ENOrphanet Journal of Rare Diseases | Global Research Landscape of Inborn Errors of Immunity: A Bibliometric Analysis (1991–2025)
Date: February 20, 2026
Classification: Frontiers
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This study systematically maps the research evolution of Inborn Errors of Immunity (IEI) over the past 35 years through large-scale bibliometric analysis, revealing the dominant role of the United States, shifts in research hotspots, and emerging frontiers such as gene therapy, providing valuable references for scientific and clinical decision-making.
Literature Overview
The article titled 'Global research landscape of inborn errors of immunity: a bibliometric analysis (1991–2025)', published in the journal Orphanet Journal of Rare Diseases, reviews and summarizes the global research trajectory on inborn errors of immunity (IEI) from 1991 to 2025. Based on 7,455 publications from the Web of Science database, the study employs bibliometric methods to systematically analyze annual publication trends, national contributions, research institutions, journal distribution, author networks, keyword co-occurrence, and citation bursts, offering a comprehensive depiction of the field's knowledge structure, evolving research foci, and emerging frontiers. The study highlights that while annual publication output continues to grow, total citation counts have recently plateaued, suggesting the field may be entering a stabilization phase requiring technological breakthroughs for further advancement. Additionally, it emphasizes the central role of the United States in global IEI research and the importance of emerging therapies such as gene therapy, hematopoietic stem cell transplantation, and targeted treatments. This work provides researchers, clinicians, and policymakers with a systematic 'knowledge map' to guide future research directions and resource allocation.Background Knowledge
Inborn Errors of Immunity (IEI) are a group of inherited immune system disorders caused by monogenic mutations, previously known as Primary Immunodeficiency Diseases (PID). With deeper understanding of immune system complexity, the clinical phenotypes of IEI have expanded from recurrent infections to include autoimmunity, allergies, inflammatory dysregulation, bone marrow failure, and malignancies, making it a multidisciplinary research hotspot spanning immunology, genetics, hematology, oncology, and rheumatology. Since Bruton's first report of X-linked agammaglobulinemia in 1952, IEI research has undergone a paradigm shift from phenotypic observation to gene localization. In the 21st century, high-throughput sequencing technologies (e.g., NGS) have greatly accelerated the discovery of disease-causing genes. The International Union of Immunological Societies (IUIS) has expanded the IEI classification to 559 diseases involving 508 causative genes as of 2024. Therapeutic approaches have evolved from supportive therapies such as immunoglobulin replacement to precise interventions including hematopoietic stem cell transplantation (HSCT), enzyme replacement therapy, targeted signaling pathway inhibitors (e.g., JAK, PI3Kδ inhibitors), and even gene therapy. Notably, the clinical translation of genome editing technologies such as CRISPR/Cas9, base editing, and prime editing brings new hope for curative treatments. However, the field still faces numerous challenges, including unequal global diagnosis, lack of universal newborn screening, insufficient long-term efficacy and safety data, and unclear genetic mechanisms underlying complex phenotypes. In resource-limited regions, many IEI patients remain undiagnosed. Moreover, although HSCT and gene therapy have achieved significant outcomes in severe IEI, issues such as donor matching, graft-versus-host disease (GvHD), and vector safety continue to limit their widespread application. Therefore, systematically reviewing the global landscape of IEI research to identify knowledge gaps and emerging frontiers is crucial for advancing the field. This study is conducted against this backdrop, aiming to provide a macroscopic perspective on the evolution and future trends of IEI research through bibliometric analysis.
Research Methods and Experiments
This study adopted a systematic literature search strategy to retrieve English articles and reviews published between January 1, 1991, and May 29, 2025, from the Web of Science Core Collection database, using search terms including 'inborn error of immunity*', 'primary immunodeficien*', and 'primary immune deficien*'. After screening and excluding retracted papers and book chapters, a total of 7,455 publications were included in the analysis. Microsoft Excel 2021 was used for basic data organization and statistics, including cumulative publication count, total citations (TC), and H-index. Additionally, professional bibliometric tools such as Bibliometrix, VOSviewer 1.6.20, and CiteSpace 6.2.R6 were employed for visualization analyses, covering co-occurrence networks of countries/regions, institutions, journals, authors, references, and keywords, collaboration networks, co-citation analysis, and burst detection. Through these multidimensional analyses, the study systematically maps research output trends, core research entities, knowledge structure evolution, and emerging research hotspots in the IEI field.Key Conclusions and Insights
Research Significance and Outlook
This study, through large-scale bibliometric analysis, provides the first systematic depiction of the IEI field’s research evolution over nearly 35 years, offering a clear knowledge map for global researchers. The revealed dominance of the U.S. and key European collaborators reflects the current concentration of global research resources while exposing structural issues of insufficient research participation from developing countries. The study emphasizes that the IEI field is undergoing a paradigm shift from 'phenotype-driven' to 'mechanism-driven' research, with precision medicine profoundly influencing clinical practice and research directions. Successful targeted therapies for diseases like APDS offer translational pathways applicable to other complex IEIs such as CVID. Furthermore, the successful implementation of newborn screening for SCID highlights the critical role of early intervention in improving outcomes and should be prioritized in policy agendas.
Future research should focus on four key directions: first, establishing standardized newborn screening and treatment outcome metrics to enable cross-regional comparisons and optimize clinical decisions; second, enhancing real-world long-term follow-up to assess the impact of different therapies on quality of life and the burden of infections and malignancies; third, conducting long-term safety and cost-effectiveness studies of gene therapy, particularly for diseases such as ADA-SCID and X-SCID; and fourth, filling data gaps in the Global South by establishing regional registries and improving diagnostic capabilities to advance global health equity. These efforts will help transform the current quantitative growth in research into qualitatively more impactful outcomes.
Conclusion
This study systematically analyzed 7,455 IEI-related publications from 1991 to 2025 using bibliometric methods, comprehensively revealing the development trajectory and research landscape of the field over the past 35 years. It finds that although annual publication output continues to grow rapidly, total citation counts have recently plateaued, suggesting the field may be entering a stabilization phase that requires technological innovation to achieve the next breakthrough. The United States dominates in research output, citation impact, and international collaboration, while European countries such as France, the UK, and Germany form the second tier. Research hotspots have shifted from traditional phenotypic classification to molecular mechanism exploration and precision therapy, with gene therapy, HSCT, and targeted inhibitors emerging as current frontiers. However, the study also reveals several critical gaps, including insufficient newborn screening implementation, lack of quality-of-life assessments, and uneven global research distribution. Future efforts should prioritize standardized metric development, long-term follow-up studies, cost-effectiveness evaluations, and capacity building in the Global South to transform quantitative growth into qualitative progress, ultimately ensuring that scientific advances benefit all IEI patient populations. This work provides a solid knowledge foundation and strategic direction for research, clinical practice, and policymaking.
