INTRODUCTION — Specific antibody deficiency (SAD) describes an inadequate antibody vaccine response to polysaccharide antigens in an individual with normal responses to protein antigens, normal serum levels of immunoglobulins (Ig), and normal IgG subclass concentrations. It is believed to be the most common form of antibody disorder in older children and adults with recurrent rhinosinusitis and/or bronchopulmonary infections.
This topic will discuss the epidemiology, pathogenesis, evaluation, diagnosis, and management of this disorder. A detailed discussion of the interpretation of vaccine responses and an overview of humoral immunodeficiencies are presented separately. (See "Assessing antibody function as part of an immunologic evaluation" and "Primary humoral immunodeficiencies: An overview".)
Definition — SAD describes an inadequate antibody vaccine response to polysaccharide antigens in an individual with normal responses to protein antigens, normal serum levels of immunoglobulins (IgG, IgA, and IgM), and normal IgG subclass concentrations . Polysaccharide nonresponse is the only identifiable abnormality.
Terminology — The terminology for SAD or polysaccharide non-response is not standardized, and other names appear in the literature, including "impaired polysaccharide responsiveness," "specific antibody deficiency with normal Ig levels and normal B cells," "selective antibody deficiency with normal immunoglobulins," and "antibody deficiency with near-normal immunoglobulins" [1,2].
Non-response or poor response to vaccines may be found in a host of distinct primary or secondary immunodeficiency disorders, such as common variable immunodeficiency or asplenia, or it may exist in isolation as the only identifiable immune problem [3-8]. In this review, we use the term "SAD" to refer to the disorder in which polysaccharide nonresponse is the sole identifiable immunologic abnormality and the descriptive term "polysaccharide nonresponse" to denote the immunologic defect, which may occur in a variety of disorders. (See 'Differential diagnosis' below.)
Background — SAD was first reported in a small group of patients in the early 1980s [9,10]. Subsequently, it was established that polysaccharide nonresponse can be seen in both children and adults [11-14].
PATHOGENESIS — The pathogenesis of SAD is not fully understood, and the various conditions in which it occurs suggest that many different defects may result in the same immunologic endpoint.
Among children younger than six months of age with normal immune systems, the inability to respond to polysaccharide antigens is common although not universal because some children can respond vigorously [12,13]. Polysaccharide responsiveness normally increases with age. It is possible that polysaccharide responsiveness does not develop equally in all individuals and that polysaccharide nonresponse in some children may simply represent delayed maturation of the immune system . Still, this apparent limitation of the infant immune system prompted the development of conjugate vaccines, in which polysaccharide antigens are complexed to more immunogenic protein antigens.
There is also evidence that polysaccharide nonresponse can result from congenital molecular abnormalities. One study described an adult patient with a mutation in Bruton tyrosine kinase, a deficiency more commonly associated with X-linked agammaglobulinemia, who had normal immunoglobulin concentrations but absent responses to polysaccharides [16,17]. In addition, polysaccharide nonresponses can be identified in some patients with congenital dysmorphic syndromes or chromosomal abnormalities associated with recurrent infections, such as patients with various phenotypes associated with 22q11 microdeletions who do not fulfill criteria for the DiGeorge syndrome. (See 'Diagnosis' below.)
PREVALENCE — SAD is not uncommon among children and adults with recurrent and/or severe sinopulmonary infections [3-5,18,19]. With the widespread use of the polysaccharide pneumococcal vaccine to assess immune function, this syndrome has become the most frequently identified immunodeficiency in clinics that evaluate patients with recurrent and/or severe infections . Studies in specific age groups include the following:
●In children older than two years of age referred for evaluation of recurrent infections, SAD was found in 5 to 10 percent [19,21].
●In 595 adults with chronic rhinosinusitis, SAD of varying severity was identified in 40 percent, compared with 10 percent of normal controls . In another study of 129 patients undergoing sinus surgery for chronic rhinosinusitis after failing medical treatment, 12 percent had SAD .
●Among adults with recurrent (≥3 episodes) community-acquired pneumonia, SAD was found in 8 percent .
CLINICAL MANIFESTATIONS — Recurrent or severe rhinosinusitis and/or bronchopulmonary infections are the primary presenting disorder.
The clinical manifestations of patients with SAD overlap with those of all antibody deficiency syndromes.
Sinopulmonary infections — The majority of patients have recurrent upper and/or lower respiratory infections due to Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, or Staphylococcus aureus. Common infections include otitis media, bronchitis, acute and chronic rhinosinusitis, and pneumonia. SAD has been identified in a subset of patients with bronchiectasis of unknown etiology .
Patients may present with symptoms suggestive of IgE-mediated diseases (such as chronic rhinitis, atopic dermatitis, and asthma), and evaluation by in vivo or in vitro methods may confirm atopy. However, failure to improve significantly with appropriate therapy should raise suspicion of additional diagnoses, including an underlying immune disorder, especially if the atopic symptoms are complicated by infections. There are no data to suggest that atopic disease is more prevalent in patients with SAD compared with the general population, and some patients with SAD have very low levels of IgE and no evidence of specific IgE sensitization to allergens.
Other disorders — Noninfectious complications such as connective tissue diseases, autoimmunity, and rarely hematopoietic malignancies have also been described in patients diagnosed with SAD . Screening for these comorbidities should be performed if there is a suggestive history or finding upon initial evaluation, and monitoring for new signs and symptoms is an important component of ongoing management.
Indications for evaluation — The diagnosis of SAD should be suspected in children and adults with recurrent and/or severe sinopulmonary infections. The table shows the infectious issues suggesting that an evaluation for a defect in the humoral immune response should be performed (table 1). (See "Approach to the adult with recurrent infections", section on 'What is an excessive number of infections?'.)
Laboratory studies — Evaluation for SAD involves the following:
●Measurement of serum levels of IgG, IgA, and IgM
●Measurement of IgG subclass levels
●Assessment of response to polysaccharide and protein vaccines
Immunologists debate the need for concomitant measurement of IgG subclasses and polysaccharide nonresponses, and differences of opinion exist. We measure IgG subclasses in patients with impaired polysaccharide responses because this is consistently found in association with IgG2 deficiency, and patients with these findings should be categorized as having IgG2 subclass deficiency rather than SAD [27,28]. (See "IgG subclasses: Physical properties, genetics, and biologic functions" and "IgG subclass deficiency", section on 'IgG2 deficiency'.)
The diagnosis of SAD is a diagnosis of exclusion, in which the only identifiable immunologic abnormality is a deficient response to polysaccharide vaccines. Levels of IgG, IgG subclasses, IgA, IgM, and IgE should be normal, and responses to protein vaccines should be normal. In addition, no other primary or secondary immune disorder should be present. (See "Assessing antibody function as part of an immunologic evaluation" and "Laboratory evaluation of the immune system".)
Referral — This evaluation may be initiated by the primary care clinician, or the patient may be referred to an allergy/immunology specialist at the outset. For patients who are requiring antibiotics regularly, we advocate for early referral to an immunology specialist. For patients who have not required multiple antibiotic treatments, it may be reasonable to complete an age-appropriate immunization schedule first and then to perform a complete immunologic evaluation only if frequent infections continue to occur. (See "Pneumococcal vaccination in children" and "Pneumococcal vaccination in adults".)
Pneumococcal vaccination — After prevaccine titers are obtained, immunization with a polysaccharide pneumococcal vaccine (eg, Pneumovax 23 or Pnu-Imune 23) is used to assess immunologic response to polysaccharide antigens in patients over two years of age (algorithm 1) . In addition to providing diagnostic information, vaccination enhances immunity to a common respiratory pathogen in patients suffering from recurrent infections, at least in those able to respond . Interpretation of vaccine response is described briefly here and reviewed in more detail separately. (See "Assessing antibody function as part of an immunologic evaluation".)
Panels of quantitative serum levels of antibodies to different pneumococcal serotypes are available through several commercial laboratories. It is recommended that the same laboratory perform the pre- and postvaccination measurements, because different laboratories may measure different serotypes. We recommend measuring antibodies to at least 14 serotypes and ideally to all 23 serotypes present in the 23-valent pneumococcal polysaccharide vaccine (PPSV23). When patients have been immunized with conjugate vaccine(s), the panel should include antibodies to serotypes not present in the 10-valent or 13-valent conjugate vaccines, as response to these serotypes is the only way to assess the response and diagnose SAD to unconjugated polysaccharides (table 2 and table 3). At least one publication has suggested that panels of pneumococcal serotypes including as few as five serotypes may be adequate to predict and diagnose SAD . However, most literature and guidance have used larger panels as suggested here. Furthermore, it may be difficult to place patients into the accepted severity classifications (see 'Degrees of nonresponse' below) if only a few serotypes are used to make the diagnosis. These severity levels were developed based upon evaluation of patients using significantly larger panels of 14 to 23 serotypes. If possible, patients should be evaluated before giving vaccines for diagnostic purposes and again at least four weeks and no more than eight weeks after vaccination with the PPSV23 .
Pneumococcal immunization is generally well-tolerated. However, patients who have protective levels of antibodies to one or more serotypes included in the vaccine prior to immunization may have exaggerated local reactions at the site of vaccine injection that can last several days. These reactions may be treated with nonsteroidal anti-inflammatory medications.
Titers may be assessed in adults who have been vaccinated with the polysaccharide vaccine within the previous five years. Patients vaccinated more than five years ago may have waning titers, so if low titers are found, the patient can be revaccinated and titers checked again in four weeks.
Unimmunized patients — Most normal unimmunized adults have protective antibodies to some pneumococcal serotypes tested as a result of clinical or subclinical infections . However, the lack of preimmunization protective antibodies is not a deficiency per se and may simply represent a lack of exposure. Most of these patients have a vigorous response to immunization. Responders cannot be differentiated from nonresponders without immunization and retesting after immunization. However, one study suggested that the presence or absence of pre-existing protective antibodies may also predict responses to immunization with PPSV23, due to the varying immunogenicity of the capsular polysaccharide unique to each serotype .
In partially or unimmunized patients, it may be necessary to update prior immunizations or to start an immunization program appropriate to the patient's age (See "Pneumococcal vaccination in children" and "Pneumococcal vaccination in adults".)
Interpreting a pneumococcal vaccine response — The interpretation of a patient's response to the polysaccharide pneumococcal vaccine is reviewed briefly here and in detail separately. (See "Assessing antibody function as part of an immunologic evaluation".)
Normal response to PPSV23 — A "normal" or protective response to an individual serotype following challenge with PPSV23 is defined as 1.3 mcg/mL or greater [29,34]. Note that if the baseline levels are ≥1.3 mcg/mL prior to immunization with PPSV23, then a two-fold increase over baseline is a satisfactory response to the vaccine.
The cut-off of 1.3 mcg/mL is based upon consensus among a panel of experts that this level is protective against pneumococcal disease following vaccination with a polysaccharide vaccine . These arbitrary levels for polysaccharide responses have been questioned, with some using 1 mcg/mL or 1.5 mcg/mL as a protective titer  and at least one group using 50 percent or more as representing a normal response in adults .
Note that an adequate response to PPSV23 is different from the response that is adequate to provide protection against invasive pneumococcal disease in a patient vaccinated with the pneumococcal conjugate vaccine, which is ≥0.35 mcg/mL. This discrepancy can be confusing but is likely due to the potential differences in the immune responses to conjugated polysaccharide antigens compared with the pure polysaccharide antigens in PPSV23. Therefore, we do not recommend making a diagnosis of an antibody deficiency based solely on results from an initial measurement of antibody titers to S. pneumoniae, which may include pre-existing antibodies developed in response to natural infection or immunization with the 13-valent pneumococcal conjugate vaccine (PCV13). The diagnosis of SAD can only be made by interpretation of an individual's response to pure polysaccharide antigens such as are included in PPSV23.
●Children aged 2 to 5 years who were previously immunized with the conjugate vaccine and are then given the polysaccharide vaccine are expected to generate protective responses to at least 50 percent of the serotypes present only in the unconjugated polysaccharide vaccine.
●Individuals aged 6 to 60 years are expected to generate protective responses to at least 70 percent of serotypes tested if they did not receive the conjugate vaccine. If they did receive the conjugate vaccine previously, only the serotypes in the polysaccharide vaccine should be considered (table 2). We consider the response adequate if a majority of the interpretable serotypes are protective following administration of the polysaccharide vaccine.
●The normal response for individuals over age 65 is not well-defined, but it is probably decreased (ie, both lower titers and fewer protective titers) compared with younger individuals. Multiple factors, including nutritional variables, may contribute to these differences .
Degrees of nonresponse — Patients can be classified into several phenotypes of polysaccharide nonresponsiveness based upon their responses to individual serotypes and by the percentage of serotype polysaccharides eliciting an adequate response (table 3) [32,34].
●The severe phenotype describes patients who have protective antibody concentrations to two or fewer pneumococcal serotypes (table 3). Antibody concentrations are usually at the lowest limit of detection.
●The moderate phenotype describes partial responses. These patients generate protective titers to fewer than the expected number of serotypes for their age group (table 3).
●There also appears to be a subset of patients with a rapid loss of antibodies over time, which is usually apparent between six months and two years after an initially successful immunization. This phenotype is not necessarily based upon poor immunologic memory, since reimmunization with a second dose of polysaccharide vaccine generally triggers a vigorous IgG antibody response. In patients who initially respond to immunization with the polysaccharide vaccine (especially with clinical improvement) but who experience increasing numbers of infections as time progresses, we re-evaluate titers to determine if they have subsequently dropped. This variant has been called the "memory phenotype" of SAD, although this terminology is problematic for the reasons just outlined.
Utility of booster doses — If a patient does not respond to an initial dose of PPSV23 (administered as part of the evaluation), it has been our experience that a second dose of PPSV23 given shortly after the first is of little benefit, because patients continue to have poor responses. In addition, repeated administration of PPSV23 is not advised because there is some risk of inducing hyporesponsiveness, especially in adults who have received an initial vaccination with PPSV23 followed by a booster with the PPSV23 or a booster with a conjugate vaccine .
In contrast, patients with SAD may respond to a conjugate vaccine, and we do administer that, but some continue to have recurrent infections, since the latter does not correct their underlying problem.
Responses to polysaccharide vaccines in patients receiving immunoglobulin — Since immunoglobulin contains antibodies to pneumococci, immune globulin therapy precludes the use of the pneumococcal vaccine as a test for SAD. Instead, a 2017 study proposed the use of the Salmonella enterica serotype Typhi (formerly S. typhi) vaccine (also called the Vi polysaccharide vaccine) as a test vaccine, since immune globulin does not contain antibodies to this microbe . (See "Assessing antibody function as part of an immunologic evaluation", section on 'Other polysaccharide vaccines'.)
Responses to other types of vaccines — The immunologic responses to conjugate and protein vaccines are generally normal in patients with SAD. (See "Assessing antibody function as part of an immunologic evaluation".)
Response to conjugate vaccines — Conjugate vaccines contain polysaccharide antigens complexed to immunogenic proteins. These vaccines were developed because normal children under the age of two years demonstrate poor responses to polysaccharide antigens alone. In children under two years, the antibody response to these vaccines, whether the antibodies are directed against polysaccharide or protein antigens, is predominately stimulated by the protein component and therefore reflects responsiveness to protein antigens. Thus, the response to these vaccines is not generally used in evaluating polysaccharide nonresponses. The response that is adequate to provide protection against invasive pneumococcal disease in a patient vaccinated with the pneumococcal conjugate vaccine is ≥0.35 mcg/mL.
Keeping in mind the significant differences in adequate antibody production after immunization with the conjugated vaccine compared with the pure polysaccharide vaccine, it is our experience that young children who appear to respond poorly to full immunization with conjugated pneumococcal vaccines may respond poorly to polysaccharide vaccines when these are given after the age of two years. Only a poor response to the polysaccharide vaccine then defines SAD. The clinical significance of a poor response to conjugate and polysaccharide vaccines as opposed to poor response to the polysaccharide vaccine serotypes only has not been rigorously tested.
Protein responses — In individuals older than two years of age suspected of having SAD, we also measure the antibody responses to tetanus and H. influenzae along with the prevaccine pneumococcal titer. Patients with SAD have normal responses to protein antigen vaccines. Poor protein antigen responses are seen in more profound immunodeficiencies, such as common variable immunodeficiency or severe combined immunodeficiency. However, low antiprotein antibody concentrations in patients with normal immunoglobulins are most likely due to a long time lapse since prior vaccines or a failure to receive the full series of vaccines or to receive booster doses.
DIAGNOSIS — The diagnosis of SAD is made in a patient older than two years of age with recurrent or severe sinopulmonary infections, in whom the only identifiable abnormality is a deficient response to polysaccharide vaccines. Other measurements of immunologic function, including serum levels of IgG, IgG subclasses, IgA, IgM, and IgE, should be normal, and responses to protein vaccines should be normal. In addition, no other primary or secondary immune disorders should be present. The diagnosis is not appropriate in a child younger than two years, because deficient polysaccharide responses are commonly seen and not considered abnormal.
DIFFERENTIAL DIAGNOSIS — Polysaccharide nonresponsiveness is seen in a variety of other immunodeficiency disorders, as well as in the context of certain systemic illnesses or during treatment with immunosuppressive medications. This section reviews secondary causes of polysaccharide nonresponsiveness.
Immunodeficiency disorders — Polysaccharide nonresponse is seen in a variety of primary immunodeficiencies, including IgG subclass deficiency, common variable immunodeficiency, 22q11 deficiency (DiGeorge syndrome), severe combined immunodeficiency, and other combined immunodeficiencies like hyperimmunoglobulin E syndrome, nuclear factor-kappa-B essential modulator (NEMO) deficiency, Wiskott-Aldrich syndrome, ataxia-telangiectasia, and others.
IgG2 subclass deficiency — The majority of antibodies to bacterial polysaccharides are of the IgG2 subclass [38-40]. Accordingly, there are particular associations between IgG2 subclass deficiencies and polysaccharide nonresponses, including the following [27,28,41]:
●Low IgG2 levels may correlate with poor response to pneumococcal polysaccharide vaccine, response to a restricted number of polysaccharides within the pneumococcal vaccine, or poor immunologic memory with IgG antibody titers returning to preimmunization levels within 6 to 12 months [27,28,41].
●IgG2 deficiency and polysaccharide nonresponses occur together in other immunodeficiency syndromes, such as ataxia-telangiectasia and mucocutaneous candidiasis [42,43].
However, since patients with IgG2 deficiency are also a heterogeneous population, no single pathogenic mechanism can be inferred. In contrast to IgG2-deficient patients, most children with IgG3 or IgG4 deficiencies appear to have normal responses to pneumococcal polysaccharides. (See "IgG subclass deficiency".)
Other disease states — Several acquired conditions can lead to immunosuppression with secondary polysaccharide nonresponses.
●Malignancy – Malignancies, such as thymoma, chronic lymphocytic leukemia, and lymphoma, can result in decreased immunoglobulin production.
●Asplenia – Functional or postsurgical asplenia or hyposplenia may result in impaired polysaccharide vaccine responses. (See "Prevention of infection in patients with impaired splenic function", section on 'Vaccinations'.)
●Viral infections – HIV can cause bone marrow suppression and poor vaccine response. (See "Immunizations in persons with HIV", section on 'General principles'.)
Medications — Immunosuppressive medications, including long-term systemic glucocorticoids, are other secondary causes of poor vaccine responsiveness. (See "Glucocorticoid effects on the immune system", section on 'Impact on vaccination' and "Secondary immunodeficiency induced by biologic therapies", section on 'Impact on vaccination'.)
TREATMENT — The prevention and treatment suggestions outlined in this topic review are working recommendations that will require further confirmation by more extensive clinical observations and follow-up .
Treatment of patients with SAD includes the following:
●Immunization with conjugate vaccines
●Aggressive management of other conditions predisposing to recurrent sinopulmonary infections (eg, asthma, allergic rhinitis, chronic rhinosinusitis)
●Increased vigilance and appropriate antibiotic therapy for infections
●Intravenous or subcutaneous immunoglobulin replacement
The degree to which an individual patient utilizes some or all of these therapies depends upon the severity of their SAD and their clinical course, and in most cases is done in a phased approach. (See 'Our approach' below.)
General measures — General measures are appropriate for patients with any severity of SAD.
Immunization with conjugate vaccine — All patients with SAD should be immunized with the 13-valent pneumococcal conjugate vaccine (PCV13):
●The PCV13 should be used to complete or initiate the series of pneumococcal conjugate vaccines in children. Among children older than two years of age who fail to respond to the polysaccharide pneumococcal vaccine, 80 to 90 percent respond to one dose of the conjugate vaccine . The response that is adequate to provide protection against invasive pneumococcal disease in a patient vaccinated with the pneumococcal conjugate vaccine is ≥0.35 mcg/mL. (See "Pneumococcal vaccination in children", section on 'Immunization of high-risk children and adolescents'.)
●The United States Committee on Immunization Practices (Advisory Committee on Immunization Practices [ACIP]) has recommended that adults with immunocompromising conditions receive the PCV13 vaccine, even if they have previously received the 23-valent pneumococcal polysaccharide vaccine (PPSV23) . Adults who fail to respond to an initial dose of conjugate vaccine sometimes respond to a second dose .
Most patients who respond to the conjugate vaccine also improve clinically, although the conjugate vaccine only confers protection against 13 common pneumococcal serotypes, and recurrent respiratory infections are caused by a much larger range of serotypes.
Management of other sinopulmonary disease — Aggressive management of other conditions predisposing to recurrent sinopulmonary infections (especially allergic rhinitis and asthma) is critical to improving the clinical outcome of these patients. Management of allergic rhinitis and asthma includes allergy evaluation and trigger avoidance, nasal and inhaled glucocorticoids, bronchodilators, and antihistamines. (See "Pharmacotherapy of allergic rhinitis" and "An overview of asthma management".)
Optimal use of antibiotics — Prompt recognition and treatment of sinopulmonary bacterial infections is a significant component of management of these patients because infections rarely clear spontaneously in patients with antibody defects. When possible, infections should be verified through culture, selective use of imaging (being mindful of cumulative radiation exposure), complete blood counts, measurement of C-reactive protein levels, and evaluation of the erythrocyte sedimentation rate. (See "Acute bronchitis in adults" and "Acute sinusitis and rhinosinusitis in adults: Clinical manifestations and diagnosis" and "Acute bacterial rhinosinusitis in children: Clinical features and diagnosis", section on 'Diagnosis' and "Community-acquired pneumonia in children: Clinical features and diagnosis", section on 'Clinical evaluation'.)
We find that prolonged courses (eg, one to three months for chronic sinusitis) are sometimes needed to clear infections completely in these patients. Thus, our approach is to administer antibiotics only when there are clinical or laboratory signs of active infection and to assure that the infection is fully resolved before discontinuation. The use of antibiotics in patients with immunodeficiency is reviewed in more detail separately. (See "Inborn errors of immunity (primary immunodeficiencies): Overview of management", section on 'Infectious disease'.)
Patients with continued infections despite general measures — For patients who continue to have sinopulmonary infections despite the general measures outlined above, prophylactic antibiotics and/or immune globulin therapy are the next steps in therapy.
Our approach — No prospective trials have specifically examined the efficacy of either intervention specifically in SAD. However, a retrospective review of 65 children and adults with SAD compared outcomes after one year of either prophylactic antibiotics or immune globulin and did not detect a difference in efficacy . Patients who failed prophylactic antibiotics often responded better to immune globulin. Those with lower IgG levels and autoimmunity had increased odds of experiencing persistent infections despite these therapies.
Prophylactic antibiotics — Our experience suggests that prophylactic antibiotics are not necessary for most patients. However, antibiotic prophylaxis could be considered if the frequency and severity of infections remain high after immunization with conjugate vaccine and careful management of atopic disease. This is particularly true in younger patients, who are more likely to outgrow their selective antibody deficiency, because prophylaxis would hopefully be required for only a limited time, such as during the winter months. Specific regimens for antibiotic prophylaxis are discussed separately. (See "Inborn errors of immunity (primary immunodeficiencies): Overview of management", section on 'Prophylactic antimicrobial therapy'.)
Evidence supporting the administration of prophylactic antibiotics is largely derived from retrospective studies of children with SAD and similar antibody deficiencies. One of the largest studies examined 120 children aged 2 to 15 years of age, most of whom had SAD . Seventy-two percent were successfully managed with prophylactic antibiotics. In a study on the use of immunoglobulin replacement therapy versus antibiotic prophylaxis in patients with IgG subclass deficiency with or without specific polysaccharide antibody deficiency, the overall efficacy of the two regimens did not differ . However, patients with persistent infections while on prophylactic antibiotics did better when switched to immunoglobulin therapy. However, the use of antibiotics in this way may promote the development of resistant organisms .
Immune globulin replacement therapy — Immune globulin replacement with intravenous immune globulin (IVIG) or subcutaneous immune globulin preparations is an option for patients with proven recurrent infections that persist after immunizing with conjugate vaccines and appropriate antibiotic treatment. These patients are a minority in our experience. We administer immune globulin replacement therapy to patients with well-documented moderate or severe polysaccharide nonresponsiveness and evidence of recurrent infections, with a proven requirement of antibiotic therapy for improvement. In the absence of severe infections or a clinical presentation with a history of life-threatening illness, we consider prophylactic antibiotics as a first-line therapy. Additional possible indications for immune globulin replacement therapy are uncontrollable recurrent otitis media with risk for permanent hearing loss, presence of bronchiectasis, and, in rare patients, multiple antibiotic hypersensitivities that interfere with appropriate treatment.
The use of immune globulin replacement therapy in patients with SAD has not been evaluated in randomized, placebo-controlled trials, although its efficacy in hypogammaglobulinemia is well-established. In case reports and retrospective series of adult and pediatric patients with SAD, significant decreases in the number of infections were consistently reported [5,47,50].
The standard IVIG dose is 400 mg/kg given intravenously every four weeks . Occasional patients require either higher doses (500 to 600 mg/kg every four weeks) or shorter intervals between infusions to prevent infections in the period prior to the next immune globulin dose. Immune globulin can also be administered subcutaneously at weekly intervals. An overview of the use of immune globulin replacement therapy is presented separately. (See "Immune globulin therapy in inborn errors of immunity" and "Subcutaneous and intramuscular immune globulin therapy" and "Overview of intravenous immune globulin (IVIG) therapy".)
In patients with SAD, the decision to shorten the interval between IVIG infusions should be based on clinical response to treatment, rather than trough IgG levels, because many patients begin therapy with normal or even higher-than-normal total IgG concentrations. Thus, serum trough levels of IgG usually are not helpful and are not used to adjust the immune globulin dose.
Duration of therapy
Children younger than six years of age — If immune globulin replacement therapy is begun in children under six years of age, it is our practice to discontinue it after one or two years and perform a reassessment of antibody-mediated immunity four to six months after discontinuation, especially in patients who develop recurrent infections. It is helpful to explain this plan to patients' caregivers when therapy is first initiated. Whenever possible, the discontinuation of immune globulin therapy should be scheduled for spring or summer time, when the incidence of infections is usually lower.
The suggestion to discontinue immune globulin replacement therapy periodically in children is based upon our observation that responses to the polysaccharide vaccine sometimes improve after treatment for 6 to 24 months . The mechanisms for this improvement are unknown. Maturation of the immune system and/or an immunomodulatory effect of the immune globulin treatment may be involved. Re-evaluation includes measurement of immunoglobulins and specific antibodies, as well as vaccine challenge with the polysaccharide vaccine at least four to six months off immunoglobulin replacement therapy. The decision to restart immune globulin replacement is based upon clinical course and the laboratory evaluation. If infections begin to occur again, it is our experience that the disorder usually persists in that patient. This approach is consistent with recommendations from the American Academy of Asthma, Allergy, and Immunology, which endorses a single trial of cessation, but resumption of immune globulin if infections recur in that patient .
Older children and adults — It is the authors' experience that SAD is persistent in older children and adults, and that successful discontinuation is unlikely.
PROGNOSIS — Patients generally do well once SAD is identified and properly managed, although there are few long-term data.
●Transient forms are common in children two to five years of age, but most outgrow the illness.
●The disorder is usually persistent in older children and adults, as mentioned previously. We have observed some older patients who developed common variable immunodeficiency over time, although this is unusual.
The differences in prognosis in different age groups may reflect distinct pathogenic mechanisms. Further insights into the pathogenesis of this syndrome in different patients should eventually result in a more reliable assessment of the risk for persistent immune abnormalities and recurrent infections in some of these patients. In the future, the assessment of B cell subsets may help predict which patients will need more prolonged treatment and follow-up. For example, one study suggests that the percentage of circulating memory B cells may predict clinical prognosis in patients diagnosed with selective antibody deficiency . Lower percentages of these memory B cells correlated with higher prevalence of bronchiectasis, splenomegaly, and autoimmunity. While this information does not translate into specific guidelines to screen for these complications, it confirms the importance of long-term follow-up and medical management of these patients. Memory B cells are discussed separately. (See "Normal B and T lymphocyte development", section on 'Memory B cells'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Inborn errors of immunity (previously called primary immunodeficiencies)".)
SUMMARY AND RECOMMENDATIONS
●An inability to respond to polysaccharide antigens is an immunologic defect that can exist in isolation or as part of various primary or secondary immune disorders. It is one of the most commonly identified immune defects among patients presenting with recurrent and/or severe sinopulmonary infections. The term "specific antibody deficiency" (SAD) is applied when this defect is the only identifiable problem and serum levels of immunoglobulins (Ig) are normal. (See 'Overview' above.)
●The diagnosis should only be considered in adults and in children over the age of two years, because younger children are normally less responsive to polysaccharide vaccines. In some patients, SAD may represent delayed maturation of the immune system, while in others it might be the result of a specific molecular defect. (See 'Pathogenesis' above.)
●The clinical manifestations include recurrent sinopulmonary infections due to Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, or Staphylococcus aureus. Infections beyond the normal frequency should prompt evaluation of antibody-mediated immunity (table 1). Many patients also have atopic diseases. (See 'Clinical manifestations' above.)
●Evaluation for this disorder involves first assuring that serum levels of IgG, IgA, IgM, and IgG subclasses are normal. Next, a panel of 23 (or at least 14) specific antipneumococcal antibody concentrations is assessed in immunized children or in adults (regardless of immunization status). If initial levels of antipneumococcal antibodies are not protective with antibody titers >1.3, the patient should be immunized with pneumococcal polysaccharide vaccine (not the conjugate vaccine), and specific antibody titers should be obtained from the same laboratory eight weeks later. (See 'Evaluation' above.)
●Nonresponse can be subdivided into severe and moderate phenotypes (table 3). An additional variant is recognized in which vaccine response is normal, but there is rapid loss of protective titers over 6 to 24 months. (See 'Degrees of nonresponse' above.)
●Management includes prompt treatment of sinopulmonary infections and aggressive treatment of atopic diseases. (See 'Treatment' above.)
●In the minority of patients in whom infections continue to occur despite vaccination with conjugate vaccine, management of atopic conditions, and aggressive use of antibiotics during infections, we suggest the administration of prophylactic antibiotics (Grade 2C). Generally, this is only needed for a limited period of time. (See 'Optimal use of antibiotics' above.)
●In the few patients in whom infections continue to occur despite all of the above measures, we suggest the administration of immune globulin replacement therapy (Grade 2C). We use standard dosing, in the range of 400 to 600 mg/kg infused once every four weeks for intravenous administration or a corresponding dose for subcutaneous administration. (See 'Immune globulin replacement therapy' above.)
●For young children (under age six years) requiring immune globulin replacement therapy, we suggest interrupting therapy after one to two years of treatment in order to reassess the response to polysaccharide vaccine, as the condition may spontaneously improve (Grade 2C). (See 'Duration of therapy' above.)
●The prognosis in young children is favorable, because the condition often resolves spontaneously over time. In older children and adults, the condition appears to persist in most cases, although infections can be minimized with appropriate management. (See 'Prognosis' above.)
ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges E Richard Stiehm, MD, who contributed as a Section Editor to earlier versions of this topic review.
The UpToDate editorial staff also acknowledges Ricardo U Sorensen, MD, who contributed as an author to earlier versions of this topic review.
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