Addressing fundamental questions on MIS-C

It is very rare in modern medicine that a truly novel condition appears. Throughout our training and ongoing education, we can always ask more experienced or more learned colleagues for advice and guidance, or seek knowledge from the published literature. For paediatricians worldwide to be faced with a totally new entity named paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) in the UK, also known as multisystem inflammatory syndrome in children (MIS-C) in the USA, in the middle of the disruption of a pandemic was unprecedented.

It is difficult to learn about an emerging condition. Identification, categorisation, and definition are fairly simple, but by its very nature, answers to the truly important questions are unknown. Three fundamental questions underpin any condition: how do we stratify patients, how do we treat them, and what is their prognosis?

Evidence on prognosis needs time to emerge, and no publications have addressed this. Initial mortality from MIS-C has been shown to be low. Emerging evidence indicates that medium-term follow-up is encouraging, with 33 (94%) of 35 patients having normal global longitudinal strain and five (14%) of 35 with mild coronary ectasia at 2 weeks.¹ Of course, truly long-term outcomes are unknown, but existing evidence points towards an acute condition with resolution.

Optimum treatment is more difficult to declare. Because of the (at times tenuous) clinical overlap with Kawasaki disease,² treatments are aligned with this condition. Evidence, however, shows substantial variation between the immunological pattern seen in patients with MIS-C and those with Kawasaki disease.3, 4 The rapid dissemination of information on how clinicians were treating MIS-C was quickly converted into perceived knowledge, despite a lack of any robust evidence. Clinicians must be very open to understanding the difference between information and knowledge. Robust trials on treatment options in patients with MIS-C have not yet been published, and might be difficult to do due to an ongoing perceived lack of equipoise. The UK RECOVERY trial (NCT04381936) is one of few trials randomly assigning patients with MIS-C. Robust data are important. This once-in-a-generation opportunity to treat a novel condition correctly from the outset might sadly already have passed.

Notwithstanding the difficulties in addressing the second and third of the fundamental questions, in The Lancet Child & Adolescent Health, Joseph Abrams and colleagues⁵ address the first: how do we identify the patients who are most at risk from MIS-C at the time of their presentation?

A subgroup of patients with MIS-C will need intensive care.⁶ Early identification of those who are most at risk of severe illness is important. In paediatrics, early intervention is of substantial benefit, and clear communication with parents allowing their expectations to be managed is only possible with clear prognostication. Outcomes that contribute to measures of severity must be carefully chosen. The risk of circular data is high, in that using intensive care admission as a measure of severity might simply validate admission policies. Although admission to intensive care is always carefully considered, using this as a metric does not infer, per se, anything about the severity of these patients' illnesses. Such effects can, however, be mitigated by a large dataset. The Article by Abrams and colleagues contains one of the largest cohorts published so far, with 1080 patients who were admitted to hospital for MIS-C in the USA between May 14 and Oct 19, 2020.

Nonetheless, the study includes many criteria that are independent of admission. The data analysis plan compared clinical variables between patients admitted to the intensive care unit on a later date than hospital admission and patients who were never admitted to the intensive care unit, showing the factors that predict onward deterioration. This method cleverly circumvents the often-seen result that patients with more severe disease have more severe outcomes and enables the clinician to be wary of the stated parameters.

Identification of which laboratory tests predict a severe outcome is important but an analogue quantification adds greatly to understanding. In general, more abnormal results were associated with more severe outcomes, but the shape and slope of the associations are important too. The findings by Abrams and colleagues show a clear hierarchy between outcomes, and the magnitude of the abnormalities compared with a reference standard. In a digital world, this analogue nuance is often lost.

Interestingly, only the N-terminal pro B-type brain natriuretic peptide (pro-BNP) and IL-6 concentrations were significantly associated with coronary artery abnormalities. This finding simultaneously implies an association with increased inflammatory state and advises caution because most of the other laboratory markers usually examined do not aid in prognostication. However, the likelihood of shock was significantly associated with almost all of the other factors—elevated D-dimer, troponin, BNP, pro-BNP, and C-reactive protein, ferritin, and IL-6, and decreased platelet and lymphocyte counts. Therefore, for the initial management of patients with MIS-C, considering the laboratory results will allow clinicians to stratify patients and ensure that everyone has access to the level of care suitable for the individual.

The ongoing emergence and rapid dissemination of knowledge around MIS-C is incredibly important for clinical teams around the world to treat their patients carefully, correctly, and with knowledge. Many of the treatments have substantial potential side-effects and resource implications (especially for low-income and middle-income countries), and should be used only when the patient's condition necessitates treatment, and when the treatment has been show to be effective.

© 2021 FangXiaNuo/iStock