**8. Immunization**

198 Immunodeficiency

ug/ml) [45, 51].

sinopulmonary infections.

concentrations after an initial normal response.

responses to polysaccharide serotypes.

of polysaccharide antibody unresponsiveness.

mild or moderate immunological abnormality.

is different from other penumococccal polysaccharides.

**6. Sad phenotypes** 

requiring frequent antibiotic treatments for improvement. Patients with asthma and selective antibody deficiency may also have chronic sinusitis or other recurrent

There are many different forms of SAD based on the immunologic and clinical phenotypes, the transient or permanent nature of the defect, and the maintenance or loss of antibody

The classic SAD with absent or poor responses to pneumococcal polysaccharides is well defined and is based on the response to polysaccharides from serotypes present in PPV23. When patients have received one or more conjugate pneumococcal vaccines, differentiating antibody responses to serotypes present in the conjugate vaccines from responses to serotypes present only in the polysaccharide vaccines is important. In specific antibody deficiency, antibody response to the conjugate serotypes may be normal with poor

The intensity of antibody responses to polysaccharides and the number of polysaccharides eliciting antibody responses vary considerably from one individual to another, even in the same age group. This variability makes it difficult to clearly define immunologic phenotypes

The severe immunologic phenotype of SAD is the easiest phenotype to define. These patients have little or no antibody response and no protective antibody concentrations to any pneumococcal serotype evaluated . Some patients with a severe immunologic phenotype have protective titers to one serotype, and the titer tends to be low (1.3 to 2.0

A moderate immunologic SAD phenotype is characterized by partial antibody responses, with less than the expected arbitrarily defined adequate response to serotypes for their age group. Some of these patients can have a severe clinical phenotype despite their relatively

Since the introduction of conjugate pneumococcal vaccines in the USA in 2000, patients with recurrent respiratory infections who are fully immunized with 4 doses of PCV may be clearly unresponsive to conjugate polysaccharides. These patients usually are able to develop protective antibody concentrations against protein antigens such as diphtheria and tetanus toxoids and to the single antigen conjugate *Haempphilus influenza* vaccine. The immunologic and clinical severity of these patients is similar to the phenotypes of patients unresponsive to PPV. There is a large subgroup of PCV-SAD patients that respond only to serotype 14, revealing that the immunologic properties of the polysaccharide in serotype 14

A different clinical phenotype of SAD occurs in patients who have an initial adequate response to a pneumococcal vaccine, followed by a rapid loss of antibody concentrations Immunization beyond the suggested regular immunization schedule should be the first step in a newly diagnosed SAD patient. Patients who fail to respond to a complete series of PCV vaccinations, PCV-SAD patients, should be immunized with one dose of PPV. This vaccine should increase the patient's protection against bacterial polysaccharide infections, and this immunization allows for assessment of the patient's immunologic response to polysaccharides. Clinical experience shows that these patients typically have good immunologic response to most or all 23 PPV serotypes (Sorensen, unpublished observations).

Patients with recurrent infections despite good response to PCV may benefit from immunization with PPV. PPV contains serotypes common to PCV and serotypes no present in PCV, so this vaccine may increase antibody response to PCV and nonPCV serotypes. For less severe mucosal infections not requiring multiple antibiotic treatments, it may be possible to immunize the patient first, with a subsequent complete immunological evaluation only if infections persist.

After immunizing with one dose of PPV initially, repeated immunization with PPV should not be considered a routine therapeutic option in patients with recurrent infections that fail to respond to PPV. If patients do not respond to one dose of PPV-23, our experience suggests that these patients likely do not have an appropriate immunologic response to polysaccharide antigens. So, a second dose of PPV-23 generally has little benefit. An exception may be re-immunization of otherwise immunologically normal patients who partially responded to PPV initially, with resulting titers slightly below protective levels.. Reimmunization of partial responders to PPV may result in protective antibody levels.

Selective Antibody Deficiency with Normal Immunoglobulins 201

IgG replacement by the intravenous or the subcutaneous route is appropriate when the infection history is well documented, when immunizations have been utilized, and most of all, when proper antibiotic prophylaxis and treatment has been optimized. Patients with any form of SAD need decreased infections to improve quality of life and to prevent

The recommended IgG dose is 400 to 600 mg/kg calculated on a monthly basis. ItgG can be given intravenously every four weeks or subcutaneously in divided doses one or twice weekly. Occasional patients require either higher doses if they have breakthrough infections

When the severity of infections warrants the use of IgG replacement treatment, patients should be advised that treatment will be discontinued after a period of one to two years and the immune response will be reevaluated four to six months after discontinuation of IgG replacement. Whenever possible, the discontinuation of IVIG should be scheduled for during the spring or summer time when the incidence of infections typically decreases.

Four to six months after the IgG dose, a complete immunological evaluation of antibody mediated immunity should be performed. This evaluation includes an additional dose of PPV and measurement of antibodies 3 to 6 weeks after immunizations. Many children do not require further IgG replacement therapy, but some continue to have persistent infections and need continue replacement IgG therapy. These patients are likely to have additional immunological abnormalities that presently under evaluation. Patient management, IgG replacement therapy, and post treatment evaluation is best done by experts in the

The immunologic phenotypes of specific antibody deficiency may be transient or permanent. Transient forms are common in children two to five years of age. Even in permanent phenotypes, the natural history of specific antibody deficiency is usually benign

Reassessment of antibody-mediated immunity should always be performed after discontinuation of IVIG therapy and in patients with recurrent infections. In particular, older patients with selective antibody deficiencies with normal immunoglobulin concentrations should be monitored closely, as they may eventually develop common

Further insights into the pathogenesis of this immunodeficiency by studying larger numbers of patients will allow further understanding of the correlation between immunologic and clinical phenotypes of specific antibody deficiency. Further study will result in a more reliable assessment of the risk for persistent immune abnormalities and recurrent

management of patients with all forms of primary immunodeficiency diseases.

complications such hearing loss, sinus damage or bronchiectasis.

**10. IgG replacement therapy** 

or complications such as bronchiectasis.

with proper management of these patients.

sinopulmonary infections in subgroups of these patients.

variable immunodeficiency.

**11. Prognosis** 

In contrast to the ineffectiveness of repeated PPV immunization, 80 to 90 percent of patients with classic PPV-SAD do have a serological response to the serotypes present in the conjugate vaccine that can be used to overcome the unresponsiveness to pure polysaccharides [56]. Conjugate vaccines were developed to immunize children younger than 2 years of age, as children below age 2 years typically demonstrate poor responses to polysaccharide antigens alone. Conjugation helps direct the immune response toward the immunogenic protein complexed to the polysaccharide antigen, thereby stimulating protective immune responses in those individuals. Therefore, it is not surprising that PPVnonresponders typically have a good serological response to PCV serotypes.

Although most patients benefit from immunization with the conjugate vaccine by improving protection against common pneumococcal serotypes, none of the conjugate vaccines has all 23 serotypes present in the polysaccharide vaccine. This clinical improvement after a PCV immunization is notable because recurrent respiratory infections are caused by a much larger variety of pathogens than just the vaccine pneumococcal serotypes.

If there is a serological response to the conjugate vaccine without clinical improvement, then the PPV-SAD persists and further treatment options need to be considered. In PPV-SAD patients who are clinically unresponsive to immunization with additional PCV, reimmunizing with PPV is generally ineffective if repeated within one year of the initial PPV vaccine. After a period of IgG therapy, many patients respond to an additional PPV dose with or without clinical improvement, so a second PPV dose should be given after completion of 1-2 years of IgG replacement therapy.

For patients with poor immunological memory (loss of antibody concentrations after an adequate initial response), immunization with a second dose of polysaccharide vaccine generally triggers a vigorous IgG antibody response. Further study is needed since this phenotype may not be attributable only to poor immunological memory.

#### **9. Antibiotics**

If the frequency and severity of infections persists after additional immunization, antibiotic prophylaxis should be considered, especially in younger patients who will likely outgrow their selective antibody deficiency. When an oral antibiotic is considered for prophylaxis, treatment doses of trimetroprim-sulfa can be very effective. Prolonged daily use of topical mupirocin intranasally, for several months to a year, is a safe alternative treatment plan.

Appropriate antibiotic selection and duration for any febrile and/or purulent respiratory infection is important. Treatment with high doses of antibiotics for periods of at least 2 to 3 weeks is necessary. When antibiotic use alone improves the patient's quality of life and prevents infectious complications, no additional treatment is needed.
