Protocol for Systematic Review on Secondary Immunodeficiency

Protocol for a Systematic Review on Secondary Immunodeficiency: Definitions, Diagnostic Frameworks, and Management Strategies Across Clinical Contexts 1. Background and Rationale Secondary immunodeficiency (SID) represents an increasingly recognized and clinically significant condition characterized by impaired immune function arising from extrinsic causes rather than inherited defects. Unlike primary immunodeficiencies, which are genetically determined, SID develops as a consequence of infections, malignancies, metabolic disorders, malnutrition, pharmacologic immunosuppression, transplantation, aging, or systemic inflammatory diseases. The expanding use of immunomodulatory and immunosuppressive therapies, combined with demographic aging and global infectious disease burdens, has led to a substantial increase in individuals at risk of immune compromise. Despite this growing prevalence, diagnostic definitions, immunological thresholds, screening pathways, and management strategies for SID remain heterogeneous across specialties and healthcare systems. The clinical consequences of SID are substantial. Patients frequently experience recurrent or severe infections, poor vaccine responses, prolonged hospitalizations, antimicrobial resistance, and increased mortality. In addition to infectious susceptibility, immune dysregulation may contribute to malignancy progression, autoimmune complications, and impaired recovery from systemic illness. Although immunoglobulin replacement therapy, antimicrobial prophylaxis, vaccination strategies, and immune monitoring are widely used in specific populations, their indications and timing differ significantly between hematology, oncology, rheumatology, transplant medicine, and infectious disease practice. Current literature addressing SID is fragmented across disease domains. Studies evaluating hypogammaglobulinemia in hematological malignancies differ methodologically from those assessing HIV-related immune suppression or post-transplant immunocompromise. Furthermore, laboratory criteria for defining clinically meaningful immunodeficiency vary widely, with inconsistent immunoglobulin thresholds, lymphocyte count cutoffs, and vaccine response criteria. The absence of standardized definitions complicates comparative evaluation of interventions and impedes evidence synthesis. Although systematic reviews have examined immunoglobulin replacement in specific malignancies or prophylaxis in particular populations, no comprehensive review has integrated diagnostic frameworks, etiologic categories, immune assessment strategies, and therapeutic approaches across the full spectrum of secondary immunodeficiency. Given the clinical and public health implications of inconsistent practice, a structured synthesis of existing evidence is warranted. This protocol outlines the methodology for a systematic review designed to synthesize evidence from 100 eligible journal articles examining secondary immunodeficiency across multiple etiologists. The review aims to evaluate definitions, diagnostic criteria, infection risk patterns, immunologic markers, and intervention strategies. By applying transparent search methods, standardized appraisal tools, and structured narrative synthesis in accordance with PRISMA and SWiM guidance, this review seeks to provide a reproducible and decision-oriented synthesis to inform clinical practice and future research. 2. Objectives Primary Objective To systematically evaluate how secondary immunodeficiency is defined, diagnosed, and managed across clinical conditions, and to assess the evidence supporting interventions aimed at reducing infection-related morbidity. Secondary Objectives 1. To identify and compare diagnostic thresholds used to define clinically significant immune compromise. 2. To assess the relationship between laboratory immune parameters and clinical infection outcomes. 3. To evaluate evidence supporting immunoglobulin replacement therapy, antimicrobial prophylaxis, vaccination strategies, and immune monitoring. 4. To determine methodological quality and risk of bias across included studies. 5. To grade certainty of evidence for major outcome domains. 3. Eligibility Criteria (PICOS Framework) Population Adults and children with secondary immunodeficiency resulting from: • Hematological malignancies • Solid tumors • HIV infection • Post-transplant immunosuppression • Autoimmune or inflammatory diseases • Metabolic or systemic disorders • Drug-induced immunosuppression • Aging-associated immune decline Primary immunodeficiencies will be excluded unless clearly distinguished from secondary causes. Intervention/Exposure Studies evaluating: • Diagnostic criteria or immune assessment frameworks • Immunoglobulin replacement therapy • Antimicrobial prophylaxis • Vaccination strategies • Immune monitoring protocols • Predictive tools or biomarkers Comparator Comparators may include: • Standard care • No intervention • Alternative therapeutic strategies • Different diagnostic thresholds • Pre- and post-intervention comparisons Outcomes Primary outcomes: • Incidence of serious or recurrent infections • Infection-related hospitalization • Infection-related mortality Secondary outcomes: • Immunoglobulin levels and immune cell markers • Vaccine response rates • Antibiotic usage patterns • Adverse effects of interventions Study Design Eligible designs: • Randomized controlled trials • Non-randomized interventional studies • Cohort studies • Case-control studies • Cross-sectional studies • Systematic reviews • Diagnostic accuracy studies • Clinical guidelines Exclusions: • Case reports • Editorials • Conference abstracts without full text • Non-peer-reviewed publications Only English-language studies will be included. 4. Databases and Search Strategy The following databases will be searched: • PubMed/MEDLINE • Scopus • Web of Science • Cochrane Library • Embase • ClinicalTrials.gov Searches will cover January 2004 to December 2024. Core PubMed Search String ("secondary immunodeficiency" OR "secondary immune deficiency" OR "acquired immunodeficiency" OR "immunosuppression") AND ("diagnosis" OR "diagnostic criteria" OR "immune monitoring" OR "immunoglobulin" OR "hypogammaglobulinemia" OR "vaccine response") AND ("infection" OR "infectious complications" OR "prophylaxis" OR "immunoglobulin replacement therapy" OR "IgRT") AND ("clinical outcomes" OR "mortality" OR "hospitalization") Database-specific adaptations using controlled vocabulary (e.g., MeSH, Emtree) will be applied. Reference lists of included articles will be manually screened. 5. Screening Process All identified records will be imported into reference management software and duplicates removed. Stage 1: Title and Abstract Screening Two independent reviewers will screen titles and abstracts against eligibility criteria. Studies will be coded as include, exclude, or unclear. Stage 2: Full-Text Screening Full texts of potentially eligible articles will be independently assessed by the same two reviewers. Disagreements will be resolved through discussion. If consensus cannot be reached, a third reviewer will adjudicate. Reasons for full-text exclusion will be documented. A PRISMA flow diagram will summarize selection. 6. Data Extraction Plan A standardized data extraction form will be developed and piloted. Extracted variables will include: • Study characteristics • Population demographics • SID definition criteria • Immune markers measured • Intervention details • Outcomes reported • Follow-up duration • Funding sources Two reviewers will independently extract data from a subset of studies to ensure consistency. Remaining studies will undergo single extraction with independent verification. Missing or unclear data will prompt attempts to contact authors when feasible. 7. Risk of Bias Assessment Risk of bias will be assessed using design-specific tools: • RoB 2 for randomized trials • ROBINS-I for non-randomized interventional studies • Newcastle-Ottawa Scale for observational studies • QUADAS-2 for diagnostic accuracy studies • AMSTAR 2 for systematic reviews • AGREE II for guidelines Two reviewers will independently assess risk of bias. Discrepancies will be resolved by consensus. Results will be presented in tabular and graphical formats. 8. Synthesis Plan Given expected heterogeneity in populations and outcomes, a meta-analysis will only be conducted if at least three studies demonstrate sufficient clinical and methodological comparability. If meta-analysis is not appropriate, synthesis will follow SWiM guidance. Studies will be grouped by: • Etiologic domain • Diagnostic approach • Intervention type • Outcome category Direction-of-effect synthesis will be used where quantitative pooling is not feasible. Evidence tables will summarize findings. 9. Certainty Assessment Plan The GRADE framework will be applied to major outcome domains: • Infection incidence • Hospitalization • Mortality • Vaccine response effectiveness • Benefit of immunoglobulin therapy Certainty will be rated as high, moderate, low, or very low based on: • Risk of bias • Inconsistency • Indirectness • Imprecision • Publication bias Summary of Findings tables will be generated. 10. Timeline Protocol finalization and registration: Month 1 Search execution and deduplication: Month 2 Screening process: Months 2–3 Data extraction and risk of bias: Months 3–4 Synthesis and certainty assessment: Months 4–5 Manuscript revision and submission: Month 6 11. Amendments Policy Any modifications to eligibility criteria, search strategy, outcomes, or analytic approach will be documented in a dated amendments log within the registration platform. If protocol registration occurs after partial review completion, deviations will be transparently described, including stage of completion at time of registration and justification for any changes. No post hoc outcome switching will occur. All amendments will be clearly reported in the final manuscript.