Rethinking secondary immunodeficiency: a cross-domain pathway framework for risk stratification.

Background: Secondary immunodeficiency (SID) arises from malignancy, immunomodulatory therapies, organ dysfunction, chronic infection, malnutrition, and aging. Despite its increasing prevalence, SID remains conceptualized within disease-specific silos, resulting in inconsistent diagnostic standards and fragmented management across specialties. Methods: Using the PRISMA 2020 guidelines and a prospectively registered OSF protocol (6qvkx), a systematic, qualitative synthesis was conducted, comprising structured screening, standardized data extraction, and a design-specific risk-of-bias assessment. A search of the MEDLINE, Embase, Scopus, and Web of Science databases resulted in 11,968 records. A Python-assisted fuzzy-matching algorithm identified 9,295 duplicate records (78%), which were confirmed in Zotero. Following deduplication, 2673 unique studies were screened; 100 met the predefined PICOS criteria and were included in the qualitative synthesis. No primary data were collected. The primary reviewer selected the studies and extracted data manually, using Python only for descriptive summarization. Thematic synthesis was presented along three predetermined axes of analysis: Results: Humoral failure, cellular disruption, and innate immune dysregulation were identified as 3 immunologic pathways common across all included clinical domains. A significant difference was noted in the type of diagnostic criteria used: IgG thresholds were used in 78% of the hematological malignancy studies and 42% of the HIV/malnutrition studies, whereas the functional assessment of antibody in the former was employed in 32% of studies compared to 67% of the latter, presumably due to the superior clinical correlation in chronic infection and nutritional deficiency settings. The most common outcome reported was infection burden (range 63-85%). Structured qualitative convergence mapping was used to create an exploratory conceptual risk stratification framework based on variables that met preset cross-domain reproducibility criteria. The framework is designed to provide a structured clinical reasoning tool, organized around convergent cross-domain evidence, which requires prospective validation before use in the clinical setting. Conclusion: Three immunological pathways converge in the selected SID-inducing conditions: humoral dysfunction, cellular disruption, and innate immune dysfunction. The proposed framework provides a structured approach to risk evaluation and management across specialties and resource settings. Systematic Review Registration: https://osf.io/6qvkx, identifier 6qvkx.