Primary Antibody Deficiency Research Articles

Clinical and experimental treatment of primary humoral immunodeficiencies.

Selective IgA deficiency (sIgAD), common variable immunodeficiency (CVID), and transient hypogammaglobulinemia of infancy (THI) are the most frequent forms of primary antibody deficiencies. Difficulties in initial diagnosis, especially in the early childhood, the familiar occurrence of these diseases, as well as the possibility of progression to each other suggest common cellular and molecular patomechanism and a similar genetic background. In this review, we discuss both similarities and differences of these three humoral immunodeficiencies, focusing on current and novel therapeutic approaches. We summarize immunoglobulin substitution, antibiotic prophylaxis, treatment of autoimmune diseases, and other common complications, i.e. cytopenias, gastrointestinal complications, and granulomatous disease. We discuss novel therapeutic approaches such as allogenic stem cell transplantation and therapies targeting-specific proteins, dependent on the patient's genetic defect. The diversity of possible therapeutics models results from a great heterogeneity of the disease variants, implying the need of personalized medicine approach as a future of primary humoral immunodeficiencies treatment.

Pulmonary Computed Tomography Screening Frequency in Primary Antibody Deficiency

BackgroundPatients with primary antibody deficiency (PAD) frequently suffer from pulmonary complications, associated with severe morbidity and mortality. Hence, regular pulmonary screening by computed tomography (CT) scanning is advised. However, predictive risk factors for pulmonary morbidity are lacking. ObjectiveTo identify PAD patients at risk for pulmonary complications necessitating regular CT screening. MethodsA retrospective longitudinal cohort study of PAD patients (median follow-up 7.4 (2.3 – 14.8) years). CTs were scored using the modified Brody-II scoring system. Clinical and laboratory parameters were retrospectively collected. Potential risk factors were identified by univariate analysis when p<0.2 and confirmed by multivariable logistic regression when p<0.05. ResultsThe following independent risk factors for progression of airway disease (AD) were identified: 1) diagnosis of X-linked agammaglobulinemia (XLA), 2) recurrent airway infections (2.5/year), 3) presence of AD at baseline. Signs of AD progression were detected in 5/11 XLA patients and in 17/80 of the other PAD patients. Of the patients who progressed, 17/22 had preexistent AD scores ≥7.0%. Increased AD scores were related to poorer FEV1 values and chronic cough. CVID and increased CD4 effector/memory cells were risk factors for an interstitial lung disease (ILD) score ≥13.0%. ILD ≥13.0% occurred in 12/80 patients. Signs of ILD progression were detected in 8/80 patients and 4/8 patients showing progression had preexistent ILD scores ≥13.0%. ConclusionWe identified risk factors that distinguished PAD patients at risk for airway disease and interstitial lung disease presence and progression which could guide future screening frequency, however independent and preferably prospective validation is needed.

Access and use of immunoglobulins in supportive cancer care: A thematic analysis of a systematic review data set.

Secondary immunodeficiency (SID) disorders are known to occur in patients with haematological malignancies (HM) due to immunosuppressive treatments. Recurring infections causing subsequent morbidity and mortality commonly occur in this patient cohort. Immunoglobulin replacement therapy (IgRT) benefits patients with primary antibody deficiencies. However, evidence supporting their therapeutic role is not as explicit in SID-associated antibody deficiencies, which raises the questions regarding its use in SID and the knock-on effects of this use on its access and availability more generally. This study aimed to learn about the use of immunoglobulins in SID, identify themes concerning its use and access and suggest methods for improving access. This study included a thematic analysis of a published data set of 43 articles concerning immunoglobulin use and access in SID. The data set used to perform the thematic analysis is based on research articles identified from Excerpta Medica Database (EMBASE) and PubMed databases, published as part of a systematic review and part 1 of this two-part publication series. A thematic synthesis was conducted to identify recurrent themes. The three primary themes included (1) the context for IgRT prescription, which included patient characteristics and cost burden of IgRT administration, and its use in different countries; (2) factors contributing to inappropriate IgRT use, including health care professionals' awareness of IgRT, disparity between guidelines and actual clinical practice, and the effect of shortages on prescription and chemotherapy-induced hypogammaglobulinemia (HGG); and (3) measures identified to improve IgRT use and access, which included multidisciplinary involvement, improved diagnostic tools and safer withdrawal and stewardship protocols. IgRT use is increasing in HM as a supportive therapy but without comprehensive clinical guidelines and appropriate prescribing recommendations, medication wastage may occur with consequences for immunoglobulin access.

Determination of Clinical and Demographic Characteristics in Patients with Primary Antibody Deficiency Evaluated in Immunology and Allergy Clinic

Determination of Clinical and Demographic Characteristics in Patients with Primary Antibody Deficiency Evaluated in Immunology and Allergy Clinic

Сучасні підходи до вакцинації в дітей з різними варіантами первинних та вторинних імунодефіцитів (огляд літератури)

Chronic disease and immunosuppression increase the risk of vaccine-preventable infections, complications, and mortality from infectious diseases. Safe vaccination and achieving an adequate serological response to vaccination are crucial aspects of the management of such patients. Purpose - to analyze data from domestic and foreign medical literature regarding modern approaches to vaccination of children with various primary and secondary immunodeficiency diseases. The majority of children with primary immunodeficiency who have preserved antibody production can demonstrate an immune response to vaccination, but this response can be rapidly lost over time. Limitations to vaccinating children with primary immunodeficiency are related to the use of live vaccines in conditions where the cellular immune system is compromised. Patients with primary antibody deficiency are treated with immunoglobulin preparations and depend on the presence of specific antibodies at a protective level against infectious pathogens, including vaccine-preventable infections. Several studies have shown the effectiveness of intravenous immunoglobulin treatment in reducing the number and severity of infections in patients with humoral deficiency. The majority of children with rheumatic diseases vaccinated according to the Schedule of Routine Immunisations before starting immunosuppressive therapy have protective antibody levels against vaccine-preventable infections. All non-live vaccines can be administered without restrictions, but should be administered two weeks before immunosuppressive therapy to increase immunogenicity. Children receiving high doses of immunosuppressive therapy should avoid receiving live attenuated vaccines. No conflict of interests was declared by the author.

Plasma Levels of mir-34a-5p Correlate with Systemic Inflammation and Low Naïve CD4 T Cells in Common Variable Immunodeficiency

PurposeCommon variable immunodeficiency (CVID) is a primary antibody deficiency that commonly manifests as recurrent infections. Many CVID patients also suffer from immune dysregulation, an inflammatory condition characterized by polyclonal lymphocytic tissue infiltration and associated with increased morbidity and mortality. The genetic cause is unknown in most CVID patients and epigenetic alterations may contribute to the broad range of clinical manifestations. MicroRNAs are small non-coding RNAs that are involved in epigenetic modulation and may contribute to the clinical phenotype in CVID.MethodsHere, we determined the circulating microRNAome and plasma inflammatory proteins of a cohort of CVID patients with various levels of immune dysregulation and compared them to healthy controls. A set of deregulated microRNAs was validated by qPCR and correlated to inflammatory proteins and clinical findings.ResultsLevels of microRNA-34a correlated with 11 proteins such as CXCL9, TNF, and IL10, which were predicted to be biologically connected. Moreover, there was a negative correlation between mir-34 levels and the number of naïve CD4 T cells in CVID.ConclusionCollectively, our data show that microRNAs correlate with the inflammatory response in CVID. Further investigations are needed to elucidate the role of miRNAs in the development of CVID-related immune dysregulation.

Association of autoimmune disorders with chronic rhinosinusitis in adults

IntroductionIncreasing evidence suggests that autoimmune disorders and their immunomodulating medications may increase the risk of rhinosinusitis compared to rhinitis. GoalTo investigate the association between autoimmune disorders and rhinosinusitis. MethodsWe performed a case-control study of patients referred to West Virginia University from August 2020 to October 2022 for rhinologic complaints. Rhinosinusitis patients were diagnosed with either chronic rhinosinusitis (CRS) or recurrent acute rhinosinusitis (RARS). These patients were compared to non-rhinosinusitis patients. Patients' characteristics, comorbidities, and type of treatment of autoimmune disorders were reviewed. ResultsThe sample consisted of 527 rhinosinusitis [184 CRS without nasal polyps (CRSsNP), 263 CRS with nasal polyps (CRSwNP) and 80 RARS patients] patients and 564 non-rhinosinusitis patients. Patients with rhinosinusitis were more likely to be older, males, have asthma, and have current and past smoking history (all with p-value < 0.05). Autoimmune disorders, primary antibody deficiency, and immunomodulator agents were more common in rhinosinusitis patients (16.5 % vs 9.4 %, OR = 1.9, p < 0.001; 5.1 % vs 0.5 %, OR = 10.1, p < 0.001; and 3.8 % vs 1.1 %, OR = 3.7, p = 0.003 respectively). Multivariate logistic regression adjusting for confounders showed that autoimmune disorders were strongly associated with rhinosinusitis [OR = 1.6, 95 % CI = 1.10–2.48], whereas the immunomodulators did not reach statistical significance [OR = 2.4, 95 % CI = 0.87–6.47]. Subgroup analysis showed the autoimmune disorders did not significantly differ between CRS and RARS groups [OR = 1.0, 95 % CI = 0.5–2.1], or between the CRSsNP and CRSwNP groups [OR = 0.9, 95 % CI = 0.5–1.7]. ConclusionAutoimmune disorders are associated with rhinosinusitis, both CRS and RARS, independently of other risk factors.

484. Clinical Description of SARS-CoV-2 Infection in Patients with Primary Antibody Deficiency Who Received Tixagevimab/Cilgavimab Prophylaxis

Abstract Background Patients with primary antibody deficiency are known to be associated with a higher risk of SARS-CoV-2 infection, complications, and mortality. Tixagevimab/Cilgavimab prophylaxis has shown efficacy in reducing hospitalization and mortality. We aim to describe the clinical characteristics and outcomes of COVID-19 cases in primary antibody deficiency patients receiving tixagevimab/cilgavimab prophylaxis in South Korea. Methods This is a descriptive analysis of COVID-19 infection in primary antibody deficiency patients at Severance Children's Hospital. From September 2021 to February 2023, we retrospectively collected data, including demographic characteristics, comorbidities, tixagevimab/cilgavimab prophylaxis status, SARS-CoV-2 vaccination, COVID-19 infection, clinical presentation, COVID-19 treatment, oxygen supplement, hospitalization, and clinical outcome. Results Thirteen patients (12 with X-linked agammaglobulinemia and 1 with common variable immunodeficiency) were enrolled in this study. Among them, 10 received tixagevimab/cilgavimab prophylaxis, while the remaining 3 did not. Three patients developed breakthrough infection after receiving prophylaxis. Patient 1 (29 years old, male) completed a SARS-CoV-2 booster mRNA vaccination, had no prior COVID-19 infection, and developed COVID-19 infection 104 days after prophylaxis. Patient 2 (33 years old, male) received 2 doses of mRNA vaccine, had no prior infection history, and developed COVID-19 infection 3 days after prophylaxis. Patient 3 (13 years old, male) had no history of previous vaccination, had an infection history before receiving prophylaxis, and developed COVID-19 infection 19 days after prophylaxis. All 3 patients experienced mild symptoms and did not require oxygen therapy or hospitalization. Of the 7 patients who were not infected with COVID-19 after prophylaxis, 6 had a history of COVID-19 infection, and all of them received SARS-CoV-2 mRNA vaccine. The follow-up period after prophylaxis ranged from 198 to 241 days.Table 1.Clinical description of the hypogammaglobulinemia patients who were diagnosed with COVID-19 with or without tixagevimab-cilgavimab prophylaxis Conclusion In this study, we observed that 3 out of 10 primary antibody deficiency patients who received tixagevimab/cilgavimab prophylaxis were infected COVID-19 but did not require hospitalization or oxygen supplementation. Disclosures All Authors: No reported disclosures

Telomere biology disorders may manifest as common variable immunodeficiency (CVID)

Telomere biology disorders (TBD) are caused by germline pathogenic variants in genes related to telomere maintenance and are characterized by critically short telomeres. In contrast to classical dyskeratosis congenita (DC), which is typically diagnosed in infancy, adult or late onset TBD frequently lack the typical DC triad and rather show variable organ manifestations and a cryptic disease course, thus complicating its diagnosis. Common variable immunodeficiency (CVID), on the other hand, is a primary antibody deficiency (PAD) syndrome. PADs are a heterogenous group of diseases characterized by hypogammaglobulinemia which occurs due to dysfunctional B lymphocytes and additional autoimmune and autoinflammatory complications. Genetic screening reveals a monogenic cause in a subset of CVID patients (15–35%). In our study, we screened the exomes of 491 CVID patients for the occurrence of TBD-related variants in 13 genes encoding for telomere/telomerase-associated proteins, which had previously been linked to the disease. We found 110/491 patients (22%) carrying 91 rare candidate variants in these 13 genes. Following the American College of Medical Genetics and Genomics (ACMG) guidelines, we classified two variants as benign, two as likely benign, 64 as variants of uncertain significance (VUS), four as likely pathogenic, and one heterozygous variant in an autosomal recessive disease gene as pathogenic. We performed telomere length measurement in 42 of the 110 patients with candidate variants and CVID. Two of these 42 patients showed significantly shorter telomeres compared to controls in both lymphocytes and granulocytes. Following the evaluation of the published literature and the patient's manifestations, we re-classified two VUS as likely pathogenic variants. Thus, 0.5–1% of all CVID patients in our study carry possibly pathogenic variants in telomere/telomerase-associated genes. Our data adds CVID to the broad clinical spectrum of cryptic adult-onset TBD. As the molecular diagnosis greatly impacts patient management and treatment strategies, we advise inclusion of all TBD-associated genes—despite their low prevalence—into the molecular screening of patients with antibody deficiencies.

Respiratory infectious burden in a cohort of antibody deficiency patients treated with immunoglobulin replacement therapy: The impact of lung pathology and gastroesophageal reflux disease.

Antibody deficiencies result from reduced immunoglobulin levels and function, increasing susceptibility to, primarily, bacterial infection. Primary antibody deficiencies comprise intrinsic defects in B-cell physiology, often due to inherited errors. Hematological malignancies or B-cell suppressive therapy are major causes of secondary antibody deficiency. Although immunoglobulin replacement therapy (IGRT) reduces infectious burden in antibody deficiency patients, respiratory tract infections remain a significant health burden. We hypothesize that lung pathology and gastroesophageal reflux disease (GORD) increase the risk of pneumonia in antibody deficiency patients, as in the general population. For our cohort of patients with primary antibody deficiency and secondary antibody deficiency, we reviewed their respiratory infectious burden and the impact of lung pathologies and GORD. The medical records of 231 patients on IGRT at a tertiary referral center, from October 26, 2014, to February 19, 2021, were reviewed to determine microbial isolates from sputum samples and prevalence of common lung pathologies and GORD. Haemophilus and Pseudomonas species represent a large infectious burden, being identified in 30.2% and 21.4% of sputum samples demonstrating growth, respectively; filamentous fungal and mycobacterial infections were rare. Diagnosed lung pathology increased the proportion of patients with Pseudomonas, Klebsiella, Stenotrophomonas, and Candida species isolated in their sputum, and diagnosed GORD increased the proportion with Enterobacter and Candida species isolated. Bacterial respiratory infectious burden remains in primary antibody deficiency and secondary antibody deficiency despite IGRT. Lung pathologies encourage growth of species less susceptible to IGRT, so specialist respiratory medicine input and additional treatments such as inhaled antibiotics are indicated to optimize respiratory outcomes.

Cellular immune response to SARS-CoV-2 in patients with primary antibody deficiencies.

Primary antibody deficiencies (PAD) are inborn defects of the immune system that result in increased susceptibility to infections. Despite the reduced response to vaccination, PAD patients still benefit from it by reducing the risk of severe infections and complications. SARS-CoV-2 vaccines are recommended in PAD patients, but their immune effects are poorly studied. Here, we analyze virus-specific T-cell responses in PAD patients after booster vaccination against SARS-CoV-2. The study included 57 adult PAD patients on long-term immunoglobulin replacement therapy (IgRT) diagnosed with X-linked agammaglobulinemia (XLA; n = 4), common variable immunodeficiency (CVID; n = 33), isotype defects or IgG subclass deficiency (n = 6), and unclassified IgG deficiency (n = 14). Of those, 49 patients (86%) received vaccination against SARS-CoV-2 using mRNA vaccine (Pfizer-BioNTech). T-cell responses were assessed at a median of 21 (13 - 30) weeks after the booster dose (mainly the third dose) using commercially available interferon-gamma release assay (IGRA) with recombinant SARS-CoV-2 spike S1 protein. Vaccinated PAD patients showed an increased (3.8-fold, p = 0.004) release of IFN-γ upon S1 stimulation. In this group, we also documented higher serum levels of anti-SARS-CoV-2 IgG (4.1-fold, p = 0.01), although they were not associated with IGRA results. Further subgroup analysis revealed very similar IGRA responses in CVID and unclassified IgG deficiencies that were 2.4-fold increased compared to XLA and 5.4-fold increased compared to patients with isotype defects or IgG subclass deficiencies (e.g., vs. CVID: p = 0.016). As expected, CVID and XLA patients showed decreased serum titers of anti-SARS-CoV-2 antibodies compared to other studied groups (e.g., CVID vs. unclassified IgG deficiency: 4.4-fold, p = 0.006). The results did not depend directly on IgRT mode or dose, number of vaccine doses and time from the last booster dose, and clinical manifestations of PAD. Interestingly, anti-SARS-CoV-2 titers were positively correlated with serum immunoglobulin levels before IgRT (e.g., for IgA: r = 0.45, p<0.001; for IgG: r = 0.34, p = 0.009) and the percentage of peripheral blood NK cells (r = 0.48, p<0.001). Our results documented satisfactory in vitro cellular immune response in PAD patients after booster SARS-CoV-2 vaccination. Therefore, even patients with agammaglobulinemia should benefit from vaccination due to the apparent induction of cell-mediated immunity, which, together with IgRT, grants comprehensive protection against the pathogen.

Patient-reported outcomes in patients with primary immunodeficiency diseases in Japan: baseline results from a prospective observational study.

Primary immunodeficiency diseases (PIDs) are rare inherited diseases resulting in impaired immunity. People with PID experience lower health-related quality of life (HR-QOL) and disease-related burdens in daily activities. This ongoing, prospective observational study aims to evaluate disease activity, treatment status, treatment-related burden, daily activities, and HR-QOL in patients with PID in Japan over a 1-year period. In this interim report (database lock: July 29, 2022), we present baseline results. Participants were enrolled between November 2021 and May 2022; data were collected four times/year per participant until May 2023 using an online electronic patient-reported outcomes system. Patients with PID and healthy volunteers aged ≥12 years, residing in Japan, and with access to a smartphone were eligible. HR-QOL (primary endpoint) was assessed by the EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) and the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36). Work productivity was assessed by the Work Productivity and Activity Impairment (WPAI) Questionnaire. Other aspects of PID and burden were assessed with a new questionnaire developed in-house. The study is registered at the University hospital Medical Information Network clinical trials registry (UMIN000045622). The full interim analysis set comprised 71 patients with PID and 47 healthy volunteers. The most common International Union of Immunological Societies PID category was primary antibody deficiency (56.3% of patients). Complications were common, especially recurrent respiratory tract infections (63.4%). Most patients with PID were treated with immunoglobulin replacement therapy (73.2%); 22.4% of these patients had serum immunoglobulin levels <700 mg/dL. Among patients who did not undergo hematopoietic cell transplantation, EQ-5D-5L (n=67) and SF-36 (n=59) Physical and Mental Component Summary scores were significantly lower than in healthy volunteers (p < 0.001). WPAI absenteeism, work productivity loss, and activity impairment scores were significantly lower in 42 working patients with PID than in 37 working healthy volunteers (p < 0.05). Other results indicated that patients with PID experience substantial burdens related to medical visits, expenses, work, and daily activities. This interim analysis confirms that patients with PID in Japan have lower HR-QOL and work productivity compared with healthy individuals and experience substantial limitations and burdens in their daily lives.

Good's syndrome: brief overview of an enigmatic immune deficiency.

Good's syndrome, an infrequent adult-onset immunodeficiency is characterized by the triad of thymoma, hypogammaglobulinemia, and increased susceptibility to recurrent infections. The clinical presentation is highly variable, with a spectrum ranging from recurrent bacterial and opportunistic infections to concomitant autoimmune diseases and, sometimes malignant pathologies. Due to heterogeneous clinical phenotypes and the lack of adequate diagnostic criteria, its recognition is often challenging, even delaying it by years. It is one of the most unusual, less studied form of the immune deficiency syndromes with a still unknown pathophysiology. It was initially considered a thymoma-associated variant of primary antibody deficiencies with a reduced or absent number of mature B cells, but it later emerged that significant defects of T cell-mediated immune functions are the underlying cause of opportunistic infections. On the basis of current evidence, Good's syndrome is evaluated as a distinct acquired form of combined immunodeficiency states and classified as a phenocopy of primary immunodeficiency diseases. Epigenetic and acquired genetic factors can play an ultimate role in its evolution.

Points to Consider in Health Assessment of Adult Patients with Primary Antibody Deficiencies.

An improved recognition of inborn errors of immunity (IEI) is associated with an increase in life expectancy and a higher incidence of complications and related conditions. The aim of the study was to analyze factors enabling the primary prevention: BMI, smoking and selected laboratory tests (morphology with smear, creatinine, eGFR, total protein, albumin, ferritin, folic acid, vitamin B12, vitamin D3) included in the protocols of standard of care for adult patients with primary antibody deficiencies (PADs). The study included 94 participants ≥ 18 years old, diagnosed with PADs. Overweight was found in 17%, obesity in 14% and underweight in 15% of patients; 11.5% of patients smoked. Leukopenia was diagnosed in 16%, neutropenia in 8.5%, lymphopenia in 22.5% and thrombocytopenia in 14% of patients. A decreased concentration of hemoglobin was found in 32%, total protein in 19%, albumin in 17%, vitamin D3 in 52%, vitamin B12 in 6.5%, folic acid in 34% and ferritin in 26% of patients. Creatinine concentrations were elevated in 16% of patients, while in 20%, eGFR was reduced. Only a holistic assessment of comorbidities and complications of deficiency, as well as regular follow-up and lifestyle changes, can yield the best results in the long-term care of patients.

Clinical Validation of a Primary Antibody Deficiency Screening Algorithm for Primary Care

PurposeThe diagnostic delay of primary antibody deficiencies (PADs) is associated with increased morbidity, mortality, and healthcare costs. Therefore, a screening algorithm was previously developed for the early detection of patients at risk of PAD in primary care. We aimed to clinically validate and optimize the PAD screening algorithm by applying it to a primary care database in the Netherlands.MethodsThe algorithm was applied to a data set of 61,172 electronic health records (EHRs). Four hundred high-scoring EHRs were screened for exclusion criteria, and remaining patients were invited for serum immunoglobulin analysis and referred if clinically necessary.ResultsOf the 104 patients eligible for inclusion, 16 were referred by their general practitioner for suspected PAD, of whom 10 had a PAD diagnosis. In patients selected by the screening algorithm and included for laboratory analysis, prevalence of PAD was ~ 1:10 versus 1:1700–1:25,000 in the general population. To optimize efficiency of the screening process, we refitted the algorithm with the subset of high-risk patients, which improved the area under the curve–receiver operating characteristics curve value to 0.80 (95% confidence interval 0.63–0.97). We propose a two-step screening process, first applying the original algorithm to distinguish high-risk from low-risk patients, then applying the optimized algorithm to select high-risk patients for serum immunoglobulin analysis.ConclusionUsing the screening algorithm, we were able to identify 10 new PAD patients from a primary care population, thus reducing diagnostic delay. Future studies should address further validation in other populations and full cost-effectiveness analyses.RegistrationClinicaltrials.gov record number NCT05310604, first submitted 25 March 2022

Evaluating immune responses to pneumococcal vaccines.

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.

Safety of Intravenous Immunoglobulin Replacement Therapy in a Group of Patients with Primary Immune Deficiency

Background Intravenous immunoglobulin (IVIG) has been used as antibody replacement therapy in primary immunodeficiency diseases for more than 50 years. Most routinely, IVIG is used in patients with predominantly antibody deficiency and combined immunodeficiency. Aim To evaluate the safety of regular intravenous immunoglobulin (IVIG) among patients with primary immunodeficiency diseases who receive IVIG as a replacement treatment. Methods Our study included 40 patients with primary immunodeficiency following up regularly in the Pediatric Allergy and Immunology Unit, Children’s Hospital, Ain Shams University, These patients were followed up for one year in order to evaluate the incidence of occurrence of adverse reactions among the patients who received IVIG monthly, Once patients with adverse reactions have been identified, the following data were taken and reviewed : a specific type of adverse reaction to IVIG; the time interval between onset of adverse reaction and beginning of IVIG infusion; IVIG preparation, dose and infusion rate; medical management done during side effects . Statistics were used to analyze and interpret the data. Results This study included 40 PID patients. They were 31 males (77.5%) and 9 females 22.5% with a male to female ratio of 3.4:1. At time of enrolment in the study, the median age was 73.5 months (14 – 218 months). In our studied population the median age of symptoms onset was 23 months (1 – 187 months), and age at diagnosis was 25 months (2-192 months). This made the diagnostic lag to have a median of 9 months (0-56 months). From our studied population only one patient (2.5%) out of the study groups developed anaphylaxis and was shifted to another brand. Conclusion IVIG is a safe drug for patients with primary antibody deficiency with minimal reported side effects.

Detection of SARS-CoV-2 Antibodies in Immunoglobulin Products.

For patients with primary antibody deficiency, the first line of therapy is replacement with immunoglobulin (Ig) products. Prior to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, Ig products did not contain antibodies with specificity for this virus, and there have been limited data on the antibodies present in the Ig products in current use. To quantitatively examine SARS-CoV-2 antibodies in current Ig products. We examined 142 unique lots of 11 different Ig products intended for intravenous and/or subcutaneous delivery for IgG-binding activities against recombinant SARS-CoV-2 receptor binding domain, spike, and nucleocapsid proteins by enzyme-linked immunosorbent assays. In addition, to assess functionality, 48 of these unique lots were assessed for their ability to inhibit the variants SARS-CoV-2 Ancestral, Alpha, Beta, Delta, and Omicron spike binding to angiotensin-converting enzyme 2 (ACE2). Significantly increased antibody values were observed for products manufactured after the year 2020 (expiration dates 2023-2024), as compared with Ig products before 2020 (prepandemic). Sixty percent and 85% of the Ig products with expiration dates of 2023 and 2024 were positive for antibody to SARS-CoV-2 proteins, respectively. The area under the curve values were significantly higher in products with later expiration dates. Later dates of expiration were also strongly correlated with inhibition of ACE2-binding activity; however, a decline in inhibition activity was observed with later variants. Overall, more recent Ig products (expiration dates 2023-2025) contained significantly higher binding and inhibition activities against SARS-CoV-2 proteins, compared with earlier, or prepandemic products. Normal donor SARS-CoV-2 antibodies are capable of inhibiting ACE2-binding activities and may provide a therapeutic benefit for patients who do not make a robust vaccine response.

Allergic Rhinitis and Other Allergic and Autoimmune Disorders in Children with IgA Deficiency

Background: Selective IgA imunodeficiency is the most frequently occurring primary antibody deficiency. Serum IgA level is decreased or even completly absened, while IgM and IgG antibodies displey normal serum levels. IgA plays an important role in immune protection in the gastrointestinal and respiratory tract. Patients with selective IgA imunodeficiency can be asimptomatic (&gt;50% of cases) and can suffer from recurrent gastointestinal and respiratory infecitions, allergies and autoimmune diseases. Allergic rhinitis (AR) is the most common cause of chronic rhinitis. Characteristic feature of allergic rhinitis is eosinophilic inflammation of the nasal mucosa. Several studied have shown that IgA represents a potent trigger of eosinophil degranulation, while other studies have shown that IgA imunodeficiency is a well-known risk factor for atopy. Objective: Objective of this study was to evaluate the frequency of allergic rhinitis and other allergic and autoimmune disorders in children with IgA immunodeficiency. Methods: The study included 36 children diagnosed with IgA imunodeficiency. The presence of allergic and autoimmune disorders was evaluated by specialist of allergology, immunology, rheumatology and otorhinolaryngology. Results: 22 (71,1%) of children were male and the mean age of the patients was 10.5 years. Among the patients 31 (86,11%) had at least one allergic disease: 20 (55,55%) had asthma, 17 (47,22%) had allergic rhinitis, 6 (16,67%) had atopic dermatitis and 5 (13,89%) had urticaria. 14 (38,89%) had at least one of autoimmune disordes: 8 (22,22%) had reactive arthritis, 5 (13,89%) had juvenile idiopathic arthritis, 2 (5,56%) had Mb Hashimoto and 1 (2,78%) had SLE. Conclusion: This study showed that the main clinical manifestations in patients with IgA deficiency were asthma and allergic rhinitis. Results also show increased frequencies in other allergic and autoimmune diseases, compared to available data from general population.

Evaluation and treatment of rhinosinusitis with primary antibody deficiency in adults: Evidence-based review with recommendations.

There is clear evidence that the prevalence of primary antibody deficiency (PAD) is higher in patients with recurrent and chronic rhinosinusitis (CRS) than in the general population. The purpose of this multi-institutional and multidisciplinary evidence-based review with recommendations (EBRR) is to thoroughly review the literature on rhinosinusitis with PAD, summarize the existing evidence, and provide recommendations on the evaluation and management of rhinosinusitis in patients with PAD. The PubMed, EMBASE, and Cochrane databases were systematically reviewed from inception through August 2022. Studies on the evaluation and management of rhinosinusitis in PAD patients were included. An iterative review process was utilized in accordance with EBRR guidelines. Levels of evidence and recommendations on the evaluation and management principles for PAD were generated. A total of 42 studies were included in this evidence-based review. These studies were evaluated on incidence of PAD in rhinosinusitis patients, incidence of rhinosinusitis in PAD patients, and on the different treatment modalities used and their outcome. The aggregate quality of evidence was varied across reviewed domains. Based on the currently available evidence, PAD can occur in up to 50% of patients with recalcitrant CRS. Despite the presence of multiple studies addressing rhinosinusitis and PAD, the level of evidence supporting different treatment options continues to be lacking. Optimal management requires a multidisciplinary approach through collaboration with clinical immunology. There is need for higher-level studies that compare different treatments in patients with PAD and rhinosinusitis.