Selective Immunoglobulin M (IgM) Deficiency

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 LSU (Shreveport) Department of Allergy and Immunology

A 70-yo Caucasian male (CM) is referred by his primary care physician (PCP) for evaluation for allergic rhinitis/conjunctivitis and chronic sinusitis. He complains of nasal congestion for 25 years which is worse over last 2 years. He has rhinorrhea in spring and fall. He has had 3-4 courses of antibiotics for sinusitis each year for the last 5-7 years.

Past medical history

Diabetes type 2 (DM2), hypertension (HTN).

Medications

Glyburide, amlodipine, Allegra D (fexofenadine and pseudoephedrine) (stopped 5 days ago for skin testing).

Physical examination

Vital signs stable (VSS).
Ears: dull tympanic mebranes (TMs), cerumen present.
Nose: leftward septal deviation, pale boggy turbinates.
Throat: mild cobblestoning.
Lymph: No cervical lymphadenopathy.
Respiratory: CTA (B).
CVS: Clear S1S2.

What tests would you suggest?

Skin prick testing.
CT scan of sinuses.

Would you consider immunodeficiency work-up in this patient?

Immunodeficiency, for example CVID, is in the differential diagnosis of the recurrent episodes of sinusitis in this patient.

Quantitative immunoglobulins were added to the work-up.

What happened?

The CT scan of the sinuses showed pansinusitis, most pronounced in the left maxillary sinus, and moderate leftward deviation of the nasal septum.

Skin prick test was positive for grasses, ragweed, trees, weeds.

We prescribed flunisolide nasal spray qd, saline nasal rinses bid and loratidine qd. He was referred to ENT and a follow-up was arranged in 8 weeks.

What happened next?

The patient came to the follow-up appointment 8 weeks later and reported that he felt 60% better.

His Ig levels were:

	Result mg/dL	Reference range
IgA	283	70 to 400
IgM	25	40 to 230
IgG	1045	700 to 1600

The repeated quantitative immunoglobulins showed similar values.


Structure of the pentameric IgM: 1. Base unit, 2. Heavy chains, 3. Light chains, 4. J chain, 5. Intermolecular disulfide bonds. Image source: Wikipedia.

What is the most likely diagnosis?

Selective immunoglobulin M deficiency (SIgMD)

What is the next step in the daignostic work-up of this patient?

Check Anti-ABO antibodies titers. IgM is the antibody against blood group antigens.

Assess biological significance of isolated low IgM level by immunizing the patient with:
- protein vaccines, e.g., tetanus, MMR
- polysaccharide vaccines, e.g. unconjugated Streptococcus pneumoniae

Assess if antigen-specific IgG responses are normal.

How to assess humoral immune response?

Inject patient with Pneumovax 23 (not Prevnar, which is a 7-valent conjugate vaccine). Check anti-polysaccharide IgG antibody to pneumococcus serotypes in 3 weeks. There should be a 3-5 fold increase in the anitbody titer to at least 50% of isotypes.

Which serotypes should be included in the order for Ig?

The same serotypes that were included in the given vaccine. Check the enclosed leaflet for this information. For example, the serotypes included in Pneumovax 23 can be found from the Merck website (PDF):

1 2 3 4 5 6B 7F 8 9N 9V 10A 11A 12F 14 15B 17F 18C 19F 19A 20 22F 23F 33F

How to collect the serum for anti-polysaccharide IgG antibodies?

Collect the serum prior to immunization with Pneumovax 23. Store the pre-immunization serum in the office refrigerator. Give the vaccine. Check the post-immunization serum 3 weeks later. Send both pre- and post-immunization serums to the laboratory at the same time.

The pneumococcal vaccine comprises purified capsular polysaccharide of 23 stereotypes that account for more than 90% of the invasive pneumococcal infections in the USA. It induces anti-polysaccharide IgG antibody levels to most or all of the component polysaccharide antigens in immunocompetent adults. Elderly adults respond equally well to vaccination as do younger adults. The current 23-valent vaccine comprises 25 μg of each of 23 pneumococcal stereotypes (namely, serotypes 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F and 33F).

The test should be ordered as follows: Pre- and post-IgM and IgG antibody titers to pneumococcal serotypes 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F and 33F

Final diagnosis

Selective immunoglobulin M deficiency (SIgMD).

What did we learn from this case?

Selective immunoglobulin M deficiency (SIgMD) is a rare form of dysgammaglobulinemia, with an incidence of less than 0.03% in the general population and 1% in hospitalized patients.

Patients with SIgMD are susceptible to infections with encapsulated bacteria, e.g., Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenzae.

Quantitative levels of IgM, IgG, IgA are measured to exclude more common immunodeficiency disorders, such as common variable immunodeficiency and IgA deficiency.

Replacement of IgM is not used since IgM is not a significant component of the commercially available intravenous immunoglobulins.

If defective antigen-specific IgG responses are found after immunization with polysaccharide vaccines, IVIG replacement may be an option.


Five immunoglobulin classes (mind map)

In order of their serum concentrations:

IgG 1000 mg/dL
IgA 200 mg/dL
IgM 150 mg/dL
IgD 4 mg/dL
IgE 0.005 mg/dL (extremely low serum concentration compared to other Ig in (GAMED)


Ig structures. Image source: Wikipedia.

Mnemonics: Adaptive Humoral Immunity: B-cells and Immunoglobulins

There are 5 immunoglobulin classes remembered by the mnemonic GAMED: Ig G, A, M, E, D.

Ig
G
Greatest serum concentration, half-life and number of sub-classes

Ig
M
Macro -- largest Ig

Ig
A
Adhesion prevention
Aggregates -- 2 units linked together
Alternative pathway of complement
Activation

References

Immunoglobulin M Deficiency. Iftikhar Hussain. eMedicine, 2006.
How to Diagnose Common Variable Immunodeficiency (CVID)?
Adaptive Humoral Immunity: B-cells and Immunoglobulins
Mnemonics: Adaptive Humoral Immunity: B-cells and Immunoglobulins

Published: 08/14/2008
Updated: 02/06/2009