Immunoglobulin replacement therapy and infection risk in chronic lymphocytic leukemia: A systematic review and meta-analysis

Table 2 Summary of methodological approaches in included studies: Definitions of key time variables, exposure, and outcome ascertainment

Ref.	Index date	IgRT definition	Person-time counted	Pre-IgRT infections excluded?	Outcome ascertainment
Boughton et al[15]	Randomization/trial entry	Assigned treatment arm (IVIg 18 g every 3 weeks vs albumin placebo); dose escalation or crossover after ≥ 3 infections	Total follow-up time from randomization over a fixed 12-month period (intention-to-treat framework)	Yes (only infections occurring after trial entry were counted)	Prospectively collected, standardized clinical definition using predefined scoring system; infections recorded at 3-weekly visits and via patient diaries; serious infections predefined
Carrillo de Albornoz et al[11]	Varies by analysis: CLL diagnosis (overall cohort) or first IgRT episode (IgRT users)	Time-varying IgRT exposure defined from hospital procedure codes (on-IgRT = IgRT use in prior 30 days; off-IgRT = no use in prior 30 days); regular vs intermittent IgRT defined by frequency and gaps	Person-time accrued longitudinally from index date until death or censoring (December 31, 2022); segmented into on-IgRT and off-IgRT periods for recurrent-event analyses	No (serious infections prior to IgRT were included and modeled as predictors of IgRT initiation and as time-varying covariates)	Serious infections identified retrospectively via ICD-10-AM and AR-DRG codes for multi-day infection-related hospitalizations
Jurlander et al[16]	Initiation of low-dose IVIg therapy	Fixed low-dose IVIg (10 g every 3 weeks) administered during treatment period only; no concurrent control group	Aggregated person-time compared between two periods: 12 months before IVIg (168 patient-months) vs during IVIg treatment (169 patient-months); rates implicitly calculated from total events over person-time	No (pre-treatment infections explicitly included as the comparator period)	Prospectively recorded clinical events: Antibiotic prescriptions, hospital admissions due to infection, febrile episodes; severe infections defined clinically; microbiology reported for selected events
Cooperative Group for the Study of Immunoglobulin in Chronic Lymphocytic Leukemia[17]	Randomization and initiation of IVIg or placebo infusion (trial enrollment start)	IVIg administered at 400 mg/kg every 3 weeks. Compared against placebo (albumin infusion)	Participants were followed prospectively for 12 months. Person-time accrued from randomization until end of follow-up, withdrawal, death, or study completion	Only infections occurring after trial entry were counted. Infections before enrollment were not included in outcome measurement	Prospectively monitored. Clinically documented. Confirmed through medical record review. Categorized as bacterial infections requiring antimicrobial therapy. Assessed during scheduled follow-up visits and interim clinical reports
Günther and Dreger[18]	Initiation of IVIg therapy	IVIg exposure defined as active treatment period only; standard dose approximately 0.35 g/kg every 3-4 weeks; no concurrent control group	Person-time compared between two periods: Infections in the 3 months prior to IVIg initiation (extrapolated to annualized rates) vs infections accrued during IVIg treatment over long-term follow-up (total 528 patient-months)	No (pre-IVIg infections explicitly included as comparator period)	Clinically documented serious bacterial infections recorded during routine care; infection type, treatment, and duration prospectively documented; some baseline data retrospectively abstracted from medical records
Molica et al[7]	Entry into study/randomization	IVIg 300 mg/kg every 4 weeks during assigned treatment periods; patients crossed over between IVIg prophylaxis and observation (no IVIg), acting as their own controls	Person-time accrued from study entry until death, loss to follow-up, or study end; segmented into observation (no IVIg) and IVIg treatment periods (36 vs 376 patient-months overall; 321 vs 292 patient-months for 6-month completers; 206 vs 215 patient-months for 12-month completers)	No (infections during observation periods served as the comparator by design)	Prospectively assessed before each infusion using predefined clinical criteria; infections graded as trivial, minor, or major; serious infections defined by need for antibiotics, hospitalization, or IV therapy
Siffel et al[19]	IgRT analysis: Re-indexed to first IgRT claim (IgRT cohort) or pseudo-index date (no-IgRT cohort)	Receipt of IgRT identified from claims; IgRT-treated patients required ≥ 2 IgRT administrations post-index; comparator was SID patients without IgRT	Fixed 12-month post-index follow-up (minimum 3 months for survival); outcomes summarized per patient over follow-up, not as continuous person-time rates	No (baseline infections and infection burden during the pre-index period were included and differed substantially between groups)	Infections identified via ICD-10-CM diagnosis codes in claims/EHR; severity inferred from antibiotic escalation, intravenous therapy, hospitalization, unusual pathogens or complications
Soumerai et al[10]	Date of first IgRT administration	IgRT initiation identified in EHR; patients required ≥ 3 months of follow-up before and after index	Fixed windows (3 months, 6 months, 12 months before vs after IgRT initiation); no continuous time-at-risk modeling	No (pre-IgRT infections are intentionally included and serve as the comparator)	Infections identified via ICD-9/10 codes; severe infections defined by hospitalization or IV antimicrobials; antimicrobial use captured via prescriptions within 30 days
Tadmor et al[20]	Date of CLL diagnosis	Monthly IVIg administered for hypogammaglobulinemia (< 500 mg/L) with recurrent infections; modeled as a time-dependent exposure	Person-time accrued from CLL diagnosis until event or censoring; patients contributed unexposed time before IVIg initiation and exposed time after initiation	Yes, for exposed time (events prior to IVIg initiation were not attributed to IgRT-exposed person-time)	Pneumonia identified via ICD-9 codes combined with antibiotic prescriptions (outpatient) or imaging and hospitalization records (inpatient); prospectively recorded within electronic health records
Visentin et al[21]	Start of IgRT (IVIg or SCIg initiation)	Continuous IgRT exposure (IVIg every 3-4 weeks or SCIg weekly/biweekly); patients switching from IVIg to SCIg reclassified at switch	Person-time accrued from IgRT initiation only until infection, discontinuation, death, or last follow-up	Yes (baseline infection rates were analyzed separately but not included in post-IgRT person-time)	Infections prospectively abstracted from clinical records; bacterial and mycotic infections of any grade; rates expressed as events per patient-year and cumulative incidence (time-to-first and second infection)

CLL: Chronic lymphocytic leukemia; IgRT: Immunoglobulin replacement therapy; IVIg: Intravenous immunoglobulin; SCIg: Subcutaneous immunoglobulin; SID: Secondary immunodeficiency; HER: Electronic health record; ICD-10-AM: International Classification of Diseases, 10^th revision, Australian modification; AR-DRG: Australian Refined Diagnosis Related Groups; ICD: International Classification of Diseases.