Medical Algorithm: Personalized Immunoglobulin Replacement Therapy for Inborn Errors of Immunity

Immunoglobulin replacement therapy (IgRT) is a cornerstone treatment for patients with inborn errors of immunity (IEIs) and is often required lifelong. To achieve optimal outcomes, IgRT should be tailored to each patient's clinical status, comorbidities, risk factors, daily life circumstances, and individual preferences when selecting the product, dose, and route of administration [1-4]. As summarized in Table 1, IgRT can be administered intravenously (IVIG) or subcutaneously as conventional (cSCIG) or facilitated by recombinant human hyaluronidase (fSCIG) routes [1-3, 5, 6]. SCIG confers several advantages, including avoidance of venous access, feasibility of home-based administration, reduced loss of working days, stable serum immunoglobulin (Ig) G levels, and a lower incidence of systemic adverse events (AEs). However, despite these advantages, SCIG is not suitable for all individuals with IEI. IVIG remains the preferred treatment for those who, themselves or through a caregiver, lack the ability to perform subcutaneous infusions, as well as situations where the subcutaneous route is contraindicated, such as in the presence of severe skin disease, bleeding diatheses, or a history of serious adverse events following prior SC administration [1-4]. IgRT preparations differ not only in their routes of administration but also in concentrations, stabilizing agents, and formulations (Table S1), each offering unique advantages and some limitations [2, 3]. The stepwise approach for individualized product and route selection, beginning with baseline evaluation, is illustrated in Figure 1A. 5–15 min manual push ~1 h infusion pump Home Self-administered Home Self-administered or hospital/infusion center IgRT is usually initiated at a cumulative monthly dose of 400–600 mg/kg, calculated based on ideal body weight [6, 7]. IVIG is typically administered every 3–4 weeks, and vital signs must be closely monitored throughout the infusion. The infusion should begin at a rate of 0.1–0.2 mL/kg/h for the first 15–30 min and can be gradually increased at 15–30-min intervals according to the patient's tolerance. The infusion rate should not exceed 2 mL/kg/h during the first 2 h and must remain below a maximum rate of 0.08 mL/kg/min during the entire infusion period [2]. SCIG is given more frequently in smaller, divided doses of 100–200 mg/kg/week. The infusion rate typically ranges between 15 and 50 mL/h per site, with up to 4–8 sites used simultaneously [1, 2, 4, 6, 7]. The first several SCIG infusions should be performed under professional supervision to ensure proper technique and patient comfort [5]. High-concentration cSCIG formulations (16.5%–20%) allow higher doses to be given in smaller volumes, enabling biweekly administration, whereas fSCIG, through the addition of recombinant human hyaluronidase, permits larger infusion volumes and longer intervals of 3–4 weeks [2-5]. Patients receiving IgRT should be monitored regularly for efficacy, safety, adherence, satisfaction, and health-related quality of life. The frequency of follow-up visits should be planned according to each patient's clinical condition and stability [2, 3]. When evaluating the efficacy of IgRT, infection burden provides a more meaningful information than serum IgG levels alone [2-7]. Serum IgG measurements for efficacy assessment should not be performed earlier than 3 months after initiating therapy. The target serum IgG level (trough for IVIG or steady-state for SCIG) should represent the lowest level that effectively prevents infections and halts the progression of organ damage [2, 3, 5-7]. This threshold varies from patient to patient and cannot be standardized [5, 6]. However, when an increased infection burden persists despite serum IgG levels exceeding 800 mg/dL (or 900 mg/dL in patients with bronchiectasis, granulomatous lymphocytic interstitial lung disease, inflammatory enteropathy, or recent immunosuppressant use) concomitant therapies such as antibiotic prophylaxis or physical therapy should be reassessed and optimized rather than increasing the IgRT dose [6-8]. The principles of monitoring and dose adjustment are presented in Figure 1B. Systemic AEs are most likely to occur during the first or second infusion or in patients with chronic infections or irregular treatment schedules, although serious or life-threatening systemic AEs are extremely rare [2-4]. SCIG is generally associated with fewer systemic AEs compared to IVIG, as the monthly dose is administered in divided doses at more frequent intervals and the subcutaneous route results in a slower increase in plasma concentration than intravenous administration. However, most SCIG-treated patients experience at least one local reaction, which typically diminishes over time [2-5]. Common and rare IgRT-related adverse events, their risk factors, and strategies to minimize them are summarized in Table S2. Even when a personalized treatment plan is initially established, patients' life circumstances and expectations may change over time. Therefore, during follow-up visits, it is essential to assess not only treatment adherence but also health-related quality of life and treatment satisfaction. Incorporating these patient-reported outcomes into treatment decisions enables clinicians to adapt ongoing care, optimize adherence, and ultimately enhance the long-term effectiveness of IgRT in individuals with IEIs [2, 3]. Switching between IVIG and SCIG may be necessary due to adverse effects, poor adherence, treatment dissatisfaction, or patient preference. Before switching, serum IgG levels should be measured, and the total monthly dose should remain equivalent. The first infusion of the new route should be administered given at least 7–10 days after the last dose of the previous route [2, 3, 5-7]. In summary, a personalized approach to IgRT in IEIs that includes individualized product and route selection, dosing, and follow-up helps maximize treatment efficacy, minimize adverse effects, and improve long-term adherence and quality of life. The authors have nothing to report. Cevdet Ozdemir: 1. Assistant Editor of Allergy (European Journal of Allergy and Clinical Immunology). 2. European Academy of Allergy and Clinical Immunology (EAACI) Allied Health & Primary Care Section Chair. Elif Karakoc-Aydiner: European Academy of Allergy and Clinical Immunology (EAACI) Immunodeficiencies Working Group Member. All other authors declare no conflicts of interest. This manuscript presents a clinically oriented algorithm derived from previously published evidence; no original data were generated or analyzed. Table S1: Characteristics and comparison of immunoglobulin products. Table S2: Immunoglobulin replacement therapy-related adverse events, risk factors, and mitigation strategies. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.