Quantitative Immunoglobulins (IgG, IgA, IgM): When to Order, What the Patterns Mean, and the Myeloma Connection

Quantitative Immunoglobulins (IgG, IgA, IgM): When to Order, What the Patterns Mean, and the Myeloma Connection

Recurrent infections, monoclonal spikes, and the difference between too much of one and not enough of everything else.

The Three Immunoglobulins

• IgG (700–1600 mg/dL): The workhorse—75% of serum immunoglobulins. Provides long-term immunity after infection or vaccination. Crosses the placenta (maternal IgG protects the newborn). Low IgG = increased risk of bacterial infections.
• IgA (70–400 mg/dL): Mucosal immunity—found in saliva, tears, respiratory and GI secretions. Selective IgA deficiency is the most common primary immunodeficiency (1 in 400–800). Connects to our celiac post (IgA deficiency causes false-negative tTG-IgA).
• IgM (40–230 mg/dL): The first responder—the initial antibody produced during acute infection. Elevated IgM on infection-specific testing = acute/recent infection. Also the antibody class in Waldenström's macroglobulinemia.

When to Order Quantitative Immunoglobulins

Order When You See

• Recurrent sinopulmonary infections (2+ pneumonias in a year, 4+ ear infections, chronic sinusitis requiring antibiotics) — evaluate for humoral immunodeficiency
• Suspected primary immunodeficiency: CVID (common variable immunodeficiency), selective IgA deficiency, X-linked agammaglobulinemia in boys
• Monoclonal gammopathy workup: SPEP shows an M-spike — quantitative Igs help characterize suppression of uninvolved immunoglobulins (immune paresis)
• Multiple myeloma monitoring: Suppressed uninvolved Igs (immune paresis) = worse prognosis and higher infection risk
• Autoimmune hepatitis evaluation: Elevated IgG is part of the diagnostic criteria (with ANA/SMA/anti-LKM)
• Suspected Waldenström's macroglobulinemia: Markedly elevated IgM with lymphoplasmacytic infiltration
• Before starting rituximab or other B-cell depleting therapy: Baseline Ig levels for monitoring secondary hypogammaglobulinemia
• Celiac workup with negative tTG-IgA: Check total IgA to rule out IgA deficiency

The Patterns

Pattern	IgG	IgA	IgM	Think About
All low (panhypogamma)	↓	↓	↓	CVID, X-linked agammaglobulinemia (boys), secondary causes (rituximab, myeloma treatment, nephrotic syndrome protein loss, chronic lymphocytic leukemia)
Selective IgA deficiency	Normal	↓↓ (<7 mg/dL)	Normal	Most common primary immunodeficiency. Usually asymptomatic. Associated with celiac disease, autoimmune conditions, and anaphylaxis to blood products containing IgA.
One Ig markedly elevated, others suppressed	One ↑↑↑, others ↓			Monoclonal gammopathy / myeloma. The elevated Ig is monoclonal (M-protein). Confirm with SPEP + immunofixation. Suppression of uninvolved Igs = "immune paresis."
All elevated (polyclonal)	↑	↑	↑	Chronic infections (HIV, HCV, TB), autoimmune diseases (SLE, RA, Sjögren's), chronic liver disease (cirrhosis), sarcoidosis
IgG elevated, others normal	↑↑	Normal	Normal	Autoimmune hepatitis (type 1), chronic infections, connective tissue diseases
IgM markedly elevated	Normal/↓	Normal/↓	↑↑↑	Waldenström's macroglobulinemia, primary biliary cholangitis (moderate IgM elevation), acute infection (transient)
IgA elevated	Normal	↑↑	Normal	IgA nephropathy, alcoholic liver disease, celiac disease (paradoxically, some celiac patients have elevated IgA), mucosal infections

The Myeloma Connection: Immune Paresis

Critical Pattern

In multiple myeloma, the malignant plasma cells produce massive amounts of one monoclonal immunoglobulin while suppressing normal immunoglobulin production. This means: IgG myeloma = very high IgG (monoclonal) with very low IgA and IgM. IgA myeloma = very high IgA (monoclonal) with very low IgG and IgM. Light chain myeloma = all immunoglobulins may be low (the paraprotein is free light chains only, not measurable as intact Ig). Immune paresis (suppressed uninvolved Igs) is a hallmark of myeloma and is the reason these patients have severe infection susceptibility. IgG <500 mg/dL in a myeloma patient indicates high infection risk and may warrant immunoglobulin replacement therapy.

CVID: The Primary Immunodeficiency to Know

Common Variable Immunodeficiency is the most clinically significant primary immunodeficiency in adults. Diagnostic criteria: markedly reduced IgG (usually <500) with low IgA and/or IgM, impaired vaccine responses, and exclusion of other causes. Patients present with recurrent sinopulmonary infections, bronchiectasis, autoimmune cytopenias, granulomatous disease, and increased lymphoma risk. Mean age of diagnosis: 20–30s. Many patients are misdiagnosed for years before the Ig levels are checked.

Pediatric Note

Neonates have high IgG (transplacental maternal IgG) that wanes by 3–6 months, creating a physiologic nadir. Transient hypogammaglobulinemia of infancy is a delayed maturation of IgG production that self-resolves by 2–4 years—distinguish from true primary immunodeficiency by the child's ability to make specific antibodies to vaccines. X-linked agammaglobulinemia (Bruton's) presents in boys at 6–12 months when maternal IgG wanes, with all Ig classes virtually absent and no circulating B cells.

Selective IgA Deficiency: The Autoimmune Crossover

IgA deficiency (<7 mg/dL with normal IgG and IgM) connects to multiple posts in this series:

• Celiac disease: IgA deficiency causes false-negative tTG-IgA; always check total IgA with celiac screening
• Autoimmune associations: Higher prevalence of SLE, RA, thyroiditis, and type 1 diabetes
• Transfusion risk: Rare patients develop anti-IgA antibodies, causing anaphylaxis to blood products containing IgA. Use IgA-deficient or washed blood products if anti-IgA antibodies are documented.
• Most IgA-deficient patients are completely asymptomatic and require no treatment.

The Pitfalls

• Don't confuse quantitative Igs with SPEP: Quantitative Igs measure total amounts. SPEP separates proteins by electrophoretic pattern and detects monoclonal spikes. Both are needed for myeloma workup—they answer different questions.
• A "normal" IgG in myeloma patients is misleading: The total IgG may appear normal because the monoclonal IgG is included in the total. Subtract the M-spike from the total IgG to get the uninvolved (polyclonal) IgG, which is often severely depleted.
• Secondary hypogammaglobulinemia is increasingly common: Rituximab, anti-CD38 antibodies (daratumumab), CAR-T therapy, and chronic corticosteroids all cause IgG suppression. Monitor Ig levels in these patients and consider replacement when IgG <400–500 with recurrent infections.
• Age-dependent norms in children: Pediatric Ig levels change dramatically with age. Use age-specific reference ranges. Neonatal IgG is high (maternal); IgM is low (produced by the infant, not transplacental).

Bottom Line

Quantitative immunoglobulins are essential for evaluating recurrent infections, characterizing monoclonal gammopathies, monitoring immunosuppressive therapy, and diagnosing primary immunodeficiencies. One Ig massively elevated with others suppressed = think myeloma. All Igs low = think CVID or secondary immunodeficiency. Selective IgA deficiency = check for celiac and autoimmune associations. And always use age-appropriate norms in children.

Stay sharp out there.