Immunoglobulin Replacement Therapy in Antibody Production Defects

Background: Inborn errors of immunity (IEIs) are a heterogeneous group of genetically determined disorders that lead to immune dysfunction, recurrent infections, and organ-specific complications. The lungs are among the most commonly affected organs, with both infectious and noninfectious manifestations that significantly contribute to morbidity and mortality. This study aimed to provide a comprehensive overview of pulmonary manifestations in IEI, with emphasis on pathophysiological mechanisms, diagnostic approaches, and therapeutic strategies. Methods: A narrative review and synthesis of current literature and clinical guidelines were conducted, focusing on pulmonary involvement in IEI as classified by the International Union of Immunological Societies (IUIS). The analysis included data on infectious and noninfectious complications, imaging findings, immunological assessments, and management strategies, supported by clinical evidence and expert consensus. Results: Pulmonary manifestations in IEI encompass a wide spectrum of conditions. Infectious complications include recurrent bacterial pneumonias, bronchitis, and opportunistic infections, frequently resulting in irreversible lung damage such as bronchiectasis. Noninfectious complications, including granulomatous–lymphocytic interstitial lung disease (GLILD) and interstitial lung disease (ILD), are common in disorders such as common variable immunodeficiency (CVID) and X-linked agammaglobulinemia (XLA). Early diagnosis using high-resolution computed tomography (HRCT) and immunological testing, combined with the timely initiation of immunoglobulin replacement therapy and anti-biotic prophylaxis, significantly improves prognosis. Conclusions: Pulmonary complications are key clinical indicators of IEI and often precede systemic manifestations. Early, integrated, and interdisciplinary diagnostic and therapeutic management are crucial for preventing irreversible lung damage and improving patient outcomes. Regular monitoring and individualized therapy, including immunoglobulin replacement, targeted immunosuppression, and vaccination, are the cornerstones of effective long-term care in IEI.

Abs tractAim: Patients with inborn errors of immunity (IEI) have a higher frequency of infections and long-term antibiotic usage.We aimed to assess the effects of immunoglobulin replacement therapy (IgRT) on infection rates, antibiotic usage, and treatment outcomes in patients with IEI. Methods:We retrospectively analyzed demographic data, infection frequency, antibiotic prescriptions, and IgRT in 122 IEI patients between March 2014 and September 2023.Specific IEI diagnoses were made following the European Society for Immunodeficiencies criteria. Results:The median age of patients was 29 years [interquartile range (IQR): 23-40], with 54.1% being male.The median age at diagnosis was 25 years (IQR: 13-36), with a diagnostic delay of 96 months (IQR: 24-180).IgRT was administered to 74.5% of patients, with a median treatment duration of 20 years (IQR: 10-33.5).Antibiotic use was higher in patients receiving IgRT (median: 27, IQR: 16-42) compared to those not on IgRT (median: 14, IQR: 8-22; p<0.001).Patients with bronchiectasis had lower baseline immunoglobulin G, CD19 + , and natural killer cell counts, with more frequent antibiotic use, though hospitalization rates were similar to those without bronchiectasis.Immunoglobulin replacement therapy use was higher in the bronchiectasis group (61.5%, p<0.001).No significant differences in antibiotic use or hospitalization rates were observed between intravenous and subcutaneous IgRT groups. Conclusion:Patients with IEI face significant respiratory infections despite IgRT and prophylactic antibiotics.Bronchiectasis is a key risk factor for increased antibiotic use.Early diagnosis and personalized treatment are crucial in reducing infection burden and improving outcomes in this population.

Background X-linked agammaglobulinemia (XLA) is a rare inherited immune deficiency characterized by absence or paucity of circulating B lymphocytes and hypogammaglobulinemia. Patients with XLA present at varying ages and have different presentations. The most common presentation is related to recurrent respiratory tract infections. Patients can also present with severe infections such as meningitis or severe sepsis. Case Report We present a case of an 8-year-old school-going boy with a history of recurrent throat infections and bilateral suppurative otitis media. In 2021, he had an episode of severe dengue infection complicated by pancytopenia presenting with mucosal bleeding, petechiae, and purpura, requiring blood and platelet transfusion. The child developed meningitis presenting with convulsions and headaches and was hospitalized for 14 days. Immunological evaluation upon referral revealed markedly reduced serum immunoglobulins (Ig) G (&amp;lt;1.1 g/L), Ig M (0.20 g/L), Ig A (&amp;lt;0.05 g/L), and Ig E (&amp;lt;2.0 KU/L) levels and CD 19+ B lymphopenia (9 cells/μL). Absolute T (4022 cells/μL) and natural killer cell (397 cells/μL) counts were normal. Targeted genetic panel testing confirmed a hemizygous pathogenic variant in the BTK gene (c.62C&amp;gt;A), establishing a diagnosis of XLA. The patient is currently on monthly intravenous immunoglobulin (IVIG) replacement therapy and prophylactic co-trimoxazole. No episode of severe infection has been reported since the onset of treatment over a year ago. He is currently doing well on regular multidisciplinary follow-up and lung-protective strategies. Discussion This case highlights the need to consider inborn errors of immunity in patients presenting with recurrent, severe, or unusual infections. Early immunological assessment is essential for timely diagnosis and intervention. IVIG remains the mainstay of treatment for XLA, significantly reducing morbidity from recurrent infections. IVIG is given either intravenously or subcutaneously every 3 to 4 weeks to the patient. There is also a role of prophylactic antibiotics in prevention of severe infections. Daily co-trimoxazole is a widely agreed choice of therapy. Thrice weekly azithromycin is also added to prevent respiratory exacerbations and to reduce the risk of developing bronchiectasis. Hematopoietic stem cell transplantation has been considered in some centers as a possible curative therapy.

Dose and outcomes in primary immunodeficiency disorders.

Immunodeficiencies in adults are increasingly recognized yet often remain underdiagnosed, leading to significant morbidity from recurrent infections, autoimmunity, and malignancy. Both primary immunodeficiencies (PIDs), now known as inborn errors of immunity (IEI), and secondary immunodeficiencies (SIDs) contribute to immune dysfunction in adults. Although SIDs are more common in adults due to factors like medications, malignancies, metabolic disorders, chronic conditions, and protein-losing conditions, IEI—particularly common variable immunodeficiency (CVID)—can also manifest in adulthood with diverse clinical features. Early recognition is crucial, with key warning signs including recurrent sinopulmonary infections, unexplained autoimmunity, poor vaccine responses, chronic diarrhea, bronchiectasis, and persistent lymphadenopathy. The diagnostic approach should be systematic. It begins with a detailed patient history and status followed by the evaluation of immunoglobulin levels, lymphocyte subsets, vaccine-specific antibody responses, and exclusion of secondary causes. Genetic testing, increasingly accessible, plays an important role in confirming the diagnosis of IEI and guiding prognosis and treatment. Management strategies focus on treating the underlying condition in SIDs. Preventive measures, including antimicrobial prophylaxis, vaccination, and immunoglobulin replacement therapy (IGRT) in patients with significant antibody deficiencies, are essential for reducing infections and complications in high-risk patients. Given the growing recognition of adult-onset immunodeficiency, clinicians should maintain a high index of suspicion and adopt a structured diagnostic and management approach to improve patient outcomes and quality of life.

SARS-CoV-2 symptomatic reinfection among patients with primary antibody deficiency

Primary immunodeficiency diseases (PID) are caused by abnormalities in molecules involved in the immune system, and there are nearly 500 genes associated with PID. The symptoms are not only susceptibile to infectious diseases but also to autoimmune diseases, malignancies, autoinflammatory diseases, and allergies. Thus, these diseases are considered inborn errors of immunity (IEI) rather than PID. IEI is typically thought to occur in childhood because IEI is associated with a genetic variant, but there are also several adult-onset IEIs. The same 10 warning signs used to diagnose IEI in children are used to diagnose the condition in adults as well, who are then given a definitive genetic diagnosis after a 4-step diagnostic process. In addition to prophylactic antimicrobial agents and immunoglobulin replacement therapy, allogeneic hematopoietic cell transplantation (HCT) is performed as a curative therapy in some patients with IEI. However, in adult patients with IEI, HCT may have to be stopped due to complications. Adult patients with IEI need to be promptly assessed for HCT, and HCT must be done before complications increase.

Clinical Journey and Immunoglobulin-Replacement Therapy Treatment Patterns in Chronic Lymphocytic Leukemia Patients

Patient-reported outcomes are critical to multidisciplinary, patient-centred approaches in diseases requiring lifelong management. Among inborn errors of immunity (IEIs), reports on this subject are typically limited to specific diagnostic subgroups or focus narrowly on the route of immunoglobulin replacement therapy (IgRT), offering a restricted perspective. We aimed to evaluate the health-related quality of life (HRQoL) and IgRT-related treatment satisfaction (TS) of a heterogeneous cohort of IEI patients and identify factors influencing these outcomes to guide improving the health and well-being of IEI patients. We conducted a cross-sectional survey targeting IEI patients on IgRT, assessing TS (TSQM-9) and HRQoL (KINDL/SF-36). Patient/caregiver-reported data were integrated with clinical data to identify outcomes and influencing factors. The survey included 500 IEI patients (356 children, 144 adults) diagnosed 54% Primary Antibody Deficiency (PAD), 36% combined immunodeficiency, 7% immune-dysregulation, and 3% other IEIs. Non-PAD diagnoses, comorbidities, absence of school/work attendance, and IgRT-related systemic adverse reactions negatively impacted HRQoL. Severe infections and related hospitalizations adversely influenced both HRQoL and TS. The subcutaneous route of IgRT, particularly at home, was associated with higher TS due to its convenience and reduced school/work absenteeism. However, the IgRT route did not influence adult HRQoL. Patient-reported well-being and satisfaction in IEIs are multifactorial and cannot be solely attributed to the route of IgRT. Minimizing negative experiences related to the disease or its treatment and, where possible, encouraging patients to maintain school/work attendance or engage in activities that promote societal participation can enhance self-esteem, coping abilities, and overall well-being.

Objective: Immunoglobulin Replacement Therapy (IgRT) via intravenous (IVIG) or subcutaneous (SCIG) routes is essential for managing a large proportion of inborn errors of immunity (IEI), offering reductions in infection rates and enhancements in Health-Related Quality of Life (HRQoL) and treatment satisfaction (TS).The assessment of HRQoL and TS among a diverse spectrum of both pediatric and adult IgRT-receiving IEI patients currently needs to be expanded.The aim of this study was to investigate both HRQoL and treatment satisfaction with current clinical status in a heterogeneous group of patients with IEI receiving IVIG and SCIG. Materials and Methods:We conducted a cross-sectional survey targeting IEI patients on IgRT, assessing TS (TSQM-9) and HRQoL (KINDL/SF-36).The survey integrated patient and caregiver perspectives with demographic, clinical, safety, and efficacy data to identify confounders of outcomes.Results: Eighty IEI patients (ages 1-45; 55 females, 45 males) participated, with 71.2% receiving IVIG and 28.8% SCIG.HRQoL scores were significantly higher for the SCIG group compared to IVIG (p=0.006), and even more so at the 20% SCIG concentration (p=0.026).History of adverse reactions to IgRT and diagnostic delay over one year showed lower TSQM-9 scores (p=0.044 and p=0.009, respectively).Patients with comorbidities also reported lower HRQoL and TSQM-9 scores compared to their peers without comorbidities (p=0.012 and p=0.046, respectively). Conclusion:SCIG, particularly at high concentration, shows an improvement in HRQoL outcomes, whereas adverse reactions to IgRT and diagnostic delay impair TS.Detrimental effect of IEI-related comorbidities on HRQoL and TS highlighted the critical role of timely and accurate diagnosis in IEI management.

Inborn errors of immunity (IEI) (also known as primary immunodeficiencies) is an umbrella term for a growing group of over 450 different disorders that are characterized by defects in some of the components of the immune system. IEI are chronic diseases of genetic origin that render individuals suffering from them susceptible to infections. The mainstay of treatments for most patients with IEI, that is, predominantly antibody deficiencies is immunoglobulin replacement therapy (IRT), which is commonly delivered intravenously. Immunoglobulin (IG) therapy contains antibodies to compensate for the defective immune system's inability to produce them. Individuals with IEI need IRT regularly throughout their lives to help combat infections and prevent organ damage. Without IRT, they are in danger of suffering from morbidity, poor quality of life, and reduced life expectancy. In the last 20 years, the use of IG preparation has tripled and this is partly attributed to the growing awareness and improved diagnoses of IEI cases. IG preparations are also used for the treatment of other medical conditions including secondary immunodeficiencies and autoimmune diseases. As IG is derived from human plasma, there are concerns about the availability of supply, particularly to treat life-threatening conditions that cannot be improved with other medications. It is estimated that 75% to 80% of IEI patients do not have access to adequate IG therapy throughout the world. This concern of supply and other challenges faced by patients with IEI in Malaysia are described from the patients' perspective.

Aims Patients with inborn errors of immunity (IEI) are predisposed to severe recurrent/chronic infections, and often require hospitalization, resulting in substantial burden to patients/healthcare systems. While immunoglobulin replacement therapies (IgRTs) are the standard first-line treatment for most forms of IEI, limited real-world data exist regarding clinical characteristics and treatment costs for patients with IEI initiating such treatment. This retrospective analysis examined infection and treatment characteristics in US patients with IEI initiating IgRT with immune globulin infusion (human), 10% (IG10%). Healthcare resource utilization (HCRU) and associated costs before and after treatment initiation were compared. Additionally, the impact of COVID-19 on infection diagnoses was evaluated. Methods Patients with IEI initiating IG10% between July 2012 and August 2019 were selected from Merative MarketScan Databases using diagnosis/prescription codes. Patients were followed 6 months before and after first IG10% claim date. Demographic and clinical characteristics were described. Treatment characteristics and HCRU before and after IG10% initiation were compared. Infection diagnoses during 2020 and 2019 (March–December) were compared. Results The study included 1,497 patients with IEI diagnoses (mean age = 43.4 years) initiating IG10%, with frequently reported comorbidities like asthma (32.1%). Following IG10% initiation, fewer severe infection diagnoses (11.6% vs 19.9%), fewer infection-related inpatient (10.8% vs 19.5%) and outpatient services (71.6% vs 79.9%), and lower infection-related total healthcare costs ($7,849 vs $13,995; p < 0.001)—driven by lower inpatient costs ($2,746 vs $9,900)—were observed than before. Fewer patients had infection diagnoses during COVID-19 (22.8%) than the prior year (31.2%). Conclusion Patients with IEI are susceptible to severe infections leading to high disease burden and treatment costs. Following IG10% initiation, we observed fewer infections, lower infection-related treatment costs, and shift in care (inpatient to outpatient) leading to significant cost savings. Among patients with IEI, 27% fewer infection diagnoses were observed during the early COVID-19 lockdown period than the prior year.

BackgroundPatients with inborn errors of immunity (IEI) have increased risk of developing cancers secondary to impaired anti-tumor immunity. Treatment of patients with IEI and cancer is challenging as chemotherapy can exacerbate infectious susceptibility. However, the literature on optimal cancer treatment in the setting of IEI is sparse.ObjectivesWe present a patient with specific antibody deficiency with normal immunoglobins (SADNI), immune dysregulation (ID), and stage III ovarian carcinoma as an example of the need to modify conventional treatment in the context of malignancy, IEI, and ongoing infections.MethodsThis is a retrospective chart review of the patient’s clinical manifestations, laboratory evaluation and treatment course.ResultsOur patient is a female with SADNI and ID diagnosed with stage III ovarian carcinoma at 60 years of age. Her ID accounted for antinuclear antibody positive (ANA+) mixed connective tissue diseases, polyarthralgia, autoimmune neutropenia, asthma, autoimmune thyroiditis, and Celiac disease. Due to the lack of precedent in the literature, her treatment was modified with continuous input from infectious disease, allergy/immunology and oncology specialist using a multidisciplinary approach.The patient completed debulking surgery and 6 cycles of chemotherapy. The dosing for immunoglobulin replacement therapy was increased for prophylaxis. Chemotherapy doses were lowered for all cycles preemptively for IEI. The therapy included carboplatin, paclitaxel, bevacizumab, and pegfilgrastim. The patient completed six-months of maintenance medication involving bevacizumab.Her treatment course was complicated by Mycobacterium avium-complex (MAC) infection, elevated bilirubin and liver enzymes attributed to excessive immunoglobulin replacement therapy, and urinary tract infection (UTI) and incontinence.Cancer genetic analysis revealed no targetable markers and primary immunodeficiency gene panel of 407 genes by Invitae was unrevealing. Lab tests revealed no evidence of Epstein-Barr Virus (EBV) infection. Post-chemotherapy imaging revealed no evidence of cancer for 1 year and 4 months, but the disease relapsed subsequently. The patient’s lung scarring requires vigilance.ConclusionsOur patient with ovarian cancer and IEI required modified treatment and prevention of complications. In cases of IEI, optimal chemotherapy should be titrated to minimize immunosuppression yet treat cancer aggressively while decreasing the risk of infection with prophylactic antibiotics and prolonged post-treatment surveillance, including pulmonary evaluation.

Background Inborn errors of immunity (IEI) are increasingly associated not only with recurrent infections but also with hematological complications. The discovery of somatic mutations leading to “IEI phenocopies” has expanded the genetic understanding of these disorders. However, the clinical and genetic scope of IEI in hematological disorders remains underexplored in large-scale studies. Methods This study recruits patients under 25 years old with hematological abnormalities, categorized into four subgroups: autoimmune cytopenias (AICs), polyclonal lymphoproliferation (PL), monoclonal lymphoproliferation (ML), and bone marrow failure/myelodysplasia (BMF/MDS). Participants undergo immunological evaluations, including immunophenotyping, cytokine profiling, and autoantibody assays. Next-generation sequencing (NGS) is used to identify germline and somatic variants, with bulk RNA sequencing applied to validate variants and explore pathways in inconclusive cases. Additionally, this study aims to establish a dedicated consortium for the comprehensive study of IEI-related hematological disorders, bringing together multiple centers to collaborate on data collection and analysis. Patient advocacy organizations (PAOs) are involved to raise awareness and support participants. Results Retrospective data from Meyer Children’s Hospital IRCCS in Florence (2020–2024) showed feasibility, identifying 71 eligible patients: 38 with AICs, 15 with PL, 20 with lymphoma, and 12 with BMF/MDS. A similar number of patients are expected to enroll at this site over three years, with collaborating referral centers projected to recruit approximately 680 participants in total. Preliminary results from the initial 71 participants show a 35% detection rate of hidden IEI, supporting the study's premise. Conclusions This research is poised to enhance the understanding of IEI and IEI phenocopies in hematological disorders, revealing novel genetic contributors and biomarkers. The findings could lead to earlier diagnoses, personalized therapies, and more timely hematopoietic stem cell transplantation. Collaboration with PAOs will improve patient education, treatment adherence, and overall outcomes, while reducing healthcare burdens. This study represents a significant advancement in addressing the unmet needs of patients with hematological complications of IEI.

COVID-19-Related Encephalitis in a Child with PIK3CD Defect