Management of Severe Hyperinflammation in the COVID-19 Era

The Role of the Rheumatologist

Charalampia Papadopoulou; Muthana Al Obaidi; Elena Moraitis; Sandrine Compeyrot-Lacassagne; Despina Eleftheriou; Paul Brogan

Disclosures

Rheumatology. 2021;60(2):911-917. 

In This Article

Abstract and Introduction

Abstract

Objectives: The objectives of this study were (i) to describe the clinical presentation, treatment and outcome of paediatric inflammatory multisystem syndrome temporally related to Sars-CoV-2 (PIMS-TS) in children; (ii) to propose a framework to guide multidisciplinary team (MDT) management; and (iii) to highlight the role of the paediatric rheumatologist in this context.

Methods: This study involved a retrospective case notes review of patients referred to a single specialist paediatric centre with suspected PIMS-TS, with a focus on clinical presentation, laboratory parameters, treatment, and outcome in the context of an MDT framework.

Results: Nineteen children of median age 9.1 years fulfilled the definition of PIMS-TS and were managed within an MDT framework: 5/19 were female; 14/19 were of Black, Asian or minority ethnicity; 9/19 also fulfilled diagnostic criteria for complete or incomplete Kawasaki disease (KD). Severe systemic inflammation, shock, and abdominal pain were ubiquitous. Treatment was stratified within an MDT framework and included CSs in all; i.v. immunoglobulin in all; anakinra in 4/19; infliximab in 1/19; and antiviral (aciclovir) in 4/19.

Conclusions: We observed significant diagnostic equipoise using a current definition of PIMS-TS, overlapping with KD. Outside of clinical trials, an MDT approach is vital. The role of the paediatric rheumatologist is to consider differential diagnoses of hyperinflammation in the young, to advise on empiric immunomodulatory therapy, to set realistic therapeutic targets, to gauge therapeutic success, to oversee timely step-down of immunomodulation, and to contribute to the longer-term MDT follow-up of any late inflammatory sequelae.

Introduction

Reports of a novel hyperinflammatory syndrome in children that could be related to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have emerged, possibly representing a rare, delayed immune-mediated response rather than direct viral sepsis in a small minority of children.[1,2] On 1st May 2020, the term PIMS-TS was proposed: paediatric inflammatory multisystem syndrome temporally related to SARS-CoV-2, defined as:

  1. a child presenting with persistent fever, inflammation, and evidence of single or multi-organ dysfunction with additional features. This may include children fulfilling diagnostic criteria for Kawasaki disease (KD);[3,4]

  2. exclusion of any other microbial cause (waiting for results should not delay seeking expert advice);

  3. SARS-CoV-2 PCR testing may be positive or negative.[5]

This pragmatic case definition, formulated in the absence of any definitive diagnostic laboratory test, attempted to exclude other infectious causes of hyperinflammation, but never purported to differentiate patients with PIMS-TS from non-infectious hyperinflammatory states such as KD.[3] As such, considerable diagnostic confusion between PIMS-TS and KD has arisen, with early reports that PIMS-TS may represent a 'KD-like' illness.[2] This has confused clinicians, and worried patients (https://www.societi.org.uk/kawasaki-disease-covid-19/).

KD is an acute self-limiting inflammatory medium-vessel vasculitis particularly affecting the coronary arteries. The aetiology of KD remains unknown.[6–10] It is currently proposed that any one of many infectious (or other wind-borne) triggers may result in an autoinflammatory response in genetically primed individuals.[11,12] It is therefore a plausible hypothesis that SARS-CoV-2 may trigger KD in susceptible individuals, although this is as yet highly speculative and unproven.

In April 2020, as cases of PIMS-TS began to emerge in London, a multidisciplinary team (MDT) was established at Great Ormond Street Hospital NHS Foundation Trust to manage critically ill paediatric patients presenting with hyperinflammation. The group comprised key individuals from teams well versed in the use of immunomodulation to treat hyperinflammation in children: paediatric rheumatology; infectious disease; immunology; haematology; cardiology and intensive care. In view of the diagnostic and therapeutic uncertainties around PIMS-TS, the remit of this group was to:

  1. formulate pragmatic clinical guidelines that gave consideration to the differential diagnosis of paediatric hyperinflammation; and to use these clinical guidelines to inform a practical pathway for therapeutic stratification;

  2. propose and implement a practical therapeutic target to facilitate a treat-to-target approach: zero fever and zero CRP (i.e. <10 mg/l), a therapeutic target successfully used for KD;[3]

  3. advise on immunomodulation to achieve this therapeutic target in the context of recently proposed (non-evidence-based) guidance for the treatment of Covid-19 in the young.[13]

The aims of this report were to summarize the clinical presentation, treatment, and outcome of cases discussed by this paediatric hyperinflammation MDT; to propose a clinical framework to help inform such MDT discussions; and to highlight the key roles of the paediatric rheumatologist in this context.

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