Immunoglobulin treatment in primary antibody deficiency

Subclinical infection and dosing in primary immunodeficiencies.

Background and ObjectiveIn recent years, two Italian non-interventional studies evaluated subcutaneous immunoglobulin (SCIG) treatment in patients affected by primary antibody deficiency (PAD). The SHIFT study considered patients who were treated with intravenous immunoglobulin (IVIG) or SCIG 16% (Vivaglobin®) and then replaced this therapy with weekly treatments of SCIG 20% (Hizentra®). The IBIS study evaluated patients previously taking a weekly SCIG 20% regimen, who instead began therapy with biweekly SCIG 20% to assess the correlation between the dose of immunoglobulin G (IgG) administered and the body mass index (BMI) of patients, determine if there is a need for dosage adjustments on a BMI basis, and identify the predictors of serum IgG trough levels in our cohort.MethodsIn this study, we analyzed the pooled data of 109 PAD patients enrolled in the SHIFT and IBIS studies. Only prospective phases were considered.ResultsThe total monthly SCIG dose showed comparable trends among weight categories, except for underweight patients. When we considered the monthly SCIG dosage per kilogram of body weight, a significant decreasing trend according to BMI was observed. Data on IgG trough levels were available for 88 patients, with a mean IgG serum level of 8.4 ± 1.6 g/L. A stepwise regression model revealed that the mean monthly dosage of SCIG 20% (p = 0.04248) and the mean monthly dosage of IgG per kilogram of body weight were the only two independent predictors associated with IgG trough levels. No association was found between BMI and IgG trough levels.ConclusionsThese findings support the concept that the cumulative monthly dose of SCIG and the dose of SCIG per kilogram of body weight affect IgG trough levels in PAD patients, irrespective of BMI.

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. 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. 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%). 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. Patients with primary antibody deficiency with structural lung disease, allergies, and splenomegaly are associated with persistent pneumonia post-IgRT.

To the Editor Primary antibody deficiency syndromes (PADs) comprise an heterogeneous group of disorders characterized by low immunoglobulin serum levels. PADs encompass a wide range of disorders with Selective IgA deficiency (SIgAD) and Common Variable Immunodeficiency (CVID) being the more frequent ones. The incidence of SIgAD varies notably depending on ethnicity, while CVID presents an estimated incidence of 1:10.000–1:25.000; both may affect pediatric and adult patients. Regarding CVID, the genetic landscape is continuously becoming broader, involving genes encoding for, among others, TACI, BAFFR, CD19, CD20, CD21, CD81 and LRBA [1]. Mutations in TACI, the most frequently mutated gene in CVID, may be present in almost 8–10 % of affected patients [1]. TACI genetic variants have also been associated with SIgAD. TACI together with BAFFR and BCMA, are members of the Tumor Necrosis Factor Receptor (TNFR) superfamily. They are only expressed on B cells, as known so far, and their ligation to BAFF (all three) or APRIL (only TACI and BCMA) affects B cell homeostasis. Mutations in TACI associated with CVID abrogate the receptor’s expression on B cells as well as its capacity to bind APRIL. Homozygous deletions in the BAFFR gene on the other hand are very rare. Only two adult onset patients affected with complete BAFFR deficiency and hypogammaglobulinemia have been reported so far [2]. Mutations in BAFFR not resulting in lack of BAFFR expression have also been reported in CVID patients [3]. The P21R mutation in BAFFR was recently reported to alter the multimerization of BAFFR on B cell surface, contributing to common variable immunodeficiency [4]. So far, mutations in BAFFR have not been associated with SIgAD. We report on three family members (father and two daughters) affected with Common Variable Immunodeficiency (patient 1), selective IgA deficiency (Patient 2) and Hypo-IgM (father) that carry the monoallelic P21R/H159Y mutations in TNFRSF13C associated with reduced BAFFR expression on B cells suggesting that the P21R/H159Y monoallelic mutations may contribute to primary antibody deficiency with variable immunological presentation. The immunological data of the reported patients are summarized in Fig. 1a. All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individuals (or their parents in case of pediatric patients) participating in this study. In brief, patient 1 presented a history of recurrent respiratory infections starting at the age of 2 years. Her clinical history was complicated by an episode of meningitis and mastoiditis at the age of 5 years. During this admission, immunological work-up showed hypogammaglobulinemia, normal peripheral B cell percentages, absent humoral response to vaccinations leading to the diagnosis of CVID. Patient 2, the sister of patient 1, presented occasional gastrointestinal and respiratory infections and was evaluated due to positive family history for CVID. IgA serum levels were below the threshold of * Vassilios Lougaris vlougaris@yahoo.co.uk

Primary antibody deficiencies (PAD) are a group of disorders characterized by reduced antibody production, leading to a common form of primary immunodeficiency. This group includes specific polysaccharide antibody deficiency, immunoglobulin G subclass deficiency, common variable immunodeficiency (CVID), and agammaglobulinemia. B cell dysfunction is a key feature of PAD, resulting in recurrent respiratory and gastrointestinal infections due to compromised mucosal protection. Preventive measures such as vaccination, prophylactic antibiotics, and immunoglobulin replacement therapy (IRT) have been effective in reducing infections but complications like bronchiectasis, hearing loss, and malnutrition can still occur. Non-infectious complications, including enteropathy, granulomatous lymphocytic interstitial lung disease (GLILD), and secondary hemophagocytic lymphohistiocytosis (HLH), contribute significantly to morbidity and mortality in CVID patients despite IRT. Enteropathy lacks effective treatment options, while GLILD and HLH require early intervention but have diagnostic challenges. Genetic studies have identified over 40 genes linked to PAD, highlighting the complexity of the disorder. Monogenic causes are found in only a small percentage of cases, emphasizing the multifactorial nature of PAD. T cell dysfunction has also been implicated in PAD, beyond the typical B cell abnormalities. CVID patients without a monogenic disease may experience T cell dysregulation, with elevated effector memory T cells and increased IFN-γ response genes. Dysregulated T cells contribute to the activation of monocytes, leading to the production of B cell activating factor (BAFF), which is linked to non-infectious complications, particularly in GLILD patients. To address knowledge gaps in PAD, the thesis aims to improve understanding of the genetic landscape, optimize strategies for preventing infections, and develop treatments for non-infectious complications. Larger cohort studies and clinical trials are needed to establish evidence-based recommendations. Identifying predictive risk factors for specific complications is crucial for effective screening and treatment decisions. T cell functionality is a focus for normalizing non-infectious complications. The thesis is divided into two parts: Diagnosis and pathophysiology of PAD, and Management of PAD. In the first part, various genetic variants associated with PAD are discussed, highlighting the complex interplay of B and T cells in the disease. In the second part, the effectiveness of prophylactic antibiotics and IRT in milder forms of PAD is compared, and treatment options for GLILD are explored, with a focus on corticosteroids as a first-line treatment. Clinical recommendations include using next-generation sequencing for diagnosis, personalized treatment approaches, and intensive monitoring for patients at risk of complications. Standardized treatment approaches for GLILD are also advocated. Collaborative efforts and further research are needed to advance our understanding and management of PAD. In conclusion, this thesis contributes to our understanding of PAD, providing insights into its genetic basis and treatment strategies. However, collaborative research and evidence-based approaches are essential to address remaining knowledge gaps and improve care for patients with this complex disease.

Secondary antibody deficiencies (SAD) may require immunoglobulin replacement therapy (IgRT). While the intravenous route (IVIG) is broadly considered effective in SAD, the use of subcutaneous immunoglobulins (SCIG) is mainly adopted from the experience in primary antibody deficiencies (PAD), where SCIG have been shown to perform as effective as IVIG. However, evidence-based data on SCIG administration in SAD patients are still insufficient. Herein we retrospectively evaluated the efficacy and safety profile of SCIG treatment in 131 SAD patients as compared to a group of 102 PAD patients. We found SCIG being equally effective in reducing annual infectious rate both in SAD and PAD patients. However, SAD patients required lower SCIG dosage and lower IgG through level to achieve similar biological effect in terms of infection burden, at the steady state. SAD patients also showed better correlation between SCIG dose and serum IgG achieved value. Furthermore, within SAD, SCIG were found to work irrespective of the underlying disease. Especially in Non-Hodgkin Lymphoma patients, whose indication to IgRT is still not included in all guidelines and for whom evidence-based data are still lacking, SCIG were as effective as in Chronic Lymphocytic Leukemia or Multiple Myeloma patients, and SCIG discontinuation, without evidence of B cell recovery, led to IgG decline and relapsed infections. Finally, treatment tolerance in SAD patients was comparable to the PAD cohort. Globally, our data suggest that SCIG, as already appreciated in PAD, represent a valuable option in SAD patients, independent on the disease leading to antibody deficiency.

Enfermedad autoinmune en inmunodeficiencias primarias de anticuerpos

Event Abstract Back to Event Common Variable Immunodeficiency and autoimmunity in two teenagers brothers in Bogotá CARLOS E. OLMOS1* and CATALINA GOMEZ PARADA1 1 Cayre IPS y Fundacion, Colombia Introduction: Common variable immunodeficiency (CVID) is the primary immunodeficiency most frequently identified in the clinical practice. Clinically, it is defined as the presence of recurrent infections, reduction in IgG serum (at least 2 standard deviations before the reference values for the subject’s age), at least another one of the Ig (IgA or IgM), and a reduction or absence of the production of antibody. The clinical spectrum include multiple recurrent respiratory infections, systemic bacterial infections, gastrointestinal complications, and autoimmunity. We report two cases of CVID occurring in siblings with infectious and autoimmunity manifestations early in school age. Case report: Male adolescents from Tolima, Colombia, diagnosed with CVID after 6 years of the onset of symptoms. The first brother was diagnosed at the 12 years of age with a history of severe insulin-depend diabetes mellitus since the age of two years associated to severe respiratory infections with multiple hospital admissions including sinusitis, otitis media, and complicated pneumonias with bronchiectasis, chronic conjunctivitis, gastroenteropathy, and lymphadenopathies with hypogammaglobulinemia G and M and specific antibody deficiency. The second patient was diagnosed at the 14 years of age after a history of recurrent moderate respiratory infections and frequent diarrheal illness since the age of 6 with development of pernicious anemia, hyperparathyroidism with clinical rickets, detection of hypogammaglobulinemia G and M, and specific antibody deficiency. Both patients are being treated with monthly intravenous immunoglobulin G [IVIG] replacement, vitamin B12 and D, additional nutritional support and multidisciplinary management. Discussion: The CVID is usually a sporadic and non-monogenic condition. The presentation in two brothers with recurrent bacterial and viral infections, autoimmunity and gastroenteropathy point us to a Mendelian susceptibility. This report also demonstrates the difficulty of diagnosing early CVID based only on the traditional alert signs such as recurrent infections. Autoimmunity manifestations should alert on additional signs suggesting CVID. References • Javier Chinen, MD, PhD,a Luigi D. Notarangelo, MD,b and William T. Shearer, MD, PhDa. Advances in basic and clinical immunology in 2014 J Allergy Clin Immunol 2015;135:1132-41. • Karakoc-Aydiner E, AO Ozen, Baris S, Ercan H, Ozdemir C, Barlan IB. Alteration in Humoral Immunity Is Common Among Family Members of Patients With Common Variable Immunodeficiency. J Investig Allergol Clin Immunol 2014; Vol. 24(5): 346-351. • Xiao X, et al, Common variable immunodeficiency and autoimmunity – an inconvenient truth, Autoimmun Rev (2014). • Jolles S. The variable in common variable immunodeficiency: a disease of complex phenotypes. J Allergy Clin Immunol Pract 2013; 1:545–56. • Ochs HD. Common variable immunodeficiency (CVID): new genetic insight and unanswered questions. British Society for Immunology, Clinical and Experimental Immunology, 178: 5–6. Keywords: Common variable immunodeficiency (CVID), hypogammaglobulinemia, Autoimmunity, recurrent respiratory infections, Pernicious anemia Conference: IMMUNOCOLOMBIA2015 - 11th Congress of the Latin American Association of Immunology - 10o. Congreso de la Asociación Colombiana de Alergia, Asma e Inmunología, Medellin, Colombia, 13 Oct - 16 Oct, 2015. Presentation Type: Poster Presentation Topic: Immunodeficiencies Citation: OLMOS CE and GOMEZ PARADA C (2015). Common Variable Immunodeficiency and autoimmunity in two teenagers brothers in Bogotá. Front. Immunol. Conference Abstract: IMMUNOCOLOMBIA2015 - 11th Congress of the Latin American Association of Immunology - 10o. Congreso de la Asociación Colombiana de Alergia, Asma e Inmunología. doi: 10.3389/conf.fimmu.2015.05.00131 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 02 Jun 2015; Published Online: 14 Sep 2015. * Correspondence: Dr. CARLOS E OLMOS, Cayre IPS y Fundacion, Bogota, Colombia, colmos.8600@gmail.com Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers CARLOS E OLMOS CATALINA GOMEZ PARADA Google CARLOS E OLMOS CATALINA GOMEZ PARADA Google Scholar CARLOS E OLMOS CATALINA GOMEZ PARADA PubMed CARLOS E OLMOS CATALINA GOMEZ PARADA Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Sera from 77 patients with common variable immunodeficiency (CVID) were tested for GB virus C (GBV-C) RNA, because they are prone to unexplained chronic hepatitis, and from 28 patients with X-linked agammaglobulinemia (XLA) who have a similar primary antibody deficiency but are not prone to hepatitis. Eight CVID and 8 XLA patients were positive; 6 positive CVID and 3 XLA patients had abnormal liver enzymes, explained in 3 by either hepatitis B or C virus infection. Most patients tested had antibodies to the E2 antigen of GBV-C, apparently passively acquired from their immunoglobulin therapy. The high prevalence of GBV-C viremia in CVID and XLA patients is probably explained by their long-term exposure to blood products. Our data indicate that GBV-C does not cause chronic hepatitis in immunocompromised XLA patients and is not the cause of chronic non-B or -C hepatitis in the majority of CVID patients.

Subcutaneous immunoglobulin replacement therapy in the treatment of patients with primary immunodeficiency disease Suzanne Skoda-Smith, Troy R Torgerson, Hans D OchsSeattle Children&rsquo;s Research Institute and Department of Pediatrics, University of Washington, Seattle, WashingtonAbstract: Antibody deficiency is the most frequently encountered primary immunodeficiency disease (PIDD) and patients who lack the ability to make functional immunoglobulin require life-long replacement therapy to prevent serious bacterial infections. Human serum immunoglobulin manufactured from pools of donated plasma can be administered intramuscularly, intravenously or subcutaneously. With the advent of well-tolerated preparations of intravenous immunoglobulin (IVIg) in the 1980s, the suboptimal painful intramuscular route of administration is no longer used. However, some patients continued to experience unacceptable adverse reactions to the intravenous preparations, and for others, vascular access remained problematic. Subcutaneously administered immunoglobulin (SCIg) provided an alternative delivery method to patients experiencing difficulties with IVIg. By 2006, immunoglobulin preparations designed exclusively for subcutaneous administration became available. They are therapeutically equivalent to intravenous preparations and offer patients the additional flexibility for the self-administration of their product at home. SCIg as replacement therapy for patients with primary antibody deficiencies is a safe and efficacious method to prevent serious bacterial infections, while maximizing patient satisfaction and improving quality of life.Keywords: subcutaneous immunoglobulin, primary immunodeficiency disease, antibody deficiency, X-linked agammaglobulinemia, common variable immune deficiency

Correlation Between Clinical Response and Specific Antibody Levels in Patients Receiving IVIG for Humoral Immunodeficiency

Selective deficits in blood dendritic cell subsets in common variable immunodeficiency and X-linked agammaglobulinaemia but not specific polysaccharide antibody deficiency

There is clear evidence that prevalence of primary antibody deficiency (PAD) is higher in children with 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 children with PAD. The PubMed, Embase, and Cochrane databases were systematically reviewed from inception through December 2023. 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 50 studies were included in this evidence-based review. These studies were evaluated on the incidence of PAD in rhinosinusitis patients, the incidence of rhinosinusitis in PAD patients, and on the different treatment modalities used and their outcome. The aggregate quality of evidence varied across the reviewed domains. Based on the currently available evidence, the incidence of PAD in children with recalcitrant CRS can be significantly elevated. 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 children with PAD and rhinosinusitis.

Patients with primary antibody deficiency (PAD) are being increasingly diagnosed in the developing world. However, care of these children continues to remain suboptimal due to financial and social constraints. Immunoglobulin (Ig) trough level is an important predicting factor for infections in children on replacement immunoglobulin therapy. There are no data on this aspect from the developing world. Therefore, we studied serial immunoglobulin G (IgG) trough levels in 14 children with X-linked agammaglobulinemia (XLA) receiving replacement intravenous immunoglobulin (IVIG). Infections during the course of enrolment were documented prospectively. Mean age at the time of diagnosis was 5.1years (range 2-11years). Mean time from onset of symptoms and initiation of therapy was 3.3years. Two children had established chronic lung disease prior to enrolment. Total numbers of major and minor infections were 7 and 40, respectively. At a mean dose of 414mg/kg/month of IVIG, mean trough IgG level was 435mg/dl. Median IgG trough levels during the episodes of major and minor infections were 244 and 335mg/dl, respectively. An escalation in IVIG dose of 100mg/kg produced an increase in serum IgG levels by 53.6mg/dl. Median trough IgG level of 354mg/dl was found to be protective with 64% sensitivity and 75% specificity. A median dose of 397mg/kg was required to keep children free of infections. Despite financial constraints and several challenges in the context of a developing country, children with XLA have good outcome on replacement immunoglobulin therapy. Furthermore, mean biological trough IgG levels are much lower than reported in for Western patients; however, studies involving larger number of subjects are required in future to draw firm conclusions.

Pathogens have well recognised patterns of infections but these rules are often violated in immunocompromised hosts leading to infections by atypical organisms at unexpected sites. While many of the immunodeficiency...