CVID Cellular and Humoral Immunity Assessment
A structured diagnostic pathway for suspected common variable immunodeficiency (CVID) and related antibody deficiencies, including lymphocyte subsets, immunoglobulins, IgG subclasses, complement screening, and interpretation of antibodies to common infections and vaccines.
Who this page is for: adults and children with recurrent sinopulmonary infections, unusually severe infections, bronchiectasis, unexplained low immunoglobulins, poor vaccine responses, autoimmune cytopenias, lymphadenopathy, splenomegaly, chronic diarrhoea, granulomatous disease, or a strong family history of immune deficiency.
Important: no single blood test confirms CVID in isolation. Diagnosis usually relies on a combination of clinical history, serum immunoglobulins, antibody function, lymphocyte phenotyping, and exclusion of secondary causes such as protein loss, nephrotic syndrome, lymphoproliferative disease, immunosuppressive medicines, haematological malignancy, and other defined inborn errors of immunity.
What is assessed in a CVID work-up?
A careful CVID assessment looks at both humoral immunity and cellular immunity. Humoral immunity covers immunoglobulin production and antibody function. Cellular immunity examines the lymphocyte populations that support immune defence and B-cell maturation. Complement screening is often added where the infection pattern, meningococcal history, or family history suggests an additional innate immune defect.
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.
Diagnostic flow for suspected CVID
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.
Humoral immunity assessment
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
Clinical point: CVID is not simply “low antibodies”. The pattern matters: a patient may have low IgG with low IgA and/or IgM, poor vaccine responses, and evidence of abnormal B-cell differentiation despite preserved overall B-cell numbers.
Cellular immunity assessment
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.
Extended B-cell phenotyping in selected patients
In specialist immunology practice, many patients benefit from deeper B-cell analysis rather than relying on total CD19 or CD20 counts alone. This may include:
- Switched memory B cells
- Non-switched memory B cells
- Naïve B cells
- Transitional B cells
- Plasmablast-related patterns where available
This can help identify whether low immunoglobulin levels reflect impaired B-cell maturation, reduced memory formation, or a different immunophenotypic pattern that may warrant further investigation.
Complement and innate screening
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.
When complement testing is especially relevant: recurrent meningococcal infection, invasive bacterial disease, family history of complement deficiency, or unexpectedly severe infection that is not fully explained by antibody deficiency alone.
Antibodies to common infections and vaccine response testing
Commonly reviewed antibody responses
Depending on the laboratory pathway, age, past immunisations and suspected diagnosis, functional antibody assessment may include some or all of the following:
- Pneumococcal antibodies
- Tetanus antibodies
- Haemophilus influenzae type b (Hib) antibodies
- Meningococcal serogroup antibodies where clinically appropriate, including MenB and MenACWY
- Other pathogen-specific antibodies when guided by history and laboratory availability
How test vaccination is interpreted
Test vaccination is not a one-size-fits-all process. Interpretation depends on:
- which vaccines the patient has already received
- whether the vaccine is conjugated or polysaccharide-based
- the time interval since the last dose
- whether immunoglobulin treatment has already started
- the patient’s age, infection history, and broader immune phenotype
For this reason, vaccine response testing should be planned and interpreted by a clinician experienced in immunodeficiency rather than used as an isolated screening shortcut.
UK vaccine update relevant to immunology testing
- Menitorix (Hib/MenC): no longer offered routinely from 1 July 2025. Manufacture has been discontinued. Remaining eligible children born on or before 30 June 2024 may still receive it while stock lasts. After depletion, the updated schedule relies on a Hib-containing hexavalent dose at the new 18-month appointment.
- MenB timing: the second infant MenB dose moved to 12 weeks, with the infant pneumococcal dose moving to 16 weeks.
- Pneumococcal programme: for most adults and those aged 2 years and above in eligible clinical risk groups, the programme has changed from Pneumovax 23 (PPV23) to PCV20. Existing PPV23 stock may still be used locally until exhausted.
This matters because an immunology test-vaccination pathway must reflect the current vaccine era. Historic testing algorithms that assumed routine Menitorix or routine new PPV23 supply may need updating.
What a consultant may add if CVID is likely
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.
BioLegend immunology learning links
For readers who would like a simple visual introduction to immune cells and laboratory immunology concepts, BioLegend’s immunology education hub is a useful starting point.
- BioLegend Immunology Hub – overview of innate and adaptive immunity, immune cells and immunology applications.
- This can help patients understand the basic roles of T cells, B cells, NK cells and the wider immune network before or after a specialist consultation.
- It is educational, but it does not replace consultant interpretation of laboratory findings or decisions about immunoglobulin treatment.
Frequently asked questions
Can normal lymphocyte counts rule out CVID?
No. Many patients with CVID have circulating B cells, and some have broadly preserved total lymphocyte numbers. The important issue is whether antibody production and B-cell maturation are functioning properly.
Why measure IgG subclasses if total IgG is already low?
Subclasses can add context, especially in borderline cases or recurrent bacterial infection. They do not replace full assessment of specific antibody function.
Are MenB and MenACWY antibodies always required?
Not always. They may be useful in selected cases, especially when reviewing previous vaccine responses or considering complement-related susceptibility, but the exact panel should be individualised.
Can immunoglobulin replacement affect vaccine antibody testing?
Yes. Once replacement immunoglobulin has started, interpretation of some specific antibody tests becomes difficult or impossible. Ideally, diagnostic vaccine-response testing is considered before immunoglobulin therapy begins, if clinically safe and appropriate.
Need a specialist immunology review?
A consultant-led assessment can help determine whether low immunoglobulins reflect CVID, IgG subclass deficiency, a specific antibody deficiency, a secondary cause, or a broader inborn error of immunity.
Request an immunology assessmentMedical note: this page is for education and service information. Test selection and interpretation should always be individualised by a qualified clinician, particularly when prior vaccinations, immunoglobulin therapy, complement disorders, immune dysregulation, or secondary causes of antibody deficiency are relevant.
Last reviewed for vaccine programme wording: April 2026.