PIMS-TS or MIS-C UK lessons for Johns Hopkins Grand Round June 15th 2020

U.K. lessons on the hyper-inflammatory
shock syndrome in kids post-COVID19;
#PIMSTS / #MISC. June 15th 2020
Dr Barney Scholefield @BarneyUoB
NIHR Clinician Scientist & Consultant Paediatric Intensivist

Learning objectives
• 1) Understand the importance of a name: PIMS-TS & MIS-C and defining a new
condition.
• 2) Describe the current knowledge (and gaps) in epidemiology, mechanisms and
management of PIMS-TS/MIS-C
• 3) Appreciate the challenges of turning the tide on diagnostic and clinical
uncertainty.
• Disclaimer: No financial COIs.
• Any treatment recommendations /drug dosing currently provisional
• Fastest moving/publishing field on the planet….
@BarneyUoB

Welcome from ‘locked down’ Birmingham
Photo by Dr Jeff Martin – for the BCH PICU 09:09 Club @BarneyUoB

Birmingham Children’s Hospital
@BarneyUoB

Dr Tomisaku Kawasaki
• 1961 – first saw a case
• ‘acute febrile mucocutaneous lymph node syndrome’
• Collected data on 50 cases over 6 years
• Published in 1967 (and 1974 in English-Language)
• 53 pages of description
• Later it retained his name ‘Kawasaki Disease’
• Sadly he died June 5th 2020 aged 95
• Washington post obituary
@BarneyUoB

Stages of an emerging condition?
Current ‘Normal’
Few intriguing cases
EVERYONE starts talking
Search for the truth
@BarneyUoB

Stages of an emerging condition
@BarneyUoB

COVID-19
• Children 1-5% of infected cases
• Significant proportion do not
appear to develop symptoms
• Lack of sero-survelliance so
proportion not known of
carriers
• Less likely to transmit to others
• Very few arrived in PICU
• Resource: DFTBs
@BarneyUoB

A few cases…
• Older children and adolescents – ’atypical Kawasaki’
• Acute hyper-inflammation: CRP, Ferritin, Troponin
• Pancarditis and shock
• Needing PICU support
• Appearing over ‘days’
• Following pattern of COVID-19 disease
@BarneyUoB

Everyone starts talking
• Clinicians managing these patients
• National experts coordinating response
• The politicians
• The press
• The public
• The academics (hopefully looking for the truth)
@BarneyUoB

Birmingham Children’s Multi-disciplinary Team
• Paediatric Intensive Care
• Cardiology
• Rheumatology
• Infectious disease
• General paediatrics
• Daily virtual MDT
• Chaired by senior hospital management
• Creation of regional protocol
• Advice to regional hospitals
• Webinar: 300 paediatricians
@BarneyUoB

UK & International Bodies
• Royal College of Paediatrics Child Health @RCPCHtweets
• Paediatric Intensive Care Society @PICSociety
• International group webinars
• WHO (world health organisation) @WHO
• European Centre for disease control and prevention (CDC&P)
• USA CDC&P @CDCgov
WHO guidanceRCPCH guidance USA CDC&P @BarneyUoB

The tweet: April 26th @PICSociety
@BarneyUoB

Paediatric Multi-system Inflammatory
Syndrome Temporally Associate with
SARS CoV-2
#PIMS-TS
Multi-system Inflammatory
Syndrome in Children
#MIS-C
Corona Shock
Syndrome
Kawashoky
CRISPS
Coronavirus Related
Inflammatory Shock
Pancarditis Syndrome
OH CRAPS
Hyperinflammation
COVID Related Abdomen
Pancarditis Shock
SCiKH
SARS CoV-2 induced
Kawasaki Like
Hyperinflammatory
Syndrome
Kawasaki-like
@BarneyUoB

Politicians, Press & the Public
May 21st 2020
@BarneyUoB

PIMS-TS graphs on social media
250,000 35
Crossing lines
misleading++
@BarneyUoB

@BarneyUoB

Fast
GoodCheap
www.ukrn.org
@BarneyUoB
NYtimes June 15th

Comparison of definitions
Organisation
RCPCH US CDC&P WHO
Name Paediatric multisystem inflammatory
syndrome temporally associated with
COVID-19 (#PIMS-TS)
Multisystem inflammatory syndrome in
Children Assocaited with COVID-19
(#MIS-C)
Multi-system inflammatory syndrome in children
and adolescents with COVID19
Release 1st May 2020 14th May 2020 15th May 2020
Age | Bloods Child Inflam markers ↑ <21 years Inflam markers ↑ 0-19 Inflam markers ↑
Fever Persistent > 38.5 >38.0 for > 24hrs Fever > 3 days
Clinical feature Single or multi-organ dysfunction
• shock,
• cardiac failure,
• respiratory,
• renal,
• gastrointestinal,
• neuro disorder
Hospital + ≥ 2 organs involved
• cardiac,
• renal,
• respiratory,
• hematologic,
• gastrointestinal,
• dermatologic
• Neurological
Two of following:
1. Rash or bilat conjunctivitis, or muco-
cutaneous
2. Hypotension or shock
3. Cardiac involvement
4. Coagulopathy
5. Acute GI
Extra • Can include Kawasaki Disease/ atypical Kawasaki
• Exclude other microbial or virus / no plausible other diagnosis
Evidence of
COVID infection
SARS CoV 2 PCR (may be positive or
negative*)
(*note antibody testing not available widely in UK at
time of release, but everyone now testing)
Positive evidence of recent SARS Co-V 2
infection (PCR, antibody, exposure
history last 4 weeks)
Positive evidence of recent SARS Co-V 2 infection
(PCR, antibody, exposure history)
@BarneyUoB

How many cases published?.... As of June 15th
USA =250+
Important Questions?
• Why Europe & N.America?
• What is the rate in Sars-CoV2 infected children?
France = 108
UK = 100+
France & Swiss n = 35
Acute heart failure 28% ECMO
Birmingham Cohort n=8+7
Cardiac features 14/15 Coronary artery
changes
CHOP n = 6
Columbia n=44
n=458 from Press
reports
n=185 from published
case series/cohorts
n=8 London
@BarneyUoB
Adapted from
UHB / BHP
infographics

Kawasaki Disease
• Genetic predisposition
• > Males
• Variation in countries
• Region specific seasonality
• Periodic outbreaks
• Spatiotemporal clusters
• Associated with: infection,
pollution, unfamiliar exposure
McCrindle JAMA June 8 2020
@BarneyUoB

Toxic Shock Syndrome
Memory notebook of nursing volume 2 Zerwekh
@BarneyUoB

Clinical feature of PIMS-TS
RCPCH guidance
@BarneyUoB

• March 23rd to May 16th 2020: 8 UK hospitals
• n=58
• Analysed by stratifying for Shock, Kawasaki diagnosis, Coronary artery
aneurysm, Evidence of SARS CoV-2.
• Race/ethnicity
• 22/58 (38%) Black
• 18/58 (31%) Asian
• 12/58 (21%) White
Date of download: 6/11/2020
Copyright 2020 American Medical Association.
All Rights Reserved.
From: Clinical Characteristics of 58 Children With a Pediatric Inflammatory Multisystem Syndrome Temporally
Associated With SARS-CoV-2
JAMA. Published online June 08, 2020. doi:10.1001/jama.2020.10369
• Clinical features
• Abdominal pain 53%
• Diarrhoea 52%
• Rash 52%
• Shock 50%
• Vomiting 45%
• Conjunctival injection 45%
• Mucous membrane 29%
• Headache 26%
• Resp symptom 21%
• Lymphadenopathy 16%
@BarneyUoB

Age: Older
9yrs (5.7-14)
WBC: Higher
17 (12-22)x109/L
Neutrophils: Higher
13 (10-19) x109/L
@BarneyUoB

Lymphocytes: Lower
0.8 (0.15-1.5) x109/L
Hb: Lower
92 (83-103)g/L
Platelets: Lower
15 (104-210) x109/L
@BarneyUoB

CRP: Higher
229 (156-338) mg/L
ALT: similar
42 (26-95)U/L
Albumin: Lower
24 (21-27)g/L
@BarneyUoB

Ferritin: Higher
610 (359-1280)mcg/L
Troponin: Higher
45 (8-294)ng/L
D-Dimer: Higher
3578 (2085-8235) ng/ml
@BarneyUoB

PIMS-TS versus Kawasaki disease
Age: Older
WBC: Higher
Neutrophils: Higher Lymphocytes: Lower
Haemoglobin: Lower
Platelets: LowerCRP: Higher
ALT: similar
Albumin: LowerFerritin: Higher
Troponin: Higher
D-Dimer: Higher
PIMS-TS
with Shock
NT-proBNP: Higher
NO differentiation of
Coronary artery
involvement or not.
@BarneyUoB

Cardiac Involvement
• Ramachanan et al Ped Cardio June 12th
• n=15 Birmingham, UK
• Cardiac or circulatory compromise
• 12/15 (80%) impaired LV ejection fraction
• 10/15 (67%) inotropic support
• 0/15 (0%) ECMO
• Vasculitis
• 14/15 (93%) had coronary artery abnormalities (which
normalised in 6)
• 7/14 ‘prominent’ coronary artery
• 6/14ectatic dilated coronaries
• 1/14 moderate fusiform aneurysm of RCA
• 8/15 small pericardial effusion, resolved.
• Whittaker et al JAMA June 8
• Cardiac
• 3/58 (5%) ECMO
• Vasculitis
• 8/58 (14%) Coronary artery
aneurysms (z-scores >2)
• 2/58 Giant Coronary artery
• Toubiana et al BMJ June 3rd
• n=21 patients in Paris
• 5/21 (24%) coronary artery abnormalities
@BarneyUoB

• n=35 France and Switzerland
• Cardiac
• 10/35 (28%) ECMO
• Vasculitis
• 6/35 (17%) Coronary artery
• 10/35 (28%) LVEF<30%
@BarneyUoB

Antibody profile of PIMS-TS
• Birmingham, UK
• n=8 (compared to adults)
• All negative PCR
• All IgG and IgA Ab
• Low IgM
Perez-Toledo et al (MedRxiv PREPRINT June 7th)
@BarneyUoB

PIMS-TS management principles
@PICSocsiety
May 14th
@BarneyUoB

Fluids and inotropes
@BarneyUoB

Ventilation, antibiotics, Immunomodulation
@BarneyUoB

Drug Evidence Base - limited so far
• Paediatric evidence
• Kawasaki Disease
• Resistant Kawasaki Disease
• Toxic Shock Syndrome
• Macrophage activation/
secondary HLH
@BarneyUoB

Immunology
Courtesy of Dr Rob Parker
Connecticut Children’s Webinar
May 22nd
@BarneyUoB

First do no harm….
• *Intravenous Immunoglobulin (IVIG)
• *Steroids (eg methylprednisolone)
• *Tocilizumab (IL-6)
• *Infliximab (Anti-TNF)
• *Anakinra (IL-1)
• Interferon-beta-1a –
• Anakinra
• Sarilumab
• Canakinumab
• Ruxolitinib
• Bemcentinib
• MEDI3506
• Acalabrutinib
• Zilucoplan
• Gemtuzumab ozogamicin
• Baricitinib + SoC – Ravulizumab
• Brensocatib
• Human umbilical cord derived CD362
enriched mesenchymal stem cells
List of drugs currently used or being investigated in adults (and
children) for COVID-19 or PIMSTS
NO EVIDENCE (yet) WHICH ONE WORKS or IS SAFEST
*drugs described in PIMS-TS / MIS-C cohort studies/case series
@BarneyUoB

PIMSTS Research pathways
PICANET COVID
Audit PIC only
REMAP-CAP-
KIDS
ISARIC All
GENOMICCS PIC only
DIAMOND PIC only
RECOVERY-
Paeds
PICANET COVID
Audit
REMAP-CAP-
KIDS
ISARIC
GENOMICCS
DIAMOND
RECOVERY-
Paeds
PICANET: National established audit of all PICU patients.
COVID+ & suspected. AND PIMS-TS phenotype entered.
OCEANIC-C PIC only
Post-PIC outcome after
critical illness –
Status: Application pending
Dr Joseph Manning
Other studies
• RASCALS – Respiratory biomarkers – Dr Nazima Pathan Cambridge
• BPSU – set up for PIMSTS
• RCPCH data collection COVID
• Child Death Overview Panel reporting & registry
Future Grants in development
• Longer term Follow up of COVID – PIMSTS patients
• OCEANIC-C amendment (J Manning)
• Canadian grant
• SAFE CHILDREN – PICS-SG led (CI: Dr Nazima Pathan)
Application pending.
National roll out of DIAMONDS Linking with Dr Nazima Pathan
(Cambridge) for UK PICS-SG biosample study – SAFE CHILDREN
study (application pending).
Linking with: NIHR Bioresource study (CI: Prof Lucy
Raymond) Trio-genetic study of children. Not currently
collecting PIMSTS patients. Status: Not open for PIMSTS
PIMS-TS – PICS
Surveillance
PICS-SG supported rapid case series
CI: Dr Patrick Davies/ PICS-SG / PICS/ PICANET
.
Genetic investigation of critically ill children – will include
PIMSTS patients.
COVID19 Research pathways
COIVD19 &/OR Paediatric Multi-system
Inflammatory syndrome – Toxic Shock
Research plan for UK PICU patients – 8rd May 2020 v 1.0
Observational studies
Interventional studies
RCPCH/BPSU
PICS Clinical
Guidance
PICS-SG UK
physiology study
Study open
https://www.reco
verytrial.net/
Grant application
pending
Neuro COVID
https://www.neurocritical
care.org/research/covid-
19-research-opportunities
Portal for site
registration www.survey
monkey.com/r/BKRKNTC
Graphics credits: Prof E Sapey & Collaboration of university of Birmingham, University hospital Birmingham and Birmingham Health Partners
@BarneyUoB

Children and Families
• RCPCH advice for families
• USA CDC&P
@BarneyUoB

Summary
What do we know?
 Condition remains ‘rare’
 Hyperinflammation post SARSCoV-2
 #PedsICU & Multiple specialties have
a role #cardio #rheum #ID
 Careful ‘best’ medicine
 These children may answer bigger
questions of immune mediated
conditions
What do we not know?
 Incidence or prevalence of
PIMS-TS / MIS-C in children
who’ve had COVID19
 Mechanism of disease
 Who to receive or which is
best immunomodulation
 Slightly longer than ‘very
short’ outcomes
@BarneyUoB

Next steps to search for the truth #PIMS-TS
 Adopt Dr Kawasaki’s humble approach
 International collaboration: #PIMS-TS / #MIS-C
 Careful reporting and evaluating of the evidence
 Understand the pathology / immunology / genetics
@BarneyUoB

Jimmy's Famous
Seafood
RCPCH advice for familiesUSA CDC&P
PIMS- TS Critical Care
guidance
Belhadjer et alPerez-Toledo et al Whittaker et al
Infographics COVID
RCPC
H
US CDC&P WHO
Miller et alChiotos et al Riphagen et al Ramachanan et alTouliana et al Grimaud et al
Verdoni et al
PIMSTS
/MIS-C
Definitions
PIMSTS /MIS-C
Case
series/cohorts
Other
guidance
Johns Hopkins Grand
Round PIMS-TS
@BarneyUoB

PIMS-TS or MIS-C UK lessons for Johns Hopkins Grand Round June 15th 2020

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PIMS-TS or MIS-C UK lessons for Johns Hopkins Grand Round June 15th 2020