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 NSU

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/dLReference range
IgA28370 to 400
IgM2540 to 230
IgG1045700 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
Interpretation of pneumococcal antibody titers - AAAAI Ask the Expert, 2011.
Cost-effectiveness of Pneumococcal Conjugate Vaccine vs. Polysaccharide Vaccine in Adults: PCV13 was better than PPSV23. JAMA, 2012.

Published: 08/14/2008
Updated: 02/06/2012

10 comments:

Michael Loren, M.D. said...

Nice review, I just saw a patient today with an IgM level of 18, IgA and IGG normal. No increased infections. But a hx of Hogkins 20yrs ago, encephalitis 10 yrs ago, and recently recurrent zoster infections last year. No issues with chronic sinus infections. Hx of chronic nasal allergies. Physical exam normal. Will be checking Pneumococcal ab titres, etc.

AnMarie Kennedy said...

Very interesting to review. I do have a question for you though not specifically about IgM but IgA. Lets say I am taking care of a patient with a PMH of IDDM x 30 years, chronic anemia, UC, hypothyroidism, and chronic sinusitis. Recently diagnosed with Celiac disease and IgA deficiency, level less than 10. Based on the treatment you described above for the patient with selective IgM deficiency, how would you proceed to treat the patient with IgA deficiency and celiac disease? Immunoglobulin replacement of any kind? Repeat immunizations?

Anonymous said...

Re: "how would you proceed to treat the patient with IgA deficiency and celiac disease? Immunoglobulin replacement of any kind?"

- No IVIG or IgG SC is indicated in IgA deficiency

"Repeat immunizations?"

- Not indicated

Treatment is similar to isolated IgM deficiency - early ABx tx. If sinus infections prediminate, sinus rinse with saline twice a day may help.

Anonymous said...

my immunoglobulina M is 61 vs a range of 65-265 - I have recently had a UTI... should I be concerned...

Anonymous said...

It's difficult to comment on specific cases without history and exam. Low Ig levels are not typically associated with UTIs. You must be evaluated by an immunologist.

Anonymous said...

I am a Neonatotoligist, 61 year female healthy in many ways. I have been getting sick with prologed viral infection leading up to 6 weeks , pharyngitis, bronchiolitis and prolonged cough.
Never had sinusitis or bacterial infection. Had herpes cold sores on the nasal septum for several years it is always precded by systemic exosted feeling, it is Type two, as I am neonatal MD and deal with congenital type two herpes. This year when I was on short corse of medrol pack, I also had herpes Zoster.
MY IGM is in 36,26 range. All oter immunoglobulins normal. This yera I have been contionosley sick lastinf 6 to 8 weeks. Trying to improve immunity by work out, antioxdants, vit c, zn other micronutrients . Nothing seems to work. Been to many DRs. What shoul I do. Xray chest, CBC, CMP ,Sinus xray, CRP, Sed rate all normal. It just takes away my productivity. Should I get fuerther evaluation for any underlying disorder ? Shoul I be worried about bacterial infections in future as I am 61 year, get immunised for bacterial infectios. I dont think I should take IGG. We live near Cleveland, who is the best Immunologist in the area that I can go to. Internal Medicine MDs's get annoyed, as I am an MD, if I go repetedley to theire office.

Anonymous said...

Dear neonatotoligist,

Since you live near Cleveland, you can see an excellent board-certified allergist/iimunologist at either Cleveland Clinic or CWRU University Hospitals.

They will be able to answer your questions.

Anonymous said...

My IgM serum level is 28, IgA 153, IgG 755. Internist didn't seem too concerned about it; however, I have had significant abdominal pains (sometimes severe) over the last year that they think are related to diverticulosis (two attacks of diverticulitis w/ no hospitalizations). Physician pretty much wrote it off as a problem with anxiety/depression. I don't think that's the whole problem. Still getting stitch-like pains; now my right hand has a decreased loss of sensation over to top of the right index finger up toward wrist. This just started a few days ago. What the heck could be going on. I am tired of all of this. Want answers.

Anonymous said...

As always, the best advice is to be evaluated by a board-certified allergist/immunologist.

Find one here: http://www.acaai.org/allergist/pages/locate_an_allergist.aspx

Anonymous said...

The incidence of Sigmd is always quoted as 0.03% in the general population and 1% of hospital patients, leading me to believe that these numbers are from a single study. Except for nasal allergies, I am asymptomatic. I have yet to read any rational explanation for the effects of low igm.