I have a 38 y/o male with Klinefelter's Syndrome, CRF and renal transplant, March 2013. Referred for history of multiple allergies. Also, multiple (3) hospitalizations for pneumonia post transplant and most recent hospitalization for sepsis following "descaling" (of the teeth)

Immune workup:
Total lymphocytes 700/mcl with suppression of lymphocyte subtypes, CD3 (348 - should be above 754), CD4, 127 (should be above 496), and B cells 45 (should be aboe 120) with NK cells and CD8 cells in nl limit. Gamma globulins nl, IgG1099, IgM 221, and IgA 95.
(Allergy tests were + including foods, pollen, mite, dander, and mold)
Pre-post immunization (prevanr-11) titers improved, but most still under 1.3. Only 4 of 11 serotypes were greater than one. 3/4 were greater than one prior to immunization.
Good news: no further fevers or hospitalizations since Dec, total lymphcytes inmproved to 900/mcl, and REnal function stable on Tacorlimus and prednisone 5 mg daily. Also on Dapsone for pneumocytis
Presumptive dx: "persistent lymphopenia" following lypmhocyte depleting treatment of transplantation.

I was concerned with the low b cells and poor response to Prevnar, but is there sufficient reason to give IVIG in this man with nl immunoglobulins?


Thank you for your inquiry.

Unfortunately, there is no true "right or wrong" strategy to follow in your patient. The issue is whether or not to begin immunoglobulin replacement therapy in a patient who has normal immunoglobulin levels. Before proceeding with your options, I would like to call to your attention that we have dealt with very similar questions on our website on multiple occasions. All of which can be accessed by going to our website and typing "immunoglobulin replacement therapy" into the search box. I think that reading through these would be helpful to you in making your final decision. In addition, just so you can get "a flavor" of the factors to assist you in making the final decision, I have copied one of the questions/responses below.

In your particular case, however, at least in my opinion, the decision to initiate immunoglobulin replacement therapy would be made on a slightly more liberal basis because of the fact that there has been an episode of sepsis, he is on drugs that could theoretically lower the immune response, and he has other immune abnormalities on laboratory assessment. The three options would be:

1. Observation only.
2. Institution of prophylactic antibiotics.
3. Initiation of immunoglobulin replacement therapy.

As noted, the answer is one based on clinical judgment, and cannot be made in a definitive manner. However, clearly, based upon the available literature (see previous answer copied below), patients who fail to respond adequately to immunization, even with normal immunoglobulin levels, can be considered for replacement treatment.

Of the three options, because of the complicating issues mentioned above, my choice would be a trial of immunoglobulin replacement therapy at this point. I would be even more likely to start this therapy if he had any signs of organ damage or organ involvement with chronic bacterial infection. In this regard, I suggest a computed tomography of his sinuses and chest, looking for chronic sinusitis and bronchiectasis.

In summary, one could not criticize employing any of the three options at this moment, but my own personal choice would be replacement therapy. This is especially true if he did show signs of chronic bacterial infection or organ damage on computed tomography of chest and sinuses.

I might mention parenthetically that most studies that have looked at the response to pneumococcal immunization do not use Prevnar but rather Pneumovax. And therefore, the statement citing that patients not responding adequately to pneumococcal immunization are candidates for replacement therapy is based primarily on studies of responses to Pneumovax (23-valent B cell vaccine).

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

Previous Posting - Question and Response:

Immunoglobulin replacement therapy in a patient with relatively normal immunoglobulins
IVIG or additional workup for 71yo man with CD4 and CD19 lymphocytopenia
hypogammaglobulinemia no response to pneumovax.

71 yo man w 10 year h/o "Low white blood count", easy bruising and no recent infections was referred to allergy clinic for hypogammaglobulinemia.

mild CKD(GFR 57),
h/o hip replacement

Significant infections occurred at
14yo: pneumonia with complicated pleural effusion requiring chest drainage
21yo: post traumatic [skull fracture] meningitis that responded quickly to Abx
32yo: Hep A

Exam- small tonsils

LOW IgG599 Lymphocytes722 IgA56 IgG- H.fluB(0.20) Plt106
WNL IgM112 IgG[Diphtheria tetanus measles mumps rubella] HIV-Ab Hep-A-IgG(reactive) SPEP UPEP
WNL Urine-Protein celiac-serology PT PTT
WNL WBC3.8 Hct44 PMN2432 monocytes456 eos190 VitB12-388 folate569
FLOW Cytometry
CD3 514 L
CD4 257 L
CD8 240
NK 233
CD19 59 L


-=-=Pre -=-=-=Post

1 1.2 0.8
12 <.3 <.3
14 1.2 0.9
19 1.1 0.6
23 0.4 <.3
26 0.5 0.3
3 1.6 1.1
4 <.3 <.3
5 0.4 0.4
51 0.8 0.4
56 <.3 <.3
68 <.3 <.3
8 0.8 0.6
9 0.8 0.6

Mitogen response
Btk protein
Hematology consult[as 2 cell lines low-plt,lymphs]
?ID consult for isolated lymphopenia

Main question: In your opinion, is he a candidate for IVIG?

Secondary question- anything you would add to next steps?

Your patient illustrates a problem which has prompted a number of inquiries to the “Ask the Expert” website. The most recent response to a similar inquiry was posted on 7/1/2013 entitled “Indications for immunoglobulin replacement therapy in a patient with normal immunoglobulin levels.” Since that response, a second published article has dealt with this issue, and to some extent refines our response to your question.

Unfortunately, there is no definitive answer to your question, and no consensus regarding the problem of when to begin immunoglobulin replacement therapy in a patient such as yours - that is, an individual with relatively normal immunoglobulin levels but a poor response to immunization. In the end, the decision is based solely upon the clinical judgment of the physician caring for the patient. Certainly, immunoglobulin replacement therapy can be indicated in your patient based upon the two excellent reviews (1, 2) from which quotes are copied below. Both reviews say that a patient with poor response to pneumococcal immunization, regardless of the absolute level of immunoglobulins, is a candidate for replacement treatment. However, as you can see from the quote from Reference 2, the decision to initiate immunoglobulin replacement therapy depends on the “clinical presentation (e.g., history and nature of infections), the response to prophylactic antibiotics, and optimal management with other comorbid conditions (e.g., allergy).” In your patient, obviously, it could be pointed out that a trial of prophylactic antibiotics might be appropriate before beginning immunoglobulin replacement therapy. However, once again, that is purely a clinical decision based upon your own personal assessment of the patient’s condition.

What is also important in your patient is whether or not there is any evidence of chronic bacterial infection in the sites most frequently involved by infections due to antibody deficiency. That is, is there any diminished lung function or evidence of bronchiectasis, or is there evidence for chronic hyperplastic sinusitis?

You asked whether or not other studies might be indicated, and I think the evaluation of these two areas as well as immunization with conjugated pneumococcal vaccine (PV13) could be considered.

If you did have evidence of chronic hyperplastic sinusitis or bronchiectasis, it would make a far stronger case for immunoglobulin replacement therapy at this time. The same is true if there was a failure to respond to conjugated vaccine. If you had no evidence for sinus disease or bronchiectasis, then you might consider a trial of prophylactic antibiotics before committing your patient to immunoglobulin replacement.

In summary:
1. Your patient can be considered a candidate for immunoglobulin replacement therapy based on his poor response to pneumococcal immunization.

2. There is no consensus, however, as to when a patient with your findings should begin immunoglobulin replacement, and the ultimate choice is based upon one’s personal clinical judgment.

3. If your patient shows clear-cut evidence of chronic bacterial infection of the lungs (bronchiectasis), or sinuses, there is a far stronger case for immunoglobulin replacement than if there is no evidence of these conditions.

4. If there is no evidence of these conditions, a trial of prophylactic antibiotic therapy should be strongly considered prior to committing the patient to immunoglobulin replacement.

Having made these comments, however, I would like to call your attention to an alternative view which states that such a patient is subject to sepsis and there are physicians who would recommend the initiation of immunoglobulin therapy in this patient automatically based upon this consideration.

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

(1) The Journal of Allergy and Clinical Immunology
Volume 130, Issue 3, Supplement , Pages S1-S24, September 2012
Use and interpretation of diagnostic vaccination in primary immunodeficiency: A working group report of the Basic and Clinical Immunology Interest Section of the American Academy of Allergy, Asthma & Immunology

"Summary "Statement 30: A diagnosis of specific antibody deficiency (SAD) can be made if the response to PPV23 is deficient but the responses to protein antigens(eg, tetanus toxoid or diphtheria toxoid), conjugate vaccines (Haemophilus influenzae type b, PCV7, or PCV13), or both are intact and total immunoglobulin levels are normal. (III C)"

(2) Annals of Allergy, Asthma & Immunology
Volume 111, Issue 3 , Pages 163-166, September 2013
A diagnosis of specific antibody deficiency is defined as a deficient response to 23vPPV. The responses to protein or conjugate vaccines are intact. Serum immunoglobulin levels are normal, although some patients may have decreased serum IgG subclass levels. Immunoglobulin replacement therapy in these patients can be considered, depending on the clinical presentation (eg, history and nature of infections), the response to prophylactic antibiotics, and optimal management of other comorbid conditions (eg, allergy).

Phil Lieberman, M.D.

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