**5. Clinical manifestations**

196 Immunodeficiency

months.

evaluation for SAD.

immunocompetence.

**4. Diagnostic criteria** 

antibody concentrations after immunization.

does not differentiate between IgM and IgG responses so is not clinical useful except for in rare instances, such as suspected Wiskott-Aldrich syndrome that needs evaluation in the first year of life. A normal child should have detectable isogglutinin titers after age 6

In patients with persistent or recurrent infections with a single pathogen, such as varicella, shingles, or a specific hepatitis, assessing the specific antibody response to a causative pathogen may be clinically relevant. However, such evaluations are usually not part of the

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

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

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,

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].

which is an immunologic abnormality that may be clinically relevant.

The clinical manifestations of patients with selective anti-polysaccharide antibody deficiency are similar to those of all antibody deficiency syndromes. The majority of patients have recurrent upper and/or lower respiratory infections such as sinusitis, otitis, bronchitis or pneumonia due to *Streptococcus pneumoniae, Haemophilus influenzae, Branhamella catarrhalis, or Staphylococcus aureus.* 

The sinopulmonary infections must be more frequent or severe that normally expected for the age group of the patient. Most of these infections require antibiotic treatment for clinical improvement, and an evaluation is warranted when multiple antibiotic treatments are needed, even when antibiotics effectively resolve each infection.

For a common infection such as otitis media, characteristics frequently found in patients with SAD include:


Very few patients with specific antibody deficiency also present with atopic diseases, including atopic dermatitis and asthma, complicated by recurrent infections

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

Selective Antibody Deficiency with Normal Immunoglobulins 199

over time. This form of SAD, based on poor persistence of IgG antibodies against pneumococci, is usually suspected when a patient who had a significant improvement with decreased infections after immunization begins again to have recurrent infections, typically

Some unimmunized patients in all age groups fail to develop protective antibody concentrations to any pneumococcal serotype tested. This lack of antibody response is unusual in individuals above two years of age who typically develop antibodies in response to natural infections. Most unimmunized adults have protective antibodies to at least 80 percent of serotypes tested. The lack of pre-immunization protective antibodies does not define an immunodeficiency, and most of these patients have a normal response to immunization. Those patients that completely fail to respond to natural infection and immunization have a severe form of selective antibody deficiency. Responders to immunization cannot be differentiated from non-responders without evaluation with

The management of SAD, including prevention and treatment of recurrent infections, can be classified into the following broad categories: additional immunization, antibiotic

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

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

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

six or more months post-immunization.

immunization and retesting after immunization.

prophylaxis and treatment, and immune serum globulin therapy.

**7. Management of SAD** 

**8. Immunization** 

observations).

evaluation only if infections persist.

### **6. Sad phenotypes**

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 concentrations after an initial normal response.

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 responses to polysaccharide serotypes.

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 of polysaccharide antibody unresponsiveness.

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 ug/ml) [45, 51].

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 mild or moderate immunological abnormality.

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 is different from other penumococccal polysaccharides.

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 over time. This form of SAD, based on poor persistence of IgG antibodies against pneumococci, is usually suspected when a patient who had a significant improvement with decreased infections after immunization begins again to have recurrent infections, typically six or more months post-immunization.

Some unimmunized patients in all age groups fail to develop protective antibody concentrations to any pneumococcal serotype tested. This lack of antibody response is unusual in individuals above two years of age who typically develop antibodies in response to natural infections. Most unimmunized adults have protective antibodies to at least 80 percent of serotypes tested. The lack of pre-immunization protective antibodies does not define an immunodeficiency, and most of these patients have a normal response to immunization. Those patients that completely fail to respond to natural infection and immunization have a severe form of selective antibody deficiency. Responders to immunization cannot be differentiated from non-responders without evaluation with immunization and retesting after immunization.

### **7. Management of SAD**

The management of SAD, including prevention and treatment of recurrent infections, can be classified into the following broad categories: additional immunization, antibiotic prophylaxis and treatment, and immune serum globulin therapy.
