Treatment of Multisystem Inflammatory Syndrome in Children

McArdle. NEJM 2021; 385: 35-45.DOI: 10.1056/NEJMoa2102968

Clinical Question

• In children with multisystem inflammatory syndrome, what affect do different treatments have on the composite of inotropic support or mechanical ventilation by day 2 or death, and disease severity by day 2?

Background

• Multisystem inflammatory syndrome in children (MIS-C) is a new, rare but serious complication of SARS-CoV-2 infection with currently limited information as to the most effective treatment. A best available treatment study was performed to provide evidence for recommendations regarding the treatment of MIS-C

Design

• Observational cohort study
• Worldwide study
• Data from patients with confirmed or suspected MIS-C was uploaded onto Web based Research Electronic Data Capture database by treating clinician
• Weighted logistic-regression methods were used in statistical analysis with weights determined by inverse probability according to covariate balancing propensity scores
• Study approved by the UK research ethics committee

Setting

• 81 hospitals in 34 countries uploaded data
• Data collected between 20th June 2020 and 24th February 2021

Population

• Inclusion: Children who met the published WHO criteria for MIS-C and those with any suspected inflammatory illness after SARS-CoV-2 infection
• Exclusion: Not clearly defined but 37 patient excluded due to incomplete or duplicate entries; 50 patients had data included in the baseline characteristics but were excluded from the weighted analysis as they had received immunomodulator before transfer to the reporting hospital
• 651 patients enrolled with 614 meeting inclusion criteria
• Comparing baseline characteristics of intervention vs control group
  • Patients in control group were younger, had lower rates of positive PCR for SARS-CoV-2, required more organ support at admission and had higher troponin levels
  • IVIG +
    Glucocorticoids vs glucocorticoids alone vs IVIG alone
    • Median age: 8.8 vs 8.8 vs 7
    • Male sex %: 61 vs 60 vs 64
    • Co-existing illness %: 2 vs 7 vs 2
    • SARS-CoV-2 +ve on PCR %: 26 vs 27 vs 15
    • SAR-CoV-2 antibody +ve %: 80 vs 70 vs 68
    • Requiring organ support on admission (mechanical ventilation, inotropic support or ECMO) %: 32 vs 20 vs 15
    • Median troponin ng/l: 50 vs 50 vs 18

Intervention

• Two intervention groups based on initial immunomodulatory therapy
  • IVIG plus corticosteroid (n=208)
  • Glucocorticoids alone (n=99)
    • Of 89 patients included in primary analysis 47 (53%) went on to receive IVIG
• Another 22 patients received other immunomodulators, and 39 received no immunomodulatory therapy – due to low numbers these groups were not used as comparison

Control

• IVIG alone (n=246)
  • Chosen as the reference treatment since it is the accepted treatment for Kawasaki’s disease and has been widely adopted in the treatment of MIS-C
  • Of 217 patients included in primary analysis 99 (46%) went on to receive steroids

Outcome

• Primary outcome:
• 2 primary outcomes
  • Composite of inotropic support or mechanical ventilation (invasive or non-invasive) by day 2 or later or death – No significant difference
    • IVIG + glucocorticoids vs IVIG alone – adjusted odds ratio 0.77; 95% CI 0.33-1.82
    • Glucocorticoids alone vs IVIG alone – adjusted odds ratio 0.54; 95% CI 0.22-1.33
  • Reduction in disease severity on a seven point ordinal scale between day 0 and day 2 – no significant difference
    • IVIG + glucocorticoids vs IVIG alone – adjusted odds ratio 0.90; 95% CI 0.48-1.69
    • Glucocorticoids alone vs IVIG alone – adjusted odds ratio 0.93; 95% CI 0.43-2.04
• Secondary outcomes:
• Escalation in the administration of immunomodulators – significantly less common in patients who received IVIG + glucocorticoids compared with IVIG alone
  • Odds ratio 0.18; 95% CI 0.10-0.33
• No significant difference in:
  • The time until a reduction of one point in disease severity on the ordinal scale
  • Left ventricular dysfunction on echocardiography
  • Coronary artery aneurysm after treatment
  • Temporal dynamics of blood markers of inflammation and organ damage
  • Any increase in cardiorespiratory supportive therapy after day 0
  • Death: 3% vs 4% vs 1%
• Drug complications were highest in patient who received glucocorticoids and were predominantly hypertension and hyperglycaemia
• Subgroup analysis – including only patients who met the WHO criteria for MIS-C
  • IVIG + glucocorticoids vs IVIG alone – no significant differences
    • 1st primary outcome event- adjusted odds ratio 0.95; 95% CI 0.37-2.45
    • 2nd primary outcome event adjusted OR; 1.09 95% CI 0.53-2.23
  • Glucocorticoids alone vs IVIG alone
    • 1st primary outcome event – significantly improved outcomes in glucocorticoids alone group
      • adjusted odds ratio 0.3; 95% CI 0.10-0.85
    • 2nd primary outcome event – no significant difference
      • adjusted odds ratio 1.95; 95% CI 0.83-4.6

Authors’ Conclusions

• No evidence of substantial differences in the two primary outcomes among children who received the three most common treatments for MIS-C

Strengths

• Worldwide study looking at treatments widely available therefore generalizable to my patient population
• Pragmatic study in a newly emerging condition which currently has limited data

Weaknesses

• No standardisation to the standard of care patients received alongside the treatments
• No randomisation of patients to different arms of the study
• A large number of patients who were initially treated with either IVIG or steroids, went on to have the other treatment
• Likely the sickest patients were given IVIG + glucocorticoids or immunomodulatory therapy sooner, leading to differences between the baseline characteristics between the groups
• The baseline characteristics includes the data of 50 patients who were excluded from the primary analysis. It is unclear if there were significant differences in the baseline characteristics of these patients
• Missing data especially in laboratory values – e.g. 50% of patients did not have a troponin result uploaded for review Trends between the groups could therefore have been missed

The Bottom Line

• This paper shows no evidence of differences in the primary outcomes between different treatment groups
• In the subgroup analysis including only patients who met the WHO criteria for MIS-C, in the glucocorticoids only vs IVIG group, there was a significant reduction in the composite of inotropic support or mechanical ventilation by day 2 or later or death. Due to methodological weaknesses and the fact that this was a subgroup analysis, this should be viewed as hypothesis generating only
• Further prospective randomised controlled studies would be beneficial in this area
• I will continue to treat patients with a combination of these interventions seeking input from the wider multidisciplinary team whilst awaiting further data

External Links

• [article] Treatment of Multisystem Inflammatory Syndrome in Children

Metadata

Summary author: Dr Joanna Davy
Summary date: 19th July 2021
Peer-review editor: Dave Slessor

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