Q:

7/18/2013
I am evaluating a 46 year old female for hypogammaglobulinemia. The patient was referred for an allergy work-up for chronic rhinitis and recurrent sino-bronchitis. Allergy work-up was negative, but immune screen revealed low IgM (<7 MG/DL), IgG(429), IgA (45), and IgE (<1.5). CBC and metabolic screen (including serum albumin) were wnl. Baseline tetanus titer was protective, and the patient had an excellent response to pneumococcal and HIB immunizations. No history of recurrent pneumonia or sepsis. Patient was on chemo(?) for cervical cancer 10 years ago.

Is this a patient you would feel comfortable observing and monitoring immunoglobulin levels and AB titers periodically? Any further work-up recommended? Thanks very much for any suggestions.

A:

Thank you for your inquiry.

In brief, in answer to your question, yes, I would feel comfortable observing and monitoring your patient, and I do not feel any further workup would be helpful. The other thing that you might consider is the use of prophylactic antibiotics. I would consider this if she had documented chronic hyperplastic sinusitis, bronchiectasis, or repeated episodes of x-ray-documented pneumonia.

We have responded to a number of similar questions regarding patients with isolated hypogammaglobulinemia M. One which might be of particular interest to you is copied below. However, there are a number of others that would give you a better perspective of the clinical significance of isolated IgM deficiency. You can access these by typing “hypogammaglobulinemia M” or “low IgM” into the search box on our Ask the Expert website. Also, there are several discussions of the appropriate use of prophylactic antibiotics which can be accessed using the search words “prophylactic antibiotics” should you wish to start this therapy.

Thank you again for your inquiry and we hope this response is helpful to you.

Isolated IgM deficiency: treatment with prophylactic antibiotics
Question:
7/18/2012
53 year old white male referred by hematologist for hypo IGM 15 (48-271) IGG normal 922 and IGA 15 (81-463).

Has frequent upper respiratory infections with normal sinus on MRI of head for headache and face numbness march 2012. He also has diagnosis of adult onset diabetes and has presumptive diagnosis of peripheral neuropathy.

Has normal tetanus titer (2.01) and h flue titer (3.82. REceived pneumovax 3 years ago and titers normal (range of 1.4 to 10.1).

Serum Protein electrophoresis and urine free light chains normal.

In reviewing previous posts I saw mention of isolated IGM deficiency and that patients can be asymptomatic. I realize IVIG not helpful but there was mention of the use of prophylactic antibiotics. He has history of rash but no hives after sulfa antibiotic.

What if any antibiotic would you recommend and how often would you repeat lab?

Answer:
Thank you for your inquiry.

First of all, for our readers' sake I want to point out the previous responses to inquiries about isolated IgM deficiency to which you allude in your inquiry. These inquiries/responses can be found on our website, and they discuss isolated IgM deficiency in detail.

Secondly, I need to make a point of clarification, also for the sake of our readers, regarding the use of immunoglobulin replacement therapy in patients with isolated IgM deficiency.

As you can see from the quote copied below, which was taken from a previous response, some patients with isolated IgM deficiency also show defective IgG responses to immunization. In these instances, replacement therapy may be helpful. So, the statement that "IVIG is not helpful" does not refer to all cases. It is simply based on the fact that IgM is not contained in replacement immunoglobulin preparations, and therefore if there is a normal immune response to immunization, administering immunoglobulins may not be helpful.

QUOTE FROM PREVIOUS POSTING:
"Unfortunately there is no specific treatment for isolated IgM deficiency. IgM, as you know, is not contained in intravenous immunoglobulin preparations. However, some patients with isolated IgM have shown defective IgG responses to immunization (e.g., pneumococcus), and therefore the assessment of an immunization response is indicated"

With that preamble, I will try and answer your question.

Unfortunately, there is no rigid regimen or consensus protocol regarding either when to initiate prophylactic antibiotics or which antibiotic to use. In addition, there is no such protocol as to the schedule for antibody replacement. Most of the information citing protocols for replacement therapy have been drawn from the literature related to replacement therapy for patients with conditions such as recurrent otitis media.

I have copied for you below three abstracts taken from this literature. As you can see, various antibiotics have been used employing several regimens. The antibiotics include amoxicillin, azithromycin, and sulfamethoxazole/trimethoprim (as well as others).

The frequency of administration can be highly variable. In some instances, prophylaxis is given only during the winter months; in others, daily; and in others, one week out of a month; et cetera.

Other agents such as amoxicillin-clavulanate, quinalones, cephalosporins and clarithromycin have also been used.

Although I am not aware of any specific trial of prophylactic antibiotics in the treatment of isolated IgM deficiency, prophylactic antibiotics have been used in other specific antibody deficiency syndromes. Patients with recurrent infections and low serum IgG subclass levels have been treated successfully with prophylactic antibiotics (1,2). Prophylactic antibiotics have also been used for many other primary immune deficiencies (3).

In summary, as noted, there is no standard regimen for antibiotic prophylaxis. However, the most commonly prescribed antibiotic for prophylaxis in primary immune deficiency disease is amoxicillin. This is true for both adult and pediatric patients. The second most utilized antibiotic was trimethoprim sulfamethoxazole (3).

In addition, there have been several reports using macrolides both in children and adults, and fluoroquinolones in adults. Over half of immunologists who treat with prophylactic antibiotics rotate these drugs with 21.8% rotating them on a monthly schedule (3).

Having said this, should you wish to use prophylactic antibiotics, a regimen which might be suitable for your patient would be the daily administration of amoxicillin at one-third the full treatment dose alternating on a monthly basis with a macrolide.

In answer to your second question, I would repeat immunoglobulin levels once every year.

Thank you again for your inquiry and we hope this response is helpful to you.

References:
(1) Barlan LB, et al. J Allergy Clin Immunol 1993 (August); 92(2):353-355.

(2) Herrod HG. Annals of Allergy 1993 (January); 70(1):3-8.

(3) Yong, et al. Clinical Immunology 2010; 135:255.

Int J Pediatr Otorhinolaryngol. 2001 Apr 6;58(1):47-51.
Comparison of amoxicillin and azithromycin in the prevention of recurrent acute otitis media.
De Diego JI, Prim MP, Alfonso C, Sastre N, Rabanal I, Gavilan J.
Source
Department of Otorhinolaryngology, La Paz Hospital, Autonomous University, Madrid, Spain.
Abstract
Objective: To compare the outcome of patients with recurrent acute otitis media (AOM) treated either with amoxicillin or with azithromycin.
Methods: This prospective, controlled, and randomized study, compares the outcome of 71 patients with recurrent AOM treated with azithromycin (31 patients) or amoxicillin (40 patients) for the prevention of AOM. azithromycin was given at a dose of 10 mg/kg once a week, whereas amoxicillin was administered daily as a single intake of one third of the therapeutic dosage (20 mg/kg per day). All treatments were prescribed for 3 months. Both groups were homogeneous with regard to the currently accepted predisposing factors of recurrent AOM. Mean age of children was 35.3 months, and average follow-up was 11.5 months. The treatment was considered effective when the number of episodes of AOM dropped to less than 50% after the prophylaxis.
Results: Patients in the azithromycin group had a clinical response to prophylaxis (80.6%) comparable to those treated with amoxicillin (89.5%) (P=0.300). The incidence of adverse effects was similar in both groups.
Conclusion: According to these results, a prophylaxis with azithromycin is as useful as amoxicillin to prevent recurrent AOM.

Antimicrob Agents Chemother. 1996 Dec;40(12):2732-6.
Comparative study of once-weekly azithromycin and once-daily amoxicillin treatments in prevention of recurrent acute otitis media in children.
Marchisio P, Principi N, Sala E, Lanzoni L, Sorella S, Massimini A.
Source
Department of Pediatrics (4), University of Milan Medical School, Italy.
Abstract
Continuous chemoprophylaxis is effective in the prevention of new episodes of acute otitis media (AOM) in otitis-prone children, but compliance can be a problem and thus efficacy can be decreased. Intermittent chemoprophylaxis has so far shown conflicting results. Azithromycin, which has a peculiar pharmacokinetics, resulting, even after a single dose, in persistently elevated concentrations in respiratory tissues, could permit a periodic administration with higher compliance. We compared a 6-month course of once-weekly azithromycin (5 or 10 mg/kg of body weight) with that of once-daily amoxicillin (20 mg/kg) in a single-blind, randomized study of prophylaxis for recurrent AOM in 159 children aged 6 months to 5 years with at least three episodes of AOM in the preceding 6 months. In the amoxicillin group, 23 (31.1%) of 74 children developed 29 episodes of AOM, while in the 10-mg/kg azithromycin group, 11 (14.9%) of 74 children experienced 15 episodes. The 5-mg/kg/week azithromycin trial was prematurely interrupted after nine cases, due to the high occurrence rate of AOM (55.5%). During the 6-month prophylaxis period, the proportion of children with middle ear effusion declined similarly in both groups. No substantial modification of the nasopharyngeal flora was noted at the end of prophylaxis in both antimicrobial groups. In the 6-month-postprophylaxis follow-up period, about 40% of children in both groups again developed AOM. Azithromycin at 10 mg/kg once weekly can be regarded as a valid alternative to once-daily low-dose amoxicillin for the prophylaxis of AOM. Although in the present study no microbiological drawback was noted, accurate selection of children eligible for prophylaxis is mandatory to avoid the risk of emergence of resistant strains.

Am J Dis Child. 1989 Dec;143(12):1414-8.
Prophylaxis of recurrent acute otitis media and middle-ear effusion. Comparison of amoxicillin with sulfamethoxazole and trimethoprim.
Principi N, Marchisio P, Massironi E, Grasso RM, Filiberti G.
Source
Department of Pediatrics, University of Milan, Italy.
Erratum in
Am J Dis Child 1990 Nov;144(11):1180.
Abstract
We compared the efficacy of amoxicillin with that of the combination drug sulfamethoxazole and trimethoprim in reducing recurrences of acute otitis media (AOM) in a single-blind, randomized, placebo-controlled trial involving 96 children. Each of the children had had three or more episodes of AOM in the preceding 6 months, and 97% (93/96) of them still had unilateral or bilateral effusion at the beginning of the study. During the 6-month study period, 9 (27%) of 33 of the children in the amoxicillin group developed 9 episodes of AOM, 9 (27%) of 33 of the children in the sulfamethoxazole and trimethoprim group experienced 11 episodes of AOM, and 19 (63%) of 30 of the children in the placebo group developed 25 episodes. Young age and day-care attendance characterized children for whom prophylaxis was more efficacious. Overall persistence of middle-ear effusion was shorter in treated children only as a consequence of the reduced number of new episodes of AOM.

Sincerely,
Phil Lieberman, M.D.

When we sent our response to this inquiry, the physician bringing the case to our attention pointed out that the IgG level was low; something that was missed on review of the case. Therefore, this addendum is being added:
 
This patient may also have, rather than isolated IgM deficiency, the early onset of common variable immune deficiency. But, with the normal response to immunization, I would still tend to follow the same strategy unless there was clear-cut evidence of bacterial infection with tissue damage such as CT scan-documented moderate to severe chronic sinusitis, CT scan-documented bronchiectasis, or a chest x-ray-documented pneumonia. However, the consideration of the administration of immunoglobulin would be stronger with a diagnosis of early onset common variable immunodeficiency rather than a case of isolated IgM deficiency.

AAAAI - American Academy of Allergy Asthma & Immunology