Given the similarities of MIS-C with Kawasaki disease, intravenous immunoglobulin was suggested as first-line treatment, in addition to glucocorticoids or other immunomodulators, or both, for severe disease.
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Coronary artery aneurysms are observed in 10–20% of patients with MIS-C.
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A retrospective cohort study in France (n=181) reported that treatment with intravenous immunoglobulin and methylprednisolone was preferred over intravenous immunoglobulin alone for an improved fever course, acute left ventricular dysfunction, and intensive care duration.
A multicentre, retrospective study in the USA (n=518) similarly reported a decreased risk of cardiovascular dysfunction and a lower proportion requiring adjunctive therapy in patients treated with intravenous immunoglobulin plus glucocorticoids versus intravenous immunoglobulin alone.
On the basis of the reports from France
and the USA,
the American College of Rheumatology recommends intravenous immunoglobulin plus glucocorticoids for MIS-C.
These studies were confined to high-income countries where intravenous immunoglobulin is more likely to be available and did not include a glucocorticoid only group for comparison. The Best Available Treatment Study (BATS) first reported in 614 children from 32 countries, including low-income and middle-income countries, that the primary outcomes of inotropic support or mechanical ventilation by day 2 or later, or death, were similar between patients treated with intravenous immunoglobulin alone, glucocorticoids alone, or intravenous immunoglobulin plus glucocorticoids.
This study included a diverse population and findings are pertinent, given the low availability and high cost of intravenous immunoglobulin limiting equal access to this drug globally, particularly in resource-limited settings.
examined the same research question with more patients and used inverse probability weighting to compare immunomodulatory treatments for MIS-C. The BATS cohort is the largest to date of children with MIS-C who have received immunomodulators and initial treatment with glucocorticoids. Of the 2009 patients (median age 8·0 years [IQR 4·2–11·4], 1191 [59·3%] male and 818 [40·7%] female, and 825 [41·1%] White) with clinically diagnosed MIS-C from 39 countries who were included for analysis, enrolled between June 14, 2020, and April 25, 2022, 680 (33·8%) had primary treatment with intravenous immunoglobulin alone, 698 (34·7%) had intravenous immunoglobulin plus glucocorticoids, 487 (24·2%) had glucocorticoids alone, 59 (2·9%) had other combinations, including biologicals, and 85 (4·2%) had no immunomodulators. In the 1586 patients with complete baseline and outcome data that were considered for primary weighted analysis after exclusions, the first primary outcome (inotropic or ventilatory support from day 2 after starting treatment, or death) was similar for intravenous immunoglobulin plus glucocorticoids (adjusted odds ratios [OR] 1·09 [95% CI 0·75–1·58]; corrected p value=1·00) and for glucocorticoids alone (0·93 [0·58–1·47]; corrected p value=1·00), versus intravenous immunoglobulin alone. The second primary outcome (time to improvement on an ordinal clinical severity scale) was also similar for intravenous immunoglobulin plus glucocorticoids (average adjusted hazard ratio 1·04 [95% CI 0·91–1·20]; corrected p value=1·00) and for glucocorticoids alone (0·84 [0·70–1·00]; corrected p value=0·22), versus intravenous immunoglobulin alone. A planned secondary analysis that compared glucocorticoids alone and intravenous immunoglobulin plus glucocorticoids suggested quicker time to improvement with combined therapy (adjusted average hazard ratio 1·25 [95% CI 1·05–1·48]; p=0·012), which was limited to those not requiring intensive care at baseline. Of the secondary outcomes, treatment escalation was less probable in patients treated with intravenous immunoglobulin plus glucocorticoids (OR 0·15 [95% CI 0·11–0·20]; pvs 40 [8·7%] of 458 glucocorticoid recipients vs 88 [12·9%] of 680 intravenous immunoglobulin plus glucocorticoid recipients). A high proportion (182 [92·9%] of 196) of coronary artery aneurysms resolved at follow-up, with no reported significant difference between groups.
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Aside from the quicker resolution of fever, no other secondary outcomes occurred more with intravenous immunoglobulin plus glucocorticoids versus intravenous immunoglobulin alone and glucocorticoids alone.
adjusted for differences between groups through propensity score weighting and subgroup analyses to address confounding bias, given the retrospective and voluntary nature of the data. The gold standard for any treatment intervention would be a large randomised controlled trial, for instance, the RECOVERY trial (ISRCTN50189673), which aims to examine the complexities of MIS-C treatment. Channon-Wells and colleagues
suggest the consideration of glucocorticoids as primary treatment instead of intravenous immunoglobulin alone or intravenous immunoglobulin plus glucocorticoids, as the clinical outcomes between treatment groups are similar and the gains using combined treatment appear to be marginal.
The use of intravenous immunoglobulin alone in MIS-C is extrapolated from past experiences in Kawasaki disease. Although MIS-C and Kawasaki disease have common features, it remains unclear whether clinical presentation alone represents related pathways of immune dysfunction to justify a similar route of management. Of crucial relevance to the future management of Kawasaki disease is the role of glucocorticoids over intravenous immunoglobulin as first-line therapy.
AVR declares speaker fees, honoraria, and consultancy work for AbbVie, Eli Lilly, Novartis, Roche, Swedish Orphan Biovitrum, Astra Zeneca, and Union Chimique Belge; and participation on a Data Safety Monitoring Board or Advisory Board for Eli Lilly and Astra Zeneca. CC is a funded National Institute of Health and Care Research Academic Clinical Lecturer in Paediatrics.
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Published: February 14, 2023
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