Intravenous immunoglobulin in pediatric critical care: Bridging evidence gaps and guiding rational use

Abstract

Intravenous immunoglobulin (IVIG) plays an important role in pediatric intensive care units (PICUs) in managing children with immune-mediated and inflammatory disorders. IVIG has been used to treat many diseases, such as Kawasaki disease, Guillain-Barré syndrome, immune thrombocytopenia, multisystem inflammatory syndrome in children, and autoimmune disorders. However, its off-label use in several ailments, including septic shock, acute encephalitis syndrome, and other hyperinflammatory states, is not uncommon. This editorial discusses a study by Varadarajan et al, published in World Journal of Clinical Pediatrics, which evaluated the pattern of IVIG use in a tertiary care hospital and found that about 21.5% patients received it off-label. The reported adverse effects were only a few. Despite plausible immunomodulatory mechanisms, various clinical trials have reported inconsistent findings regarding mortality benefits in children with sepsis. In addition, insufficient data on the dose, duration, safety, and cost-effectiveness of IVIG need to be considered before its widespread use in the PICU. Although the adverse effects of IVIG are generally mild and infrequent, judicious stewardship of IVIG use is necessary, given its high cost and reliance on human plasma. This editorial discusses the patterns of IVIG use in different diseases in PICUs, dosages, outcomes, consensus-driven guidelines, and the need for pediatric trials.

Key Words: Children; Intravenous immunoglobulin; Immunomodulation; Mortality; Off-label use; Pediatric intensive care; Side effects

Core Tip: Intravenous immunoglobulin is increasingly being utilized in pediatric intensive care units for its diverse immunomodulatory effects, even beyond established indications. The study by Varadarajan et al highlights substantial off-label use with only a few adverse effects. This editorial provides a practical, evidence-based framework for the use of intravenous immunoglobulin in critically ill children, including indications, strength of evidence, and stewardship principles to guide its rational use.

This editorial refers to "Study on intravenous immunoglobulin use in a pediatric intensive care unit of a tertiary care center" by Varadarajan et al, 2026; https://dx.doi.org/10.5409/wjcp.v15.i2.118421.

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INTRODUCTION

Immunoglobulin is a plasma derivative with many immunomodulatory and anti-inflammatory properties. Since the early 1980s, intravenous immunoglobulin (IVIG) has been licensed for pediatric use by the European Medicines Agency and the Food and Drug Administration (FDA)[1]. It is an established therapy for selected pediatric conditions, such as Kawasaki disease (KD), Guillain-Barré syndrome (GBS), and primary immune thrombocytopenia (ITP)[1]. Currently, more than 25 IVIG formulations are licensed worldwide, and their use has expanded substantially in pediatric intensive care units (PICUs), often extending to conditions supported by limited or low-quality evidence[2]. The objective of the editorial is to critically analyze the findings of the study by Varadarajan et al[3], published in World Journal of Clinical Pediatrics, which investigated the indications, dosing practices, and adverse effects of IVIG therapy in children admitted to the PICU. The editorial further reviews the literature and discusses FDA-approved and off-label uses of IVIG therapy in PICU patients.

OVERVIEW OF THE STUDY

Varadarajan et al[3] reported the pattern of IVIG use over five years in 455 children aged 1 month to 12 years admitted to PICU. Indications, dosing practices, and adverse effects were analyzed. The indications were categorized by level of evidence (I-IV) and strength of recommendation (A-D), with category D indicating off-label use[4]. In their study, 445 children (11.9% of PICU admissions) received IVIG with a male-to-female ratio of 1.2:1. The common indications were immunological (42.4%), neurological (33.6%), infectious (13.2%, n = 60), and hematological (9.2%) disorders, and coronavirus disease-associated multisystem inflammatory syndrome in children was the most common disease (37.8%, n = 172).

Overall, 78.5% of children received IVIG per guideline recommendations, while off-label use was reported in 21.5% patients. Many studies reported on the off-label use of IVIG in children, which was as high as 79%[5]. They reported minimal adverse effects from IVIG therapy, fewer than those reported in previous studies[6]. It could be due to the underreporting of common adverse effects, such as myalgia, arthralgia, nausea, and vomiting, as the majority of children were ventilated and sedated. Overall mortality in this study was 22.4%, and survival among the recommended group was higher than that in the off-label group (81.0% vs 68.4%; P = 0.008). The dose of IVIG (in g/kg) was among survivors (1.8 ± 0.40 vs 1.6 ± 0.56 in non-survivors; P = 0.00) and in the recommended group (1.86 ± 0.5 vs 1.49 ± 0.5 in off-label group; P = 0.00).

CRITICAL APPRAISAL OF THE INDEX STUDY

Although Varadarajan et al’s study[3] offers valuable insights into IVIG use through this observational data, several methodological considerations limit causal interpretation: A critical concern is confounding by indication, as children receiving IVIG for guideline-supported diagnoses (e.g., KD, GBS) are intrinsically different in illness phenotype and trajectory and have a more predictable outcome than those receiving it off-label (e.g., refractory sepsis). Therefore, the observed survival advantage in the recommended group (81.0% vs 68.4%; P = 0.008) cannot be attributed to IVIG efficacy alone without accounting for this selection bias. Similarly, the observed dose-response relationship (higher IVIG doses correlating with improved survival) may reflect underlying disease categories rather than a true therapeutic effect, as conditions with established dosing protocols (e.g., 2 g/kg for KD) may inherently carry better prognoses than the heterogeneous off-label indications in which lower empirical doses were used. Therefore, the reported survival advantage in the guideline-supported group should be interpreted cautiously and not as evidence of treatment efficacy.

Another important consideration when interpreting the results is the lack of severity adjustment using validated scoring systems (e.g., PRISM), which limits the interpretation of mortality differences between groups. Other issues include ambispective design, which is susceptible to temporal and information biases arising from incomplete data capture and a single-center study, making generalizability to other settings difficult. Without multivariate adjustment or propensity score matching for illness severity, diagnostic category, drug doses, and comorbid conditions, the clinical meaning of the survival differences observed in this study remains uncertain. Therefore, it is imperative for future observational studies to pre-specify the adjustment variables and consider survival analysis methods that account for competing risks.

MECHANISM OF ACTION OF IVIG

The rationale for therapeutic use of IVIG in a variety of disorders lies with multiple mechanisms by which IVIG exerts its immunomodulatory effects. IVIG has two main components: The Fab variable and the Fcγ constant regions, which exert distinct functions. In hematological disorders, ITP, and acquired hemophilia and complement-mediated diseases, particularly systemic lupus erythematosus (SLE), IVIG acts by inhibition of complement activation, saturation of Fc receptors on mononuclear cells, prevention of immune complex binding to cellular Fc receptors, interaction with anti-idiotypic antibodies, modulation of complement activation, and regulation of cytokine production[7,8]. IVIG helps in rheumatological disorders, such as arthritis, nephritis, and myopathy, hyperinflammatory diseases, such as KD, and other diseases, such as GBS, and graft-versus-host diseases by inhibiting dendritic cell effects, and activation and differentiation of T and B lymphocytes, and modulating interleukin secretions[9-11].

INDICATIONS AND DOSES OF IVIG

FDA has approved IVIG for the following eight indications: (1) Primary immunodeficiencies; (2) Prevention of recurrent bacterial infections due to B-cell chronic lymphocytic leukemia and hypogammaglobulinemia; (3) Prevention of infections, pneumonitis and acute graft-versus-host diseases after bone marrow transplantation; (4) Patients with human immunodeficiency virus to prevent serious bacterial infections; (5) KD in acute phase for prevention of coronary artery aneurysms; (6) Primary ITP; (7) Chronic inflammatory demyelinating polyradiculoneuropathy; and (8) Multifocal motor neuropathy in adult patients. The FDA expanded IVIG’s basic indications and permitted its use for people aged 2 years and older[4,12]. High-dose IVIG therapy in GBS, in severe forms presenting with an inability to walk independently, is approved by the European Medicines Agency but not by the FDA.

In recent years, the off-label use of IVIG has expanded considerably, often outside the recommended indications. When used off-label, IVIG is mostly used as a second-line or third-line treatment in multi-refractory conditions[5,6,12-14]. Several immune-mediated neurological disorders are being treated with IVIG, such as Acute Disseminated Encephalomyelitis[15], chronic inflammatory demyelinating polyradiculoneuropathy[16], febrile infection-related epilepsy syndrome, myasthenia gravis, Opsoclonus-myoclonus-ataxia syndrome, pediatric acute-onset neuropsychiatric syndrome, autoimmune encephalitis, especially N-methyl D-aspartate receptor antibody encephalitis, and Rasmussen's syndrome[17].

IVIG has been used to treat many hematological disorders, such as ITP, thrombotic thrombocytopenic purpura, autoimmune hemolytic anemia, autoimmune neutropenia, and acquired hemophilia[1,18], and inflammatory disorders, including Juvenile Idiopathic Arthritis, Juvenile Dermatomyositis, Childhood-onset SLE, Henoch-Schönlein-Purpura, KD, and multisystem inflammatory syndrome in children[1,18,19]. Although the FDA has not approved the use of IVIG in neonates, it is used off-label for conditions such as neonatal sepsis, hemolytic disease of the newborn, alloimmune thrombocytopenia, and newborn KD[20].

According to the American Academy of Allergy, Asthma, and Immunology, low-dose IVIG replacement therapy is given to patients with primary immunodeficiency at 400-600 mg/kg every 3-4 weeks, resulting in plasma levels of 1200-1400 mg/dL[13]. In high-dose immunomodulatory and anti-inflammatory therapy, IVIG is administered at 1-3 g/kg, divided into 400 mg/day for 2-5 days, to achieve peak plasma concentrations of 2500-3500 mg/dL[20]. The starting rate of IVIG infusion is 0.5-1 mL/kg/hour for the first 15-30 minutes, followed by gradual increments every 15-30 minutes to a maximum of 3-6 mL/kg/hour, if no adverse reaction occurs. When used off-label, the optimal dosage, duration, and frequency of IVIG therapy often vary across centers and are usually based on expert opinions, availability, affordability, and comorbidities.

BIOLOGICAL PLAUSIBILITY VS CLINICAL EVIDENCE

Diverse mechanisms of IVIG provide a strong biological rationale for its use in a wide range of inflammatory and immune-mediated conditions. However, this biological plausibility must not be conflated with demonstrated clinical benefit. Robust evidence supports the use of IVIG including KD, GBS, and primary immunodeficiency. For several PICU indications discussed above, including septic shock, acute encephalitis syndrome, and hyperinflammatory syndromes, the clinical evidence remains inconsistent or insufficient despite its biologically plausibility. The presence of a credible immunomodulatory mechanism should motivate rigorous clinical investigation, not justify routine use.

CLINICAL DECISION-MAKING IN PICU: A PRAGMATIC FRAMEWORK

To support bedside decision-making in the PICU, a simplified evidence-based framework can be used, as summarized in Table 1[1,4,15,17,18,21-28]. The level of evidence is graded into 4 categories according to the American Academy of Allergy, Asthma, and Immunology: (1) Level I: Randomized controlled trials or meta-analyses; (2) Level II: Non-randomized controlled studies or large cohorts; (3) Level III: Case series or retrospective studies; and (4) Level IV: Expert opinion and the strength of recommendation are categorized into four categories: A = definitely beneficial; B = probably beneficial; C = may provide benefit; D = unlikely to provide benefit/insufficient evidence (off-label)[4].

Table 1 Clinical decision guidance for intravenous immunoglobulin use in pediatric intensive care unit.

Indication	Approval status	Level of evidence	Typical IVIG dose	Clinical message
KD[4,21]	FDA and EMA approved	I-A	2 g/kg single dose + aspirin	Use
Primary immunodeficiency (CVID, XLA, SCID)[18]	FDA and EMA approved	I-A	0.4-0.6 g/kg every 3-4 weeks (replacement)	Use
CIDP[4]	FDA and EMA approved	I-A	2 g/kg induction; 1 g/kg maintenance	Use
ITP[4]	FDA approved	I-A	0.8-1 g/kg single dose	Use
Guillain-Barré syndrome[4,22]	EMA approved; not FDA approved	I-A	2 g/kg over 5 days	Use
MIS-C[4]	Guideline-recommended (AAP, WHO)	I-B (cohort data, expert consensus)	2 g/kg single dose	Use with adjunct therapy
Autoimmune encephalitis (anti-NMDAR)[17]	Off-label	II-B (cohort studies, case series)	1-2 g/kg	Consider with caution
ADEM[15]	Off-label	II-B (cohort studies)	1-2 g/kg	Consider with caution
FIRES[18]	Off-label	III-C (case series, expert opinion)	1-2 g/kg	Consider with caution
Refractory myasthenia gravis[17]	Off-label in children	II-B (small studies)	1-2 g/kg	Consider with caution
Acute myocarditis[4,23]	Off-label (AAAAI: “may provide benefit”)	III-C (small studies, expert opinion)	2 g/kg	Selective use only
Juvenile dermatomyositis[1]	Off-label	II-B (cohort, open-label trials)	1-2 g/kg monthly	Consider with caution
Secondary HLH (non-KD)[18,24]	Off-label	III-C (case series)	1-2 g/kg	Cautious use
Septic shock (without defined immune defect)[1,25]	Off-label	I-D (RCT data: Inconsistent; no survival benefit in meta-analyses)	Not defined	Not routinely recommended
Neonatal sepsis[26]	Off-label	I-D (Cochrane review showed no mortality benefit)	Not defined	Not Recommended
Rh/ABO hemolytic disease of the newborn[27]	Off-label (previously used)	I-D (latest guidelines do not recommend routine use)	Not defined	Not routinely recommended
Viral encephalitis/dengue[28]	Off-label	I-D (RCT data: Inconsistent; no survival benefit in meta-analyses)	Not defined	Not recommended for outside rescue use

AAAAI: American Academy of Allergy, Asthma, and Immunology; AAP: American Academy of Pediatrics; ADEM: Acute disseminated encephalomyelitis; CIDP: Chronic inflammatory demyelinating polyradiculoneuropathy; CVID: Common variable immunodeficiency; EMA: European Medicines Agency; FDA: Food and Drug Administration; FIRES: Febrile infection-related epilepsy syndrome; HLH: Hemophagocytic lymphohistiocytosis; ITP: Immune thrombocytopenia; IVIG: Intravenous immunoglobulin; KD: Kawasaki disease; MIS-C: Multisystem inflammatory syndrome in children; NMDAR: N-methyl-D-aspartate receptor; RCT: Randomized clinical trial; SCID: Severe combined immunodeficiency; WHO: World health organization; XLA: X-linked agammaglobulinemia.

ADVERSE EFFECTS OF IVIG

IVIG is generally thought to be safe and doesn’t have many side effects, typically seen with steroids and other immunosuppressive medications. Despite IVIG’s safety, many adverse effects have been documented following IVIG infusion. Adverse reactions may occur in approximately 3%-20% of patients; of those, serious reactions occur in approximately 2%-6%[3,29,30]. The majority of IVIG infusion-related adverse effects are mild, such as chills, fever, nausea, rash, myalgia, and fatigue, while moderate reactions include headache, vomiting, and chest pain. Although rare, there are reports of severe adverse reactions such as acute kidney failure, aseptic meningitis, hemolytic anemia, thromboembolic events, transfusion-related acute lung injury, hepatitis, arthritis, arrhythmias, myocardial infarction, and pleural effusion. As IVIG is derived from blood products, there is a theoretical risk of transmission of bloodborne infections like human immunodeficiency virus and Hepatitis B[29,30].

COST, RESOURCE UTILIZATION, AND STEWARDSHIP IN PICU PRACTICE

IVIG is a costly, plasma-derived biologic with limited global supply. Therefore, the economic dimension of IVIG use warrants special attention. The cost of a single treatment course (2 g/kg) for a 10-kg child can range from USD 1000 to USD 3000, placing a substantial burden on health systems, especially in low-income and middle-income countries[31]. Indiscriminate use of IVIG may lead to inequitable allocation and reduced availability of a potentially life-saving therapy for patients with established indications (e.g., primary immunodeficiency). Studies on the cost-effectiveness of IVIG in many off-label indications are lacking. Therefore, clinical decisions should balance expected benefit, disease severity, cost, and resource availability. Given these challenges, implementation of institutional IVIG stewardship programs is essential. The framework should include strategies to stratify indications by quality of evidence and therapeutic urgency; preauthorization or multidisciplinary review for off-label requests; avoidance of routine use in low-evidence conditions; adoption of standardized dosing protocols; and periodic audits of prescribing patterns. A clinical algorithm to guide IVIG use is presented in Figure 1.

Figure 1 A clinical algorithm for rationale use of Intravenous immunoglobulin in pediatric intensive care. GBS: Guillain-Barré syndrome; IVIG: Intravenous immunoglobulin; KD: Kawasaki disease; MIS-C: Multisystem inflammatory syndrome in children.

FUTURE DIRECTIONS

IVIG therapy has been widely used in a variety of diseases; however, many of these indications are not based on controlled studies, such as myasthenia gravis, SLE, autoimmune encephalitis, septic syndrome, etc. Pediatric studies are even fewer, and most are non-randomized or have small sample sizes; therefore, multicenter randomized controlled trials are needed to establish appropriate indications and standardize dosing regimens for IVIG therapy in children. Given the high cost and global shortages of IVIG, formal cost-effectiveness analyses across IVIG indications are needed, especially in resource-limited settings.

CONCLUSION

IVIG remains a valuable but resource-intensive therapeutic option in pediatric critical care for several immune-mediated disorders. However, its use has expanded beyond the bounds of strong evidence, as confirmed by Varadarajan et al[3], who reported off-label use in 1 in 5 patients. Given the lack of cost-effectiveness data, high cost, limited availability, uncertain benefit in several conditions, and potential adverse reactions, IVIG must be prescribed with caution in clinical settings, particularly in resource-limited areas. Its use should be guided by evidence-based stewardship principles, and further multicentric trials should be conducted to strengthen the evidence on IVIG use across indications. Until stronger evidence emerges, rational and judicious use of this scarce biological product is essential.