12/22/2012
This is related to a recurring question that is on this site about interpretation of pneumococcal vaccine. The most current reference I wish to address is:
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
J Allergy Clin Immunol
September 2012
Orange ET AL pages S1-S24

I understand the guidelines stating that pre-vaccination titers less than 1.3 mg/ml must either increase 4 X or go above 1.3 mg/ml. I however, have had a couple of patients recently who have recurrent infections whose majority of pre-vacciantion titers were above 1.3 mg/ml, and they had almost no response at all, and definitely not even a 2X response. It would seem from this article that one would expect at least a 2 fold increase above 1.3 mg/ml. If no two fold response, would these patients be considered immunodeficient? If I send some of my patients to a university immunologist for second opinion, I don't wish to be told that patients I labeled as abnormal response are normal.

Summary Statement 24:
The higher the preimmunization titer for a specific pneumococcal serotype, the less likely that the titer will have a significant increase after vaccination.

(III C). An adequate response to pneumococcal vaccination has historically been defined as a postvaccine titer of greater than 1.3 mg/mL or up to a 4-fold increase in antibody titers over baseline levels. It has been established previously that the presence of a high preimmunization antibody titer does not necessarily neutralize the response to the serotype in the vaccine.Patients are still capable of mounting a biologic response on vaccine administration. However, high preimmunization antibody titers to specific pneumococcal serotypes are less likely to significantly increase after immunization when compared with low preimmunization antibody titers.

Summary Statement 25:
Most patients with a prevaccine titer of greater than 1.3 mg/mL can mount a 2-fold increase in titers on immunization. A minority of patients with high initial titers will be capable of mounting a 4 fold increase in antibody titers after vaccination. (III C)

It is not uncommon for adults and children to have prevaccination titers of greater than 1.3 mg/mL for several pneumococcal serotypes. Interpretation of the response to vaccination when the preimmunization titer is greater than 1.3 mg/mL is not entirely clear. Few studies assess the postvaccine response when the prevaccination titer is greater than 1.3 mg/mL. In a recent study directly addressing this issue, postvaccine antibody titers increased approximately 2-fold for most of the 14 serotypes analyzed. This was true for both adults and children. Only 10% to 40% of patients attained a 4-fold response when the initial titer was greater than 1.3 mg/mL. Thus in patients who are consideredto have a protective prevaccine antibody titer (ie, initial serotype titer >1.3 mg/mL), the postvaccine response can still be used in assessing the immune response. However, for these serotypes, a 2-fold response would be considered appropriate. Importantly, as stated above, the need to interpret these data in light of clinical correlation is essential. Caution is also suggested in the management of patients who only marginally meet responses considered to be adequate.

Thank you for your inquiry.

Unfortunately, there is no definitive answer to your question. I think the most appropriate summary statement in the document you cited that deals with the type of patients you described can be found in Summary Statement Number 32. This summary statement classifies the degree of polysaccharide nonresponsiveness into 4 phenotypes. In your particular case, the patient would be classified as possibly “mild.” A description of these patients is that they have either multiple vaccine-containing serotypes to which they did not generate protective titers or an inability to increase titers twofold in 50% or more of children under 6 years of age, and 70% or more of patients age 6 to 65. That is, assuming the prevaccination titers are less than the threshold levels specified in Summary Statement 26 in the presence of a history of infection. In actuality, the patients you described have protective levels to start with and therefore they may also be considered normal, depending on the surrounding clinical manifestations. This is discussed further under this summary statement, and I have quoted the statement per se for you below.

“Patients with any of the above might warrant prophylactic antibiotics, immunoglobulin replacement therapy, or both given the appropriate clinical context. Immunoglobulin replacement therapy should always be considered in patients with severe and moderate phenotypes and might be appropriate for those with memory and even mild phenotypes, depending on the clinical characteristics and/or response to antibiotic prophylaxis and optimal management of comorbid conditions.Overdiagnosis of humoral immunodeficiency must be avoided.”

SOURCE: Orange j et al: 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. Journal of Allergy and Clinical Immunology Vol. 130, Issue 3, Supplement, Pages S1-S24, 2012.

This quote is important in that it emphasizes the need to use clinical judgment based upon the manifestations that the patient exhibits. For example, it is key as to whether or not the patient demonstrates a clear end organ malfunction or end organ evidence of bacterial infection. Recurrent respiratory tract infections in the absence of documented bacterial pneumonias, chronic hyperplastic sinusitis, or bronchiectasis would be far less likely to be considered for preventive therapy than a patient with declining lung functions, bronchiectasis, documented bacterial sinusitis by CT scan, and recurrent bacterial pneumonias.

You did not describe these manifestations in the patients about which you are concerned, but if none of these complications were present, I personally would not consider anything other than treatment of the acute episodes based upon your clinical judgment. The only other two considerations would be the initiation of prophylactic antibiotics and/or immunoglobulin replacement therapy. If you do find evidence of end organ involvement, these therapies can be considered, and in my opinion you may get different answers from different consultants as to what might be appropriate therapy (e.g., prophylactic antibiotics, immunoglobulin replacement, or both).

So, in summary, based upon the information you supplied, I believe that these patients might be classified as having a mild immunodeficient phenotype at the worst. But these type patients, in the final analysis, are treated according to their clinical manifestations and the judgment of the physician administering the therapy. In my personal judgment, without evidence of end organ involvement as mentioned above, I would simply treat these patients as infections occur. But others might consider at this phase prophylactic antibiotics and perhaps even immunoglobulin replacement therapy. However, from a practical standpoint, considering the cost and inconvenience of immunoglobulin replacement therapy in this patient group, I would personally choose not to do so.

I personally would only institute immunoglobulin replacement therapy in the presence of clear-cut and at least moderately severe evidence of tissue damage and the presence of chronic and recurrent bacterial infections.

Once again, this is just an opinion, and I think management strategies would probably vary amongst consultants given this clinical history. Thus all I can offer you is my personal strategy based upon the information you presented.

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

Sincerely,
Phil Lieberman, M.D.