Clinical trial NCT04761913: Paediatric Inflammatory Multisystem Syndrome During COVID-19 Pandemic
Official title: Investigating Cytokine Storm Biomarkers in Children Presenting to Acute Paediatric Services (Non-intensive Care) With Paediatric Inflammatory Multisystem Syndrome During the Covid-19 Pandemic. An Observation Study
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Paediatric Inflammatory Multisystem Syndrome Temporally Associated With SARS-Cov-2
Keywords: cytokine storm
biomarkers
PIMS-TS
children
COVID-19
Lead sponsor: Anglia Ruskin University
Sponsor class: OTHER
First posted: 2021-02-21
Enrollment: 40
Sex: ALL
Minimum age (years): 3
Maximum age (years): 16
Standard ages: CHILD
Accepts healthy volunteers: no
Observational model: CASE_ONLY
Time perspective: RETROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Children (aged 3 months to ≤ 16 years) presenting to acute paediatric services (non-ICU) with symptoms of PIMS during the period of the COVID-19 pandemic

Brief summary: During the COVID-19 pandemic, a small minority of children have been presenting to acute paediatric services with a new syndrome, Paediatric Inflammatory Multisystem Syndrome temporally associated with SARS-Cov-2 (PIMS-TS). Children with PIMS-TS present with symptoms of inflammation caused by the immune system going into overdrive - this is likely to be in response to the virus. More severe cases involve inflammation and damage to the heart.

The focus of this project is to identify children with milder forms of PIMS-TS who are at risk of progression to more severe disease. Being able to predict the disease course of PIMS-TS at an early stage is important as it will allow clinicians to decide which patients should be treated with immunosuppressants, which have been shown to reduce the severity of the illness but have side effects.

Early data suggests that children with PIMS-TS have elevated biomarkers associated with an over-reaction of the body's immune system (also known as a 'cytokine storm') reaction. This study will explore whether children presenting with milder PIMS-TS have elevated 'cytokine storm' blood profiles and whether these profiles differ between children who continue to have a mild disease course compared to those who develop severe disease.

Detailed description: During the COVID-19 pandemic a minority of children have presented to acute services with clinical features of a new syndrome known as Paediatric Inflammatory Multisystem Syndrome temporally associated with SARS-Cov-2 (PIMS-TS). This high inflammatory state, likely triggered by the virus, has overlapping features of Kawasaki's and Toxic Shock Syndrome.

The focus of this study is to identify which children presenting with mild PIMS-TS symptoms will go on to develop severe disease requiring intensive care unit (ICU) admission. This is important as data suggests that early aggressive treatment with immunosuppression can lead to a relatively quick resolution in symptoms. The results of this study could allow clinicians to be selective in treating patients in whom the benefits of treatment outweigh the risks.

Early data suggests a 'cytokine storm' is involved in the PIMS-TS disease process. This proposed observational study will investigate whether children presenting to the non-ICU setting with features of PIMS-TS have raised cytokine storm biomarkers and whether these may be used to predict which children go onto develop severe disease.

The proposed study will include up to 15 hospitals across East of England. NHS clinical care teams will identify patients meeting the inclusion criteria and upload anonymised data into a secure web-based study database. Data will be retrieved for retrospective cases from 1st March 2020 and prospective data entered up until September 2021.

One hundred children presenting to acute (non-ICU) paediatric services with symptoms of PIMS-TS during the study period will be included.

The primary objective of the study is to describe the 'cytokine storm' biomarker profiles of children aged between 3 months to 16 years presenting with PIMS-TS to the non-ICU setting, focussing on those biomarkers which are readily accessible to district general hospitals (Pro-Beta Natriuretic peptide \[BNP\], ferritin, and CRP).

The secondary aims of the study are to:

1. Compare cytokine storm biomarker profiles of children who have a mild disease course to those who develop severe disease to identify whether there are any differences between these groups
2. Evaluate the association between cytokine storm biomarker profiles and severe events
3. Compare i) demographic characteristics (including pre-existing disease), and ii) other routine clinical investigations of children who have a mild disease course and those who develop severe disease to identify any differences between these 2 groups
4. Evaluate the association between vaccination status and disease severity
5. Compare cytokine storm biomarker profiles of children testing positive and those testing negative for SARS-CoV-2 via PCR on 2x nasopharyngeal swabs to identify any differences between these 2 groups.

Eligibility criteria: Inclusion Criteria:

* Within the age range of 3 months to ≤16 years
* Presenting clinically to non-ICU paediatric acute services at hospitals in the East of England region with symptoms suggestive of PIMS (e.g. incomplete Kawasaki's disease/Toxic Shock Syndrome) i.e. having: persistent fever (\>38.0oC for 5 or more days) AND high CRP (\>80) AND with one or more of additional features listed in Appendix 1 of the RCPCH document 'Guidance: paediatric multisystem inflammatory syndrome temporarily associated with COVID-19'
* Having either a positive or negative SARS-Cov-2 PCR test

Exclusion Criteria:

* Aged below 3 months old or above 16 years old
* Confirmation of any microbial cause other than SARS-Cov-2 (including bacterial sepsis, staphylococcal or streptococcal shock syndromes, infections associated with myocarditis such as enterovirus). Determination of such microbial causes is by routine testing i.e. blood culture; pneumococcal, meningococcal, group A strep, staph aureus blood PCR; ASOT; EBV, CMV, adenovirus, enterovirus PCR on blood; urine and stool culture; throat swab culture; stool virology.

Primary outcomes:
measure: Blood biomarker associated with a cytokine storm - Pro-Beta Natriuretic Peptide (measured in pg/mL).
timeFrame: From date of admission to date of discharge from hospital assessed up to 18 months
measure: Blood biomarker associated with a cytokine storm - Ferritin (measured in µg/L)
timeFrame: From date of admission to date of discharge from hospital assessed up to 18 months
measure: Blood Biomarker associated with a cytokine storm - C-Reactive Protein (measured in mg/L)
timeFrame: From date of admission to date of discharge from hospital assessed up to 18 months
Secondary outcomes:
measure: Demographic characteristics including age, sex, ethnicity and pre-existing morbidities
timeFrame: At admission to hospital
measure: Hospital stay data
timeFrame: From date of admission to date of discharge from hospital assessed up to 18 months
measure: Cytokine storm biomarker measured in mg/L (CRP)
timeFrame: From date of admission to date of discharge from hospital assessed up to 18 months
measure: Cytokine storm biomarkers measured in pg/mL (pro-beta natriuretic peptide, IL-6, IFN-gamma, IL-10, TNF-alpha)
timeFrame: From date of admission to date of discharge from hospital assessed up to 18 months
measure: Full blood count measures in 10^9/L (white cell count - neutrophil and lymphocyte count and platelet)
timeFrame: From date of admission to date of discharge from hospital assessed up to 18 months
measure: Full blood count measures in L/L (haematocrit)
timeFrame: From date of admission to date of discharge from hospital assessed up to 18 months
measure: Haemoglobin in g/L or g/dL (measured as part of full blood count and blood gas analysis)
timeFrame: From date of admission to date of discharge from hospital assessed up to 18 months
measure: Blood gas analysis measured in KPa (pCO2, pO2)
timeFrame: From date of admission to date of discharge from hospital assessed up to 18 months
measure: Blood gas analysis measured in mmol/l (glucose, lactate, Na, K and Cl)
timeFrame: From date of admission to date of discharge from hospital assessed up to 18 months
measure: Blood gas analysis measured in mmol/l or mEq/L (HCO3, BE)
timeFrame: From date of admission to date of discharge from hospital assessed up to 18 months
measure: Liver function tests measured in g/L (protein, albumin, globulin)
timeFrame: From date of admission to date of discharge from hospital assessed up to 18 months
measure: Liver function tests measured in U/L (ALP/ALT)
timeFrame: From date of admission to date of discharge from hospital assessed up to 18 months
measure: Liver function tests measured in µmol/L (bilirubin)
timeFrame: From date of admission to date of discharge from hospital assessed up to 18 months
measure: Troponin measured in ng/ml or ng/L
timeFrame: From date of admission to date of discharge from hospital assessed up to 18 months
measure: vitamin D measured in nmol/L
timeFrame: From date of admission to date of discharge from hospital assessed up to 18 months
measure: Amylase, CK, LDH measured in U/L
timeFrame: From date of admission to date of discharge from hospital assessed up to 18 months
measure: Glucose and triglycerides measured in mmol/L
timeFrame: From date of admission to date of discharge from hospital assessed up to 18 months
measure: Urea and electrolytes measured in mmol/L (Na, K, urea)
timeFrame: From date of admission to date of discharge from hospital assessed up to 18 months
measure: Urea and electrolytes measured in µmol/L (creatinine)
timeFrame: From date of admission to date of discharge from hospital assessed up to 18 months
measure: ferritin measured in µg/L
timeFrame: From date of admission to date of discharge from hospital assessed up to 18 months
measure: fibrinogen measured in g/L
timeFrame: From date of admission to date of discharge from hospital assessed up to 18 months
measure: D-dimer measured in ng/ml
timeFrame: From date of admission to date of discharge from hospital assessed up to 18 months
measure: PT and APTT measured in seconds
timeFrame: From date of admission to date of discharge from hospital assessed up to 18 months
measure: INR as a ratio (Patient PT/Control PT)
timeFrame: From date of admission to date of discharge from hospital assessed up to 18 months
measure: Acute Kidney Injury graded as no AKI or stage of AKI (1-3)
timeFrame: From date of admission to date of discharge from hospital assessed up to 18 months
measure: Positive or negative COVID-19 antibody test
timeFrame: From date of admission to date of discharge from hospital assessed up to 18 months
measure: Presence or absence of clinical conditions as assessed by ECG/echocardiography
timeFrame: From date of admission to date of discharge from hospital assessed up to 18 months
measure: Presence or absence of clinical conditions as assessed by chest x-ray/chest CT
timeFrame: From date of admission to date of discharge from hospital assessed up to 18 months
measure: Presence or absence of clinical conditions as assessed by abdominal ultrasound
timeFrame: From date of admission to date of discharge from hospital assessed up to 18 months
measure: Proteinuria as assessed by urinalysis graded as no protein, protein ++ or protein +++
timeFrame: From date of admission to date of discharge from hospital assessed up to 18 months
measure: Positive or negative COVID swab result as assessed by PCR
timeFrame: From date of admission to date of discharge from hospital assessed up to 18 months
measure: Positive or negative NPA or throat swab result for respiratory panel as assessed by PCR
timeFrame: From date of admission to date of discharge from hospital assessed up to 18 months
measure: Vaccination status
timeFrame: At admission to hospital
Other outcomes:
Locations:
city: Chelmsford
country: United Kingdom
facility: Mid Essex Hospital Trust
state: Essex
city: Colchester
country: United Kingdom
facility: East Suffolk and north Essex NHS Foundation Trust
state: Essex
city: Harlow
country: United Kingdom
facility: The Princess Alexandra Hospital NHS Trust
state: Essex
city: Great Yarmouth
country: United Kingdom
facility: James Paget University Hospitals NHS Foundation Trust
state: Norfolk
city: Norwich
country: United Kingdom
facility: Norfolk and Norwich University Hospitals NHS Foundation Trust
state: Norfolk
city: Ipswich
country: United Kingdom
facility: East Suffolk and North Essex Foundation Trust
state: Suffolk
Study officials:
affiliation: Anglia Ruskin University
name: Jo-Anne Johnson, MRCPCH, PhD
role: PRINCIPAL_INVESTIGATOR
References: