Specific Antibody Deficiency Research Articles

Chronic rhinosinusitis (CRS) is prevalent and causes a great negative impact on quality of life. Primary antibody deficiency (PAD) is highly prevalent with CRS compared to the background population. There are efficient treatment options to consider when CRS is a symptom of PAD. The condition seems to be underdiagnosed. A prospective cohort study investigating adults with CRS for PAD. One hundred and thirty-eight patients were included in the study. Mean age was 49 years. Twenty-nine (21%) had hypogammaglobulinemia. Nine of 83 (11%) patients had insufficient response to pneumovax polysaccharide vaccine, but insufficient clinical history for diagnosis of Specific Antibody Deficiency (SPAD). Four patients met the clinical criteria for PAD; one had Common Variable Immune Deficiency (CVID), one had IgA deficiency, and two had IgG subclass deficiency. No clinical characteristic was predictive of PAD, and severity of CRS was not indicative of hypogammaglobulinemia or insufficient vaccine response. Immunoglobulin testing should be a routine part of the diagnostic work-up in chronic rhinosinusitis before considering biologics, as primary antibody deficiency is an under-recognised but treatable cause of refractory disease.

Children with recurrent infections present a diagnostic challenge due to the wide overlap between normal childhood infections and primary immunodeficiency diseases (PIDs). Predominantly antibody deficiencies (PADs) are the most common category of PID in this population. While many PAD cases are identified through markedly low immunoglobulins levels or reduced B cell counts, some demonstrate subtler forms such as IgG subclass deficiency (IGGSD) or specific antibody deficiency (SAD), which may present similar clinical symptoms but normal standard laboratory parameters. Diagnosing these conditions in children is particularly challenging due to the overlap with physiological immune immaturity and the high incidence of infections in early childhood. Clinicians must carefully distinguish between benign infection patterns and true immunodeficiencies to avoid missed diagnoses and unnecessary investigations. This review summarizes key findings on IGGSD and SAD, highlights their clinical relevance in paediatric practice, and evaluates current challenges in diagnosis and classification. We also discuss the overlap between these conditions and propose a structured approach to improve diagnostic consistency. Addressing these knowledge gaps is essential to optimize care for children with recurrent infections and suspected antibody deficiencies.

Lessons from the American College of Allergy, Asthma and Immunology inborn errors of immunity survey: Advancing diagnostic and therapeutic strategies for the practicing allergist-immunologist.

PurposeDespite the worldwide decrease in the incidence of serious pneumococcal infections following the introduction of the 13-valent pneumococcal conjugate vaccines (PCV13), invasive infections still occur. This study aimed to investigate the immunological function of children with severe parapneumonic effusion (PPE) both during their hospitalization and after full recovery.MethodsThis was a prospective, single-center study. Children with PPE were admitted to our clinic between 1 January 2011 and 30 June 2023, and participated in the study. Due to the severity of the effusion, all PPE cases required thoracic drainage and some children also underwent fibrinolysis and/or video-assisted thoracoscopic surgery. Demographic and clinical data and laboratory results were collected at admission. Extended immunological testing was performed at the time of clinical admission and again 6–8 weeks after discharge.ResultsA total of 66 episodes of PPE were identified. During hospitalization, one patient was diagnosed with human immunodeficiency virus infection and another with immunoglobulin A deficiency. Extended immunological evaluation was performed during follow-up in 49 patients. Within this cohort, seven patients were diagnosed with mannose-binding lectin deficiency and three with specific antibody deficiency. In total, immune dysfunction was confirmed in 12 patients. When comparing the immunocompromised and non-immunocompromised groups, the duration of hospitalization was longer in the immunocompromised group, with no other differences observed.ConclusionAlthough the incidence of severe PPE has declined since the introduction of PCV13, immunological evaluation remains essential for identifying underlying immunodeficiencies. Despite vaccination, screening patients with PPE for immune dysfunction is crucial. Early diagnosis and timely treatment can help prevent organ damage and reduce long-term morbidity.

Introduction/Background Patients with antibody deficiency commonly receive immunoglobulin replacement therapy (IgRT), but markers for disease control vary. The normal range for IgG ranges from 600 to 1700 mg/dL, with providers commonly aiming for a lower threshold of at least 550 mg/dL in these patients. A case series of two patients suggested that levels >800 mg/dL could provide significantly increased protection against infection and advocated tailoring IgRT doses based on specific patient outcomes (1). Methods Data collection was completed for 75 antibody-deficiency patients receiving subcutaneous immunoglobulin (SCIG) or intravenous immunoglobulin (IVIG). Of 75 patients, 13 were adults and all had CVID. Among pediatric patients, 55 had primary immunodeficiencies (PID): 9 CVID, 29 hypogammaglobulinemia, 7 Bruton’s agammaglobulinemia, 3 STAT-1 gain-of-function (GOF) mutation, 3 autoimmune lymphoproliferative syndrome (ALPS), and 4 specific antibody deficiency (SAD) with normal immunoglobulins and B cells. Seven remaining pediatric patients had secondary immunodeficiencies (SID) caused by end-stage renal disease or lymphoma. Data were annualized and patients were divided into “well-controlled” and “uncontrolled” disease. Lack of disease control was defined as greater than three courses of oral antibiotics or steroids yearly and >1 ED/ICU admission annually. Data/Results On average, well-controlled patients had three to four infections per year, while uncontrolled patients had six despite consistent IgRT treatment. The upper limit of IgG levels for any patient in this study did not exceed 1,394 mg/dL. The calculated average steady state IgG levels across the key subgroups are as follows: Well-controlled CVID: 844 mg/dL Well-controlled hypogammaglobulinemia: 899 mg/dL Suboptimally-controlled CVID: 635 mg/dL Suboptimally-controlled hypogammaglobulinemia: 606 mg/dL Bruton’s patients had no fewer than 4 infections annually, and an average IgG level of 637 mg/dL. Patients with SAD and ALPS had better disease control with an average steady-state IgG of 1,012 mg/dL. Patients with STAT-1 GOF had the highest steady-state IgG levels (988 mg/dL). In SID, IgG levels were difficult to capture due to inconsistent therapy use. There was no statistically significant difference between the adult and pediatric cohorts. Conclusion These results indicate the optimal IgG level for treatment should change based on diagnosis, but likely begins at least 800 mg/dL.

Background Humoral immune disorders, such as common variable immunodeficiency (CVID) and specific antibody deficiency (SAD), require functional testing for proper assessment and management. The most common testing involves the measurement of pre- and post-vaccination pneumococcal titers to assess polysaccharide antibody response to the 23-valent pneumococcal vaccine (PPSV23). Guidelines for this testing remain controversial and have become increasingly challenging with the widespread use of pneumococcal conjugate vaccines (PCV) such as PCV20, which have decreased the number of unique serotypes contained in PPSV23 that are available for assessing anti-polysaccharide antibody responses. Objective To determine the diagnostic utility in evaluating the polysaccharide antibody response to the four or eleven pneumococcal serotypes unique to PPSV23 in patients previously vaccinated with PCV20 or PCV13, respectively. Methods We performed a retrospective chart review using electronic medical records of patients aged 2-65 years old seen in University of Virginia Health Immunodeficiency Clinics who received PPSV23 and had pneumococcal titers measured within 8 weeks of vaccination (see table). Pneumococcal titers were measured using a 23-serotype bead-based multiplex immunoassay panel via Mayo Clinic Laboratories. A protective response was defined as ≥1.3 µg/mL, and a response to PPSV23 was classified as “positive” based on responding to ≥70% of the unique serotypes not contained in previously received PCV for each subject. Table 1.Pneumococcal Vaccine SerotypesSerotypesPCV-7aPCV-13bPCV-15cPCV-20dPCV-21ePPSV231–111–12–––––23–3333344444–45–555–56A–6A6A6A6A–6B6B6B6B6B–6B7F–7F7F7F7F7F8–––8889N––––9N9N9V9V9V9V9V–9V10A–––10A10A10A11A–––11A11A11A12F–––12F12F12F1414141414–1415A––––15A–15B–––15B–15B15C––––15C–16F––––16F–17F––––17F17F18C18C18C18C18C–18C19A–19A19A19A19A19A19F19F19F19F19F–19F20––––202022F––22F22F22F22F23A––––23A–23B––––23B–23F23F23F23F23F–23F24F––––24F–31––––31–33F––33F33F33F33F35B––––35B–a16 serotypes contained in PPSV23 that are not contained in PCV7: 1, 2, 3, 5, 7F, 8, 9N, 10A, 11A, 12F, 15B, 17F, 19A, 20, 22F, 33Fb11 serotypes contained in PPSV23 that are not contained in PCV13: 2, 8, 9N, 10A, 11A, 12F, 15B, 17F, 20, 22F, 33Fc9 serotypes contained in PPSV23 that are not contained in PCV15: 8, 10A, 11A, 12F, 15B, 2, 9N, 17F, 20d4 serotypes contained in PPSV23 that are not contained in PCV20: 2, 9N, 17F, 20e11 serotypes contained in PPSV23 that are not contained in PCV21: 1, 4, 5, 6B, 9V, 14, 18C, 19F, 23F, 15B, 2 Table 2.Diagnostic agreement summary between the pneumococcal antibody 4 and 11 serotype panel findings and the pneumococcal antibody 23 serotype panel findings when the pneumococcal antibody 23 serotype panel finding is considered the gold standard.23 Serotype Response11 Serotype ResponseResponder (≥70% Positive)Non-responder (<70% Positive)Responder (≥70% Positive)230Non-responder (<70% Positive)412Diagnostic Agreement SummaryDiagnostic ParameterEstimate [95% CI]Sensitivity96.7 [82.8, 99.9]Specificity66.7 [48.2, 82.0]PPV72.5 [56.1, 85.4]NPV95.7 [78.0, 99.9]FPER33.3 [18.0, 51.8]FNER3.3 [ 0.1, 17.2]Accuracy81.0 [69.1, 89.8]23 Serotype Response4 Serotype ResponseResponder (≥70% Positive)Non-responder (<70% Positive)Responder (≥70% Positive)222Non-responder (<70% Positive)510Diagnostic Agreement SummaryDiagnostic ParameterEstimate [95% CI]Sensitivity81.5 [61.9, 93.7]Specificity83.3 [51.6, 97.9]PPV91.7 [73.0, 99.0]NPV66.7 [38.4, 88.2]FPER16.7 [ 2.1, 48.4]FNER18.5 [ 6.3, 38.1]Accuracy82.1 [66.5, 92.5]11 Serotype Response4 Serotype ResponseResponder (≥70% Positive)Non-responder (<70% Positive)Responder (≥70% Positive)337Non-responder (<70% Positive)320Diagnostic Agreement SummaryDiagnostic ParameterEstimate [95% CI]Sensitivity91.7 [77.5, 98.2]Specificity74.1 [53.7, 88.9]PPV82.5 [67.2, 92.7]NPV87.0 [66.4, 97.2]FPER25.9 [11.1, 46.3]FNER8.3 [ 1.8, 22.5]Accuracy84.1 [72.7, 92.1] Results We initially analyzed responses in 39 subjects who received PPSV23 but no prior PCV. We analyzed diagnostic agreement between the responsiveness as determined by evaluating all 23 serotypes compared with the 11 unique serotypes not found in PCV13 or those 4 unique serotypes not found in PCV20. When comparing 23 serotypes to 11 serotypes, we found the accuracy to be 81%. When comparing 23 serotypes to 4 serotypes, we found the accuracy to be 82%. For 63 subjects who previously received PCV13, we examined the diagnostic agreement between the 11 serotype and 4 serotype panels and found the accuracy to be 84%. Conclusion Even in subjects who have previously received PCV13 or PCV20, there is still diagnostic utility in administration of PPSV23 and evaluation of the response to the unique serotypes as a means of assessing anti-polysaccharide antibody responses.

The patient is a 3-year-old female with a history of hypoxic-ischemic encephalopathy, cerebral palsy, global developmental delay, hypotonia, epilepsy, feeding intolerance with known aspirations, and chronic lung disease who presented to immunology for evaluation of recurrent, severe upper and lower respiratory tract infections. In the past year, she reported monthly upper respiratory infections, three of which progressed to pneumonia requiring antibiotic treatment, and two of which required hospitalization for severe respiratory failure. She denied lifetime otitis, sinusitis, cutaneous, or other invasive or serious infections. Immunological evaluation demonstrated normal lymphocyte subsets, B cell phenotyping, naïve/memory T cell phenotyping, immunoglobulins, non-protective tetanus titer, protective diphtheria titer, and protective hepatitis B titer. The patient had 2/23 Streptococcus pneumoniae titers protective above 1.3 mcg/mL after initial Prevnar 13 administration and then only 4/14 S. pneumoniae titers protective above 1.3 mcg/mL after Pneumovax 23 booster. The patient had normal lymphocyte proliferative responses to PHA, PWM, soluble anti-CD3, and anti–CD3+IL-2 though decreased to soluble anti–CD+anti-CD28. Genetic testing detected a heterozygous known pathogenic VARS2 variant (c.1546G>T and p.Glu516*) associated with autosomal recessive combined oxidative phosphorylation deficiency in addition to 9p24.2 duplication. VARS2 encodes a key enzyme for mitochondrial protein synthesis 1. 9p duplication is associated with global developmental delay similar to the patient’s phenotype but has not been specifically linked to abnormalities in the immune system. Despite initial treatment with prophylactic azithromycin and revaccination for S. pneumoniae, the patient developed COVID-19 pneumonia and rhino enterovirus with severe respiratory failure requiring two separate hospitalizations over three months and no significant improvement in strep pneumoniae titers. Subcutaneous immunoglobulin replacement therapy was initiated, and she has been on biweekly subcutaneous immunoglobulin replacement for four months with symptomatic improvement and no further infectious diagnosis. This case highlights that patients with 9p duplication and other rare genetic disorders are at risk for immune dysfunction and can benefit from replacement immunoglobulin. Patients with rare genetic disorders that have not been previously linked to immune dysfunction should be evaluated by an immunologist if recurrent infections.

Introduction A STAT3 gain-of-function (GOF) mutation leads to enhanced STAT3 signaling, leading to generalized autoimmunity caused by impaired regulatory T cell development and enhanced Th17 cell function. It is characterized by fevers, lymphoproliferation, recurrent infections, hypogammaglobulinemia, low IgE levels, and multiorgan autoimmunity, including type 1 diabetes and enteropathy. Case Description An 11-year-old male with a history of recurrent otitis media and asthma presented with two weeks of intermittent umbilical pain, non-bloody nonbilious diarrhea, and emesis. On physical exam he was afebrile, had splenomegaly (13.8 cm), and generalized lymphadenopathy. Infectious and oncologic evaluation was negative, including a cervical lymph node biopsy. Immune workup was notable for hypogammaglobulinemia, including IgG 457 [568-1490 mg/dL], IgA 28 [58-358 mg/dL], IgM 30 [48-226 mg/dL], IgE 4 [≤100 KU/L], unprotected vaccine titers, and CD4+ lymphopenia to 504 [650-1500 cell/μL]. Given his profound lymphadenopathy, autoimmune lymphoproliferative syndrome (ALPS) screening was pursued, which revealed an increased double-negative T cell population; however, caspase-10, FAS, and FASLG gene sequencing were normal. Whole-exome sequencing revealed a pathogenic, dominant, and heterozygous GOF mutation in STAT3 (variant c.2144C>T [p.Pro715Leu]). Of note, family history of this child’s 43-year-old father was positive for autoimmune lung (with a partial lung resection), intestinal, and liver disease, followed since childhood as “idiopathic” multiorgan disease. The father’s genetic screening returned positive with the same GOF mutation in STAT3. Discussion This case highlights the need to consider STAT3 GOF in patients with multiorgan autoimmune disease, lymphadenopathy, hypogammaglobulinemia with specific antibody deficiency, and T cell lymphopenia with low serum IgE levels. Low serum IgE levels in patients can be a simple and cost-effective way to distinguish between STAT3 GOF versus loss of function, seen in Job Disease.

Introduction Variants in EIF2AK2 are associated with leukoencephalopathy, developmental delay, and episodic neurologic regression (LEUDEN) syndrome. EIF2AK2 regulates stress response and lymphocyte transcription factors. Presentations of LEUDEN syndrome vary and include developmental delay, abnormal myelination, tone differences, neurologic regression, seizures, and movement disorders. Neurologic regression classically follows systemic stressors such as febrile illness. Case Presentation A 30-month-old boy with LEUDEN syndrome experiencing episodic neurologic regression after viruses presented to Immunology. His parents, informed through community groups, sought evaluation due to reported benefits from immunoglobulin replacement therapy (IgRT). Around 4-5 months old, the patient experienced viral infections, requiring hospitalizations for feeding difficulty, weakness, and head lag. Despite meeting early developmental milestones, developmental delay was diagnosed at 1 year, and he began therapies. Delays improved until 22 months when he presented to the ED for parainfluenza and acute otitis media, where he was prescribed antibiotics and discharged. A few days later, he re-presented for head lag and lethargy. He received empiric antibiotics for possible meningitis. EEG showed diffuse slowing. Brain MRI showed extensive white matter abnormalities. Broad infectious and metabolic workup was unrevealing besides low IgG (478 mg/dL). Post-discharge with intensive therapy, the patient gradually improved starting 2-3 weeks after his initial illness, regaining milestones. Whole-genome sequencing identified a likely pathogenic variant in EIF2AK2 (c.1382C>G, p.Ser461Cys), confirming LEUDEN syndrome. Immune evaluation at 30 months showed reassuring T/B/NK cell counts, IgG/IgA/IgM/IgE, and vaccine titers. The patient continued to have intermittent viruses with variable neurologic impacts. Immune re-evaluation one year later showed protective but waning titers to tetanus (0.65 IU/mL) and diphtheria (0.11 IU/mL) and poor pneumococcal protection with <50% of serotypes with titers >1.0 ug/mL. This antibody pattern with normal IgG (666 mg/dL) suggested specific antibody deficiency, and IgRT was offered. After starting monthly IVIG (∼450 g/kg) at 4 years old, his infections decreased in frequency and severity. He showed neurological improvements without regression during viral illnesses. Conclusion This single case report highlights subtle antibody deficiencies in a patient with LEUDEN syndrome and his improvement following IgRT. Further studies are needed to characterize the immune profiles and the potential utility of IgRT in LEUDEN syndrome.

We investigated the genetic cause of disease in five affected individuals from two unrelated families with an autosomal dominant pattern of invasive Streptococcus pneumoniae infection associated with a clinical phenotype of specific antibody deficiency. In Family A, two male siblings presented at <5 years with sepsis due to S. pneumoniae. The father had a history of meningitis and recurrent pneumonias, and a female sibling had less severe infections. In Family B, a male presented during infancy with S. pneumoniae meningitis with no family history of immunodeficiency. All patients had significantly decreased switched (CD27+IgD-) and unswitched (CD27+IgD+) memory B cells with normal serum immunoglobulin (Ig) levels, but poor responses to the polysaccharide pneumococcal vaccine or the serotype of S. pneumoniae causing infection. Primary B cells from patients had normal BCR spectratyping. Despite a hyperproliferative phenotype, plasmablast differentiation was diminished in vitro. Whole-genome sequencing identified similar ∼650-kb tandem duplication events on Chr14q32.2 encompassing part of the IGH locus and upstream genes, with complete penetrance in all patients from both families. Bulk and scRNA-seq revealed B cell–specific massive overexpression (100-fold) of one gene within the duplication, JAG2, encoding the Notch ligand jagged-2. Primary B cells and patient-derived B-LCLs expressed high JAG2 protein. Long-read sequencing demonstrated the 3’ regulatory region (3’RR) of the IGH locus in close proximity to JAG2 due to the duplication, and we hypothesize this leads to enhancer hijacking and dysregulation of JAG2 in B cells. Enhancer hijacking is a well-described mechanism leading to cancer but has never been described in IEI and very rarely in Mendelian genetics. Consistently, Hi-C analysis of patient-derived B-LCLs demonstrated a new interaction of JAG2 with the IGH 3’RR. A bone marrow chimera model demonstrated that overexpression of human JAG2 leads to a defect in marginal zone B cell development. Together, these findings demonstrate the discovery of a novel genetic mechanism of IEI, a new role for JAG2 in B cell differentiation, and a genetic cause of specific antibody deficiency. Ongoing work is focused on the effects of JAG2 overexpression on B cell function in vitro and using an in vivo model of vaccination.

PurposeTo investigate the efficacy, safety, tolerability, and serum IgG trough levels of hyaluronidase-facilitated subcutaneous immunoglobulin (fSCIG) 10% in US pediatric patients with primary immunodeficiency diseases (PIDDs).MethodsThis phase 3, open-label, prospective study (NCT03277313) was conducted at 17 US centers. Eligible patients aged 2 to < 16 years had PIDDs and had received immunoglobulin G (IgG) at a consistent dose for ≥ 3 months before screening. Participants received fSCIG 10% via dose ramp-up for up to 6 weeks (Epoch 1), then every 3–4 weeks for ≤ 3 years (Epoch 2). The primary endpoint was the rate of acute serious bacterial infections (ASBIs).ResultsData were provided by 44 participants for Epoch 1 (mean ± SD age: 9.0 ± 3.6 years) and 43 (97.7%) for Epoch 2; 34 (77.3%) completed the study. Two ASBIs (both bacterial pneumonia) were reported in one participant with specific antibody deficiency. The mean rate of ASBIs was 0.04 events/participant-year (99% upper confidence interval limit: 0.20), significantly lower than the regulatory-defined threshold of 1.0 (p < 0.001). The mean rate of all infections was 3.12 events/participant-year. Stable mean serum IgG trough levels were maintained during Epoch 2 (10.4, 9.2, and 9.2 g/L at Months 0, 6, and 12, respectively). Most related treatment-emergent adverse events were mild or moderate in severity. No participant developed anti-recombinant human hyaluronidase neutralizing antibodies; 1/44 participants (2.3%) developed binding antibodies.ConclusionfSCIG 10% effectively prevented ASBIs in pediatric patients with PIDDs, with a favorable safety profile consistent with previous clinical studies.

Patients with Inborn Errors of Immunity (IEI) are at higher risk of severe SARS-CoV-2 infection. We evaluated humoral and cellular responses to COVID-19 vaccines in Brazilian patients with IEI and healthy controls. Fifty-five patients with IEI (13-61 years) and 60 controls (13-71 years) received inactivated SARS-CoV-2 (CoronaVac), non-replicating virus-vectored (ChAdOx1 nCoV-19, AstraZeneca) or monovalent mRNA (Original strain of BNT162b2, Pfizer-BioNTech) and bivalent mRNA (Original/Omicron BA.1, Pfizer-BioNTech) vaccines and were sampled five times. Diagnoses included common variable immunodeficiency (n=25), specific antibody deficiency (n=9), ataxia-telangiectasia (n=5), X-linked agammaglobulinemia (n=4), PIK3CD-related disorders (n=4), hyper-IgM syndrome (n=4), combined immunodeficiency (n=3), and STAT1 gain-of-function (n=1). Humoral immunity was assessed via multiplex microarray for Spike, Nucleocapsid, RBD-Wuhan, RBD-Delta, RBD-BA.1, RBD-BA.2 and RBD-BA.5 neutralizing antibodies. T-cell responses to Spike and Nucleocapsid were assessed using ELISpot. Patients with IEI exhibited significantly lower levels of Nucleocapsid and RBD-neutralizing antibodies (p < 0.05). Notable differences in RBD-BA.2 (p = 0.008) and IgG-Nucleocapsid (p = 0.010) levels emerged over time. T-cell responses to Spike were stronger in patients with IEI post-booster (405 vs. 149 spot-forming cells/million PBMC; p = 0.002). Both groups showed enhanced Nucleocapsid-specific cellular responses over time (p = 0.017). COVID-19 hospitalization rates among patients with IEI with SARS-CoV-2 diagnosis dropped from 33.3% to zero after the first booster dose. While humoral responses to SARS-CoV-2 vaccines were weaker in patients with IEI, their cellular immunity was similar to controls. Boosters enhanced both humoral and cellular responses. After completion of the vaccination protocol, none of the patients with IEI were hospitalized with COVID-19. Robust T-cell responses may play a critical role in protecting patients with IEI from severe COVID-19 and mortality.

Functional testing of humoral immunity in the Prevnar 20 era.

Characterization of B Cell Subsets in Pediatric Patients with Humoral Immunodeficiency and Specific Antibody Deficiency

Introduction. Specific antibody deficiency is an innate error of humoral immunity characterized by normal levels of immunoglobulin isotypes, recurrent infections, and a reduced reaction to polysaccharide antigens in vaccines. Objective. To describe the clinical and immunological characteristics of patients with specific antibody deficiency attending a pediatric hospital in Bogotá between May 2021 and September 2023. Materials and methods. We reviewed the medical records of 16 patients with specific antibody deficiency. Results. The median age at diagnosis was six and a half years. Nine were male, and 7 had a history of prematurity. Eleven patients had adequate nutritional status, and 7 had standard height. The most frequent recurrent infection was pneumonia, affecting 12 patients; more than half of them experienced some associated complications. The most common phenotype was moderate, and 15 of the individuals received immunoglobulin as definitive treatment. Conclusion. Specific antibody deficiency is a frequently underdiagnosed functional alteration of the immune system. It should be suspected in patients experiencing recurrent otitis media and pneumonia or in cases complicated by septic shock, pleural effusion, or necrotizing pneumonia.

Specific antibody deficiency (SAD) is a common primary immunodeficiency disorder that should be considered in older children and adults with recurrent and/or severe sinopulmonary infections. The diagnosis is characterized by inadequate antibody response to polysaccharide vaccine, specifically, pneumococcal, with normal responses to protein antigens and normal levels of serum immunoglobulins as well as immunoglobulin G (IgG) subclasses. The underlying mechanism for SAD is not completely elucidated. It is understood that young children have limited polysaccharide responsiveness, which develops with increased age. Due to this phenomenon, the consensus is that there is adequate immune maturity after age 2 years, which is the earliest for the SAD diagnosis to be established. There remains a lack of consensus on thresholds for polysaccharide nonresponse, and there are several commercial laboratories that measure a range of serotypes, with the recommendation for patients to have their diagnostic evaluation with serotype testing both before vaccination and after vaccination to be conducted by the same laboratory. Once a diagnosis has been made, the management of SAD is based on the clinical severity. Clinicians may consider prophylactic antibiotics as well as immunoglobulin replacement. These patients should be closely followed up, with the possibility of discontinuation of IgG replacement after 12 to 24 months. Children are more likely to demonstrate resolution of SAD than are adolescents and adults. Patients with SAD may also progress to a more severe immunodeficiency; therefore, continued monitoring remains a crucial principle of practice in the care of patients with SAD.

187 Diagnostic approach in a young adult with RAG1 variants initially diagnosed with specific antibody deficiency and bronchiectasis

Who's your data? Primary immune deficiency differential diagnosis prediction via machine learning and data mining of the USIDNET registry

Streptococcus pneumoniae (pneumococcus) is a significant cause of bacterial infections ranging from mild infections affecting the respiratory tract such as otitis media and sinusitis to severe diseases including bacteremia, pneumonia, and invasive pneumococcal disease (IPD) (eg, meningitis, septic arthritis, and endocarditis). Pneumococcal vaccines were first developed in the 1970s as capsular pneumococcal polysaccharide vaccines, which were T-cell independent and hence lacked immunologic memory. Subsequently in the year 2000, pneumococcal conjugate vaccines (PCV) conjugated to a protein to increase immunogenicity were developed and made commercially available. The increasing number of pneumococcal serotypes identified and the expanding pipeline of PCV vaccines with improved immunogenicity have significantly reduced the morbidity and mortality associated with IPD in high-risk patients. Pneumococcal vaccines also play an important role in the diagnosis and immunophenotyping of children and adults with inborn errors of immunity (IEI) given the increasing diversity/heterogeneity of IEI presenting with primary and/or specific antibody deficiency. Other than the quantitation of serotype levels in routine clinical care, other measurements of immune response including the functional activity of antibodies, antibody avidity, cell-mediated immunity, and immunological memory remain limited to clinical trials during vaccine development.

In settings with universal conjugate pneumococcal vaccination, invasive pneumococcal disease (IPD) can be a marker of an underlying inborn error of immunity. The aim of this study was to determine the prevalence and characterize the types of immunodeficiencies in children presenting with IPD. Multicenter prospective audit following the introduction of routinely recommended immunological screening in children presenting with IPD. The minimum immunological evaluation comprised a full blood examination and film, serum immunoglobulins (IgG, IgA and IgM), complement levels and function. Included participants were children in whom Streptococcus pneumoniae was isolated from a normally sterile site (cerebrospinal fluid, pleura, peritoneum and synovium). If isolated from blood, features of sepsis needed to be present. Children with predisposing factors for IPD (nephrotic syndrome, anatomical defect or malignancy) were excluded. Overall, there were 379 episodes of IPD of which 313 (83%) were eligible for inclusion and 143/313 (46%) had an immunologic evaluation. Of these, 17/143 (12%) were diagnosed with a clinically significant abnormality: hypogammaglobulinemia (n = 4), IgA deficiency (n = 3), common variable immunodeficiency (n = 2), asplenia (n = 2), specific antibody deficiency (n = 2), incontinentia pigmenti with immunologic dysfunction (n = 1), alternative complement deficiency (n = 1), complement factor H deficiency (n = 1) and congenital disorder of glycosylation (n = 1). The number needed to investigate to identify 1 child presenting with IPD with an immunologic abnormality was 7 for children aged under 2 years and 9 for those 2 years and over. This study supports the routine immune evaluation of children presenting with IPD of any age, with consideration of referral to a pediatric immunologist.