South Thames Retrieval Service in London, UK, provides paediatric intensive care support
and retrieval to 2 million children in South East England. During a period of 10 days
in mid-April, 2020, we noted an unprecedented cluster of eight children with hyperinflammatory
shock, showing features similar to atypical Kawasaki disease, Kawasaki disease shock
syndrome,
1
or toxic shock syndrome (typical number is one or two children per week). This case
cluster formed the basis of a national alert.
All children were previously fit and well. Six of the children were of Afro-Caribbean
descent, and five of the children were boys. All children except one were well above
the 75th centile for weight. Four children had known family exposure to coronavirus
disease 2019 (COVID-19). Demographics, clinical findings, imaging findings, treatment,
and outcome for this cluster of eight children are shown in the table
.
Table
Demographics, clinical findings, imaging findings, treatment, and outcome from PICU
Age; weight; BMI; comorbidities
Clinical presentation
Organ support
Pharmacological treatment
Imaging results
Laboratory results
Microbiology results
PICU length of stay; outcome
Initial
PICU referral
Patient 1 (male, AfroCaribbean)
14 years; 95 kg; BMI 33 kg/m2; no comorbidities
4 days >40°C; 3 days non-bloody diarrhoea; abdominal pain; headache
BP 80/40 mmHg; HR 120 beats/min; RR 40 breaths per min; work of breathing; SatO2 99%
NCO2
MV, RRT, VA-ECMO
Dopamine, noradrenaline, argipressin, adrenaline milrinone, hydroxicortisone, IVIG,
ceftriaxone, clindamycin
RV dysfunction/elevate RVSP; ileitis, GB oedema and dilated biliary tree, ascites,
bilateral basal lung consolidations and diffuse nodules
Ferritin 4220 μg/L; D-dimers 13·4 mg/L; troponin 675 ng/L; proBNP >35 000; CRP 556
mg/L; procalcitonin>100 μg/L; albumin 20 g/L; platelets 123 × 109
SARS-CoV-2 positive (post mortem)
6 days; demise (right MCA and ACA ischaemic infarction)
Patient 2 (male, AfroCaribbean)
8 years; 30 kg; BMI 18 kg/m2; no comorbidities
5 days >39°C; non-bloody diarrhoea; abdominal pain; conjunctivitis; rash
BP 81/37 mmHg; HR 165 beats/min; RR 40 breaths/min; SVIA
MV
Noradrenaline, adrenaline, IVIG, infliximab, methylprednisolone, ceftriaxone, clindamycin
Mild biventricular dysfunction, severely dilated coronaries; ascites, pleural effusions
Ferritin 277 μg/L; D-dimers 4·8 mg/L; troponin 25 ng/L; CRP 295 mg/L; procalcitonin
8·4 μg/L; albumin 18 g/L; platelets 61 × 109
SARS-CoV-2 negative; likely COVID-19 exposure from mother
4 days; alive
Patient 3 (male, Middle-Eastern)
4 years; 18 kg; BMI 17 kg/m2; no comorbidities
4 days >39°C; diarrhoea and vomiting; abdominal pain; rash; conjunctivitis
BP 90/30 mmHg; HR 170 beats/min; RR 35 breaths/min; SVIA
MV
Noradrenaline, adrenaline, IVIG ceftriaxone, clindamycin
Ascites, pleural effusions
Ferritin 574 μg/L; D-dimers 11·7 mg/L; tropinin 45 ng/L; CRP 322 mg/L; procalcitonin
10·3 μg/L; albumin 22 g/L; platelets 103 × 109
Adenovirus positive; HERV positive
4 days; alive
Patient 4 (female, AfroCaribbean)
13 years; 64 kg; BMI 33 kg/m2; no comorbidities
5 days >39°C; non-bloody diarrhoea; abdominal pain; conjunctivitis
BP 77/41 mmHg; HR 127 beats/min; RR 24 breaths/min; SVIA
HFNC
Noradrenaline, milrinone, IVIG, ceftriaxone, clindamycin
Moderate-severe LV dysfunction; ascites
Ferritin 631 μg/L; D-dimers 3·4 mg/L; troponin 250 ng/L; proBNP 13427 ng/L; CRP 307
mg/L; procalcitonin 12·1 μg/L; albumin 21 g/L; platelets 146 × 109
SARS-CoV-2 negative
5 days; alive
Patient 5 (male, Asian)
6 years; 22 kg; BMI 14 kg/m2; autism, ADHD
4 days >39°C; odynophagia; rash; conjunctivitis
BP 85/43 mmHg; HR 150 beats/min; RR 50 breaths/min; SVIA
NIV
Milrinone, IVIG, methylprednisolone, aspirin, ceftriaxone
Dilated LV, AVVR, pericoronary hyperechogenicity
Ferritin 550 μg/L; D-dimers 11·1 mg/L; troponin 47 ng/L; NT-proBNP 7004 ng/L; CRP
183 mg/L; albumin 24 g/L; platelets 165 × 109
SARS-CoV-2 positive; likely COVID-19 exposure from father
4 days; alive
Patient 6 (female, AfroCaribbean)
6 years; 26 kg; BMI 15 kg/m2; no comorbidities
5 days >39°C; myalgia; 3 days diarrhoea and vomiting; conjunctivitis
BP 77/46 mmHg; HR 120 beats/min; RR 40 breaths/min; SVIA
NIV
Dopamine, noradrenaline, milrinone, IVIG, methylprednisolone, aspirin, ceftriaxone,
clindamycin
Mild LV systolic impairment
Ferritin 1023 μg/L; D-dimers 9·9 mg/L; troponin 45 ng/L; NT-proBNP 9376 ng/L; CRP
mg/L 169; procalcitonin 11·6 μg/L; albumin 25 g/L; platelets 158
SARS-CoV-2 negative; confirmed COVID-19 exposure from grandfather
3 days; alive
Patient 7 (male, AfroCaribbean
12 years; 50kg; BMI 20 kg/m2; alopecia areata, hayfever
4 days >39°C; 2 days diarrhoea and vomiting; abdominal pain; rash; odynophagia; headache
BP 80/48 mmHg; HR 125 beats/min; RR 47 breaths/min; SatO2 98%; HFNC FiO2 0.35
MV
Noradrenaline, adrenaline, milrinone, IVIG, methylprednisolone, heparin, ceftriaxone,
clindamycin, metronidazole
Severe biventricular impairment; ileitis, ascites, pleural effusions
Ferritin 958 μg/L; D-dimer 24·5 mg/L; troponin 813 ng/L; NT-proBNP >35 000 ng/L; CRP
251 mg/L; procalcitonin 71·5 μg/L; albumin 24 g/L; platelets 273 × 109
SARS-CoV-2 negative
4 days; alive
Patient 8 (female, AfroCaribbean)
8 years; 50 kg; BMI 25 kg/m2; no comorbidities
4 days >39°C; odynophagia; 2 days diarrhoea and vomiting; abdominal pain
BP 82/41 mmHg; HR 130 beats/min; RR 35 breaths/min; SatO2 97% NCO2
MV
Dopamine, noradrenaline, milrinone, IVIG, aspirin, ceftriaxone, clindamycin
Moderate LV dysfunction
Ferritin 460 μg/L; D-dimers 4·3 mg/L; troponin 120 ng/L; CRP 347 mg/L; procalcitonin
7·42 μg/L; albumin 22 g/L; platelets 296 × 109
SARS-CoV-2 negative; likely COVID-19 exposure from parent
7 days; alive
ACA= anterior cerebral artery. ADHD=attention deficit hyperactivity disorder. AVR=atrioventricular
valve regurgitation. BMI=body mass index. BP=blood pressure. COVID-19=coronavirus
disease 2019. CRP=C-reactive protein. FiO2=fraction of inspired oxygen. HERV=human
endogenous retrovirus. HFNC=high-flow nasal canula. HR=heart rate. IVIG=human intravenous
immunoglobulin. LV=left ventricle. MCA=middle cerebral artery. MV=mechanical ventilation
via endotracheal tube. NIV=non-invasive ventilation. PICU=paediatric intensive care
unit. RA=room air. RR=respiratory rate. RRT=renal replacement therapy. RV=right ventricle.
RVSP=right ventricular systolic pressure. SARS-CoV-2=severe acute respiratory syndrome
coronavirus 2. SatO2=oxygen saturation. SVIA=self-ventilating in air. VA-ECMO=veno-arterial
extracorporeal membrane oxygenation.
Clinical presentations were similar, with unrelenting fever (38–40°C), variable rash,
conjunctivitis, peripheral oedema, and generalised extremity pain with significant
gastrointestinal symptoms. All progressed to warm, vasoplegic shock, refractory to
volume resuscitation and eventually requiring noradrenaline and milrinone for haemodynamic
support. Most of the children had no significant respiratory involvement, although
seven of the children required mechanical ventilation for cardiovascular stabilisation.
Other notable features (besides persistent fever and rash) included development of
small pleural, pericardial, and ascitic effusions, suggestive of a diffuse inflammatory
process.
All children tested negative for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
on broncho-alveolar lavage or nasopharyngeal aspirates. Despite being critically unwell,
with laboratory evidence of infection or inflammation
3
including elevated concentrations of C-reactive protein, procalcitonin, ferritin,
triglycerides, and D-dimers, no pathological organism was identified in seven of the
children. Adenovirus and enterovirus were isolated in one child.
Baseline electrocardiograms were non-specific; however, a common echocardiographic
finding was echo-bright coronary vessels (appendix), which progressed to giant coronary
aneurysm in one patient within a week of discharge from paediatric intensive care
(appendix). One child developed arrhythmia with refractory shock, requiring extracorporeal
life support, and died from a large cerebrovascular infarct. The myocardial involvement
2
in this syndrome is evidenced by very elevated cardiac enzymes during the course of
illness.
All children were given intravenous immunoglobulin (2 g/kg) in the first 24 h, and
antibiotic cover including ceftriaxone and clindamycin. Subsequently, six children
have been given 50 mg/kg aspirin. All of the children were discharged from PICU after
4–6 days. Since discharge, two of the children have tested positive for SARS-CoV-2
(including the child who died, in whom SARS-CoV-2 was detected post mortem). All children
are receiving ongoing surveillance for coronary abnormalities.
We suggest that this clinical picture represents a new phenomenon affecting previously
asymptomatic children with SARS-CoV-2 infection manifesting as a hyperinflammatory
syndrome with multiorgan involvement similar to Kawasaki disease shock syndrome. The
multifaceted nature of the disease course underlines the need for multispecialty input
(intensive care, cardiology, infectious diseases, immunology, and rheumatology).
The intention of this Correspondence is to bring this subset of children to the attention
of the wider paediatric community and to optimise early recognition and management.
As this Correspondence goes to press, 1 week after the initial submission, the Evelina
London Children's Hospital paediatric intensive care unit has managed more than 20
children with similar clinical presentation, the first ten of whom tested positive
for antibody (including the original eight children in the cohort described above).