INTRODUCTION

Paediatricians in many countries worldwide are seeing rapidly increasing numbers of children with a new spectrum of inflammatory diseases temporarily associated with the COVID-19 pandemic. Since the first reports of a paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 infection, and establishment of a case definition in the UK (RCPCH, 1st May 2020), the disorder has been reported from many countries. However in addition to the critically ill children in the first reports, a wider spectrum of childhood inflammatory illness has emerged. Three related childhood syndromes have emerge which appear to represent a spectrum of illness temporally associated with SARS-CoV-2 pandemic:

1.  

2. PAEDIATRIC INFLAMMATORY MULTISYSTEM SYNDROME – TEMPORALLY ASSOCIATED WITH SARS-COV-2 (PIMS-TS).

1. • A child presenting with persistent fever, inflammation (which may be characterised by neutrophilia, elevated CRP and lymphopenia) and evidence of single or multi-organ dysfunction (shock, cardiac, respiratory, renal, gastrointestinal or neurological disorder) with additional features. This may include children meeting full or partial criteria for Kawasaki disease.
   • Exclusion of any other microbial cause, including bacterial sepsis, staphylococcal or streptococcal shock syndromes, infections associated with myocarditis such as enterovirus (waiting for results of these investigations should not delay seeking expert advice).
   • SARS-CoV-2 PCR testing may be positive or negative.

2.  

3. TYPICAL KAWASAKI DISEASE – TEMPORALLY ASSOCIATED WITH SARS-COV-2 (KD-TS).

   • Increasing numbers of children meeting the classical criteria for Kawasaki disease, but with evidence of SARS-CoV-2 infection or exposure. SARS-CoV-2PCR may be positive or negative, and SARS-CoV-2 antibodies positive or negative.

4.  

5. FEBRILE INFLAMMATORY SYNDROME – TEMPORALLY ASSOCIATED WITH SARS-COV-2 (FIS-TS).

   • Definition: Febrile children, without features of 1 or 2, but with inflammatory blood markers (such as raised CRP, neutrophilia, lymphopenia, elevated D-Dimers, ferritin), in whom other infectious or inflammatory causes cannot be identified, SARS-CoV-2 may be positive or negative by PCR and antibody.

Different acronyms and definitions for the syndrome have been proposed by the USA Centre for Disease Control and the WHO. CDC and WHO use the term: Multisystem Inflammatory Syndrome (MIS / MIS-C); these definitions are overlapping, and patients meeting any of the three definitions can be included.

These emerging disorders appear to be an unusual response to SARS-Cov-2 infection mediated by the host innate and acquired immune systems.

THE STUDY

While randomised trials are needed to establish which of the available treatments are optimal for this new  syndrome, they will take time to establish, and many children world wide are currently being treated on clinicians “best Guess”.  Our proposed study will compare the treatments administered by each clinician trying to deliver their “best available care” in a systematic  manner  that will provide information on which treatments may work, and will inform design of randomised trials.

We invite paediatricians in any country to join a study which we term “best available treatment study”.  We believe that the approach outlined below will enable rapid evaluation of the available therapeutic modalities and rapidly provide answers on the questions as to which patients to treat, which treatments work, and which may be harmful. 

The principles of the proposed study are:

• We do not know which immunomodulating treatments are beneficial or harmful for SARS-CoV-2 associated inflammatory conditions.
• Paediatricians try to provide the best available care to their patients.
• Anti-inflammatory and immuno-modulatory treatments are in short supply as their use in adults with COVID-19 are exhausting supplies of many of the biological agents. The numbers of cases with Kawasaki like syndromes may also strain supplies of intravenous immunoglobulin.
• Faced with variable availability of treatment options paediatricians will offer their patients their “best guess” of which of the available therapies are likely to be beneficial in their setting.
• We have excellent biological markers of the inflammatory process. Elevation of CRP, ferritin, troponin, BNP, D-dimers, liver function tests and conventional blood markers are indicative of the intensity of the inflammatory process and return to normal as inflammation subsides.
• We have simple clinical markers to evaluate improvement, need for intensive care, need for oxygen, inotropes or other support.
• We have accurate clinical markers of outcome: frequency and severity of coronary artery aneurysms, length of stay in hospital, requirements for inotropes and ventilation, and overall survival.
• We can compare the response to the treatment each clinician chooses for their patient if your patient’s data are uploaded onto the BATS data base. Once we have a large number of patients on the data base, different treatments can be compared ( for examples IVIG, Steroids, or biological agents, or no specific treatment) using statistical approaches to adjust for severity of illness, and comparing rate of improvement in inflammatory markers support required and outcome.
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The STUDY Team

BATS is a truly international collaborative study. All clinicians and Institutions  enrolling patients into the study will become members of the BATS study group. The study is being coordinated and the data is being managed by the Paediatric Infectious Disease Research Group at Imperial College London (Chief Investigator, Professor Mike Levin). It has been designed in collaboration and discussion with many researchers and organisations across the world. The Study steering group will include representatives of the Paediatric Intensive Care society, UK, World Federation of Pediatric Intensive care societies , European Academy of Paediatrics, Association Espanol de Pediatria, and Sociedad Latinoamericana de infectiologia Pediatrica. All those contributing data to the study will be included as members of the BATS study team.