What are the diagnostic criteria for common variable immunodeficiency?

CVID needs a markedly low IgG (at least 2 standard deviations below normal for age) together with low IgA and/or IgM, poor antibody responses to vaccines, and exclusion of secondary causes such as rituximab, chronic lymphocytic leukemia, myeloma or protein loss. The 2019 ESID registry definition is stricter: IgG and IgA must both be low, levels are measured at least twice, the patient must have infections, autoimmunity, granulomas, lymphoproliferation or an affected relative, diagnosis is made after age 4, and profound T-cell deficiency must be absent.

How is CVID different from X-linked agammaglobulinemia?

In CVID, B cells are present but fail to mature into plasma cells; in X-linked agammaglobulinemia (Bruton), a BTK mutation stops B-cell development, so B cells are absent. XLA affects boys and starts after about 6 months of age, when maternal antibody wanes, with very small tonsils and no palpable lymph nodes. CVID affects both sexes, is usually diagnosed between ages 20 and 40, and adds autoimmunity, granulomatous disease and lymphoma to the infection risk.

What infections are most common in CVID?

Recurrent sinopulmonary infections dominate: otitis, sinusitis and pneumonia caused by encapsulated and other pyogenic bacteria such as Haemophilus influenzae, Streptococcus pneumoniae, Moraxella catarrhalis and Staphylococcus aureus. Repeated lung infections lead to bronchiectasis in about 20% of patients. The gut is the other target, with chronic diarrhea from Giardia, Clostridioides difficile or bacterial enterocolitis. Infections usually improve once immunoglobulin replacement is started.

What are the complications of CVID besides infection?

About 30-40% of patients develop autoimmunity, most often immune thrombocytopenia and Coombs-positive autoimmune hemolytic anemia. Others develop granulomatous-lymphocytic interstitial lung disease (a sarcoidosis mimic), an enteropathy with malabsorption, nodular lymphoid hyperplasia of the gut, splenomegaly, lymphadenopathy or nodular regenerative hyperplasia of the liver. Cancer risk is higher too: B-cell non-Hodgkin lymphoma develops in 2-8% of patients, and gastric cancer, though less common than lymphoma, has a relative risk raised up to 50-fold.

The core treatment is lifelong immunoglobulin replacement, given as IVIG, typically 300-600 mg/kg every 3-4 weeks, or as subcutaneous immunoglobulin weekly or every 2 weeks, with the dose adjusted to IgG trough levels and infection control. Infections are treated early, and prophylactic antibiotics such as azithromycin help patients who keep getting sinopulmonary infections. Autoimmune cytopenias and granulomatous lung disease are treated first with corticosteroids, adding rituximab, azathioprine or mycophenolate when disease is refractory or steroid-dependent.

Can people with CVID receive live vaccines?

Mostly no. CDC lists MMR, MMRV, intranasal influenza, yellow fever, BCG, oral typhoid, oral polio, smallpox and dengue vaccines as contraindicated in severe antibody deficiencies such as CVID. Inactivated vaccines such as pneumococcal and recombinant zoster vaccines, and Hib in young children, are recommended, although any protection that depends only on antibody is uncertain. Immunoglobulin replacement also interferes with the response to measles vaccine and possibly varicella vaccine.

Common Variable Immunodeficiency (CVID): Mnemonic & Criteria

Common variable immunodeficiency (CVID) is a primary antibody deficiency in which B cells are present but fail to mature into antibody-secreting plasma cells, so IgG is low together with IgA and/or IgM, and vaccine responses are poor. It is the most common symptomatic primary immunodeficiency, is usually diagnosed between ages 20 and 40, and causes recurrent sinopulmonary infections with encapsulated bacteria, Giardia diarrhea and, over time, bronchiectasis. Unlike X-linked agammaglobulinemia, CVID also brings immune dysregulation: autoimmunity (especially ITP and autoimmune hemolytic anemia), granulomatous disease, lymphoma and gastric cancer. Treatment is lifelong IgG replacement (IVIG or SCIG), and live vaccines such as MMR are contraindicated.

The acronym trick: C.V.I.D.

Letter	Stands for	What to remember
C	Common, Comes late	Most common symptomatic primary immunodeficiency (about 1 in 25,000 to 50,000); most diagnoses come after puberty, peaking at 20-40 years; diagnosis has historically lagged symptoms by 4-5 years
V	Very low IgG, Vaccines fail	IgG at least 2 SD below the mean for age, plus low IgA and/or IgM; poor responses to protein (e.g., tetanus) and/or polysaccharide (e.g., pneumococcal) vaccines
I	Infections of sinuses, lungs and gut	Otitis, sinusitis and pneumonia from H. influenzae, S. pneumoniae, Moraxella and S. aureus; Giardia and C. difficile diarrhea; bronchiectasis in about 20%
D	Differentiation defect, Diagnosis of exclusion	B-cell numbers are usually normal, but switched memory B cells and plasma cells are reduced; rule out drugs, protein loss and blood cancers first

One-liner: a young adult with a fourth pneumonia, low IgG and IgA, normal B-cell numbers and flat vaccine titers has CVID until proven otherwise.

...and they're never G.L.A.D.: the complications

Infections are only half of CVID. The other half is immune dysregulation, and it is often what brings the patient in (autoimmunity affects about 30-40%).

Letter	Complication	Details
G	Granulomas, GI disease and gastric cancer	GLILD (granulomatous-lymphocytic interstitial lung disease), which mimics sarcoidosis; enteropathy with chronic diarrhea, malabsorption and villous atrophy; nodular lymphoid hyperplasia of the gut; gastric cancer (less common than lymphoma, but relative risk raised up to 50-fold)
L	Lymphoma, Lymphoproliferation, Liver	B-cell non-Hodgkin lymphoma in 2-8%; splenomegaly and lymphadenopathy; nodular regenerative hyperplasia of the liver, a cause of noncirrhotic portal hypertension
A	Autoimmunity	ITP (10-12%) and Coombs-positive autoimmune hemolytic anemia (5-7%) lead; also pernicious anemia, thyroiditis, rheumatoid arthritis, SLE, Addison disease, alopecia areata
D	Damaged bronchi	Bronchiectasis from recurrent bacterial infection; pulmonary complications and malignancy are key predictors of death

Merck's summary figure: gastric carcinoma or lymphoma develops in about 10% of patients. For the downstream topics, see bronchiectasis, non-Hodgkin lymphoma and gastric cancer.

Exam pearls: sarcoid-like granulomas plus recurrent infections plus low immunoglobulins suggests CVID with GLILD, not sarcoidosis. And when IgA is low, IgA-based celiac serology can't be trusted.

Diagnostic criteria: what makes it CVID

The ESID registry working definition (2019) needs all of the following:

At least one clinical feature: increased susceptibility to infection, autoimmune manifestations, granulomatous disease, unexplained polyclonal lymphoproliferation, or a family member with antibody deficiency.
Marked decrease of IgG and IgA, with or without low IgM, measured at least twice and below 2 SD for age.
At least one of: poor antibody response to vaccines (and/or absent isohemagglutinins), or low switched memory B cells (under 70% of the age-related normal value).
Secondary causes of hypogammaglobulinemia excluded.
Diagnosis made after the 4th year of life.
No profound T-cell deficiency (otherwise think combined immunodeficiency).

Merck's shorter version, and the classic exam framing, is low IgG (at least 2 SD below the mean) with low IgA, IgM or both, impaired vaccine responses, and exclusion of other immunodeficiencies. The ESID definition is stricter about IgA, which must be low too.

Secondary causes to exclude first:

Drugs: rituximab and other immunosuppressants, corticosteroids
Blood cancers: chronic lymphocytic leukemia, multiple myeloma
Protein loss: nephrotic syndrome, protein-losing enteropathy

Work-up in order: quantitative IgG, IgA and IgM; specific antibody titers before and after protein and polysaccharide vaccines; flow cytometry for B-cell number and switched memory B cells; T-cell studies; then genetic testing, since 15-35% of cases now have an identified single-gene cause.

Why it happens: B cells present, plasma cells missing

The block is late. Merck describes phenotypically normal B cells that can proliferate but don't become immunoglobulin-producing cells. Germinal centers fail to make high-affinity, class-switched antibody, so switched memory B cells are low.
T-cell dysregulation (for example, fewer regulatory T cells) helps explain the autoimmunity and granulomas.
Genetics: more than 90% of cases are sporadic. Single-gene causes include TNFRSF13B (TACI), NFKB1, NFKB2, ICOS and CD19; CTLA4 and LRBA defects belong in the differential.
Classic exam framing: defective B-cell differentiation, low plasma cells, low immunoglobulins, cause unknown in most patients.

Treatment

IgG replacement for life: IVIG, typically 300-600 mg/kg every 3-4 weeks, or SCIG weekly or every 2 weeks (StatPearls; Merck's usual doses are 400 mg/kg monthly IV or 100-150 mg/kg weekly subcutaneously). Doses are adjusted to the IgG trough and, above all, to infection control.
Antibiotics: treat infections early; prophylaxis (for example, azithromycin 250 mg three times weekly) helps patients who still get sinopulmonary infections despite IgG.
Dysregulation: autoimmune cytopenias respond first to glucocorticoids, with rituximab or other immunosuppressants for refractory disease and splenectomy as a last resort; GLILD often needs corticosteroids, with azathioprine, mycophenolate, rituximab, sirolimus, abatacept or (from case reports) JAK inhibitors as steroid-sparing options (StatPearls). Merck also lists TNF inhibitors and vedolizumab for complications such as immune enteropathy and granulomatous inflammation.
Vaccines (CDC): in severe antibody deficiencies such as CVID, MMR, MMRV, intranasal influenza, yellow fever, BCG, oral typhoid, oral polio, smallpox and dengue vaccines are contraindicated. Pneumococcal, recombinant zoster and (for children 12-59 months) Hib vaccines are recommended, but any response that relies only on antibody is uncertain, and IVIG blunts the response to measles and possibly varicella vaccine.

How USMLE tests it: look-alikes

	CVID	X-linked agammaglobulinemia	Selective IgA deficiency	X-linked hyper-IgM
Who, when	Either sex, usually 20-40 years	Boys, after about 6 months	Any age; most asymptomatic	Infancy, usually first 2 years
Defect	B-cell differentiation	BTK	Unknown	CD40 ligand on T cells
B cells	Present (usually normal)	Absent	Present	Present
IgG / IgA / IgM	Low / low / low or normal	All very low	Normal / under 7 mg/dL / normal	Low / low / normal or high
Signature	Autoimmunity, granulomas, lymphoma, Giardia	Tiny tonsils, no lymph nodes; enteroviruses, oral polio vaccine danger	Rare anaphylaxis to IgA-containing blood products; celiac; can progress to CVID	PJP, Cryptosporidium, neutropenia

More on each: X-linked agammaglobulinemia (Bruton), hyper-IgM syndrome and Giardia lamblia.

Adult with recurrent pneumonia plus ITP or hemolytic anemia: check quantitative immunoglobulins.
Low IgG on rituximab, or with CLL, myeloma or nephrotic syndrome: secondary hypogammaglobulinemia, not CVID.
Known IgA deficiency, now with falling IgG and new infections: progression to CVID.
B cells absent: XLA, not CVID.
High IgM: hyper-IgM, not CVID.

Practice question

A 31-year-old woman has had pneumonia three times in 4 years and chronic sinusitis. She now has 6 weeks of greasy, foul-smelling diarrhea with a 4-kg weight loss, and a stool antigen test is positive for Giardia. Two years ago she was treated for immune thrombocytopenia. She takes no medications, and her serum albumin and urinalysis are normal. Serum IgG is 220 mg/dL, IgA 12 mg/dL and IgM 25 mg/dL, all below normal. Flow cytometry shows a normal number of CD19+ B cells. Antibody titers do not rise after tetanus and 23-valent pneumococcal polysaccharide vaccination. Which of the following best explains her immunodeficiency?

A. Failure of B cells to differentiate into plasma cells B. Mutation in Bruton tyrosine kinase blocking pre-B-cell maturation C. Absent CD40 ligand on activated helper T cells D. Isolated failure of IgA production E. Loss of immunoglobulin through the kidney or gut F. Thymic aplasia with absent T cells

Answer: A. Low IgG, IgA and IgM, normal B-cell numbers and failed protein and polysaccharide vaccine responses, in an adult with sinopulmonary infections, Giardia and an autoimmune cytopenia, is CVID: B cells are present but do not mature into plasma cells. She needs her Giardia treated and lifelong IgG replacement.

B: a BTK defect (XLA) leaves B cells absent and presents in boys after maternal IgG wanes, at about 6 months.
C: CD40 ligand deficiency (X-linked hyper-IgM) gives normal or high IgM and presents in infancy, often with Pneumocystis.
D: selective IgA deficiency spares IgG and IgM; it can progress to CVID, but these levels are already CVID.
E: protein-losing enteropathy or nephrotic syndrome would bring a low albumin (and, from the kidney, proteinuria); the problem there is loss of antibody, not failure to make it.
F: thymic aplasia (DiGeorge) is a T-cell defect of infancy with hypocalcemia and heart defects, not an adult antibody deficiency.

Key takeaways

C.V.I.D.: Common and Comes late (20-40 years), Very low IgG with Vaccines failing, Infections of sinuses, lungs and gut, and a Differentiation defect that is a Diagnosis of exclusion.
Never G.L.A.D.: Granulomas (GLILD), GI disease and gastric cancer; Lymphoma and lymphoproliferation; Autoimmunity (ITP, AIHA); Damaged bronchi (bronchiectasis).
B cells are present; that separates CVID from XLA, and low IgM separates it from hyper-IgM.
Criteria: low IgG plus low IgA (ESID) or IgA and/or IgM (Merck), poor vaccine responses, age over 4, and secondary causes excluded.
Treat with lifelong IVIG or SCIG; avoid MMR and other live vaccines.