Study on intravenous immunoglobulin use in a pediatric intensive care unit of a tertiary care center

Abstract

BACKGROUND

Intravenous immunoglobulin (IVIG), an immunomodulatory therapy/agent has been increasingly used and its off label use is on the rise in critical care units. We planned to analyze the indications of IVIG in different disease conditions in pediatric intensive care unit (PICU). This is a single- center ambispective audit on IVIG use.

AIM

To study the usage pattern of IVIG among children admitted at a pediatric tertiary care unit.

METHODS

This was an ambispective study in which data was collected retrospectively from January 2021 to February 2025 and prospectively from March 2025 to November 2025 in a PICU of a tertiary care center. Details of age, sex, indications, strength of recommendation and survival in each disease group were documented.

RESULTS

Four hundred and fifty five children received IVIG during the study period. The commonest indication was immunological diseases (42.4%, n = 193), followed by neurological illness (33.6%, n = 153), infections (13.19%, n = 60), hematological diseases (9.2%, n = 42) and cardiac diseases (all acute myocarditis) (1.5%, n = 7). Use of IVIG as per strength of recommendation A, B, C, D were 89 (19.5%), 176 (38.5%), 92 (20.2%) and 98 (21.5%) respectively. Overall mortality was 22.42% (n = 102). The off label usage of IVIG in the unit was 21.5%.

CONCLUSION

IVIG was commonly used in immunological and neurological diseases in our cohort. 78.5% received IVIG as per strength of recommendation A, B, C. Off label use was 21.5%.

Key Words: Intravenous immunoglobulin; Pediatric intensive care unit; Off label use; Strength of recommendation; Level of evidence

Core Tip: This study evaluates intravenous immunoglobulin (IVIG) use in a pediatric intensive care unit, highlighting indications, dosing, evidence support, and outcomes. The commonest indication was immunological diseases followed by neurological illness, infections, hematological diseases and cardiac diseases. Strength of recommendation varies in different diseases. Off label use was seen in about one -fifth of patients. Adverse effects were minimal. Evidence is lacking regarding the use of IVIG in many diseases. The study suggests multicentric trials to define proper indications of IVIG.

INTRODUCTION

Immunoglobin is a plasma derived medicinal product produced from pooled plasma of healthy donors. It was used as replacement therapy in inborn errors of immunity in 1952[1] and Food and Drug Administration approved its use in 1981. European Medicine Agency (EMA) approved the use of intravenous immunoglobulin (IVIG) in primary immunodeficiency with impaired antibody production, secondary immunodeficiency, Kawasaki disease (KD), primary immune thrombocytopenic purpura, Guillain Barre syndrome (GBS), chronic inflammatory demyelinating neuropathy, multifocal motor neuropathy, hypogammaglobinemia in chronic lymphocytic leukemia, multiple myeloma and in hemopoietic stem cell transplantation[2]. However, IVIG use is practically extended to different diseases by clinicians worldwide[3]. IVIG acts by different mechanisms including inhibition through Fc receptors, modulation of T cells, B cells, dendritic cells, balance between pro and anti-inflammatory cytokine production, impairment of natural killer cells, inhibition of complement system[3]. The dose of IVIG varies in each indication. For primary and secondary antibody deficiency states, the starting dose is between 0.4 g/kg and 0.6 g/kg of bodyweight and needs to be adjusted based on clinical outcome. For neurological diseases one or two courses of 2 g/kg of bodyweight over five days for each course and if required second course six weeks apart is given. For hematological conditions, a dose of 0.8 g/kg to 1 g/kg is used[4]. The half-life should be longer than 20 days and the monomeric IgG should be higher than 90%. Common adverse effects of IVIG are usually mild including headache, malaise, nausea, low-grade fever, urticaria, arthralgias, and myalgia. They resolve within a few days after their onset. Some rare and serious adverse effects are anaphylactic reactions, aseptic meningitis, acute renal failure, stroke, myocardial infarction, and other thrombotic complications. As IVIG is a blood product, there is a risk of transmission of infectious agents likes HIV and viral hepatitis by contaminated products, though it is very rare[5]. Because of its high safety profile and immunomodulator action, IVIG is being used in a number of disease conditions in children both on label and off label. Adult literature had shown increasing age and critical care unit as factors associated with IVIG off label use but we do not have standard guidelines for use of IVIG in sick children in pediatric intensive care unit (PICU). Hence, this study was undertaken to identify the common indications, usage as per strength of recommendation, side effects and outcomes of IVIG use in critically ill children in a PICU.

MATERIALS AND METHODS

This was an ambispective study conducted at PICU of an 837 bedded public sector children’s hospital in South India. Data on IVIG use was collected retrospectively from January 2021 to February 2025 and prospectively from March 2025 to November 2025. Institute’s ethics committee approval was obtained and consent from parents/care givers was waived by ethics committee as it was data collection from the patient file registry system of the unit. Two investigators cross verified twenty percent of the data extraction. All children aged 1 month to 12 years who received IVIG during treatment at PICU were studied. Children who received IVIG prior to admission to PICU, children who died before receiving the IVIG course and children who were discharged against medical advice were excluded. Study parameters included demographic parameters like age and gender, weight, indications and dose of IVIG, number of courses, adverse effects, final diagnosis and outcomes. Death at PICU or recovery and transfer out of PICU were the outcomes recorded. IVIG was given in a dedicated intravenous line under strict vital sign monitoring as a slow infusion avoiding fluid overload. It was given over 8 hours to 12 hours starting at a dose of 0.5-1 mL/kg/hour for the first 30 minutes and increasing the rate if there were no adverse reactions. IVIG was given in our unit as per American academy of Allergy, Asthma and Immunology, including primary and secondary immunodeficiency and as an immunomodulator in neurological diseases (Guillain-Barre syndrome, chronic inflammatory demyelinating neuropathy), hematological (immune thrombocytopenic purpura) and rheumatological (KD)[6,7]. Other indications were autoimmune encephalitis (AIE), febrile infection related epilepsy syndrome (FIRES), acute disseminated encephalomyelitis (ADEM), multisystem inflammatory syndrome in children (MIS-C), toxic shock syndrome etc. Any off label use (outside evidence based guidelines recommendations) was decided based on risk- benefit assessment to each child individually by the primary physician or as per recommendations of pediatric subspecialty consultants like pediatric neurology, hemato-oncology, nephrology, cardiology and pulmonology and rheumatologist. IVIG usage in our unit had pre authorization approval committee through a IVIG request form during the study period. IVIG was used in acute encephalitis with refractory status epilepticus, with concurrence of pediatric neurologist based on the consensus guidelines[8]. The dose of IVIG used and duration of infusion are as per recent guidelines[4]. Level of evidence is graded into 4 categories I-IV and strength of recommendation A to D[7]. Category D was considered as off label use. Grading was based on the final diagnosis. Adverse effects if any were documented. All children who received IVIG at the critical care unit were given specific instruction regarding rescheduling for subsequent live vaccines at the time of discharge from the unit.

Statistics analysis

Analysis were performed using Epi Info 7 and Microsoft Excel[2025]. Descriptive data of age were summarized in proportions with mean ± SD or as median (IQR) depending on the distribution. Shapiro-Wilk testing was used to assess normality of continuous variables. The qualitative data was expressed as n (%). The χ² test was used to compare the qualitative data. P < 0.05 was considered statistically significant.

RESULTS

There were 3821 admissions in PICU during the study period. Four hundred and sixty six children received IVIG in PICU. Four of them had IVIG initiated elsewhere and referred to our hospital, two of them left against medical advice and five children died before completion of course. All these children were excluded from the study. Four hundred and fifty five children, constituting 11.9% of the admissions, received IVIG. Males were 54.6% (n = 248) and female 45.4% (n = 207) with a male female ratio of 1.2:1. Age group of the children ranged from 1 month to 144 months with a median (IQR) 51 (18-98) months. All the children received immunoglobin through intravenous route only without any premedication. The indications for IVIG use, survival, evidence category and the strength of recommendation were summarized in Tables 1 and 2. The commonest indication was immunological diseases (42.4%, n = 193), followed by neurological illness (33.6%, n = 153), infections (13.2%, n = 60), hematological diseases (9.2%, n = 42) and cardiac diseases (all acute myocarditis) (1.5%, n = 7). Multisystem inflammatory syndrome associated with coronavirus disease 2019 (COVID-19) (MIS-C) was the most common disease in PICU to receive IVIG (37.8%, n = 172). Use of IVIG as per strength of recommendation A, B, C, D were 89 (19.5%), 176 (38.7%), 92 (20.2%) and 98 (21.5%) respectively. Overall, 78.5% of children received IVIG as per American academy of allergy, asthma and immunology recommendation and 19.6% of children as per EMA. Off label use was in 21.5% of children. Survival rates in each disease group is given in Table 1. Overall mortality was 22.4% (n = 102). Among the 455 children, only 9 (2%) received 2 courses of IVIG for a diagnosis of GBS. The dose /kg of IVIG used, their indications, survival were given in Table 3. The dose of IVIG in g/kg among those who survived was 1.8 ± 0.40 (mean ± SD) in comparison to those who did not survive 1.6 ± 0.56 and this was statistically significant with P = 0.00. The mean dose per kg among recommended group was 1.86 ± 0.5 vs 1.49 ± 0.5 in off label group and was statistically significant (P = 0.00). Comparison of survival among recommended group IVIG use and off label use was 81.0% vs 68.4% and was statistically significant (P = 0.008). Children with GBS who developed hypertension and hypotension were considered a part of the autonomic imbalance and were not included under IVIG adverse events. Among the reported adverse events, 3 children (0.7%) developed hypotension and 9 children (2.0%) developed transient rashes.

Table 1 Neurological and infectious indications, outcomes, and evidence for intravenous immunoglobulin use, n (%).

Condition (% of total)	Received IVIG	Survived	Recommendation	Evidence	Strength
Neurological (33.6)	153	123 (80.4)
AES	38	26 (68.4)	No	III	D
ADEM	9	9 (100)	No	IIb	C
ALERD	2	2 (100)	No	III	C
ANEC	5	4 (80)	No	III	C
FIRES	11	7 (63.6)	No	II	C
Guillain-Barré syndrome	68	57 (83.8)	Yes	Ib	A
Myasthenia gravis	1	1 (100)	No	Ib	B
Autoimmune encephalitis	19	17 (89.5)	No	II	C
Infections (13.2)	60	40 (66.7)
Dengue encephalitis	32	25 (78.1)	No	IV	D
Dengue MODS/cytokine storm	12	7 (58.3)	No	IV	D
Disseminated adenovirus infection	14	7 (50)	No	IV	D
Mycoplasma encephalitis/SE	2	1 (50)	No	IV	D

Categorization of evidence and basis of recommendation Ia from meta-analysis of randomized controlled studies, Ib from at least one randomized controlled study, IIa from at least one controlled trial without randomization, IIb from at least one other type of quasi-experimental study, III From nonexperimental descriptive studies, such as comparative, correlation, or case-control studies, IV From expert committee reports or opinions or clinical experience of respected authorities or both. Strength of recommendation A based on category I evidence, B based on category II evidence or extrapolated from category I evidence, C based on category III evidence or extrapolated from category I or II evidence, D based on category IV evidence or extrapolated from category I, II, or III evidence. IVIG: Intravenous immunoglobulin; AES: Acute encephalitis syndrome; ADEM: Acute disseminated encephalomyelitis; ALERD: Acute leukoencephalitis with restricted diffusion; ANEC: Acute necrotizing encephalopathy of childhood; FIRES: Febrile infection related epilepsy syndrome; MODS: Multiorgan dysfunction syndrome; SE: Status epilepticus.

Table 2 Hematological, cardiac and immunological indications, outcomes, and evidence for intravenous immunoglobulin use, n (%).

Condition (% of total)	Received IVIG	Survived	Recommendation	Evidence	Strength
Hematological (9.2)	42	25 (59.5)
AIHA	3	3 (100)	No	II	B
Secondary HLH	39	22 (56.4)	No	III	C
Cardiac (1.5)	7	6 (85.7)
Myocarditis	7	6 (85.7)	No	III	C
Immunological (42.4)	193	154 (79.8)
PID	11	5 (45.5)	Yes	Ia	A
Kawasaki disease	10	7 (71)	Yes	Ia	A
MIS-C	172	142 (82.6)	No	Ib	B

IVIG: Intravenous immunoglobulin; AIHA: Autoimmune hemolytic anemia; HLH: Hemophagocytic lymphohistiocytosis; PID: Primary immunodeficiency; MIS-C: Multisystem inflammatory syndrome in children.

Table 3 Dose of intravenous immunoglobulin used in diseases, frequency and survival, n (%).

Dose of IVIG (g/kg)	Indications	Received IVIG	Survived
0.5	PID	2	2 (100)
1	AES, FIRES, Dengue, adenovirus, mycoplasma, HLH, PID, KD, myocarditis	105	61 (58.1)
2	AES, ADEM, ALERD, ANEC, GBS, MG, autoimmune encephalitis, Dengue, HLH, AIHA, myocarditis, KD, MIS-C	339	282 (83.2)
4	Guillain-Barré syndrome	9	8 (89)

IVIG: Intravenous immunoglobulin; PID: Primary immunodeficiency; AES: Acute encephalitis syndrome; FIRES: Febrile infection related epilepsy syndrome; HLH: Hemophagocytic lymphohistiocytosis; KD: Kawasaki disease; ADEM: Acute disseminated encephalomyelitis; ALERD: Acute leukoencephalitis with restricted diffusion; ANEC: Acute necrotizing encephalopathy of childhood; GBS: Guillain Barre syndrome; MG: Myasthenia gravis; AIHA: Autoimmune hemolytic anemia; MIS-C: Multisystem inflammatory syndrome in children.

DISCUSSION

IVIG is used in the PICU for infectious and non infectious conditions by providing antibodies for replacement and modulating immune system. Being a powerful immunomodulant, its use in PICU is expanding and needs to be updated frequently. This is mainly due to non immunosuppressive nature of IVIG when compared to its counterpart- corticosteroids. Over the past few decades, the use of IVIG has tremendously increased with better understanding of the pathology of illness related to the immune system in sick children. Earlier, the indications were limited to immunodeficiency disorders, GBS, immune thrombocytopenic purpura, KD etc. However, its use has expanded multifocal for various infectious, post infectious and inflammatory conditions, for example, multisystem inflammatory syndrome associated with COVID-19, IVIG was one of the commonly used drug with steroids in the management of coronary involvement. Despite the use of IVIG in multiple diseases and their evolving evidence, FDA has approved IVIG only in a few diseases[2]. Though not approved by FDA, there exists evidence based guidelines for IVIG in various diseases. IVIG is not approved by FDA even in neurological diseases like GBS, ADEM, AIE etc. In the year 2014, Cochrane review stated that IVIG hastens recovery in children with GBS, if given within 2 weeks of onset of illness[9]. There are several case reports and case series showing the beneficial effects of IVIG in ADEM[10]. IVIG use is documented in AIE, FIRES, acute leukoencephalitis with restricted diffusion and acute necrotizing encephalopathy of child hood[11-14]. Beneficial effects of IVIG was reported in children with acute encephalitis syndrome to control acute brain inflammation[15].

Among the tropical infections Dengue was the common infection for which IVIG was used in our unit. IVIG is used as “rescue therapy” in Dengue encephalitis, hemophagocytic lymphohistiocytosis (HLH), myocarditis and in dengue infections which is refractory to standard treatment[16]. IVIG use as an adjuvant therapy in acute encephalitis was found to reduce hospital stay, time to reduce spasms and regain consciousness, and resolution of neuropathic symptoms[4]. Role of IVIG in children with adenovirus encephalitis and disseminated adenovirus infections were documented in immunocompromised children[17]. But Adenovirus is found to cause acute encephalitis and disseminated infections even in immunocompetent children[18]. IVIG was used in severe adenovirus infections even in immunocompetent children[19]. We used IVIG in 14 children with disseminated adenovirus infection during a surge in adenovirus infection in 2023 and early 2024. There are a few studies with small sample size, which found IVIG along with corticosteroid, improved ventricular function and survival in children with acute myocarditis, without need for cardiac transplant[20]. American academy of allergy, asthma and Immunology recommends that IVIG might be useful in acute myocarditis[7]. On the other hand, IVIG along with corticosteroids showed improvement in cardiovascular dysfunction in children with MIS-C, and IVIG is recommended in MIS-C[21]. In KD and secondary HLH, IVIG is standard of care[22].

The strength of recommendation of use in this study was similar to recent study by Basavaraja et al[23]. Off label of IVIG is not uncommon and is reported in many parts of the world due to its immunomodulatory effect without immunosuppression in various conditions in critically ill children[24]. In one study, the off label use was as high as 79%[25].

Overall children who received IVIG as per recommendation had received higher dose compared to off label group. Children who survived in this cohort had received higher dose in comparison to those who did not survive. Survival rates in children under recommended group was higher than off label use group, however causality/effectiveness cannot be inferred due to the confounding by indication. Although the incidence of IVIG-related side effects are reported among previous studies from 3%-20%, the side effects were very minimal in this group. Majority of these children were ventilated and sedated and hence the common side effects like myalgia, arthralgia, nausea and vomiting could not be documented and hence may be under reported. IVIG use beyond clearly labelled indications is increasing world wide for various clinical indications without high level evidence. There is a need to address these indications with multicentric trials for evidence in children. Until then, there is a need for nationwide survey to know the IVIG prescription pattern. That might serve as a framework for framing national guidelines for IVIG based on input from various experts.

Strength and limitation

The strengths of the study include a large sample size, longer duration of study period, almost 5 years, included diseases in various systems, compared the strength of recommendation and survival in each disease condition. This study has shown the prescribing patterns of IVIG from a large pediatric tertiary care unit from public sector. Ambispective nature of study, samples taken from a single center, possible under reporting of adverse events are limitations of this study.

CONCLUSION

IVIG was used for immunological and neurological indications in 76% in our cohort. Off label use was 21.5%. Adverse effects were minimal. Existing challenges includes robust evidence for the wide use of this costly drug. Though it is a drug with minimal adverse effects, high quality evidence of the use of IVIG is lacking in conditions like infections and its related complications. There is a need for multicentric trials to standardize indications.

ACKNOWLEDGEMENTS

Mrs Kavitha M for data entry in Excel sheet.