Tests
1st tests to order
CBC
Test
Iron deficiency anemia, autoimmune hemolytic anemia, and idiopathic thrombocytopenic purpura can be seen in common variable immunodeficiency (CVID). Lymphopenia is seen in CVID, severe combined immunodeficiency, intestinal lymphangiectasia, and hematologic malignancy. Lymphocytosis is seen in hematologic malignancy.
It is important to note that adult and infant reference ranges for total lymphocyte count differ.
Result
normal or reduced Hb; normal, reduced, or elevated lymphocytes; normal or reduced platelets
serum IgG
Test
May be reduced in common variable immunodeficiency, severe combined immunodeficiency, transient hypogammaglobulinemia of infancy, and hyper-IgM syndrome. Is normal in selective IgA deficiency. In IgG subclass deficiency, laboratory testing shows ≥1 of: reduced IgG1, reduced IgG2, reduced IgG3, or reduced IgG4 (total IgG may be normal).
First-line test for suspected immunodeficiency. Test is repeated to confirm result. Age-related reference ranges are used. Immunoglobulins in infants <1 year of age may be of maternal origin and therefore results will not reflect ability to synthesize immunoglobulins.
Result
normal or reduced
serum IgA
Test
May be reduced in common variable immunodeficiency, severe combined immunodeficiency, transient hypogammaglobulinemia of infancy, hyper-IgM syndrome, and IgG subclass deficiency. May also be normal in IgG subclass deficiency. Is absent in selective IgA deficiency.
First-line test for suspected immunodeficiency. Test is repeated to confirm result. Age-related reference ranges are used. Immunoglobulins in infants <1 year of age may be of maternal origin and therefore results will not reflect ability to synthesize immunoglobulins.
Result
normal, reduced, or absent
serum IgM
Test
May be reduced in common variable immunodeficiency and severe combined immunodeficiency. May be normal in selective IgA deficiency and IgG subclass deficiency. Is elevated in hyper-IgM syndrome.
First-line test for suspected immunodeficiency. Test is repeated to confirm result.
Result
normal, reduced, or elevated
serum and urine electrophoresis
Test
Performed in older patients. Presence of paraprotein may indicate hematologic malignancy and secondary hypogammaglobulinemia.
Result
normal or presence of paraprotein
serum free light chains
Test
Detects excessive free light chains and changes in kappa:lambda ratio.
Complementary to serum and urine electrophoresis.
Result
normal or excessive free light chains
urine dipstick
Test
May be positive in nephrotic syndrome and infection.
Result
normal or presence of protein, leukocytes, nitrites
serum creatinine
Test
Elevated in some renal conditions resulting in nephrotic syndrome.
Result
normal or elevated creatinine
serum albumin
Test
May be reduced in protein-losing enteropathy, malabsorption, nephrotic syndrome, and sepsis.
Result
normal or reduced
LFTs
Test
Alkaline phosphatase/gamma-glutamyl transferase (gamma-GT) may be elevated in granulomatous common variable immunodeficiency disease.
Result
normal or elevated alkaline phosphatase/gamma-GT
sputum culture
Test
If positive, it is typically for encapsulated bacteria (e.g., Streptococcus pneumoniae, Haemophilus influenzae), but it can also be positive for nonencapsulated Haemophilus.
Cryptosporidium may be detected in hyper-IgM syndrome.
Result
normal, or positive for encapsulated/nonencapsulated bacteria
stool culture
Test
Cryptosporidium may be detected in hyper-IgM syndrome.
Result
normal, or positive for Campylobacter/Giardia/Cryptosporidium
chest x-ray
Test
Useful for acute infection, bronchiectasis, lymphadenopathy, and granulomatous disease. Absent/small thymus or structural thymic abnormalities may be seen in severe combined immunodeficiency. Thymoma is seen in Good syndrome.[28] Pneumatoceles may occur in hyper-IgE syndrome.
Less sensitive than CT at picking up mild degrees of bronchiectasis, but much less radiation exposure.[29]
Result
normal; or evidence of infection, lymphadenopathy, thymic mass, or chronic damage
Tests to consider
flow cytometry: lymphocyte subsets
Test
Usually performed by referral centers. Offers information about the immune cell counts and percentages (B-, T-, and natural killer [NK] cells).[30] Absolute counts are the important measure. Age-related reference ranges must be used, as normal ranges can vary widely (e.g., between infants and adults).
X-linked agammaglobulinemia: significantly reduced or absent B cells (cell surface markers CD19, CD20).
Severe combined immunodeficiency: significantly reduced or absent T cells; B and NK cells may be normal or reduced.
Autoimmune lymphoproliferative syndrome: elevated double CD4 and CD8 negative population.
Chronic lymphocytic leukemia, lymphoma: monoclonal population.
Result
variable
specific antimicrobial antibodies
Test
Usually performed by referral centers. Looks for specific antimicrobial antibodies to common bacterial and/or viral antigens (e.g., antibodies to Streptococcus pneumoniae, tetanus, Haemophilus influenzae).
Result
specific antibody deficiency/primary disease: reduced or absent
test immunization response
Test
Test immunizations are usually performed by referral centers when specific antibody levels are reduced. Repeat testing is done at 4 to 6 weeks.
It is essential to remember that live vaccines (e.g., bacillus Calmette-Guérin [BCG], measles-mumps-rubella [MMR], yellow fever) are avoided in patients with suspected or known severe immunodeficiency. This must be considered following a case-by-case risk/benefit analysis.
Result
normal or reduced
IgG subclasses
Test
Usually performed by referral centers. A less dynamic evaluation of antibody response than specific antibody tests. Disadvantages include presence of several technical issues; poorly defined normal ranges in young children; and lack of sufficient data on development in early childhood.
A low IgG subclass may not be associated with clinically significant disease.
Result
normal or reduced
flow cytometry: protein expression
Test
Usually performed by referral centers when testing for Wiskott-Aldrich syndrome protein, Bruton tyrosine kinase protein expression in X-linked agammaglobulinemia, and CD40 ligand expression in X-linked immunodeficiency with hyper-IgM.
Result
normal, reduced, or absent
genetic testing
Test
Usually performed by referral centers to confirm underlying genetic mutation. Important for diagnosis, family screening, and prenatal counseling/diagnosis (e.g., for hyper-IgM syndrome, X-linked agammaglobulinemia).
Demonstrating biallelic mutations in the ADA gene confirms severe combined immune deficiency caused by adenosine deaminase deficiency.
Genetic testing is likely to become clinically important with the rapidly increasing identification of genetic primary immunodeficiency disorders.
Result
normal or mutation
enzyme assays
Test
Usually performed by referral centers in cases of suspected severe combined immunodeficiency (SCID).
The adenosine deaminase level may be low or absent in SCID.[25]
Result
variable
abdominal ultrasound
Test
Performed to check for the presence of a spleen and rule out differential diagnosis of hyposplenism.
Look for hepatosplenomegaly: this may occur in hematologic malignancy causing hypogammaglobulinemia, and also in common variable immunodeficiency (reactive, granulomatous, infection, lymphoma).
Result
normal, splenomegaly/hepatomegaly, or hyposplenism
CT chest/sinuses
Test
Usually performed by referral centers. Useful to detect bronchiectasis, lymphadenopathy, and granulomatous disease.[29] Disadvantages include a much higher radiation dose than chest x-ray; some patients with hypogammaglobulinemia may be radiosensitive (e.g., ataxia-telangiectasia, common variable immunodeficiency).
Result
normal; or evidence of infection, lymphadenopathy, or chronic damage
CT abdomen
Test
Usually performed by referral centers.
Result
normal; hepatosplenomegaly; lymphadenopathy
pulmonary function test
Test
Usually performed by referral centers. Obstructive defect typically seen in bronchiectasis. Low diffusion capacity (transfer factor) of the lung typically seen in granulomatous lung disease (part of common variable immunodeficiency).
Result
normal; obstructive defect; or reduced diffusion capacity
lymph node biopsy
Test
Lymphadenopathy may be infectious or lymphoproliferative.
Infection may occur in any hypogammaglobulinemia.
Lymphoid hyperplasia, granulomatous disease, and lymphoma associated with common variable immunodeficiency.
Result
normal, granulomatous disease, lymphoid hyperplasia, infection, or lymphoma
small- and large-bowel biopsy
Test
Usually performed by referral centers.
Result
normal, celiac-like enteropathy, or inflammatory bowel disease lesions; common variable immunodeficiency: nodular lymphoid hyperplasia
polymerase chain reaction (PCR) for viral infection
Test
Usually performed by referral centers, as serology provides unreliable evidence of viral infection for hypogammaglobulinemia. PCR provides direct demonstration of the infectious agent (e.g., hepatitis C).
Result
normal or positive
hepatitis B surface antigen, hepatitis B and C PCR
Test
Usually performed by referral centers before starting immunoglobulin replacement therapy, as there is a theoretical risk of infection. It is also performed as part of replacement immunoglobulin monitoring. Standard viral serology based on antibody detection is not useful in hypogammaglobulinemia.
Result
negative
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