Pediatrics

Selective Antibody Deficiency

OVERVIEW: What every practitioner needs to know

Selective Antibody Deficiency (SAD), also known as specific antibody deficiency or partial antibody deficiency with impaired polysaccharide responsiveness, is a primary immune deficiency disease (PIDD) resulting from an individual's inability to make antibodies to polysaccharide antigens found within encapsulated bacteria. Total immunoglobulin (Ig) levels and other assessments of immune function are normal, including numbers of blood T and B lymphocytes.

SAD is among the four most common primary antibody deficiency conditions, which include transient hypogammaglobulinemia of infancy (THI), selective IgA deficiency, and IgG subclass deficiency.

There are controversies surrounding the definitive diagnosis and specific treatment of this condition, as discussed below.

Are you sure your patient has SAD? What are the typical findings for this disease?

The most common symptoms are recurrent sinopulmonary infections, almost always caused by infection with encapsulated bacteria such as Streptococcus pneumoniae, Staphylococcus aureus, and Haemophilus influenzae (H flu). The three most common types of infections are chronic maxillary, ethmoid and sphenoid sinusitis, recurrent otitis media (OM), and bacterial pneumonia.  The Jeffrey Modell Foundation consensus panel defined recurrent sinopulmonary infections as four or more new episodes of OM per year in children (two or more in adults), two or more sinus infections per year, or two or more episodes of pneumonia per year.

Severe infections such as meningitis, sepsis, osteomyelitis, and abscesses are rare in SAD. However, asthma and other atopic conditions are seen in up to 50% of cases. Asthma is frequently triggered by sinusitis or other upper respiratory infections. Purulent rhinitis, streptococcal pharyngitis, mastoiditis, and bronchitis are other associated conditions, with some patients developing bronchiectasis and chronic lung disease due to repeated episodes of pneumonia. Physical exam often reveals sclerotic tympanic membranes, tonsillar and adenoidal hypertrophy, and cervical adenopathy.

What other diseases/conditions shares some of these symptoms?

The clinical manifestations are very similar to other antibody deficiency disorders, particularly selective IgA deficiency, transient hypogammaglobulinemia of infancy (THI), and IgG subclass deficiency. Taken together, these disorders are not commonly associated with severe, life-threatening infections, and many individuals are completely asymptomatic.  The latter raises some controversy surrounding how aggressively these patients should be treated.  Recurrent infections associated with THI generally resolve as the child ages past 3 to 4 years.  Individuals with selective IgA deficiency are also at risk for gastrointestinal infections, particularly chronic enteritis with Giardia lamblia as well as celiac disease, autoimmunity, and asthma.

Most severe immune deficiency disorders can initially appear similar to SAD, but symptoms become more frequent and severe over time if severe immunodeficiency remains unrecognized and untreated.

These disorders can easily be identified through targeted laboratory testing.  Such conditions include X-linked agammaglobulinemia (XLA), autosomal recessive agammaglobulinemia, X-linked (XLHIGM) and autosomal recessive forms of hyper IgM syndrome, and common variable immune deficiency (CVID). The hallmarks of these conditions are life-threatening bacterial infections such as bacterial sepsis, pneumonia, and meningitis. In the case of XLA and XLHIM syndrome, the initial symptoms frequently occur in infancy or early childhood. The clinical presentation of CVID typically begins in the second or third decade of life with, in addition to infections, autoimmune cytopenias and granulomatous disease in the liver, spleen, and lungs.  

Cellular immune deficiencies such as the variants severe combined immune deficiency (SCID) and DiGeorge syndrome are all associated with recurrent bacterial sinopulmonary infections, but these conditions also are associated with opportunistic infections such as mucocutaneous candidiasis or pneumocystis pneumonia. 

Children with Wiscott-Aldrich syndrome have recurrent otitis media and sinusitis but also have eczema and thrombocytopenia. 

HIV infection causes poor antibody response to encapsulated organisms; thus, HIV-infected children and adults share clinical manifestations of SAD.

Complement deficiencies and other disorders of the innate immune system can also manifest with recurrent sinopulmonary infections. Among the complement deficiencies, mannose-binding lectin (MBL) deficiency is most similar to SAD in type and frequency of infections. Patients who have recurrent streptococcal infections but who do not have fevers may have IRAK-4 deficiency.

Non-immune conditions that can mimic SAD include cystic fibrosis (CF), protein-losing enteropathy, ciliary dyskinesia, atopic asthma, and anatomical conditions such as cleft palate that predispose to sinusitis and OM.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

The clinical and laboratory approach to evaluating a patient for the diagnosis of SAD is summarized in Figure 1.

Figure 1.

Clinical Diagnostic Criteria: Age > 2 years

The diagnosis of SAD should be considered in patients older than 2 years with recurrent upper and/or lower respiratory tract infections.

Additional diagnostic laboratory criteria include normal quantitative immune globulins (IgG, IgA, IgM) based on age-appropriate reference values.  SAD is characterized by normal serum IgG, IgA, IgM and IgG subclasses.  Pre- and post-immunization responses to T-dependent (Tetanus and Diphtheria) vaccines are other criteria to be considered.  Isolated decreased IgG subclass levels can be found in normal individuals and do not always correlate with increased susceptibility to infections. 

The interpretation of anti-pneumococcal antibody concentration is determined based on antibody increases over pre-immunization concentrations and on the final concentration following immunization.  Measurement of pneumococcal antibody titers should be done 4 to 8 weeks after vaccination. Adequate response is considered when the post-immunization antibody titer for each individual serotype is >1.3 mcg/mL to more than 50% of serotypes in children between 2 and 5 years of age or to more than 70% of serotypes in patients 6 - 65 years of age. There can also be a  >4-fold increase for at least 50% of serotypes tested in children between 2 and 15 years of age. The probability of a 4-fold antibody response approaches zero if the preimmunization titer is between 4.4 and 10.3 mg/mL depending on the pneumococcal serotype.

Individuals who have been previously immunized with 13-valent or heptavalent pneumococcal conjugate vaccines present a special challenge in diagnosing SAD.  The pneumococcal conjugate vaccines contain many of the same pneumococcal serotypes as does the 23-valent pure polysaccharide vaccine, making the interpretation of the adequacy of the antibody response to immunization challenging.  The serotypes found in these vaccines and the 14 commonly tested serotypes performed in commercial diagnostic laboratories are shown in Table I

Table 1.

Green highlights denote serotypes that have antibody titers that have been validated and are commonly available. *Denotes a serotype within the 13 valent conjugated pneumococcal vaccine, 7 denotes a serotype within the 7 valent pneumococcal vaccine. A normal response is considered titers .1.3 .g/mL or 4 fold increases in at least 50% (2 to 5 years) or 70% (>6 years) of serotypes tested.

Recently, testing for all 23 serotypes found within the 23-valent vaccine has become available and can be used to interpret the results in patients who have been previously immunized with polysaccharide conjugate vaccines.  There are currently no criteria that specify the magnitude and number of serotypes in response to conjugate pneumococcal vaccines in the evaluation of PIDD. 

The clinical and laboratory approach to evaluating a patient for the diagnosis of SAD is summarized in Figure 1.  It requires the demonstration of poor response to polysaccharide antigens but normal response to protein antigens (i.e., Tetanus, Diphtheria).  Testing for the latter is useful in the evaluation of other PIDDs that more commonly affect the antibody response to this type of antigen, as seen in CVID.  

A recent working group report of the Basic and Clinical Immunology Interest Section of the American Academy of Allergy, Asthma & Immunology (AAAAI) offered a recommendation for 4 phenotypes of polysaccharide non-responsiveness in SAD (category IV D evidence).

  • Memory phenotype: These individuals have an adequate initial response to pneumococcal polysaccharide vaccine 23 (PPV23) but lose this response wtihin 6 months. They might respond to a second administration of PPV23 after 1 year.

  • Mild phenotype: These patients have either multiple vaccine-containing serotypes to which they did not generate protective titers or an inability to increase titers 2-fold, assuming the prevaccination titers are less than the established threshold levels in the presence of the history of infection.

  • Moderate phenotype: These patients have fewer than the expected number of protective titers to specific serotypes for their age but demonstrate protective titers to 3 or more serotypes.

  • Severe phenotype: These patients have protective titers to no more than 2 serotypes, and the titer, if present, tends to be low (1.3 - 2.0 mcg/mL).

Patients who only marginally meet the standards of protective responses after vaccination should be monitored clinically.

Diagnostic testing to evaluate for other PIDDs that can mimic SAD include T cell, B cell and NK cell evaluation using flow cytometry analysis of blood lymphocytes.  These tests can be used to evaluate for SCID and XLA. Abnormal results of quantitative immunoglobulins and IgG subclass assessments suggest the possibility of XLA, XLHIGM syndrome, CVID,s or IgG subclass deficiency.

The best screening test for HIV infection is an HIV ELISA. 

Patients with MBL deficiency have low sera MBL levels but normal total hemolytic complement levels. 

Diagnostic testing to evaluate for non-immune conditions that can mimic SAD are based on associated clinical findings.

Sweat chloride testing for CF, ciliary biopsy for ciliary dyskinesia, total IgE, and skin testing as part of the evaluation of allergic conditions are additional diagnostic evaluations for patients with recurrent sinopulmonary infections.

Would imaging studies be helpful? If so, which ones?

Imaging studies of the head and chest are helpful in evaluating the extent of sinopulmonary infections and to determine the best treatment options. CT or MRI are often helpful in assessing the anatomy of the paranasal sinuses and middle ear in patients with chronic, severe, or complicated upper respiratory tract bacterial infections. 

The usefulness of plain sinus radiography, particularly in children, is controversial. If possible, imaging should be avoided when patients have acute infections because interpretations of chronicity are difficult in this circumstance. Findings indicating chronic sinus disease include polyposis, mucosal thickening, air fluid levels, and masses. 

Magnetic resonance imaging (MRI) provides better imaging of the soft tissues and is useful in the evaluation of upper airway malignancies.

Signs of chronic lower respiratory tract infections should initially be evaluated with plain chest x-ray and pulmonary function testing. A low FEV1 (<80% predicted) that is reversible with short acting bronchodilators suggests airway hyperactivity, while fixed reduction of the FEV1 with or without decreased forced vital capacity suggests chronic obstructive pulmonary disease and perhaps bronchiectasis as a result of recurrent episodes of pneumonia. 

The most sensitive evaluation for occult bronchiectasis is high resolution CT (HRCT) and should be performed in patients with SAD who have more than two documented episodes of bacterial pneumonia.

If you are able to confirm that the patient has SAD, what treatment should be initiated?

The treatment of SAD is controversial, with few studies comparing the efficacy of different treatment options. There is no therapy that completely reverses the condition; thus, the goal is to prevent infections and improve quality of life using modalities that do not cause complications and are cost-effective. 

Because the B cell defect is limited to polysaccharide antigens, immunization with conjugated vaccines such as H flu vaccine and 13-valent pneumococcal vaccine has theoretical efficacy but has not been systematically tested to show efficacy in preventing infections. However, many patients with SAD can produce protective titers following immunization with these vaccines.  A limitation of pneumococcal vaccines is that they do not include all serotypes of Streptococcus pneumoniae that cause upper respiratory tract infections.

Effective antibiotic treatments against the H flu and Streptococcus pneumoniae include amoxicillin, cephalosporins, and macrolide antibiotics. Prolonged treatment courses, sometimes exceeding 21 days, may be necessary to fully eradicate the disease.  Development of antibiotic resistance is common. The use of daily prophylactic antibiotics is common, but also may increase the risk of organisms developing drug resistance.

Immunoglobulin replacement therapy is the most commonly used treatment modality for SAD.  It has been shown to reduce the frequency of serious lower respiratory tract infections to less than one infection per patient per year.  It is less effective in preventing upper respiratory tract infections such as sinusitis and OM. Prophylactic immunoglobulin can be given intravenously (IVIG) or subcutaneously (SCIG). IVIG is given monthly, while SCIG is given weekly.

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. Co-morbid conditions that should be considered for IVIG immune prophylaxis are those patients with bronchiectasis, recurrent pneumonia, or other severe bacterial infections as they are most likely to show clinical improvement.

The recommended dose for prophylactic IVIG is 600 to 800 mg/kg/dose given at a maximum rate of 4 mg/kg/min.  SCIG is self-administered in the home setting, with dosing recommendations that are 1.3 or 1.5 times higher than IVIG, depending on the particular product prescribed.  The weekly dose is roughly 25% of the IVIG monthly dose. SCIG products are available as 10%, 16%, or 20% solutions and are infused at multiple sites in the abdomen, thigh, or upper arms using a 27-gauge subcutaneous needle. The maximum recommended volume per site is 15 to 25 milliliters.

What are the adverse effects associated with each treatment options?

As previously mentioned, conjugated vaccines may not be effective in reducing the severity or frequency of infections.

Chronic and prophylactic antibiotics can lead to selecting antibiotic resistant organisms.

IVIG and SCIG are costly, inconvenient, and are associated with certain adverse reactions. The most common reactions include fevers, rigors, myalgia, and infusion-associated headaches. Adverse reactions can be avoided by slowing the infusion rate or by premedication with antihistamines, corticosteroids, and analgesics.  However, some reactions to IVIG are severe or refractory and necessitate using SCIG. The most common adverse event associated with SCIG is local site reactions, primarily burning or itching at the site but lasting less than 24 hours.

What are the possible outcomes of SAD?

The overall prognosis of SAD is good. Chronic lung disease and progression to bronchiectasis is rare, particularly in patients receiving aggressive therapy. Chronic poorly controlled asthma, triggered by upper respiratory bacterial infections, is more common. In addition, chronic sinusitis and OM can lead to chronic facial pain and congestion with upper airway obstruction. Recurrent OM can result in chronic hearing loss.

Patients and families need to be aware that SAD is a lifelong condition. If immune globulin therapy is warranted and initiated, it is unlikely that the patient will be able to discontinue treatment. There may be a risk for patients with SAD to develop CVID.

What causes this disease and how frequent is it? 

The exact pathogenesis of SAD is unknown but stems from the inability of B cells to become activated and produce protective antibody to polysaccharide antigens. Bacterial cell wall polysaccharides are classified as T independent antigens, meaning they can stimulate B cells directly and do not require help from CD4 T cells. In contrast, T dependent antigens, such as proteins, undergo antigen processing and presentation to T cells through macrophages, phagocytosis, and direct cognate T cells to B cell interactions. These processes amplify the signals to stimulate antibody production (see Figure 2). This pathway is intact in the majority of patients with SAD, but T independent pathways are abnormal.

Figure 2.

Antibody Responses to T-cell dependent and Independent Antigens in SAD

It has recently been postulated that the T independent pathway for B cell activation relies on innate immune receptors such as Toll-Like Receptors, but the relationship to SAD is not yet proven.  Alternative mechanisms for SAD may relate to an intrinsic defect in B cell activation pathways.  Even normal children under the age of 2 years often fail to produce a T cell independent B response to polysaccharide antigens. Thus, they may fail to produce protective antibodies following infection or immunization.

The poor immunogenicity of polysaccharide vaccines in young children relates to an inability of antibody produced by B cells in young children to undergo affinity maturation.  By conjugating polysaccharide antigens with proteins, as in the heptavalent and 13-valent pneumococcal polysaccharide vaccines and in the HIB vaccine, B cells can be induced to make a protective antibody response. 

It is unknown if the defect in B cell maturation seen in young children is the same defect in older children and adults with SAD.  Among the most common of the B cell immune deficiencies, it is estimated that 5 - 10% of children referred for evaluation of recurrent infection suffer from this condition.

How do encapsulated bacteria cause SAD?

Polysaccharide antigens in the cell walls of Streptococcus pneumoniae and the pentose polyribose phosphate polysaccharide antigen of H. flu elicit T cell independent immune responses by directly binding to the B cell immunoglobulin receptor on the surface of B cells. If this pathway is impaired and rapid production of protective antibodies opsonizing these bacteria fails to occur in all immunoglobulin isotypes, there will in turn be an increased susceptibility to sinopulmonary infection. There is likely some degree of antibody protection because, unlike young children with delayed B cell ontogeny to polysaccharide antigens, severe infections are rare in SAD.

Are additional laboratory studies available; even some that are not widely available?

Several studies have demonstrated that in patients with recurrent sinopulmonary infections, the presence of reduced functional antibody is directly related to low antibody avidity but is not necessarily a result of low antibody titer. The avidity of antibody induced by a vaccine is an independent correlate of protection, and this information may be a valuable supplement to the measurement of antibody titer.  However, antibody avidity is not currently easily measured and is considered unnecessary to diagnose SAD. 

There are emerging studies of activation pathways involved in B cell activation and antibody production.  In particular, there appears to be a block in B cell differentiation as transitional B cells enter the germinal center, encounter antigen, and differentiate in memory B cells. In the future, B cell phenotyping may become part of the evaluation for SAD.

How can SAD be prevented?

The genetics and etiology of SAD are unknown. There is no known way to prevent the condition. Administration of conjugated vaccines to polysaccharide antigens may prove to be effective in preventing infections by stimulating the production of protective antibodies.

What is the evidence for the management and treatment options you've recommended?

The 2005 Practice Parameter for the Diagnosis and Management of Primary Immunodeficiency (reference #1 below) lists SAD among the group of mild antibody deficiencies. The use of antibiotic prophylaxis for this condition is considered as evidence category C (directly based on category III evidence or extrapolated from category I or II evidence). The specific indications for the use of gamma globulin in SAD remain controversial, but its use is approved in this condition by the AAAAI work group report on the appropriate use of IVIG.

References

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(The authors have defined a new classification of phenotypes of polysaccharide non-responsiveness in SAD based on category IV D evidence. Although further research will likely result in the refinement and improvement of this guideline, the phenotypes can serve as a starting point to investigate response to therapy in the context of the different SAD subcategories.

Ongoing controversies regarding etiology, diagnosis, treatment 

SAD does not have a known pathogenesis or identified genetic defect. As a result, patients tend to be lumped based on clinical criteria that have been inconsistently used from study to study, creating a great heterogeneity and confusion regarding its diagnosis and treatment

All case definitions include the presence of recurrent bacterial sinopulmonary infections in a patient over the age of 2 years who has impaired antibody responses to unconjugated polysaccharide vaccines, and in which other primary and secondary immune deficiencies have been ruled out.

Further controversy emerges in defining the age-dependent normal response to pneumococcal immunization as qualitative assessment of antibody function seems to be an evolving topic. The criteria of a 4-fold rise in titer to 50% or more of the serotypes within the vaccine is arbitrary and has only been validated in one study. The AAAAI is currently re-reviewing the criteria for defining a normal response to pneumococcal immunization.

This lack of clear clinical and laboratory criteria to define SAD not only makes the diagnosis questionable but also applies to determining the best therapy for the condition. There is no strong evidence that gamma globulin replacement therapy is effective in preventing infections, and third party payers often do not authorize its use for SAD.

Further research is needed to refine best practice applied to individuals with specific SAD phenotypes.

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