Q:

9/12/2013
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.

PMH:
CAD w ASA,
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

LABS:
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

Pneumovax
-=-=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

NEXT STEPS BEING CONSIDERED
Mitogen response
Btk protein
?IVIG
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?

A:

Thank you for your inquiry.

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).

Sincerely,
Phil Lieberman, M.D.

AAAAI - American Academy of Allergy Asthma & Immunology