**4. Diagnostic criteria**

The interpretation of anti-pneumococcal antibody concentration results is based on increased post-immunization antibody concentrations over pre-immunization concentrations (immune response) and on the final post-immunization antibody concentrations, regardless of increase from pre-immunization concentrations (antibody concentration). Patients who already have high baseline antibody concentrations of specific antibodies to a pneumococcal serotype are less likely to have a significant increase in antibody concentrations after immunization.

The definition of adequate response to individual pneumococcal polysaccharides is not well defined. Protection against invasive disease, as assessed in clinical vaccine trials, may require lower antibody concentrations that protection against mucosal diseases like sinusitis and otitis [10]. Immunocompetence, as a reflection of the ability of producing a response for clinical protection against mucosal infections and pneumonia, has been arbitrarily defined as a post-immunization antibody concentration ≥1.3 mcg/mL. This antibody concentration can be used as a marker of immunocompetence, regardless of degree of response over pre-immunization baseline antibody concentrations [56]. For instance, a patient with a pre-immunization titer of 0.15 mcg/mL may have a 4-fold increase to 0.6 mcg/ml, still significantly below the level needed to show immunocompetence.

The number of individual polysaccharide responses required in the immunologic evaluation for a reliable assessment of the antibody response to polysaccharides has not been established. Response to a single serotype-specific polysaccharide does not predict the ability or inability to respond to most or all other serotypes. Therefore, measuring response of at least **six** different antibodies to vaccine serotypes is recommended to obtain a reliable estimate of the spectrum of responses of a given patient. For patients who received one or more doses of the conjugate pneumococcal vaccine, at least six or more non-conjugate vaccine serotypes (present only in polysaccharide vaccine) need to be measured. A patient that responds to the conjugate vaccine may still be unresponsive to pure polysaccharides, which is an immunologic abnormality that may be clinically relevant.

The age of the patient significantly affects the intensity of the antibody response to individual serotypes and the number of serotypes inducing an adequate response [56]. Normal children between two and five years of age are expected to have an adequate response to >50 percent of serotypes evaluated. Older patients are expected to respond to >70 percent of serotypes evaluated. These criteria have not been tested critically; however, they have allowed us to predict a clinical course and decide upon treatment options in over 1000 patients of all ages tested since 1995 (Sorensen et al, unpublished observations).

Other factors that affect pneumococcal antibody concentrations in the evaluation of SAD include treatment with intravenous or subcutaneous gammaglobulin within the previous 6 months and underlying diseases and/or treatments possibly affecting immune response. Examples include long-term steroid therapy, malignancy, and chemotherapy.

In addition to immunization, responses to natural, often subclinical, infection influence the antibody concentrations in patients. In fact, absent protective antibodies in unimmunized patients above 2 years of age are unusual. However, upon vaccination, older patients who never developed protective antibodies to pneumococcal serotypes often have adequate response to most serotypes. Low antibody concentrations in an unimmunized individual do not define an immunodeficiency syndrome unless there is inadequate response to immunization.
