IVIG as first line therapy in MIS-C

1. Dr. Vinaykumar S Appannavar MD
• MBBS at Shimoga Institute of Medical Sciences, Shimoga
• MD at Vijayanagar institute of Medical Science, Ballari
• Currently working as Senior Resident in the Department of Pediatrics,
VIMS, Ballari
Area of Interests : Pediatric Intensive care, Child Nutrition and Lactation management

2. IVIG IN MIS-C
Dr. Vinaykumar S Appannavar, MD
Senior Resident,
Department of Pediatrics,
VIMS - Ballari

3. BACKGROUND
▪ MIS- C is defined as acute onset of fever that may be variably associated with rash,
conjunctival injection, mucocutaneous erythema, coagulopathy, cardiovascular
complications, including shock and coronary artery dilation, and gastrointestinal symptoms,
including abdominal pain, diarrhea, and vomiting.
and
▪ Elevated markers of inflammation – ESR, CRP and procalcitonin
and
▪ No other obvious microbial cause of inflammation
and
▪ Evidence of COVID- 19 or likely contact with patients with COVID- 19
*AIIMS , New Delhi , Covid 19 in children guidelines

4. BACKGROUND
▪ MIS-C differs from Kawasaki Disease in that it is more common in older children, and
gastrointestinal symptoms are frequently reported.
▪ Given the similarity of MIS-C with Kawasaki disease and the macrophage activation
syndrome complicating many rheumatic disorders, intravenous immunoglobulin (IVIG) and
steroids formed the sheet anchor for MIS-C management 2
▪ Nearly 2/3rd of patients need Intensive care treatment 3
▪ Mortality is 1.9% 3
▪ Neutrophils in MIS-C has High expression of IL- 1B (beta) 4
▪ Increased expression of CD32 and CD16 was more on MIS-C neutrophils Compared to KD 4
2 Indian Journal of Pediatrics, Narendra Kumar Bagri and M. Khan Et.al
3 Spotlight Unraveling the mechanisms of IVIG immunotherapy in MIS-C – Ganigara Et.al
4 Immune response to intravenous immunoglobulin in patients with Kawasaki disease and MIS-C – Zhu Et.al

5. IVIG - Introduction
▪ Donor pool – Derived from 2,000 – 10, 000
donors, up to 60,000 donors
▪ Composition – Monomeric IgG upto > 95%
with small amounts of IgM and IgA present
▪ Antibody content – 01gm of IVIG contains
4*1018 molecules of antibody
▪ Stabilized with sugars or amino acids
Precipitation , agglutination and
neutralization of antigens
Activation of phagocytosis,
Complement mediated cytolysis,
NK cell – mediated cytolysis
- Neutralization of autoantibodies
- Downregulation of B and T cell function
- Cytokine regulation
- Fc receptor blockage
- Neutralization
of superantigens
- Elimination of
complement
activating
circulating
immune
complexes
Anti – infective MOA
Immunomodulatory
MOA
The Role of
IVIGs

6. Management
IVIG is superior in MIS-C
▪ Neutrophilic activation is the basic mechanism in MISC 5
▪ Neutrophils in MIS-C has High expression of IL- 1B (beta) 3
▪ IVIG Reduces more than 50% of neutrophils and more than 90% of IL- 1B
expressing neutrophils in MIS-C 3
3 Spotlight Unraveling the mechanisms of IVIG immunotherapy in MIS-C – Ganigara Et.al
5 Lee, M.S. Et.al Front Pediatr. 9, 640118.

7. Enhances the recovery rate
▪ IVIG targets IL-1b+ neutrophils to ameliorate the inflammation in this
inflammatory condition 6
▪ IVIG and its F(ab’)2 fragments exert cytotoxic effects on neutrophils 7
6 Henderson, Et.al American College of Rheumatology clinical guidance for multisystem inflammatory
7. Galeotti, C., Kaveri, S.V., and Bayry, J. (2017). IVIG-mediated effector functions in autoimmune and
inflammatory diseases. Int. Immunol.
Management

8. MOA
▪ IVIG has been shown to induce autophagy in he
peripheral blood mononuclear cells by F(ab’)2- and
PI3K-dependent pathways 7
▪ IVIG has been shown to suppress the activation of
T cells, monocytes, dendritic cells, and endothelial
cells that are activated in MIS-C 7
IVIG targets IL-1b+ neutrophils to exert anti-inflammatory
effects in MIS-C and Kawasaki disease (KD)
7. Galeotti, C., Kaveri, S.V., and Bayry, J. (2017). IVIG-mediated effector functions
in autoimmune and inflammatory diseases. Int. Immunol.

9. Merits - IVIG
1. There is evidence to show that faster initiation of IVIG in children with MIS-C was
associated with reduction in length of PICU and hospital stay 8
2. Cases with mild disease, treatment with IVIG (2g/kg over 12–24 h, maximum dose
100 g)
3. Mortality- 7% 3
4. Doses can be repeated - In children having risk of fluid overload, the duration of IVIG
infusion can be increased to 24–48 h 9
3 Spotlight Unraveling the mechanisms of IVIG immunotherapy in MIS-C – Ganigara Et.al
8 Jonat B et.al Pediatr Crit Care Med 2021;22:e178–e191
9 Williams Va Et.al systematic review an meta-analysis. J Pediatr Intensive Care 2020. doi:10.1055/s-0040-1719173.

10. Merits - IVIG
- In the management of immunocompromised state
- In fungal infections
- Ideal for use in MIS-C with co-morbidities
- Can be used in Kawasaki-disease like mimics

11. Take home message
IVIG Remains the drug
of choice in MIS- C
Enhances the
recovery rate
Reduces the length of
ICU and hospital stay
Ideal for use in MIS-C
with co-morbidities

12. References
• AIIMS , New Delhi , Covid 19 in children guidelines
• Indian Journal of Pediatrics, Narendra Kumar Bagri and M. Khan Et.al
• Spotlight Unraveling the mechanisms of IVIG immunotherapy in MIS-C – Ganigara Et.al
• Immune response to intravenous immunoglobulin in patients with Kawasaki disease and MIS-C – Zhu Et.al
• Lee, M.S. Et.al Front Pediatr. 9, 640118.
• Henderson, Et.al American College of Rheumatology clinical guidance for multisystem inflammatory syndrome in children
• Galeotti, C., Kaveri, S.V., and Bayry, J. (2017). IVIG-mediated effector functions in autoimmune and inflammatory diseases.
• Jonat B et.al Pediatr Crit Care Med 2021;22:e178–e191
• Williams Va Et.al systematic review an meta-analysis. J Pediatr Intensive Care 2020. doi:10.1055/s-0040-1719173.

13. “
The person who takes medicine must
recover twice,
Once from the disease and once from
the medicine.
- Sir William Osler