbilical cord separation may suggest Leukocyte Adhesion Deficiency . Other characteristic findings tentatively suggest a clinical diagnosis (see table Characteristic Clinical Findings in Some Primary Immunodeficiency Disorders ). If a specific secondary immunodeficiency disorder is suspected clinically, testing should focus on that disorder (eg, Diagnosis , Tests are needed to confirm a diagnosis of immunodeficiency (see table Initial and Additional Laboratory Tests for Immunodeficiency ). Initial screening tests should include Complete blood count (CBC) with manual differential Quantitative immunoglobulin (Ig) measurements Antibody titers Skin testing for delayed hypersensitivity 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. If clinicians suspect that immunodeficiency may be still developing, tests may need to be repeated, with monitoring over time, before a definitive diagnosis is made. CBCcan detect abnormalities in one or more cell types (eg, white blood cells, platelets) characteristic of specific disorders, as in the following: Neutropenia(absolute neutrophil count<1200 cells/mcL [1.2 x 109/L]) may be congenital or cyclic or may occur in aplastic anemia. /L] in older children or adults) suggests a Cellular immunity deficiencies because 70% of circulating lymphocytes are T cells. that persists between infections may occur in Leukocyte Adhesion Deficiency . in male infants suggests Wiskott-Aldrich Syndrome . may suggest Anemia of Chronic Disease or However, many abnormalities are transient manifestations of infection, drug use, or other factors; thus, abnormalities should be confirmed and followed. should be examined for Howell-Jolly bodies (residual fragments of the nucleus in red blood cells [RBCs]) 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 ). 200 mg/dL (< 2 g/L) usually indicates significant antibody deficiency, although such levels may occur in protein-losing enteropathies or Overview of Nephrotic Syndrome . IgM antibody functioncan be assessed by measuring isohemagglutinin titers (anti-A, anti-B). All patients except infants<6 months and people with blood type AB have natural antibodies at a titer of≥1:8 (anti-A) or≥1:4 (anti-B). Antibodies to blood groups A and B and to some bacterial polysaccharides are selectively deficient in certain disorders (eg, Wiskott-Aldrich syndrome, complete IgG2 deficiency). IgG antibody titerscan be assessed in immunized patients by measuring antibody titers before and after administration of vaccine antigens (Haemophilus influenzaetype B, tetanus, diphtheria, conjugated or nonconjugated pneumococcal, and meningococcal antigens); a less-than-twofold increase in titer at 2 to 3 weeks suggests antibody deficiency regardless of Ig levels. Natural antibodies (eg, antistreptolysin O, heterophil antibodies) may also be measured. Withskin testing,most immunocompetent adults, infants, and children react to 0.1 mL ofCandida albicansextract (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 hours, excludes a T-cell disorder. Lack of response does not confirm immunodeficiency in patients with no previous exposure toCandida. Chest x-raymay 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. 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 Cellular immunity deficiencies is suspected, a complete blood count with differential can be done to identify infants with low absolute lymphocyte counts. If tests show that lymphocytes are low in number or absent, a flow cytometry assay followed by in vitro mitogen stimulation studies are done to assess T-cell quantity and function. If major histocompatibility complex (MHC) antigen deficiency is suspected, serologic (not molecular) human leukocyte antigen (HLA) typing is indicated. All US states now screen newborns with T-cell receptor excision circles (TREC) to assess for absent or dysfunctional T cells. Circles of DNA are normally created as T cells pass through the thymus and undergo rearrangement of their receptor genes, and the presence of these circles on TREC analysis provides a measure of T cell maturation. Absence of these circles on screening TREC analysis is a feature of SCID. If Humoral immunity deficiencies is suspected, patients may be tested for specific mutations—for example, in the genes that encode for Bruton tyrosine kinase (BTK), CD40 and CD40 ligand, and nuclear factor-kappa-B essential modulator (NEMO). A sweat test is typically done during the evaluation to rule out cystic fibrosis. If Combined humoral and cellular immunity deficiencies is impaired and SCID is suspected, patients can be tested for certain typical mutations (eg, in the interleukin (IL-2) receptor gamma [ If Phagocytic cell defects are suspected, CD15 and CD18 are measured by flow cytometry and neutrophil chemotaxis is tested. A flow cytometric oxidative (respiratory) burst assay (measured by dihydrorhodamine 123 [DHR] or nitroblue tetrazolium [NBT]) can detect whether oxygen radicals are produced during phagocytosis; no production is characteristic of chronic granulomatous disease. If the type or pattern of infections suggests Complement deficiencies , the serum dilution required to lyse 50% of antibody-coated red blood cells is measured. This test (called CH50) detects complement component deficiencies in the classical complement pathway but does not indicate which component is abnormal. A similar test (AH50) can be done to detect complement deficiencies in the alternative pathway. If examination or screening tests detect abnormalities suggesting lymphocyte or phagocytic cell defects, other tests can more precisely characterize specific disorders (see table Specific and Advanced Laboratory Tests for Immunodeficiency* ). Gene sequencing techniques are becoming increasingly used to elucidate immunodeficiency disorders with unusual features. Identification of monogenetic defects in the setting of primary immunodeficiency has become robust, and improvements are gradually changing how we approach the diagnosis and treatment of these diseases ( Evaluation reference ). An increasing number of primary immunodeficiency disorders can be diagnosed prenatally using Chorionic Villus Sampling , cultured amniotic cells, or X-linked Agammaglobulinemia , Sex determination by ultrasonography can be used to exclude X-linked disorders. 1.Chinn IK, Orange JS: A 2020 update on the use of genetic testing for patients with primary immunodeficiency.Expert Rev Clin Immunol16(9):897–909, 2020. doi: 10.1080/1744666X.2020.1814145 