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Immunodeficiency

16 min

  • Choose first tests for a suspected antibody, T-cell, or phagocyte deficiency
  • Recognize when low immunoglobulins or lymphocytes need tests for an inherited deficiency
  • Send a low TREC newborn screen for lymphocyte subsets and confirmatory testing

Read the full reference

Try first

Try first

A 6-year-old has had pneumonia twice and sinusitis four times this year, each time with common encapsulated bacteria. Which first tests fit this pattern?

Right. The next section explains why.

The next section explains it.

The next section explains it.

The next section explains it.

The next section explains it.

Get the idea

Start from the infection pattern

The organism, the site and the severity of infections point to the part of the immune system that is failing. Each compartment has its own first tests.1

ClueCompartmentFirst tests
Recurrent sinus and lung infections with encapsulated bacteriaAntibodyIgG, IgA and IgM; vaccine antibody responses; B-cell count
Viral, fungal or opportunistic infections, severe infection in infancyT cell or combinedAbsolute lymphocyte count; T-, B- and NK-cell counts; naïve T cells
Deep bacterial or fungal abscesses, poor pus formationPhagocyteNeutrophil count and morphology; dihydrorhodamine oxidative burst
Invasive Neisseria infectionComplementCH50 and AH50 together

1

A count within the reference interval does not prove function. Neutrophils can be plentiful and unable to kill, and B cells can be present and unable to make specific antibody.1

Secondary causes come first

Low immunoglobulins and low lymphocyte counts often have a secondary cause: protein loss, HIV, a hematologic malignancy or an immune-modifying drug such as rituximab. These are checked before a result is attributed to an inborn error of immunity.1 Inherited patterns show in several results read together. X-linked agammaglobulinemia shows very low B cells and immunoglobulins with normal T cells. Selective IgA deficiency shows undetectable IgA with normal IgG and IgM. Severe combined immunodeficiency (SCID) shows markedly low T cells, and its B- and NK-cell counts sort the genetic follow-up.1,2

A low TREC screen is a screen

Newborn screening for SCID measures T-cell receptor excision circles (TRECs) in a dried blood spot. TRECs are DNA left over when a new T cell rearranges its receptor, so they reflect thymic output. A low result is reported promptly under the screening program's procedure. Prematurity, 22q11.2 deletion, athymia and secondary lymphopenia also lower TRECs. Confirmation needs lymphocyte subset counts, naïve T-cell and functional testing, and genetic testing.1

References
  1. Orange JS, Chinen J, Horner CC, et al. 2025 inborn errors of immunity practice parameter: guidance from the Joint Task Force on Practice Parameters, the American Academy of Allergy, Asthma & Immunology, the American College of Allergy, Asthma and Immunology, and the Clinical Immunology Society. Ann Allergy Asthma Immunol. 2026;136(4):426-493.e1. doi:10.1016/j.anai.2025.10.026
  2. Abbas AK, Lichtman AH, Pillai S, Henrickson S. Cellular and Molecular Immunology. 11th ed. Elsevier; 2025. Elsevier.

Watch one

Mateo Arriaga, 2, loves stacking cups higher than his head. He has had a Staphylococcus aureus liver abscess and now has Aspergillus pneumonia. He takes no medications.

Which test comes next?

TestResultPreviousReference intervalFlag
WBC12.4 10^3/µL5.0–15.5 10^3/µL
Absolute neutrophil count7.1 10^3/µL1.5–8.5 10^3/µL
Absolute lymphocyte count4.2 10^3/µL2.0–8.0 10^3/µL
IgG1,020 mg/dL450–1,200 mg/dL

Specimen: H 2, L 6, I 1. EDTA whole blood, collected 11:05

  1. Read the infections first. A deep bacterial abscess and an invasive mold infection point to phagocytes.

    The kind of infection points to the compartment that is failing.

  2. Check the neutrophil count. It is 7.1 × 10³/µL, within the reference interval.

    An absent neutrophil population would explain the infections without a functional defect.

  3. Keep function open. A normal count does not exclude a defect in the oxidative burst.

    Plentiful neutrophils can still fail to kill what they engulf.

  4. Glance at the rest. IgG and the lymphocyte count are within their intervals.

    Normal antibody and lymphocyte results make the other compartments less likely.

  5. Choose the dihydrorhodamine oxidative-burst test, read beside a concurrently handled control.

    The dihydrorhodamine test shows whether neutrophils produce oxidants.

A dihydrorhodamine oxidative-burst test. An abnormal result is a screen that leads to confirmatory testing.

Your turn

Problem 1 of 3

A term newborn's dried-blood-spot screen reports low T-cell receptor excision circles (TRECs). What does this result lead to?

Correct. Low TRECs show reduced new T-cell production, so confirmation starts promptly with lymphocyte enumeration, naïve T-cell assessment, functional testing, and directed genetic testing.

Incorrect. A low TREC result calls for urgent diagnostic follow-up. Waiting weeks for a repeat screen delays confirmation of possible severe combined immunodeficiency (SCID).

Incorrect. Confirmation also needs lymphocyte enumeration and naïve T-cell and functional testing, because athymia, 22q11.2 deletion, and secondary lymphopenia also lower TRECs.

Hint
  1. A low TREC means few new T cells. Ask what would confirm that on a blood specimen.
  2. Weigh how fast follow-up has to happen in a newborn who may have no working T cells.

Review SCID newborn screening

Problem 2 of 3

A dihydrorhodamine (DHR) flow cytometry screen shows a markedly reduced neutrophil response. How is the result interpreted?

Incorrect. Complete myeloperoxidase (MPO) deficiency can markedly reduce the DHR signal even when oxidase function is preserved, so the low signal alone leaves chronic granulomatous disease unconfirmed.

Correct. DHR fluorescence depends on peroxidase activity as well as oxidant generation. The result is read with a concurrently handled control, and preserved superoxide production in an independent assay points toward myeloperoxidase deficiency.

Incorrect. Handling can lower the signal, which is why a concurrently handled control is read with the patient. A markedly reduced response still needs confirmatory studies.

Hint
  1. The dye's signal depends on more than one enzyme.
  2. Ask what else could lower the signal when oxidase works normally.

Review Inborn errors of immunity with leukocyte findings

Problem 3 of 3

A 63-year-old man with chronic lymphocytic leukemia has had two pneumonias this winter. IgG is 410 mg/dL (reference 700–1,600 mg/dL), IgA 60 mg/dL (70–400 mg/dL) and IgM 32 mg/dL (40–230 mg/dL). What does the laboratory pattern call for first?

Chronic lymphocytic leukemia commonly lowers immunoglobulins. A known secondary cause is weighed before an inherited defect is pursued.

Read one low immunoglobulin as a genetic disorder

Protein loss, medications, hematologic malignancy, and other secondary causes lower immunoglobulins. Calling a deficiency inherited needs immunoglobulin levels, lymphocyte counts, and functional tests read together. Reading one low value as an inherited defect mislabels a secondary deficiency and misdirects confirmation.

A hematologic malignancy is a common secondary cause of low immunoglobulins. Vaccine responses show how well he makes specific antibody.

Low immunoglobulins with pneumonia point to the antibody compartment. The oxidative-burst test looks at phagocytes.

TRECs measure new T-cell output and are used for newborn screening. They do not address low immunoglobulins in an adult.

Review Characteristic IEI patterns

Use it

  • Rafferty Lin was born at 39 weeks and at 9 days old feeds greedily and sleeps through anything.
  • His newborn screen reports a low TREC result.
  • He has no known infection and no family history of immune disease.
  • A lymphocyte subset panel is run the next day.
TestResultPreviousReference intervalFlag
CD3 T cells120 cells/µL2,500–5,500 cells/µLLow
CD19 B cells1,400 cells/µL300–2,000 cells/µL
CD16/CD56 NK cells40 cells/µL170–1,100 cells/µLLow

Specimen: H 5, L 3, I 9. EDTA whole blood, collected 08:30, day 10 of life

Decision 1 of 3

When the low TREC screen arrives, how is it reported?

Low TRECs show low new T-cell output. Other conditions do the same, so SCID needs confirmatory testing.

Reported low TRECs as a confirmed SCID diagnosis

Low T-cell receptor excision circles (TRECs) show reduced new T-cell output, which prematurity, athymia, 22q11.2 deletion, and secondary lymphopenia can also cause. Reporting severe combined immunodeficiency (SCID) from the screen skips the lymphocyte enumeration, functional testing, and genetic testing that confirm it.

A low TREC is a screening result. The program's procedure calls for prompt reporting and lymphocyte subset counts.

Waiting weeks leaves a newborn who may have no working T cells unprotected. Follow-up happens promptly.

Review SCID newborn screening

Decision 2 of 3

Which pattern do his lymphocyte subsets show?

His B cells are within the reference interval. This pattern needs absent B cells.

That is the pattern of X-linked agammaglobulinemia. His T cells are the ones missing.

CD3 T cells and NK cells are markedly low, and B cells are within the interval. This pattern guides the genetic follow-up.

His B cells are present at 1,400 cells/µL. This pattern needs all three to be low.

Review Characteristic IEI patterns

Decision 3 of 3

What completes the confirmation?

Counts show how many T cells there are. Confirmation also needs naïve T-cell and functional testing and genetic testing.

Reported low TRECs as a confirmed SCID diagnosis

Low T-cell receptor excision circles (TRECs) show reduced new T-cell output, which prematurity, athymia, 22q11.2 deletion, and secondary lymphopenia can also cause. Reporting severe combined immunodeficiency (SCID) from the screen skips the lymphocyte enumeration, functional testing, and genetic testing that confirm it.

The screen has done its job. Another screen adds nothing to the subset counts.

These show whether the few T cells work and where they came from, and the genetic test names the cause.

Review SCID newborn screening

The clue that settled this case is the T-negative, B-positive, NK-negative subset pattern after a low TREC screen. The screen called for prompt follow-up. The subset counts showed very few T cells and pointed the genetic testing that confirms the cause.

Keep

Sources checked