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

Table 1 Characteristics of the included studies

Ref.	Study design	Setting	Intervention vs comparator	Number of participants IgRT/non-IgRT	IgRT administration and indications	Outcome	Incidence of infections
Boughton et al[15]	Prospective, double-blind RCT	Multicenter, United Kingdom, 12-month duration	IVIg vs albumin placebo	IVIg: 24/18 (placebo)	18 g IVIg every 3 weeks in patients with serum IgG levels < 5.5 g/L and a history of two or more recent infections	Number of patients experiencing infections and severe infections whilst treated with IVIg or albumin placebo	IVIg group: 7 failures1/24 albumin placebo: 11 failures/18
Carrillo de Albornoz et al[11]	Retrospective cohort	Australia, January 2008 to December 2022, 12-month duration	IVIg vs no IVIg	IVIg: 524/524	IVIg	Proportion of patients exhibiting serious infections	IVIg group: 0.672 events/patient/year. No IVIg group (cessation period): 0.456 events/patient/year
Jurlander et al[16]	Uncontrolled before-after observational study	Single center, Denmark	IVIg vs no IVIg	IVIg: 15/15	IVIg 10 g every 3 weeks in patients with serum IgG level below lower reference limit, a history of recurrent infections and a performance status enabling outpatient setting	Number of infection-related events (antibiotic prescriptions, hospital admissions due to infections, febrile episodes, severe infections) in the 12-month period that preceded IgRT compared to the number of infection-related events during the period of IgRT	IVIg group: 3/15. No IVIg group: 6/15
Cooperative Group for the Study of Immunoglobulin in Chronic Lymphocytic Leukemia[17]	Prospective double-blind RCT	International, multicenter, Germany, Luxembourg, United States, United Kingdom, Italy, 12 months duration	IVIg vs 0.9% sodium chloride solution placebo	IVIg: 28/29 (placebo) (completed 12 months of study)	IVIg 0.4 g/kg body weight every 3 weeks in patients with IgG < 50% LLN for the hospital laboratory or a history of one or more serious infections requiring systemic antibacterial therapy	Number of patients experiencing infections whilst treated with IVIg or sodium chloride placebo	IVIg group: 10/28. Sodium chloride placebo: 13/29
Günther and Dreger[18]	Prospective cohort	Single center, Germany, April 1997 to November 2010	IVIg vs no IVIg	IVIg: 5/5	IVIg 0.35 g/kg body weight every 3-4 weeks in patients with secondary immune deficiency with recurrent serious bacterial infections	Incidence of bacterial infections before and after starting IVIg	IVIg group: 8 events/patient/year. No IVIg group: 9 events/patient/year
Molica et al[7]	Cross sectional	Multicenter, Italy, 24-month duration	IVIg vs no IVIg		300 mg/kg IVIg every 4 weeks for at least 6 months in patients with IgG levels < 600 mg/dL and/or a history of at least one serious infectious episode in the 6-month period preceding entry into the study	Number and type of infections occurring. During the 24-month treatment period
Siffel et al[19]	Retrospective cohort	Single center, United States, October 2015 to March 2020, 12-month duration	IgRT vs no IgRT	IgRT: 118/118	serum IgG levels < 5.0 g/L, hypogammaglobulinemia diagnosis codes, and ≥ 1 major infection	Number of infections, severe infections, inti-infective use, hospitalizations, length of hospital stay for IgRT-treated and no-IgRT matched cohorts of patients with SID at 12-month follow-up	IgRT group: 7.93 events/patient/year. No IgRT group: 3.56 events/patient/year
Soumerai et al[10]	Retrospective cohort	Multicenter, United States, January 2010 and February 15, 2023, 12-month duration	IgRT vs no IgRT	IgRT: 137/137	Immune globulin infusion (human) 10%	Rate of infections, severe infections and associated antimicrobial use were compared 3 months, 6 months, and 12 months before vs after the index date	IgRT group: 71/137. No IgRT group: 87/137
Tadmor et al[20]	Retrospective cohort	Single center, Israel	IVIg vs no IVIg	IVIg: 326/4206	IVIg monthly Infection prevention in patients with IgG < 500 mg/L and recurrent infections (2 infections in 6 months or 3 in a year)	Pneumonia episodes over one year, hospitalizations for pneumonia	IVIg group: 13/326. No IVIg group: 463/4206
Visentin et al[21]	Retrospective cross sectional	Multicenter, Italy	IVIg vs no IVIg SCIg vs no SCIg	IVIg: 49/49; SCIg: 88/88	SCIG or IVIG every 3 weeks or 4 weeks to patients with hypogammaglobulinemia and recurrent infections according to AIFA indications	Rate of bacterial or mycotic infections of any grade before and after treatment with SCIg or IVIg. Incidence of grade ≥ 3 infections	IVIg group: 3.14 events/patient/year. No IVIg group: 2.31 events/patient/year. SCIg group: 2.59 events/patient/year. No SCIg group: 1.43 events/patient/year. The incidence of grade ≥ 3 infections remained stable with IVIg (0.80 events/patient the year before and during IVIg), while it decreased from 1.43 to 0.64 with SCIg

¹If individuals experienced three more infections during the course of the study, they were classified as treatment failures.

RCT: Randomized controlled trial; IVIg: Intravenous immunoglobulin; IgRT: Immunoglobulin replacement therapy; SCIg: Subcutaneous immunoglobulin; IgG: Immunoglobulin G; LLN: Lower limit of normal; SID: Secondary immunodeficiency; AIFA: Agenzia Italiana del Farmaco.

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.