Redefining Secondary Immunodeficiency: a Systematic Review of Therapy-Driven Risk, Functional Immune Deficits, Diagnostic Inconsistencies, and Global Gaps in Standardized Care

Secondary immunodeficiency is an acquired immune deficiency caused by various factors, including cancer treatment, organ failure, chronic disease, nutritional deficiency, and physiological aging. It impairs antibody production, attenuates T-cell immune function, disrupts mucosal immunity, and increases the risk of several severe infections. This review compiles evidence on treatment approaches from 2011 to 2026, including impacts on secondary immunodeficiency, clinical reviews, disease patterns, and therapeutic interventions. Heterogeneous definitions and therapeutic challenges of immunoglobulin replacement therapy are explored. It explores the use of serum IgG testing as the primary tool for clinicians to evaluate functional antibody production. This study was conducted through systematic literature searches in PubMed, Scopus, Web of Science, and the Cochrane Library, in accordance with PRISMA 2020 guidelines. A screening process was conducted, and 100 studies across five clinical areas were identified. The three main outcomes were hypogammaglobulinemia, reduced vaccine response, and increased infections. The study found that 20–50% of patients developed clinically significant hypogammaglobulinemia following anti-CD20 treatment, while CAR-T patients showed extended immune system deficits. The study showed that people with normal IgG levels exhibited functional antibody deficiency, complicating the identification of their condition. The region faced ongoing challenges because of limited access to both therapy and essential preventive services. SID warrants recognition as a clinically significant and undertreated syndrome. The development of worldwide standards requires urgent prioritization of functional assessment frameworks alongside equitable therapeutic access.