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Immunodeficiency

16 min

Skills you'll build3 skills
  • 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

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. Keep going to follow the reasoning.

Keep going to see the reasoning.

Keep going to see the reasoning.

Keep going to see the reasoning.

Keep going to see the reasoning.

Get the idea

Use the explanation to check your first decision.

Start from the infection pattern

The organism, the site and the severity of infections suggest which part of the immune system 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 are recognized from several results 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 guide the genetic follow-up.1,2

Newborn TREC screening

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

Follow the bench demonstration

Sources for this step
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

Read each decision and its explanation.

Mateo Blank, 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?

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

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

  1. Review the infections first. A deep bacterial abscess and an invasive mold infection suggest a phagocyte defect.

    The type of infection suggests which compartment 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. Consider function. A normal count does not exclude a defect in the oxidative burst.

    Plentiful neutrophils can still fail to kill what they engulf.

  4. Review the other results. 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, interpreted with a control handled at the same time.

    The dihydrorhodamine test shows whether neutrophils produce oxidants.

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

Practice this skill

Your turn

Problem 1 of 3 · Hints available

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. Consider how fast follow-up must happen in a newborn who may have no functional T cells.

Review SCID newborn screening

Problem 2 of 3 · Hints available

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 a low signal does not confirm chronic granulomatous disease.

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 · On your own

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 considered before testing for an inherited defect.

Read one low immunoglobulin as a genetic disorder

Protein loss, medications, hematologic malignancy, and other secondary causes lower immunoglobulins. Classifying a deficiency as inherited requires immunoglobulin levels, lymphocyte counts, and functional tests interpreted together. Reading one low value as an inherited defect mislabels a secondary deficiency and leads to the wrong confirmatory tests.

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

Low immunoglobulins with pneumonia suggest an antibody defect. The oxidative-burst test evaluates 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

Read the case evidence, then make each decision. The step is complete without 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.
TestResultReference intervalFlag
CD3 T cells120 cells/µL Low2,500–5,500 cells/µL2,500–5,500Low
CD19 B cells1,400 cells/µL300–2,000 cells/µL300–2,000
CD16/CD56 NK cells40 cells/µL Low170–1,100 cells/µL170–1,100Low

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 also lower TRECs, 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 delays follow-up in a newborn who may have no functional T cells. Follow-up testing is done 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 requires absent B cells.

That is the pattern of X-linked agammaglobulinemia. Here the T cells are low and the B cells are within the interval.

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 requires 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 subset counts have already followed up the screen. Another screen adds no information.

These show whether the few T cells function and whether they are maternal, and the genetic test identifies the cause.

Review SCID newborn screening

The finding that matters is the T-negative, B-positive, NK-negative subset pattern after a low TREC screen. The low screen required prompt follow-up. The subset counts showed very few T cells and guide the genetic testing that identifies the cause.

For reference

Sources checked