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Bacterial respiratory tract infections are the hallmark of primary antibody deficiencies (PADs). Because they are also among the most common infections in healthy individuals, PADs are usually overlooked in these patients. Careful evaluation of the history, including frequency, chronicity, and presence of other infections, would help suspect PADs. This review will focus on infections in relatively common PADs, discussing diagnostic challenges, and some management strategies to prevent infections.

Background:Inadequate titers of pneumococcal antibody (PA) are commonly present among patients with recurrent respiratory infections. Objective:We sought to determine the effect of the degree of inadequacy in baseline PA titers on the subsequent polysaccharide vaccine response, the incidence of sinusitis, and allergic conditions. Methods:A total of 313 patients aged 6 to 70 years with symptoms of recurrent respiratory infections were classified by baseline-pPA (percentage of protective [≥1.3 µg/mL] PA serotypes/total tested serotypes) and postvaccination pPA (post-pPA): Group A (adequate baseline-pPA), Group B (inadequate baseline-pPA, adequate post-pPA, responders), and Group C (inadequate baseline-pPA, inadequate postpPA, nonresponders, specific antibody deficiency [SAD]). Immunity against Streptococcus pneumoniae was defined as adequate when the pPA was ≥70%. Each group and combined groups, Group AB (inadequate baseline-pPA), and Group BC (adequate post-pPA) were analyzed for demographics, history of sinusitis, recurrent sinusitis in the following year, allergic conditions, and association with inadequate individual serotype titers. Results:Over 80% of patients with respiratory symptoms had inadequate baseline-pPA. Baseline-pPA and SAD prevalence are inversely related (odds ratio = 2.02, 95% CI: 1.15-3.57, P = .01). Inadequate serotype 3 antibody titer is highly associated with SAD (odds ratio = 2.02, 96% CI: 1.61-5.45, P

Humoral immune disorders such as common variable immunodeficiency (CVID) and specific antibody deficiency (SAD) are prevalent in clinical practice and require accurate functional testing of humoral immunity for diagnosis and to guide treatment approach. Traditionally, the 23-valent pneumococcal polysaccharide vaccine (PPSV23) has been used to assess polysaccharide antibody responses by measuring pre- and post-vaccination pneumococcal titers. However, the recent introduction of pneumococcal conjugate vaccines (PCVs), such as PCV13, PCV15, and PCV20, into the childhood and adult vaccine schedules has significantly reduced the number of unique serotypes available for testing and in turn has complicated the evaluation process. We retrospectively analyzed serotype-specific antibody responses in patients aged 2-65 years who received PPSV23 at the University of Virginia Health System to compare diagnostic outcomes using all 23 serotypes versus the limited number of unique serotypes not included in prior PCVs-11 serotypes for PCV13 recipients and 4 for PCV20 recipients. Our findings demonstrate that although prior PCVs mean there is a reduced number of serotypes available for interpretation, PPSV23 testing maintains diagnostic accuracy between 81% and 84%. Despite limitations, the use of PPSV23 remains a valuable tool for identifying patients with clinically significant humoral immune deficiencies. In the future, alternative diagnostic approaches like Salmonella typhi polysaccharide vaccine response and opsonophagocytosis assays may become more commonly utilized as part of the evaluation of humoral immune disorders., (Copyright © 2024. Published by Elsevier Inc.)

Specific antibody deficiency against pneumococcal serotypes was detected in a patient with recurrent episodes of fever. A 21-year-old man presented with a two-month history of recurrent episodes of fever and shaking chills. He was diagnosed with recurrent episodes of pneumonia caused by Streptococcus pneumoniae serotype 19A and treated with amoxicillin. Serotype-specific antibodies were not produced against most of the serotypes, which were consistent with moderate specific antibody deficiency. After pneumococcal 13-valent conjugate vaccination and pneumococcal polysaccharide vaccination, he adequately responded to the infecting serotype with an antibody titer of 1.1 µg/mL. There were eventually no recurrent episodes of fever with pneumonia.

Background: Despite immunoglobulin replacement (IgRT) therapy, some patients with primary antibody deficiency (PAD) continue to develop respiratory infections. Recurrent and severe respiratory infections, particularly pneumonia, can lead to significant morbidity and mortality. Therefore, we sought to determine the risk factors of developing pneumonia in PAD patients, already receiving IgRT. Methods: We evaluated clinical and laboratory features of PAD patients enrolled in the US Immune Deficiency Network (USIDNET) registry by April 2017. Patients were included if they met the following criteria: (1) PAD diagnosis (common variable immunodeficiency (CVID), agammaglobulinemia, hypogammaglobinemia, and specific antibody deficiency (SAD) and (2) available data on infections before and after IgRT. Patients were excluded if they were not receiving IgRT, or if no pre/post infections data were available. Descriptive and multivariable logistic regression analyses were used to identify factors associated with pneumonia post-IgRT. Results: A total of 1232 patients met the inclusion criteria. Following IgRT, 218 patients (17.7%) were reported to have at least one pneumonia episode. Using multivariate logistic regression analysis, we found a statistically significant increased risk of pneumonia in patients with asthma (OR: 2.55, 95% CI (1.69–3.85), p < 0.001) bronchiectasis (OR: 3.94, 95% CI (2.29–6.80), p < 0.001), interstitial lung disease (ILD) (OR: 3.28, 95%CI (1.43–7.56), p < 0.005), splenomegaly (OR: 2.02, 95%CI (1.08–3.76), p < 0.027), allergies (OR: 2.44, 95% CI [1.44–4.13], p = 0.001), and patients who were not on immunosuppressives (OR: 1.61; 95%CI [1.06–2.46]; p = 0.027). For every 50 unit increase in IgA, the odds of reporting pneumonia post IgRT decreased (OR: 0.86, 95% CI [0.73–1.02], p = 0.062). Infectious organisms were reported in 35 of 218 patients who reported pneumonia after IgRT. Haemophilus influenzae was the most frequently reported (n = 11, 31.43%), followed by Streptococcus pneumoniae (n = 7, 20.00%). Conclusion: Our findings suggest PAD patients with chronic and structural lung disease, splenomegaly, and allergies were associated with persistent pneumonia. However, our study is limited by the cross-sectional nature of the USIDNET database and limited longitudinal data. Further studies are warranted to identify susceptible causes and explore targeted solutions for prevention and associated morbidity and mortality. Clinical Implications: Patients with primary antibody deficiency with structural lung disease, allergies, and splenomegaly are associated with persistent pneumonia post-IgRT. [ABSTRACT FROM AUTHOR]

Immune responses to coronavirus disease 2019 (COVID-19) mRNA vaccines in primary antibody deficiencies (PADs) are largely unknown. We investigated antibody and CD4+ T-cell responses specific for SARS-CoV-2 spike protein (S) before and after vaccination and associations between vaccine response and patients' clinical and immunological characteristics in PADs. The PAD cohort consisted of common variable immune deficiency (CVID) and other PADs, not meeting the criteria for CVID diagnosis (oPADs). Anti-S IgG, IgA, and IgG subclasses 1 and 3 increased after vaccination and correlated with neutralization activity in HCs and patients with oPADs. However, 42% of CVID patients developed such responses after the 2nd dose. A similar pattern was also observed with S-specific CD4+ T-cells as determined by OX40 and 4-1BB expression. Patients with poor anti-S IgG response had significantly lower levels of baseline IgG, IgA, CD19+ B-cells, switched memory B-cells, naïve CD8+ T-cells, and a higher frequency of EM CD8+ T-cells and autoimmunity compared to patients with adequate anti-S IgG responses. Patients with oPADs can develop humoral and cellular immune responses to vaccines similar to HCs. However, a subset of CVID patients exhibit impairment in developing such responses, which can be predicted by the baseline immune profile and history of autoimmunity. [ABSTRACT FROM AUTHOR]

Assessing T-cell independent antibody response to polysaccharide vaccines is crucial for diagnosing humoral immune deficiencies. However, immunocompetence criteria based on S. pneumoniae vaccination remain unclear. We evaluated IgG antibody vaccine response in healthy individuals to establish interpretive criteria. Pre- and 4-week post-vaccination sera were collected from 79 adults. Antibody concentrations to PNEUMOVAX 23 serotypes were measured using a multiplexed platform. Immunocompetence was determined by fold increase in post-vaccination response, percentage of serotypes achieving 4- or 2-fold antibody ratio, and post-vaccination concentration ≥ 1.3 μg/mL. Immunogenicity varied widely across the 23 serotypes (26.6% to 94.9% for ≥4-fold increase, 51.9% to 98.7% for ≥2-fold increase). Immunocompetence based on historic criteria of ≥4-fold increase in antibody ratio to ≥70% of serotypes was low (72.2%), but increased to 98.7% with criteria of at least a 2-fold increase and/or post-vaccination concentration ≥ 1.3 μg/mL. Current criteria for assessing immunocompetence may be overly stringent and require updating. [ABSTRACT FROM AUTHOR]

Although selective IgM deficiency (SIGMD) was described almost five decades ago, it was largely ignored as a primary immunodeficiency. SIGMD is defined as serum IgM levels below two SD of mean with normal serum IgG and IgA. It appears to be more common than originally realized. SIGMD is observed in both children and adults. Patients with SIGMD may be asymptomatic; however, approximately 80% of patients with SIGMD present with infections with bacteria, viruses, fungi, and protozoa. There is an increased frequency of allergic and autoimmune diseases in SIGMD. A number of B cell subset abnormalities have been reported and impaired specific antibodies to Streptococcus pneumoniae responses are observed in more than 45% of cases. Innate immunity, T cells, T cell subsets, and T cell functions are essentially normal. The pathogenesis of SIGMD remains unclear. Mice selectively deficient in secreted IgM are also unable to control infections from bacterial, viral, and fungal pathogens, and develop autoimmunity. Immunological and clinical similarities and differences between mouse models of deficiency of secreted IgM and humans with SIGMD have been discussed. Patients with SIGMD presenting with recurrent infections and specific antibody deficiency responses appear to improve clinically on immunoglobulin therapy.

Background: Inborn errors of immunity, mainly Predominantly Antibody deficiencies with normal IgG levels are unrecognized in adults with lung diseases such as bronchiectasis or recurrent pneumonia. Objective: To determine IgM, IgA, IgG2 subclass deficiencies, and Specific antibody deficiency (anti-pneumococcal polysaccharide antibodies) in adults with non-cystic fibrosis bronchiectasis or recurrent pneumonia. Methods: Cross-sectional study. Consecutive patients with non-cystic fibrosis bronchiectasis or recurrent pneumonia were recruited in Cali, Colombia. IgG, IgA, IgM, and IgE, IgG2subclass and IgG anti-pneumococcal serum levels were measured. Results: Among the 110 participants enrolled, Antibody deficiencies with normal serum IgG levels were found in 11(10%) cases. IgA deficiency (3 cases), IgM deficiency (2 cases) and IgG2 deficiency (2 cases) were the most frequent primary immunodeficiencies. In addition, IgG2+IgA deficiency, Ataxia-telangiectasia, Hyper-IgE syndrome and Specific Antibody Deficiency(anti-polysaccharides) were found in one case each. Conclusions: Predominantly antibody deficiencies with normal IgG levels are an important etiology of non-cystic fibrosis bronchiectasis and recurrent pneumonia in adults. [ABSTRACT FROM AUTHOR]

Bacterial respiratory tract infections are the hallmark of primary antibody deficiencies (PADs). Because they are also among the most common infections in healthy individuals, PADs are usually overlooked in these patients. Careful evaluation of the history, including frequency, chronicity, and presence of other infections, would help suspect PADs. This review will focus on infections in relatively common PADs, discussing diagnostic challenges, and some management strategies to prevent infections.

Purpose: Although common variable immunodeficiency (CVID) is considered the most prevalent symptomatic primary antibody deficiency (PAD), there is a population with symptomatic PADs that do not meet criteria for CVID. We analyzed clinical and immunological profiles of patients with different PADs to better understand the differences and similarities between CVID and other PADs. Methods: We extracted clinical and laboratory data of patients with PADs from electronic medical records. Patients were categorized into CVID, IgG subclass 2 deficiency (IgG2D), IgG deficiency (IgGD), and specific antibody deficiency (sAbD) based on basal immunoglobulin levels and pneumococcal vaccine responses. We compared clinical and immunological characteristics in these groups. Results: All patients, regardless of PAD types, showed similar frequencies of infections, bronchiectasis, and interstitial lung disease (ILD). Hematopoietic malignancies were more frequently found in the CVID than in the IgG2D, IgGD, and sAbD groups, while the latter groups trended towards an increased frequency of connective tissue diseases (CTD). Low counts of natural killer (NK) cells were associated with malignancy, autoimmunity, and ILD in CVID but not in other PAD groups. Conclusions: Higher frequency of hematopoietic malignancy in CVID than in the other PADs and association of lower NK cell counts with non-infectious complications in CVID suggest a relationship between immune alterations and the development of non-infectious manifestations in PADs. [ABSTRACT FROM AUTHOR]

Purpose: Prophylactic antibiotics (PA) and immunoglobulin replacement (IGRT) are commonly used in specific antibody deficiency (SAD); however, optimal treatment is not well-established. Our purpose is to compare treatment outcomes with IGRT and/or PA among SAD patients. Methods: A retrospective chart review of SAD patients treated at two tertiary centers between January 2012 and May 2017 was performed. Clinical and laboratory data, and rates of infections prior to and after treatment with IGRT or PA were analyzed. Descriptive analyses, between-group comparisons of rates of infection after 1 year of treatment, and a stepwise logistic regression model were employed to explore factors contributing to treatment outcomes. Results: We identified 65 SAD patients with mean age were 18 years (2–71 years). The baseline mean number of infections in the PA group and IGRT group was 4.71 (SD 3.15) and 7.73 (SD 6.65), respectively. Twenty-nine (44.6%) received IGRT, 7 (10.7%) received PA, 7 (10.7%) received both IGRT and PA, 15 (23.1%) failed PA and switched to IGRT, and 7 did not receive any specific treatment. After 1 year of treatment, the difference in the mean number of infections in PA vs. IGRT was not statistically significant [2.86 (2.73) vs. 4.44 (4.74), p = 0.27]. Reporting autoimmunity increased the odds for persistent infections (OR = 4.29; p = 0.047), while higher IgG levels decreased the odds for persistent infections (OR = 0.68, p = 0.018). Conclusions: PA and IGRT are equally effective as first line in preventing infections in SAD patients. However, patients who fail PA would benefit from IGRT. [ABSTRACT FROM AUTHOR]

Background: The correlation between different methods for the detection of pneumococcal polysaccharide vaccine (PPV) responses to diagnose specific polysaccharide antibody deficiency (SAD) is poor and the criteria for defining a normal response lack consensus. We previously proposed fifth percentile (p5) values of PPV responses as a new cutoff for SAD. Objective: To analyze the association of SAD (determined by either World Health Organization (WHO)-standardized ELISA or multiplex bead-based assay) with abnormal response to Salmonella (S.) typhi Vi vaccination in a cohort of patients with recurrent infections. Methods: Ninety-four patients with a clinical history suggestive of antibody deficiency received PPV and S. typhi Vi vaccines. Polysaccharide responses to either 3 or 18 pneumococcal serotypes were measured by either the WHO ELISA or a multiplex in-house bead-based assay. Anti-S. typhi Vi IgG were measured by a commercial ELISA kit. Allohemagglutinins (AHA) were measured by agglutination method. Results: Based on the American Academy of Allergy, Asthma and Immunology (AAAAI) criteria for WHO ELISA, 18/94 patients were diagnosed with SAD and 22/93 based on serotype-specific p5 cutoffs for bead-based assay. The association between the two methods was significant, with 10 subjects showing abnormal response according to both techniques. Abnormal response to S. typhi Vi vaccination was found in 7 patients, 6 of which had SAD. No correlation was found between polysaccharide response and AHA, age, or clinical phenotype. Conclusion: The lack of evidence-based gold standards for the diagnosis of SAD represents a challenge in clinical practice. In our cohort, we confirmed the insufficient correlation between different methods of specific PPV response measurement, and showed that the S. typhi Vi response was not contributive. Caution in the interpretation of results is warranted until more reliable diagnostic methods can be validated. [ABSTRACT FROM AUTHOR]

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The article offers a study that reveals selective antibody deficiency (SAD) among patients with recurrent sinopulmonary infections. Topics discussed include SAD is an impaired response to polysaccharide antigens that can be detected in 15 percent of children older than two years old; information on the adequate response to 23‐PPV recommended by a task force of the American Academy of Allergy; mentions the test like T tests, and chi‐square test for comparison of baseline characteristics.

Background: Predominantly antibody deficiencies (PADs) are the most common type of primary immunodeficiency in adults. PADs frequently pass undetected leading to delayed diagnosis, delayed treatment, and the potential for end-organ damage including bronchiectasis. In addition, PADs are frequently accompanied by comorbid autoimmune disease, and an increased risk of malignancy. Objectives: To characterize the diagnostic and clinical features of adult PAD patients in Victoria, Australia. Methods: We identified adult patients receiving, or having previously received immunoglobulin replacement therapy for a PAD at four hospitals in metropolitan Melbourne, and retrospectively characterized their clinical and diagnostic features. Results: 179 patients from The Royal Melbourne, Alfred and Austin Hospitals, and Monash Medical Centre were included in the study with a median age of 49.7 years (range: 16-87 years), of whom 98 (54.7%) were female. The majority of patients (116; 64.8%) met diagnostic criteria for common variable immunodeficiency (CVID), and 21 (11.7%) were diagnosed with X-linked agammaglobulinemia (XLA). Unclassified hypogammaglobulinemia (HGG) was described in 22 patients (12.3%), IgG subclass deficiency (IGSCD) in 12 (6.7%), and specific antibody deficiency (SpAD) in 4 individuals (2.2%). The remaining four patients had a diagnosis of Good syndrome (thymoma with immunodeficiency). There was no significant difference between the age at diagnosis of the disorders, with the exception of XLA, with a median age at diagnosis of less than 1 year. The median age of reported symptom onset was 20 years for those with a diagnosis of CVID, with a median age at diagnosis of 35 years. CVID patients experienced significantly more non-infectious complications, such as autoimmune cytopenias and lymphoproliferative disease, than the other antibody deficiency disorders. The presence of non-infectious complications was associated with significantly reduced survival in the cohort. Conclusion: Our data are largely consistent with the experience of other centers internationally, with clear areas for improvement, including reducing diagnostic delay for patients with PADs. It is likely that these challenges will be in part overcome by continued advances in implementation of genomic sequencing for diagnosis of PADs, and with that opportunities for targeted treatment of non-infectious complications. [ABSTRACT FROM AUTHOR]

Although selective IgM deficiency (SIGMD) was described almost five decades ago, it was largely ignored as a primary immunodeficiency. SIGMD is defined as serum IgM levels below two SD of mean with normal serum IgG and IgA. It appears to be more common than originally realized. SIGMD is observed in both children and adults. Patients with SIGMD may be asymptomatic; however, approximately 80% of patients with SIGMD present with infections with bacteria, viruses, fungi, and protozoa. There is an increased frequency of allergic and autoimmune diseases in SIGMD. A number of B cell subset abnormalities have been reported and impaired specific antibodies to Streptococcus pneumoniae responses are observed in more than 45% of cases. Innate immunity, T cells, T cell subsets, and T cell functions are essentially normal. The pathogenesis of SIGMD remains unclear. Mice selectively deficient in secreted IgM are also unable to control infections from bacterial, viral, and fungal pathogens, and develop autoimmunity. Immunological and clinical similarities and differences between mouse models of deficiency of secreted IgM and humans with SIGMD have been discussed. Patients with SIGMD presenting with recurrent infections and specific antibody deficiency responses appear to improve clinically on immunoglobulin therapy.

Specific antibody deficiency (SAD) is a primary immunodeficiency disease characterized by normal immunoglobulins (Igs), IgA, IgM, total IgG, and IgG subclass levels, but with recurrent infection and diminished antibody responses to polysaccharide antigens following vaccination. There is a lack of consensus regarding the diagnosis and treatment of SAD, and its clinical significance is not well understood. Here, we discuss current evidence and challenges regarding the diagnosis and treatment of SAD. SAD is normally diagnosed by determining protective titers in response to the 23-valent pneumococcal polysaccharide vaccine. However, the definition of an adequate response to immunization remains controversial, including the magnitude of response and number of pneumococcal serotypes needed to determine a normal response. Confounding these issues, anti-polysaccharide antibody responses are age- and probably serotype dependent. Therapeutic strategies and options for patients with SAD are often based on clinical experience due to the lack of focused studies and absence of a robust case definition. The mainstay of therapy for patients with SAD is antibiotic prophylaxis. However, there is no consensus regarding the frequency and severity of infections warranting antibiotic prophylaxis and no standardized regimens and no studies of efficacy. Published expert guidelines and opinions have recommended IgG therapy, which are supported by observations from retrospective studies, although definitive data are lacking. In summary, there is currently a lack of evidence regarding the efficacy of therapeutic strategies for patients with SAD. We believe that it is best to approach each patient as an individual and progress through diagnostic and therapeutic interventions together with existing practice guidelines.

BackgroundSerotype-specific antibody responses to unconjugated pneumococcal polysaccharide vaccine (PPV) evaluated by a World Health Organization (WHO)-standardized enzyme-linked immunosorbent assay (ELISA) are the gold standard for diagnosis of specific polysaccharide antibody deficiency (SAD). The American Academy of Allergy, Asthma and Immunology (AAAAI) has proposed guidelines to interpret the PPV response measured by ELISA, but these are based on limited evidence. Additionally, ELISA is costly and labor-intensive. Measurement of antibody response to Salmonella typhi (S. typhi) Vi vaccine and serum allohemagglutinins (AHA) have been suggested as alternatives. However, there are no large cohort studies and cutoff values are lacking.ObjectiveTo establish cutoff values for antipneumococcal polysaccharide antibody response, anti-S. typhi Vi antibody, and AHA.MethodsOne hundred healthy subjects (10–55 years) were vaccinated with PPV and S. typhi Vi vaccine. Blood samples were obtained prior to and 3–4 weeks after vaccination. Polysaccharide responses to 3 serotypes were measured by WHO ELISA and to 12 serotypes by an in-house bead-based multiplex assay. Anti-S. typhi Vi IgG were measured with a commercial ELISA kit. AHA were measured by agglutination method.ResultsApplying AAAAI criteria, 30% of healthy subjects had a SAD. Using serotype-specific fifth percentile (p5) cutoff values for postvaccination IgG and fold increase pre- over postvaccination, only 4% of subjects had SAD. One-sided 95% prediction intervals for anti-S. typhi Vi postvaccination IgG (≥11.2 U/ml) and fold increase (≥2) were established. Eight percent had a response to S. typhi Vi vaccine below these cutoffs. AHA titer p5 cutoffs were ½ for anti-B and ¼ for anti-A.ConclusionWe establish reference cutoff values for interpretation of PPV response measured by bead-based assay, cutoff values for S. typhi Vi vaccine responses, and normal values for AHA. For the first time, the intraindividual consistency of all three methods is studied in a large cohort.

Measurement of IgG subclass concentrations is a standard laboratory test run as part of a panel to investigate the suspicion of antibody deficiency. The assessment is clinically important when total IgG is within the normal age-specific reference range. The measurement is useful for diagnosis of IgG subclass deficiency, to aid the diagnosis of specific antibody deficiency, as a supporting test for the diagnosis of common variable immunodeficiency, as well as for risk stratification of patients with low IgA. The measurement of IgG subclasses may also help determine a revaccination strategy for patients and support patient management. In certain circumstances, the measurement of IgG subclasses may be used to monitor a patient's humoral immune system. In this review, we discuss the utility of measuring IgG subclass concentrations. [ABSTRACT FROM AUTHOR]

Specific antibody deficiency (SAD) is a primary immunodeficiency disease characterized by normal immunoglobulins (Igs), IgA, IgM, total IgG, and IgG subclass levels, but with recurrent infection and diminished antibody responses to polysaccharide antigens following vaccination. There is a lack of consensus regarding the diagnosis and treatment of SAD, and its clinical significance is not well understood. Here, we discuss current evidence and challenges regarding the diagnosis and treatment of SAD. SAD is normally diagnosed by determining protective titers in response to the 23-valent pneumococcal polysaccharide vaccine. However, the definition of an adequate response to immunization remains controversial, including the magnitude of response and number of pneumococcal serotypes needed to determine a normal response. Confounding these issues, anti-polysaccharide antibody responses are age- and probably serotype dependent. Therapeutic strategies and options for patients with SAD are often based on clinical experience due to the lack of focused studies and absence of a robust case definition. The mainstay of therapy for patients with SAD is antibiotic prophylaxis. However, there is no consensus regarding the frequency and severity of infections warranting antibiotic prophylaxis and no standardized regimens and no studies of efficacy. Published expert guidelines and opinions have recommended IgG therapy, which are supported by observations from retrospective studies, although definitive data are lacking. In summary, there is currently a lack of evidence regarding the efficacy of therapeutic strategies for patients with SAD. We believe that it is best to approach each patient as an individual and progress through diagnostic and therapeutic interventions together with existing practice guidelines. [ABSTRACT FROM AUTHOR]

Background: Serotype-specific antibody responses to unconjugated pneumococcal polysaccharide vaccine (PPV) evaluated by a World Health Organization (WHO)-standardized enzyme-linked immunosorbent assay (ELISA) are the gold standard for diagnosis of specific polysaccharide antibody deficiency (SAD). The American Academy of Allergy, Asthma and Immunology (AAAAI) has proposed guidelines to interpret the PPV response measured by ELISA, but these are based on limited evidence. Additionally, ELISA is costly and labor-intensive. Measurement of antibody response to Salmonella typhi (S. typhi) Vi vaccine and serum allohemagglutinins (AHA) have been suggested as alternatives. However, there are no large cohort studies and cutoff values are lacking. Objective: To establish cutoff values for antipneumococcal polysaccharide antibody response, anti-S. typhi Vi antibody and AHA. Methods: One hundred healthy subjects (10-55 years) were vaccinated with PPV and S. typhi Vi vaccine. Blood samples were obtained prior to and 3-4 weeks after vaccination. Polysaccharide responses to 3 serotypes were measured by WHO ELISA and to 12 serotypes by an in-house bead-based multiplex assay. Anti-S. typhi Vi IgG were measured with a commercial ELISA kit. AHA were measured by agglutination method. results: Applying AAAAI criteria, 30% of healthy subjects had a SAD. Using serotype-specific fifth percentile (p5) cutoff values for postvaccination IgG and fold increase pre-over postvaccination, only 4% of subjects had SAD. One-sided 95% prediction intervals for anti-S. typhi Vi postvaccination IgG (⩾11.2 U/ml) and fold increase (⩾2) were established. Eight percent had a response to S. typhi Vi vaccine below these cutoffs. AHA titer p5 cutoffs were 1/2 for anti-B and 1/4 for anti-A. Conclusion: We establish reference cutoff for interpretation of PPV responce measured by bead-based assay, cutoff values for S. Typhi vi vaccince responses and normal values for AHA. For the first time, the intraindividual consistency of all three method is studied in a large cohort. [ABSTRACT FROM AUTHOR]

Introduction: Chronic rhinosinusitis (CRS) is a prevalent disease with a high annual cost of treatment. Immune deficiencies are more common in individuals with CRS and should be especially considered in those patients who are refractory to medical and surgical therapy. Areas covered: We performed a literature search in PubMed of the terms “immunodeficiency” and “sinusitis” or “rhinosinusitis” from 2006 through March 2016. All abstracts were reviewed to determine if they pertained to human disease; relevant articles were evaluated in their entirety and included in this review. Expertcommentary: CRS is a common disease; in those patients with frequent exacerbations or who are refractory to treatment, an immunodeficiency evaluation should be considered. Treatment includes vaccination, antibiotic therapy, immunoglobulin replacement and surgery. [ABSTRACT FROM AUTHOR]

Background: Specific antibody deficiency (SAD) is an inborn error of immunity, in patients older than 2 years, characterized by normal immunoglobulin levels and IgG subclasses, but with recurrent infections and decreased antibody responses to polysaccharide antigens. Case report: A 10-year-old female, previously healthy, with no significant family history. She is known in this institution for symptoms of headache, vomiting and paresis. A CT scan of the skull was performed, where 4 brain abscesses, edema and displacement of the midline were observed, a right frontal trephine was performed and abscess drainage, antimicrobial management for infectology, blood cultures, Gram staining and cultures of negative drainage material. Assessed for allergy and immunology, for abscesses in deep focus, an approach was performed to rule out inborn error of immunity, immunoglobulins, isohemagglutinins, flow cytometry and response to normal protein antigens. Antibodies against post-vaccination polysaccharide antigens are requested, where a response to only 2 serotypes (18.1% response) is observed, with normal IgG subclasses, a diagnosis of specific antibody deficiency is integrated and management with immunoglobulin at replacement doses is started, as well as annual vaccination with 13 valent. Conclusion: SAD has been considered a problem that can be resolved over time, especially in children, but in others it can evolve into more severe forms of humoral immunodeficiency. Decisions to treat with prophylactic antibiotics and/or gamma globulin are guided by clinical judgment, small studies, and recent consensus documents, which may evolve over time. [ABSTRACT FROM AUTHOR]

Background Patients with primary antibody deficiencies have an increased frequency of sinonasal and pulmonary infections. Immunoglobulin (Ig) replacement is a standard therapy for common variable immunodeficiency (CVID) and other antibody deficiency diseases. Although there is convincing evidence that Ig replacement reduces pulmonary infections, there is little evidence that it reduces sinus infections or abates chronic rhinosinusitis (CRS). This study aims to identify the impact of Ig replacement on CRS in antibody deficiencies. Methods A single-center, retrospective chart review of adult patients from 1995 to 2015 was performed. Inclusion criteria were diagnosis of CVID or specific antibody deficiency (SAD), history of CRS requiring medical and/or surgical management within the year prior to presentation, treatment with Ig replacement therapy, and follow-up interval of at least 1 year after initiating Ig replacement. Patients with secondary immune deficiencies were excluded. Thirty-one patients met criteria. Data collected included pretreatment and posttreatment Lund-Mackay scores, and frequency of sinusitis and pulmonary infections requiring rescue antibiotics. Statistical analysis was performed using Wilcoxon signed-rank tests. Results A significant decline in the Lund-Mackay score was evidenced from pretreatment to posttreatment ( p < 0.01). Treatment also resulted in significantly lower rates of sinusitis ( p < 0.01) and pulmonary infections ( p < 0.01). Additionally, 56% of patients who were on prophylactic antibiotics prior to Ig replacement were able to discontinue their use. Conclusion We present objective evidence showing that Ig replacement therapy has a positive impact on the frequency of sinusitis and confirm its positive impact on pulmonary infections in adult patients with CVID and SAD. [ABSTRACT FROM AUTHOR]

During the past 10 years, pneumococcal conjugate vaccine (PCV) has become part of the standard childhood vaccination programme. This may impact upon the diagnosis of polysaccharide antibody deficiency by measurement of anti-polysaccharide immunoglobulin (Ig)G after immunization with unconjugated pneumococcal polysaccharide vaccine (PPV). Indeed, contrary to PPV, PCV induces a T-dependent, more pronounced memory response. The antibody response to PPV was studied retrospectively in patients referred for suspected humoral immunodeficiency. The study population was divided into four subgroups based on age (2-5 years versus ≥ 10 years) and time tested (1998-2005 versus 2010-12). Only 2-5-year-old children tested in 2010-12 had been vaccinated with PCV prior to PPV. The PCV primed group showed higher antibody responses for PCV-PPV shared serotypes 4 and 18C than the unprimed groups. To a lesser extent, this was also found for non-PCV serotype 9N, but not for non-PCV serotypes 19A and 8. Furthermore, PCV-priming elicited a higher IgG2 response. In conclusion, previous PCV vaccination affects antibody response to PPV for shared serotypes, but can also influence antibody response to some non-PCV serotypes (9N). With increasing number of serotypes included in PCV, the diagnostic assessment for polysaccharide antibody deficiency requires careful selection of serotypes that are not influenced by prior PCV (e.g. serotype 8). Further research is needed to identify more serotypes that are not influenced. [ABSTRACT FROM AUTHOR]

Diagnostic vaccination is an integral component in the evaluation of patients suspected to have a B cell or humoral deficiency. Evaluation of antibody production in response to both protein- and polysaccharide-based vaccines aids in distinguishing between specific categories of humoral deficiency. Although assessment of pneumococcal polysaccharide responses is widely available and included in diagnostic guidelines, significant variability still exists in the measurement and interpretation of these responses. Interpretation can also be complicated by age, vaccination history and treatment with immunoglobulin replacement therapy. Despite the challenges and limitations of evaluating pneumococcal polysaccharide vaccine responses, it can provide valuable diagnostic and prognostic information to guide therapeutic intervention. Future efforts are needed to further standardize measurement and interpretation of pneumococcal antibody responses to vaccination and to identify and establish other methods and/or vaccines as alternatives to pneumococcal vaccination to address the challenges in certain patient populations. • Diagnostic vaccination is integral in evaluation of humoral immune deficiency. • Poor antibody responses can be of diagnostic and prognostic value and guide treatment. • Variability exists in measurement and interpretation of polysaccharide IgG responses. • Age, vaccination history and IGRT can complicate interpretation of vaccine response. • Alternative methods for evaluating polysaccharide antibody response are needed. [ABSTRACT FROM AUTHOR]

Polysaccharide antibody deficiency is characterized by a poor or absent antibody response after vaccination with an unconjugated pneumococcal polysaccharide vaccine. Allohaemagglutinins ( AHA) are antibodies to A or B polysaccharide antigens on the red blood cells, and are often used as an additional or alternative measure to assess the polysaccharide antibody response. However, few studies have been conducted to establish the clinical significance of AHA. To investigate the value of AHA to diagnose a polysaccharide antibody deficiency, pneumococcal polysaccharide antibody titres and AHA were studied retrospectively in 180 subjects in whom both tests had been performed. Receiver operating characteristic curves for AHA versus the pneumococcal vaccine response as a marker for the anti-polysaccharide immune response revealed an area under the curve between 0·5 and 0·573. Sensitivity and specificity of AHA to detect a polysaccharide antibody deficiency, as diagnosed by vaccination response, were low (calculated for cut-off 1/4-1/32). In subjects with only low pneumococcal antibody response, the prevalence of bronchiectasis was significantly higher than in subjects with only low AHA (45·5 and 1·3%, respectively) or normal pneumococcal antibody response and AHA (2·4%). A logistic regression model showed that low pneumococcal antibody response but not AHA was associated with bronchiectasis (odds ratio 46·2). The results of this study do not support the routine use of AHA to assess the polysaccharide antibody response in patients with suspected immunodeficiency, but more studies are warranted to clarify the subject further. [ABSTRACT FROM AUTHOR]

Chronic rhinosinusitis (CRS) is estimated to affect over 35 million people. However, not all patients with the diagnosis respond to standard medical and surgical treatments. Although there are a variety of reasons a patient may be refractory to therapy, one possible etiology is the presence of an underlying immunodeficiency. This review will focus on the description, recognition, and treatment of several antibody deficiencies associated with CRS, including common variable immunodeficiency (CVID), selective IgA deficiency, IgG subclass deficiency, and specific antibody deficiency (SAD). The diagnosis of antibody deficiency in patients with CRS is important because of the large clinical implications it can have on sinus disease management. CVID is treated with immunoglobulin replacement, whereas SAD may be managed symptomatically and sometimes with prophylactic antibiotics and/or immunoglobulin replacement. [ABSTRACT FROM AUTHOR]

Introduction: Clinical observations in patients with specific antibody deficiency treated for periods of time with IgG infusion have suggested that IgG may have a positive immunoregulatory effect on the production of specific antibodies against pneumococcal polysaccharides. We developed an in vitro model to test the effect of an IgIV preparation on the antibody production in response to a pneumococcal polysaccharide serotype and on the antibody and cytokine production in response to both a protein antigen and a pneumococcal polysaccharide antigen. Methods: We studied 37 consecutive patients referred to our clinics for evaluation of their recurrent respiratory infections. Subjects were divided into two groups: 22 patients without SAD and 15 patients with SAD. PBMCs were left unstimulated or were stimulated with tetanus toxoid or pneumococcal polysaccharide serotype 19, in the presence of human albumin or IgIV. IgG anti-Pn-19 antibody, IL-4 and IFN-γ concentrations in culture supernatants were determined by ELISA. Results: An increase in IgG anti-Pn-19 antibodies, associated with an increase in IFN-γ and a decrease in IL-4 production was observed in cultures stimulated with pneumococcal polysaccharide in the presence of IgIV when patients were analyzed together. The enhancing effect of IgIV was more significant for both IgG anti-Pn19 antibodies and IFN-γ in patients without SAD. In contrast, IgIV caused a significant decrease in IL-4 secretion in patients with SAD, which was associated with an increase in IgG anti-Pn19 antibodies in 3 of 7 of these patients. Conclusions: These results suggest that IgIV has some immunomodulatory effect on the in vitro production of IgG anti-Pn19 antibodies and cytokine production in cell cultures stimulated with Pn-19 antigen and that this modulation may be associated with a Th1/Th2 regulatory mechanism. Further studies at a cellular and molecular level are in progress to examine if the differences in the in vitro modulatory response to IgIV in these two groups of patients may point to a functional defect in patients with SAD. [ABSTRACT FROM AUTHOR]

Abstract: Coexisting morbidities in CVID include bronchiectasis, autoimmunity and malignancies. The incidence of autoimmune disease in CVID patients may approach 20% of cases. The most common autoimmune disease found in CVID patients is autoimmune cytopenia, but rheumatoid arthritis, lupus, and now primary biliary cirrhosis have also been reported. The coexistence of immunodeficiency and autoimmunity appears paradoxical, since one represents a hypoimmune state and the other a hyperimmune state. However, this paradox may not actually be all that implausible due to the complex nature of immune cells, signaling pathways and their interactions. The cellular alterations in combined variable immunodeficiency include a range of T and B cell abnormalities. Selective immune derangements found in CVID include a downregulation of regulatory T cells (Treg cells), accelerated T cell apoptosis, abnormal cytokine production secondary to cytokine gene polymorphisms and increased autoreactive B cell production. The impact of these abnormalities on T and B cell interaction may not only explain the immunodeficiency but also the development of autoimmunity in select groups of patients with CVID. The variability in the clinical manifestations of CVID as a result of this immune interaction suggests that CVID is not one disease but many. This is important because it follows that the treatment of CVID may not always be the same, but may need to be directed specifically towards each individual patient. [Copyright &y& Elsevier]

Immunoglobulin M (IgM) provides the initial response to foreign antigen and plays a regulatory role in subsequent immune response development, accelerating the production of high-affinity IgG. Though selective IgM deficiency was described more than 45 years ago in children with fulminant meningococcal septicemia, it has been largely an ignored primary immunodeficiency. It appears to be more common than originally realized. Selective IgM deficiency is observed in both children and adults with no gender bias. The most common clinical manifestation of selective IgM deficiency is infections with extracellular and intracellular bacteria, viruses, and fungi. Allergic diatheses are the second commonest presentation of selective IgM deficiency. There is an increased prevalence of autoimmune diseases, which in both humans and mice appear to be secondary to selective IgM deficiency rather IgM deficiency secondary to autoimmune diseases. Selective IgM deficiency, in some cases, is associated with 22q11.2 chromosome deletion and few familial cases of selective IgM deficiency have been reported. Innate immunity is relatively intact. T cells, T cell subsets, and T cell functions are normal. However, several patients with selective IgM deficiency and T cell and NK cell defects with Mycobacterium avium intracellulare infections have been reported. In a subset of patients with selective IgM deficiency circulating IgM+ B cells are decreased or completely lacking. Specific IgG antibody responses against pneumococcus polysaccharides are impaired in a subset of patients with selective IgM deficiency. The pathogenesis of selective IgM deficiency is unclear; decreased T helper activity, increased isotype-specific suppressor T cell activity, and intrinsic B cell defects have been reported. Patients with selective IgM deficiency and impaired pneumococcal antibody responses appear to respond to immunoglobulin therapy. [ABSTRACT FROM AUTHOR]

Purpose: To study the changes in the immunological status in 2 children with cartilage hair hypoplasia (CHH). Methods: A 4-6 year immunological follow-up from infancy. Results: In infancy the children presented a combined T cell and B cell immunodeficiency which partly resolved in time. Mitogen-induced T cell proliferation values fluctuated but lymphopenia has remained constant. Both patients had no recent thymic emigrants (TREC). Both children have suffered from a prolonged viral infection. Hypogammaglobulinemia normalized during the first years of life but both children have a specific antibody deficiency (SAD). Conclusions: The changes in the immunological status in CHH patients emphasize the importance of a regular follow-up. SAD should be searched for in CHH. The absence of TRECs supports combined immunodeficiency and possible need of hematopoietic stem cell transplantion. [ABSTRACT FROM AUTHOR]