Humoral immunity

IgG, IgA, IgM, IgE, IgG subclasses, specific antibodies to prior infection or vaccination, and pre- to post-immunisation antibody responses where clinically appropriate.

Cellular immunity

Lymphocyte subsets including CD3, CD4, CD8, CD16/CD56, CD19 and CD20, with further B-cell subset analysis in selected patients to assess switched memory and related maturation defects.

Complement and innate screening

MBL, C3, C4 and CH50, especially if there is invasive bacterial disease, recurrent meningococcal infection, unusual infection severity, or concern about complement pathway dysfunction.

Clinical review and red flags

Review recurrent chest, sinus or ear infections, need for repeated antibiotics, pneumonia, bronchiectasis, chronic cough, chronic diarrhoea, malabsorption, weight loss, autoimmune disease, lymphadenopathy, splenomegaly, granulomatous disease, family history, and previous vaccine history.

First-line blood tests

Core panel: FBC, film, renal profile, liver profile, CRP or ESR as clinically indicated, total protein, albumin, globulin, serum electrophoresis where relevant, and baseline immunoglobulins.

Immunoglobulins: IgG, IgA, IgM, IgE, plus IgG1, IgG2, IgG3 and IgG4 when antibody deficiency is suspected or borderline.

Cellular immunity and lymphocyte subsets

Measure CD3 (total T cells), CD4 (helper T cells), CD8 (cytotoxic T cells), CD16/CD56 (NK cells), CD19 and CD20 (B-cell markers). In selected cases, add extended B-cell phenotyping to evaluate switched memory B cells, non-switched memory B cells, naïve B cells, transitional B cells and plasmablast-related patterns.

Specific antibody function

Review existing antibodies to common vaccine-preventable infections and previous immunisation history. Depending on age, previous vaccines, and clinical context, this may include pneumococcal, tetanus, Hib, and selected meningococcal antibodies such as MenB and MenACWY.

Where clinically appropriate, assess function by measuring antibodies before and after test vaccination using a vaccine strategy that reflects current UK availability and the patient’s prior schedule.

Complement and secondary cause screen

Add MBL, C3, C4 and CH50 where the infection pattern suggests complement involvement. Exclude secondary hypogammaglobulinaemia from protein-losing enteropathy, nephrotic syndrome, immunosuppressive therapy, B-cell depleting treatment, lymphoid malignancy, or other systemic disease.

Specialist interpretation and next steps

Results are interpreted in the context of symptoms, infection burden, imaging, vaccine history, and coexisting immune dysregulation. Further steps may include CT chest, sinus imaging, stool testing, protein loss assessment, genetic testing, and discussion of prophylactic antibiotics, immunoglobulin replacement, and vaccination strategy.

Core immunoglobulins

• IgG – the principal immunoglobulin assessed in CVID
• IgA – often low alongside IgG
• IgM – may be low, normal or occasionally raised in other disorders
• IgE – helpful for broader immune context, atopy and differential diagnosis

IgG subclass profile

• IgG1
• IgG2
• IgG3
• IgG4

Subclass deficiency does not diagnose CVID on its own, but it can be useful where the history suggests recurrent bacterial infections or where total IgG is borderline.

Functional antibody assessment

• Antibodies to previous infections or vaccines
• Baseline antibody titres before vaccination where needed
• Repeat titres after test vaccination where appropriate
• Interpretation in light of age, prior vaccine exposure and time since immunisation

CD3

Total T-cell population. A marked reduction may suggest a broader combined immune defect rather than isolated antibody deficiency.

CD4

Helper T cells support antibody production, immune regulation and memory responses. Low counts can alter infection risk and vaccine interpretation.

CD8

Cytotoxic T cells. The CD4:CD8 balance can provide additional context in complex immune phenotypes.

CD16/CD56

Natural killer cells. Helpful when infection severity, viral susceptibility or a broader inborn error of immunity is suspected.

CD19

B-cell lineage marker used for quantifying circulating B cells and for extended B-cell phenotyping.

CD20

B-cell marker that may be especially relevant if there has been previous anti-CD20 treatment or concern about secondary B-cell depletion.

MBL

Mannose-binding lectin may be helpful in selected patients with recurrent infections, especially if the wider picture suggests an additional innate immune vulnerability.

C3

A core complement component that can be low in pathway activation or complement consumption.

C4

Useful alongside C3 when classical pathway activation or immune complex disease is a concern.

CH50

A functional overview of the classical complement pathway and a practical screening tool when invasive meningococcal disease or complement deficiency is suspected.

Imaging and organ assessment

CT chest for bronchiectasis or interstitial change, sinus imaging where needed, abdominal ultrasound for splenomegaly or lymphadenopathy, and targeted gastroenterology review for chronic diarrhoea or enteropathy.

Secondary cause exclusion

Urine protein testing, stool protein-loss evaluation where relevant, coeliac screening as clinically indicated, and review of drugs that can suppress B cells or immunoglobulin production.

Genetic review

Selected patients may benefit from genetic testing, particularly if there is early onset disease, autoimmunity, lymphoproliferation, unusual infections, or a strong family history.