---
title: "Consensus recommendations to prevent and manage immunoglobulin therapy adverse reactions in primar"
id: "frontiers-in-immunology-4-expert-consensus-recommendations-for-the-prevention-and-management-of"
canonical_url: "https://medichelpline.com/clinical-feed/frontiers-in-immunology-4-expert-consensus-recommendations-for-the-prevention-and-management-of"
content_type: "clinical_feed_article"
specialty: "Infectious Disease"
source_name: "Frontiers in Immunology"
source_url: "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1901301"
published_at: "2026-08-06T00:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Consensus recommendations to prevent and manage immunoglobulin therapy adverse reactions in primar
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/frontiers-in-immunology-4-expert-consensus-recommendations-for-the-prevention-and-management-of
- **Specialty:** [Infectious Disease](https://medichelpline.com/clinical-feed/infectious-disease.md)
- **Primary Source:** Frontiers in Immunology
- **Source URL:** [Original Journal Publication](https://www.frontiersin.org/articles/10.3389/fimmu.2026.1901301)
- **Published At:** 2026-08-06T00:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- This article is a national **Delphi** consensus from the Immunodeficiency Group of the Spanish Society of Immunology addressing prevention and management of adverse reactions related to **immunoglobulin therapy**. - The recommendations target both **primary immunodeficiencies** (PID) and **secondary immunodeficiencies** (SID). - The work is presented as expert consensus guidance intended to inform clinicians who prescribe and administer immunoglobulin products. - The source excerpt provided contains only site navigation and metadata; the detailed content of the consensus (methods, participant panel, specific recommendations, grading, or implementation strategies) was not included. - Because the full article text was not present in the provided source content, specifics such as recommended preventative measures, management algorithms for infusion reactions, monitoring protocols, or evidence summaries are not reported here. - Readers seeking the full set of statements, rationales, and practical implementation advice should consult the complete article on the Frontiers in Immunology website for the published Delphi results and recommendations. - The document is published in Frontiers in Immunology and framed as national guidance produced by a professional society subgroup; details on endorsement, peer review, and conflict-of-interest declarations are not reported in the excerpt provided.
## Clinical Analysis & Structured Key Points
Frontiers | Expert consensus recommendations for the prevention and management of immunoglobulin therapy-related adverse reactions in primary and secondary immunodeficiencies: a national Delphi study from the Immunodeficiency Group of the Spanish Society of Immunology ORIGINAL RESEARCH article Front. Immunol. , 06 August 2026 Sec. Primary Immunodeficiencies Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1901301 Published in Frontiers in Immunology Primary Immunodeficiencies 7 impact factor 11.3 citescore Part of a Research Topic Optimizing Immunoglobulin Therapy in Primary and Secondary Immunodeficiencies Submission open 3160 views 2 articles Editor & Reviewers Edited by Q L Qiao Liu Reviewed by E K Elif Karakoc Aydiner M B Mark Ballow Outline Figures and Tables Figure 1 View in article Figure 2 View in article Table 1 Clinical specialty and geographic distribution of the experts participating in the Delphi panel. View in article ORIGINAL RESEARCH article Front. Immunol. , 06 August 2026 Sec. Primary Immunodeficiencies Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1901301 Expert consensus recommendations for the prevention and management of immunoglobulin therapy-related adverse reactions in primary and secondary immunodeficiencies: a national Delphi study from the Immunodeficiency Group of the Spanish Society of Immunology A F Andrea Ferranti-Ramos 1 M A Marta Aguilar-Criado 2 C L Carmen L. Avendaño-Monje 3 M D María de las Mercedes Díaz Luna 4,5 C M Cinthya M. Fusi-Velarde 6 J P Jaime Pons 7,8,9 * On behalf of the Immunodeficiencies Group of the Spanish Society of Immunology (GISEI) 1. Immunology Genetics Unit, Complejo Hospitalario Universitario de Cáceres, Cáceres, Spain 2. Department of Immunology and Genetics, Complejo Hospitalario Universitario de Badajoz, Badajoz, Spain 3. Department of Immunology, Complejo Asistencial Universitario de León, León, Spain 4. Primary Immunodeficiency Unit, Internal Medicine Department, Hospital Universitario y Politécnico La Fe, Valencia, Spain 5. Research Group of Chronic Diseases and HIV Infection, Health Research Institute La Fe, Valencia, Spain 6. Immunology Department, Hospital General Universitario Dr. Balmis, Alicante, Spain 7. Immunology Department, Hospital Universitario Son Espases, Palma, Spain 8. Health Research Institute of the Balearic Islands (IdISBa), Palma, Spain 9. University of the Balearic Islands (UIB), Palma, Spain See more Article metrics View details Abstract Introduction: Human immunoglobulin (IG) therapy, administered intravenously (IVIG) or subcutaneously (SCIG), is a cornerstone treatment for primary and secondary immunodeficiencies (PID and SID) and is increasingly used in autoimmune and inflammatory diseases. Although generally safe, adverse drug reactions (ADR) may affect treatment adherence, patient safety, and quality of care. Practical recommendations for the prevention and management of IG-associated ADR remain limited. Objective: To develop expert-based recommendations for the prevention, monitoring, classification, and management of ADR associated with IVIG and SCIG therapy in patients with PID and SID. Methods: A modified Delphi consensus was conducted by the Immunodeficiency Group of the Spanish Society of Immunology (GISEI). An expert coordinating committee developed 44 preliminary statements based on scientific evidence and clinical experience. Statements covered eight domains, including administration practices, ADR classification, premedication, acute management, complementary studies, anti-IgA antibodies, and SCIG-related issues. A national panel of specialists evaluated each statement using a 6-point Likert scale. Consensus was defined as ≥75% agreement. Results: Forty-two recommendations achieved consensus and were included in the final document. High agreement was reached regarding individualized risk assessment, infusion rate adjustment, patient monitoring, and early ADR management. Most IVIG-related ADR were considered mild, occurring during or shortly after infusion, and generally not requiring treatment discontinuation. Premedication was recommended only for selected high-risk patients. SCIG was recognized as a safe and effective alternative associated with fewer systemic reactions and predominantly mild local ADR. The panel also highlighted the limited utility of serial anti-IgA antibody testing and emphasized patient education and periodic retraining for home-based SCIG administration. Discussion: This Delphi-based consensus provides practical and clinically applicable recommendations for the prevention and management of ADR associated with IVIG and SCIG therapy. These recommendations may contribute to standardizing clinical practice, improving patient safety, optimizing treatment tolerability, and reducing variability in IG administration across healthcare settings. Further prospective studies are needed to better define risk factors and preventive strategies for severe ADR associated with IG therapy. 1 Introduction Human immunoglobulin (IG) therapy, administered intravenously (IVIG) or subcutaneously (SCIG), represents a cornerstone treatment for inborn errors of immunity, also referred to as primary immunodeficiencies (PID) ( 1 ), secondary immunodeficiencies (SID), and a wide range of autoimmune, neurological, and inflammatory diseases, either as replacement therapy or for immunomodulation. Over recent decades, IVIG and SCIG have demonstrated comparable efficacy ( 2 , 3 ), differing primarily in their pharmacokinetic and safety profiles, thereby allowing for individualized treatment ( 4 ). In particular, SCIG has become established as an effective and safe alternative by providing more stable IgG levels, fewer systemic adverse drug reactions (ADR), and greater patient autonomy ( 5 ). The favorable safety profile of current IG products is the result of decades of pharmaceutical refinement. Since the first therapeutic use of IG in 1952, manufacturing processes have undergone continuous optimization to enhance product safety, stability, and clinical tolerability. Initial preparations were limited by the presence of IgG aggregates capable of activating the complement system, resulting in frequent infusion-related ADR. During the early 1960s, manufacturing strategies incorporating enzymatic digestion and chemical modification were implemented to reduce anticomplementary activity. The subsequent development of second-generation IVIG products, based on diethylaminoethyl (DEAE) anion-exchange chromatography, represented a major advance by enabling efficient purification while preserving the structural and functional integrity of IgG molecules. Early IVIG formulations were predominantly lyophilized to provide prolonged storage stability, typically for 2–3 years. In the mid-1980s, the introduction of low-pH formulations (approximately pH 4.25) further improved product stability and contributed to enhanced viral safety. Modern IVIG products are manufactured using sophisticated fractionation, purification, and pathogen-reduction technologies, yielding highly purified, iso-osmolar, low-sodium preparations formulated with safer stabilizing excipients. Collectively, these technological advances have markedly improved the safety profile of IVIG while preserving its efficacy for both IG replacement and immunomodulatory indications ( 6 ). Despite these advances, ADR may still occur with variable incidence depending on the product, patient population, and route of administration ( 2 ). ADR associated with IG therapy have a multifactorial origin and may be related to product characteristics, administration-related factors, and patient-specific conditions ( 3 ). In this context, individualized risk assessment, adequate hydration, and close monitoring during infusion are essential to reduce ADR ( 2 – 4 ). ADR may be classified according to their timing and severity, facilitating their recognition and clinical management. Most are mild or moderate, transient, and reversible, commonly presenting as headache, fever, chills, myalgia, or cutaneous reactions during or shortly after infusion ( 2 ). In contrast, severe ADR are uncommon but clinically significant and include anaphylaxis, thromboembolic events, acute kidney injury, aseptic meningitis, hemolysis, and transfusion-related acute lung injury (TRALI), potentially requiring hospital management ( 5 ). Although international recommendations regarding IG therapy are available, these guidelines mainly focus on diagnostic and therapeutic aspects and do not specifically address the prevention and practical management of infusion-related ADR ( 7 , 8 ). In Spain, the absence of a unified national protocol contributes to heterogeneous clinical practices among centers. To address this need, the Immunodeficiency Group of the Spanish Society of Immunology (GISEI) promoted a nationwide Delphi consensus involving experts in PID and SID management from across the country. The aim of this document is to establish practical recommendations to improve patient safety and quality of care in the management of ADR associated with IG therapy. This manuscript constitutes a recommendation guideline based on expert consensus from GISEI and the available evidence. Its objective is to standardize clinical practice, optimize the prevention and early recognition of ADR, guide their therapeutic management, and promote patient safety and quality of care during IVIG and SCIG treatment. These recommendations should be applied individually according to patient characteristics and clinical context. 2 Materials and methods 2.1 Study design and expert panel A set of recommendations (R) was developed using a modified Delphi methodology. A GISEI coordinating committee defined the scope of the document and drafted the initial statements based on the available evidence and clinical experience in the management of ADRs associated with IVIG and SCIG. The consensus process was conducted at a national level, with the participation of specialists experienced in the use of IG therapy from different fields and regions across Spain, representing the main specialties involved in the management of primary and secondary immunodeficiencies and immunoglobulin therapy. All panelists were selected based on their recognized expertise in the field and had more than 10 years of clinical experience in the use of immunoglobulin therapy ( Table 1 ). Table 1 Spanish autonomous community Immunologists Pediatricians Internists Allergists Madrid 4 2 Catalonia 2 3 Valencian Community 2 1 Extremadura 3 Balearic Islands 1 1 Castile and León 1 Cantabria 2 Canary Islands 1 Andalusia 1 Region of Murcia 1 Total 16 6 2 1 Clinical specialty and geographic distribution of the experts participating in the Delphi panel. 2.2 Development of statements and consensus process The 44 preliminary statements were organized into thematic blocks covering IG administration, classification and management of ADR, premedication, complementary tests, anti-IgA antibodies, and subcutaneous (SC) administration. Each statement was rated using a 6-point Likert scale. Consensus was defined as at least 75% of responses being “mostly agree” or “strongly agree”. Statements reaching this threshold were included in the document as formal recommendations. This cut-off was selected in accordance with commonly accepted thresholds used in Delphi studies in healthcare research, where agreement levels ranging from 70% to 80% are generally considered indicative of consensus ( 9 ). Statements that did not reach consensus in the first round were reviewed by the coordinating committee, refined based on panelists’ comments, and submitted for a second voting round. Of the statements re-evaluated in the second round, all but two achieved the predefined consensus threshold and were incorporated into the final set of recommendations. The two statements that did not reach consensus in either round are included in this document for transparency, explicitly noted as having failed to achieve consensus and therefore not endorsed as formal recommendations by the panel. A third Delphi round was considered unnecessary because most statements had already achieved consensus after the first round, whereas the remaining statements showed only minor changes in the level of agreement after the second round. Therefore, additional rounds were considered unlikely to substantially modify the results and might have increased participant fatigue and attrition. This approach is consistent with modified Delphi methodologies, in which two rounds are frequently considered sufficient when stability of responses has been achieved. 2.3 Statistical analysis and final document The analysis of responses was descriptive, with calculation of response frequencies and percentages, as well as the overall percentage of agreement for each item. The final version included 42 recommendations, accompanied where necessary by comments based on the available evidence and the clinical consensus of the group. 2.4 Ethics statement This study was conducted as an expert consensus exercise using a modified Delphi methodology. No individual patient data were collected, no clinical interventions were performed on human subjects, and no biological samples were obtained. In accordance with applicable national and institutional regulations, this type of consensus study does not require formal approval by an ethics committee or institutional review board. All participants were informed of the purpose and scope of the study and provided their implicit consent by participating in the consensus process. 3 Results A total of 42 recommendations achieved consensus and are presented in Supplementary Table 1 , along with their corresponding levels of agreement. The following sections provide a detailed description of each recommendation and its supporting rationale, organized by thematic domain. 3.1 General considerations regarding the administration of IG R1. Before the administration of IVIG or SCIG, all patients must be informed about the characteristics of the treatment and possible ADR. They must receive clear instructions on when to contact the medical center if they experience post-infusion symptoms (96% consensus). The administration of IVIG and SCIG must be preceded by a structured process of informing the patient about the indication, benefits, possible ADR, and recommended actions in the event of symptoms during or after the infusion. This process is considered essential for treatment safety, patient understanding, and early detection of ADR, especially in higher-risk patients ( 10 – 13 ). While the panel evaluated the process of informing the patient prior to treatment rather than the use of a written consent form, obtaining and documenting informed consent is considered good clinical practice; its specific format and documentation should follow each institution’s policies and applicable national regulations. R2. The use of IVIG and SCIG should be assessed on an individualized basis for each patient, considering different factors, including comorbidities (renal failure, heart failure, hypertension, diabetes mellitus, etc.) (96% consensus). Guidelines recommend individualizing the indication, regimen, and administration of IG, as some ADR are more frequent during first administrations or after prolonged intervals between doses. In IVIG, the infusion rate should be adjusted according to risk factors, comorbidities, and previous tolerance. In addition, for both IVIG and SCIG, renal function assessment and adequate hydration are recommended to reduce renal and thrombotic complications ( 10 , 11 , 13 ). Hemolysis is another recognized, although uncommon, complication of IVIG, caused by the passive transfer of anti-A and anti-B isohemagglutinins contained in the product; the risk is greatest in recipients of non-O blood group receiving high-dose IVIG, particularly in the context of an underlying inflammatory state ( 14 ). R3. In patients receiving IVIG for the first time, the infusion should always be started at the lowest possible rate, even when premedication has been administered. Subsequently, the rate may be increased gradually and in a controlled manner, according to the patient’s clinical tolerance and without ever exceeding the maximum recommended rate for the product (92% consensus). Guidelines recommend initiating the first IVIG infusion at the minimum rate, especially in treatment-naïve patients or after switching products. Many acute ADR are associated with rapid administration and can be prevented by a slow initiation. In addition, each commercial preparation has specific infusion rate recommendations ( 15 ). Although premedication may reduce some ADR, it does not replace cautious administration. Guidelines consider it a complementary measure while maintaining slow initiation of the first infusion as a basic safety recommendation. Once good tolerance has been confirmed, the administration rate may be progressively increased in subsequent cycles ( 10 , 11 , 13 ). Active or intercurrent infection at the time of infusion has been identified as a predisposing factor for a higher frequency of ADR ( 16 ); in this setting, a slower infusion rate and closer clinical monitoring are advisable. Some experts have additionally proposed administering a reduced dose during the first infusion to improve tolerability, although this practice is based on clinical experience rather than on controlled evidence. 3.2 General considerations and classification of ADR R4. ADR such as facial erythema, fever, chills, asthenia, general malaise, mild headache, and pruritus are considered mild ADR (88% consensus). ADR associated with IG are classified according to severity as mild, moderate, or severe. Mild immediate reactions are the most frequent, occurring in approximately 1–15% of infusions ( 17 ), and include headache, fever, chills, asthenia, and general malaise ( 2 , 4 ). They are usually transient, low in intensity, and appear during or within the first hours after infusion, generally related to the rate of administration and improving when the infusion rate is reduced ( 2 , 3 ). This classification facilitates monitoring in outpatient settings and, according to expert panels, supports that these reactions do not contraindicate IVIG administration ( 18 ), reinforcing its overall safety profile. R5. ADR such as urticaria, wheezing, myalgias, vomiting, chest pain, lower back pain, dizziness, arthralgias, nausea, hypertension, or severe headache are considered moderate ADR (84% consensus). Available data show that a relevant proportion of ADR associated with IG therapy correspond to moderate forms. Among the most frequent manifestations are headache, fever, and nausea, accounting for approximately one quarter or more of the ADR described in some studies ( 19 , 20 ). R6. ADR such as hypotension, bronchospasm, anaphylaxis, aseptic meningitis, thromboembolic events, acute renal failure, TRALI, or alterations in mental status are considered severe ADR (92% consensus). Severe ADR associated with IVIG are uncommon (less than 5%) ( 18 ), although they may be potentially life-threatening, and include anaphylaxis, bronchospasm, hypotension, thromboembolic events, acute renal failure, and TRALI ( 3 , 8 ). Manifestations such as aseptic meningitis and neurological alterations have also been described, although they are infrequent ( 21 ). Aseptic meningitis shows variability in its classification and may be considered moderate or severe depending on its clinical presentation and course ( 3 , 22 ). R7. Most ADR to IVIG are mild, occur during the infusion or within the first 24 hours, and do not constitute a contraindication to continuing treatment (92% consensus). ADR associated with IG usually occur during the infusion or within the first hours afterward, especially during the first 30 minutes and, in most cases, within the first 72 hours ( 18 , 19 ). They generally do
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