Antibody titer responses to pneumococcal vaccination in common variable immunodeficiency (CVID)

Author: V. Dimov, M.D., Allergist/Immunologist and Assistant Professor at University of Chicago
Reviewer: S. Randhawa, M.D., Allergist/Immunologist and Assistant Professor at NSU

A 54-year-old Caucasian male (CM) is evaluated by the Allergy and Immunology clinic for recurrent sinusitis for the last 20-30 years with 5-6 episodes per year. His IgG level was 470 mg/dL two months ago and IgM and IgA levels were normal. He reports no other significant infections. The patient reports seasonal exacerbations of his nasal symptoms in the spring, fall and winter. His last sinus infection was 9 months ago and he has not had such a recurrence free period in years.

Past medical history

Hypertension (HTN), hyperlipidemia (HLP), sinusitis, non-allergic rhinitis (non-AR), dermatographism.


Fexofenadine, flunisolide nasal spray, lisinopril.

Physical examination


What is the most likely diagnosis?

Common Variable Immunodeficiency (CVID).
Allergic or non-allergic rhinitis.

What tests would you order?

Pre- and post-pneumococcal immunization titers.
B and T-cell flow cytometry.
RAST to aeroallergens.

What happened?

Skin prick testing: uninterpretable due to dermatographism. RAST to aeroallergens: negative.

HIV, ANA, RF were negative. CXR and U/A without evidence of malignancy. He had a colonoscopy in the past 3 years and it was negative.

Pre-immunization titers (left). Post-immunization titers (right) (click to enlarge the images).

Pre- and post-pneumococcal immunization titers 4 weeks apart showed an insufficient increase in the antibody titers: only 30% (4 out of 13 titers) of specific antibodies increased by the magnitude of 2 fold.

Flow Cytometry. Specimen: Peripheral Blood. Processing: Lyse, cytospin, stain with monoclonal antibodies. Cell Count: 8.2 10*6 total cells. Viability: 89%.

Total events analyzed = 42415

A gate Bright CD45 positive events = 5758 (17% of total events analyzed)

CD45+ 100%
CD19+/CD20 3%
CD19+/CD38 2%
CD19+/CD10 less than 2%
CD3+/CD5+ 85%
CD3+/CD7+ 82%
CD3+/CD4+ 60%
CD3+/CD8+ 22%
CD3-/CD56+ 11%
Total CD25 9%
CD25+/CD3+ 9%
CD25+/CD5+ 9%

Interpretation: Lymphocytes comprise 17% of the total events analyzed, with 3% B-cells, 85% T-cells, and 11% NK cells. The CD4:CD8 ratio is 2.7:1. 9% of the lymphocytes are CD25 (dim) positive T-cells.

In healthy subjects, B cells constitute 18-47% of the peripheral lymphocytes. B cell count can be either low or normal in patients with CVID.

What happened next?

The patient was diagnosed with common variable immunodeficiency (CVID).

Would you start intravenous immunoglobulin G (IVIG) therapy for this patient?

Historically, the level of IgG of 470 mg/dL did not typically require replacement with IVIG in the absence of severe recurrent infections. Some of the newer studies point to an optimal replacement level of IgG of 600-800 mg/dL.

We decided to repeat the quantitative serum immunoglobulins in 4-6 months and to decide about IVIG replacement at that point.

Final diagnosis

Common Variable Immunodeficiency (CVID).

What did we learn from this case?

Evaluation of the response to pneumococcal vaccination is best accomplished by comparing pre-vaccination and post-vaccination antibody levels. A 2 to 4 fold increase in type-specific antibodies measured 4-6 weeks after vaccination is expected in immunocompetent adults. The number of serotypes for which a 2 to 4 fold increase is observed varies greatly among individuals; a consensus panel has suggested that individuals older than 5 years should respond to at least approximately 70% of pneumococcal serotypes. Adults older than 65 years may exhibit a smaller (less than 2 fold) increase in type specific antibody levels.

The "rule of thumb" is that 2/3 of titers have to increase 2-3 fold.

The patient did not have evidence of allergen sensitization on ImmunoCAP test for aeroallergens, therefore the intranasal steroids and oral antihistamine were discontinued. He was advised to use nasal saline rinses BID.

What are the normal serum immunoglobulin levels (IgG, IgA, IgM)?

Serum levels of IgM, IgG and IgA vary with age, gender and race.

The IgG and IgA concentrations in children show a gradual rise with increasing age. The IgA level is generally about the same in both sexes. Girls typically have higher IgM and IgG levels than boys.

The confidence interval bounded by two standard deviations about the mean excludes 5% of apparently healthy controls.

Elevated IgM, low IgA, low IgG, low IgM, and elevated IgA are the commonest changes observed in apparently healthy humans.

Humoral immunodeficiency is commonly defined as IgG, IgM or IgA level that is two standard deviations (2 SD) below the mean level for IgG, IgM or IgA, respectively, for the particular age group and gender.

Serum levels of IgM, IgG and IgA. Source: Pediatrics, 1966 and Immunologic disorders in infants and children, by E. Richard Stiehm, Hans D. Ochs, Jerry A. Winkelstein.

Typical pattern of immunoglobulin levels (IgG, IgA, IgM) in humoral immunodeficiency. Click here to enlarge the table.

What is a normal response to pneumococcal immunization? 

Protection against infection and colonization is associated with specific IgG concentrations of 1.3 mcg/ml.

A second component in judging response is the final concentration of antibodies after immunization regardless of increase from preimmunization concentration. An adequate response is a post-immunization antibody concentration of more than 1.3 mcg/ml, even in the absence of a fourfold increase.

Children 2 to 5 years of age are normally expected to have an adequate response to more than 50% of serotypes tested. Patients 6 years or older are normally expected to respond to more than 70% of the serotypes tested. Source: Assessment and clinical interpretation of polysaccharide antibody responses. Kenneth Paris and Ricardo Sorensen. Annals of Allergy, Asthma, and Immunology, 2007; volume 99, Issue 5, Pages 462-464, and AAAAI Ask the Expert, 2012.


Serum immunoglobulin levels in healthy children and adults. J. W. Stoop, B. J. M. Zegers, P. C. Sander, and R. E. Ballieux. Clin Exp Immunol. 1969 January; 4(1): 101–112.

The relationship of race, sex, and age to concentrations of serum immunoglobulins expressed in international units in healthy adults in the USA. S. E. Maddison, C. C. Stewart, C. E. Farshy, and C. B. Reimer. Bull World Health Organ. 1975; 52(2): 179–185.

Serum immunoglobulin concentrations in preschool children measured by laser nephelometry: reference ranges for IgG, IgA, IgM. D Isaacs, D G Altman, C E Tidmarsh, H B Valman, and A D Webster. J Clin Pathol. 1983 October; 36(10): 1193–1196.

Serum Immunoglobulin Levels Throughout the Life-Span of Healthy Man. Ann of Int Med, November 1, 1971, Vol. 75 no. 5 673-682.

Diagnostic Criteria for Common Variable Immunodeficiency (CVID): Probable and Possible Diagnosis

The diagnostic criteria are divided into three categories: definitive, probable, and possible. There are no criteria for definitive diagnosis of Common Variable Immunodeficiency (CVID) at this time.

To guard against the inclusion of patients who have polymorphic variants in the genes associated with immunodeficiency and to specify the clinical or laboratory finding that is most consistently abnormal in a particular disorder, the patient must fulfill an inclusion criterion that is characteristic of the disorder.

Definitive diagnosis

Patients with a definitive diagnosis are assumed to have a greater than 98% probability that in 20 years they will still be given the same diagnosis. Mutation detection is the most reliable method of making a diagnosis but a single mutation is rarely found in CVID.

Probable diagnosis

Patients with a probable diagnosis are those with all of the clinical and laboratory characteristics of a particular disorder but who do not have a documented abnormality in the gene, the mRNA, or the protein that is known to be abnormal in the disorder. They are assumed to have a greater than 85% probability that in 20 years they will be given the same diagnosis.

Probable diagnosis of CVID:

Male or female patient who has a marked decrease (at least 2 SD below the mean for age) in serum IgG AND IgA and fulfills all of the following criteria:

1. Onset of immunodeficiency at greater than 2 years of age.

2. Absent isohemagglutinins and/or poor response to vaccines.

3. Defined causes of hypogammaglobulinemia have been excluded

Possible diagnosis

Patients with a possible diagnosis are those that have some but not all of the characteristic clinical or laboratory findings of a particular disorder.

Possible diagnosis if CVID:

Male or female patient who has a marked decrease (at least 2 SD below the mean for age) in one of the major isotypes (IgM, IgG, and IgA) and fulfills all of the following criteria:

1. Onset of immunodeficiency at greater than 2 years of age.

2. Absent isohemagglutinins and/or poor response to vaccines.

3. Defined causes of hypogammaglobulinemia have been excluded

Clinical features of CVID

Most patients with CVID are diagnosed with immunodeficiency in the second, third, or fourth decade of life, after they have had several pneumonias; however, children and older adults may be affected.

Viral, fungal, and parasitic infections as well as bacterial infections may be found.

The serum concentration of IgM is normal in about half of the patients.

Abnormalities in T cell numbers or function are common. The majority of patients have normal numbers of B cells; however, some have low or absent B cells.

Approximately 50% of patients have autoimmune manifestations. There is an increased risk of malignancy.

Differential diagnosis of hypogammaglobulinemia includes drug-induced, for example secondary to glucocorticoids (steroids).


Diagnostic Criteria for Primary Immunodeficiencies. Mary Ellen Conley, Luigi D. Notarangelo, and Amos Etzioni Representing PAGID (Pan-American Group for Immunodeficiency) and ESID (European Society for Immunodeficiencies). Clinical Immunology, Vol. 93, No. 3, December, pp. 190–197, 1999.
Recognizing Primary Immune Deficiency in Clinical Practice. Clinical and Vaccine Immunology, March 2006, p. 329-332, Vol. 13, No. 3.
Common Variable Immunodeficiency. eMedicine.
Common Variable Immunodeficiency. eMedicine.
Common Variable Immunodeficiency: A Multifaceted And Puzzling Disorder. Expert Review of Clinical Immunology, Medscape, 2009.
Assessment of antibody response to pneumococcus immunization. AAAAI, Ask the Expert, 2011.
Heptavalent pneumococcal conjugate vaccine (PCV7) targets only 7 of the more than 92 pneumococcal serotypes. Lancet, 2011.
Cost-effectiveness of Pneumococcal Conjugate Vaccine vs. Polysaccharide Vaccine in Adults: PCV13 was better than PPSV23. JAMA, 2012.

Published: 02/06/2009
Updated: 02/07/2012

1 comment:

Anonymous said...

My lab test showed a deficiency of IGG and I have been given the pneumonococcus vacination and am to return in 6 weeks to have a titer drawn to see if I have produced any antibody's to the pneumonia vaccine. If I havent they are to start immunogloblin therapy (IV) for every week for the rest of my life.. I suffer from infections like pneumonia, staff infections, bladder infections, and vaginal infections quiet often. What will be the outcome if I do agree to have the IV immunogloblin once a week for the rest of my life? will I feel better and heal better than before??? This is new to me and I'm a bit upset over the diagnosis. I suffer from chonic pain syndrome from two fusions in my back and constant pain in my back and legs.. Will this improve once I get my level up? Also have neurophathy from the back fusion I had done in 2008.. I feel bad all the time, no energy.. I want to be well.. Anyone been thru similar things and if there hope for me??