IV immunoglobulins + methylprednisolone tied to better outcomes in MIS-C

The addition of methylprednisolone to intravenous immunoglobulins (IVIG) was associated with more favourable fever course and secondary outcomes in multisystem inflammatory syndrome in children (MIS-C) compared with IVIG alone, a French retrospective analysis has shown.

Severe systemic hyperinflammatory disease in children after SARS-CoV-2 infection has been reported in the US and Europe. [N Engl J Med 2020;383:334-346; BMJ 2020;369:m2094; Euro Surveill 2020;25:2001010] Otherwise known as PIMS-TS*, MIS-C is a novel entity associated with haemodynamic failure, with acute cardiac dysfunction necessitating haemodynamic support in most cases, and, at times, death. [N Engl J Med 2020;383:347-358]

“MIS-C is the most severe paediatric disease associated with SARS-Cov-2 infection. [It is] potentially life-threatening, but the optimal therapeutic strategy remains unknown,” said the researchers.

Of 181 suspected MIS-C cases reported, 111 were deemed ‘confirmed’ cases as per WHO criteria. Five children did not receive treatment, leaving 106 (median age 8.6 years, 52 percent female) to receive either IVIG-methylprednisolone (combination arm; n=34) or IVIG alone (n=72) as first-line treatment. IVIG dosage was 2 g/kg. Methylprednisolone was given at 0.8–1.0 mg/kg Q12H (30 mg max for 12 hours) for 5 days (n=30) or as a bolus of 15–30 mg/kg/day for 3 days (n=4). [JAMA 2021;325:855-864]

Fifty-two children had initial left ventricular dysfunction (LVD), 74 were initially admitted to a PICU**, 46 received haemodynamic support, and 29 received ventilatory support. There were no deaths reported.

After propensity score matching, rate of treatment failure*** was significantly lower in the combination vs the IVIG-alone arm (9 percent vs 38 percent; odds ratio [OR], 0.25; p=0.008).

The combination vs the IVIG-alone arm also had lower rates of second-line treatment (9 percent vs 31 percent; OR, 0.19; p=0.004), haemodynamic support (6 percent vs 23 percent; OR, 0.21; p=0.01), and secondary acute LVD (17 percent vs 35 percent; OR, 0.20; p=0.007), as well as shorter duration of PICU stay (median, 4 vs 6 days; p=0.005).

There were also no long-term cardiovascular complications or persistent inflammatory syndrome reported on follow-up (up to January 6, 2021).

The corticosteroid effect

“Corticosteroid use is currently one of the few validated therapeutics in severe respiratory adult forms of COVID-19. [Our findings] suggest that corticosteroids may also be beneficial in MIS-C, possibly acting systematically as a potent inhibitor of SARS-CoV-2-induced inflammation,” they explained.

“Combined with … studies reporting MIS-C cases in young adults, there may be common pathways between severe respiratory adult forms of COVID-19 and MIS-C. Additional studies are warranted to understand the mechanisms underlying a possible corticosteroid effect in MIS-C and in severe forms of COVID-19,” they continued.

This benefit is further highlighted in other MIS-C studies showing shorter cardiac recovery and hospital length of stay with corticosteroids and IVIG, as opposed to IVIG alone. [Circulation 2020;142:2282-2284; Pediatr Crit Care Med 2020;22:e178-e191]

However, recent UK guidelines for MIS-C management suggest using IVIG alone as first-line therapy or, in some cases, no therapy. [Lancet Child Adolesc Health 2020;5:133-141] “[These were] developed using a Delphi method and [without] comparative studies … [Our] findings may warrant reconsidering these recommendations,” the researchers stressed.

Limitations

The study may have been limited by the nonrandomized design, noted the researchers. “However, given the rarity and severity of MIS-C, conducting randomized trials may be highly challenging. [O]bservational methods … may provide the best level of evidence.” It is also uncertain whether all children indeed had MIS-C despite fulfilling the WHO criteria for MIS-C.

The two different methylprednisolone dosages used should also be taken into context, added the researchers. Future studies should compare the effects of these two dosages, and look into the potential of other therapeutic regimens (ie, methylprednisolone alone, biologic therapies).

“[Also,] initial treatment with IVIG-methylprednisolone has a theoretical risk of worsening an unrecognized bacterial infection,” they noted. As symptoms of septic shock may be present in some MIS-C patients, empirical antibiotic treatment may be required to avoid this risk until a definitive diagnosis is made.