Paediatric Cardiology Guideline for managing referrals with pediatric multisystem inflammatory syndrome temporally associated with COVID-19 (PIMS-TS)

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Scope

This document gives background information and presents a Standard Operating Procedure for Cardiology assessment, investigation, management and follow up of patients aged 17 and younger, with no past history of heart disease, referred to acute inpatient service at the RHC Glasgow with a suspected Paediatric Inflammatory Multisystem Syndrome temporally associated with COVID-19 (PIMS-TS), as defined in RCPCH UK criteria1 (Appendix 1). The Cardiology team is involved in care as part of multidisciplinary group led by and including Paediatric ID, Paediatric Rheumatology, PICU, General Paediatrics, Haematology, Surgery and Neurology.

Background

SARS-CoV-2 infection pandemic

On 31 December 2019, a cluster of pneumonia cases of unknown aetiology was reported in Wuhan, Hubei Province, China. On 9 January 2020, China CDC reported a novel coronavirus (now called SARS-CoV-2) as the causative agent of this outbreak. As of 22nd June 2020, 8 926 399 cases have been recorded worldwide, of them 1 511 801 cases in the EU/EEA and the UK. Of them, 468 257 deaths have been reported worldwide, whereof 174 791 deaths in the EU/EEA and UK.

In Scotland, the index adult case of SARS-CoV-2 infection2 was registered on 1st March 2020. As of 22nd June 2020, Scottish Government reported 18 170 confirmed cases who tested positive for SARS-CoV-2. Of the people who have tested positive, 2 472 have died.

Data from population-based and cross-sectional studies indicate that children are unlikely to be primary source cases. Child-to-adult transmission appears to be uncommon3. It appears that COIVD-19, just like SARS and MERS, is less frequently observed in children, and children tend to present with milder symptoms than adults, although severe disease has also been reported in children. The most commonly reported symptoms of infection include fever and cough. Supportive care and oxygenation as required may be sufficient for mild and moderate cases. Cases presenting with severe respiratory distress and/or shock involve mechanical ventilation (usually of shorter duration than in adults) and use of IVIG.

At present, European Centre for Disease Prevention and Control Rapid Risk Assessment is as follows:

The overall risk of COVID-19 in children in the EU/EEA and UK is considered low, based on a low probability of COVID-19 in children and a moderate impact of such disease3

Emerging paediatric “cytokine storm” syndrome

From early April 2020, several countries affected by the coronavirus disease (COVID-19) pandemic reported cases of children that were hospitalised due to a rare paediatric inflammatory multisystem syndrome (PIMS)4-7.

Following the initial UK National Health Service alert and publication of the Royal College of Paediatrics and Child Health definition1 of PIMS-TS, the World Health Organisation (WHO)9, US Centers for Disease Control and Prevention (CDC), and the European Centre for Disease Prevention and Control have all produced definitions for the childhood inflammatory disorder that has emerged as the COVID-19 pandemic evolved in different countries. All were based on a limited number of unpublished cases3 (Appendix 1).

At present, European Centre for Disease Prevention and Control Rapid Risk Assessment is as follows:

The overall risk of PIMS-TS in children in the EU/EEA and the UK – is considered low, based on a very low probability of PIMS-TS in children and a high impact of such disease3.

As of 22nd June 2020, RHC Glasgow multidisciplinary team combined Scottish experience of PIMS-TS consists of 9 cases: 3 cases fulfilling PIMS-TS WHO criteria, 3 cases of Kawasaki disease with ectasia, 1 case of Kawasaki disease with aneurysm, 1 case with clinically suspected myocarditis and 1 case with appendicitis, both tested positive for SARS-CoV-2 PCR. (data presented by Dr Kirsty McLellan and Dr Louisa Pollock at Hyperinflammatory MDT held on MS Teams on 22nd June, 2020)

Pathophysiology and cardiovascular impact of PIMS-TS

PIMS-TS cases present with signs and symptoms similar to Kawasaki disease (KD) and Toxic Shock Syndrome (TSS). The current pathophysiological understanding is that SARS-CoV-2 replicates in respiratory and interstitial epithelial cells, suppressing early type I interferon responses, ad can infect monocytes and macrophages, accelerating viral replication and amplifying proinflammatory cytokine release, which mediates a dysregulated hyperinflammatory response4. This response can contribute to “cytokine storm syndrome” and organ damage, including ARDS accounting for some respiratory symptoms3,4, and myocarditis. Most frequent symptoms include prolonged fever, abdominal pain and other gastrointestinal symptoms (50-60%) as well as conjunctivitis, rash, irritability and, in some cases, shock.

A possible temporal association with SARS-CoV-2 infection has been hypothesised because some of the children were either positive by polymerase chain reaction (PCR) or serology. A secondary multi-system inflammatory disease is diagnosed based on clinical symptoms and laboratory investigations, including lymphopenia, anaemia, thrombocytopenia, increased acute phase proteins, coagulopathy, increased liver enzymes and hypertriglyceridaemia4. Immune complex generation and deposition could, in addition to endothelial activation, contribute to activation of the complement and clotting cascades. However, thromboembolic complications are not as frequent as in adults.

On June 1, 2020, Grimaud et al6 published an observational cohort study of 20 children admitted to PICU with cardiogenic shock secondary to acute myocarditis in 4 tertiary academic hospitals in Paris. Acute myocarditis was defined with the following criteria: elevated troponin, ST segment elevation or depression on ECG, regional wall motion abnormalities with decreased left ventricular function on Echocardiography7. All children received IVIG within 2 days of their PICU stay and 18 were thereafter afebrile. Two patients received corticosteroids and two others received biological agents. All children survived to discharge from PICU with full LV systolic function recovery. Nineteen of the 20 patients had identified SARS-CoV-2 infection on PCR or by serology. Authors discuss this presentation differing from those infected by SARS-CoV-2 previously reported in literature (older, have no co-morbidity nor any respiratory failure), delayed time of occurrence respective to the beginning of the lockdown and the remarkably high rate of IgG and IgA identification strongly suggesting a post-viral immunological reaction impacting on myocardium. All patients were described to show dramatic cardiac function improvement, as well as the significant decrease of inflammatory biomarkers following intravenous immunoglobulin, reinforcing the hypothesis of SARS-CoV-2 post-infective disease. All patients had standard systematic microbiological and virology screening for usual aetiologies of acute myocarditis, including the testing of a large panel of non-SARS-CoV-2 viruses. The myocarditis described in this series was less severe than usually seen in children, and was characterised by some unusual findings: intense systemic inflammation, some features usually seen in Kawasaki disease but differing in proportion of myocarditis (higher) and age (older), and vasoplegia. None of the patients had an endomyocardial biopsy, so the exact underlying mechanism of heart damage remains unclear. Authors suggested close follow-up of cardiac recovery with Echocardiography to detect the potential occurrence of coronary artery dilatation.

On the 8th June 2020, Whittaker et al7 published a UK case series including 58 children, to describe characteristics of patients meeting criteria for PIMS-TS but without proof of SARS-CoV-2 exposure, and to compare them with other pediatric inflammatory disorders. Using AHA criteria for Kawasaki disease (KD)8, authors described three distinct clinical patterns of presentation: shock, KD and a group with persistent fever and elevated inflammatory markers, but not having features of shock nor fulfilling criteria for KD. Clinical features of cases were compared with historic (2002-2019) San Diego cohort of patients with KD and with KD shock syndrome (KD-SS), and with paediatric presentations of toxic shock syndrome (TSS) from the European PERFORM and EUCLIDS studies (2012-2020).

Authors found that 8 of 58 children developed coronary artery aneurysms, and 2 developed giant coronary artery aneurysms. They had a variety of clinical presentations, and not all of them had features of KD. Authors hypothesized that vascular injury may be mediated by immune complexes through activation of inflammatory responses (neutrophil activation, and others), as was previously documented in KD, and went on to suggest that in view of extremely high CRP levels, IL-6 may be involved in myocardial depression, however these potential mechanisms need further evaluation. Similar to the case series from Paris, here authors described the following differences when comparing PIMS-TS with KD, KD-SS and TSS: patients with PIMS-TS were generally older, had more intense inflammation and had higher levels of markers of cardiac injury. Authors suggest that PIMS-TS differs from these other pediatric inflammatory entities, however one of the major study limitations was no possibility of direct comparison of UK children with PIMS-TS and usual prevalence of KD and TSS due to the lack of UK national registry.

Whittaker et al7 found that children with PIMS-TS who developed shock, had higher CRP and higher Troponin and NT-proBNP concentrations compared with those without shock. No difference was detected in clinical or laboratory markers between children who developed coronary artery dilatation or aneurysms, and those who did not. There were also no laboratory marker differences between groups who did and who did not meet KD criteria. This lack of association, and also occurrence of coronary aneurysms in all 3 clinical presentation groups of PIMS-TS suggests that the coronary changes are not solely a consequence of severity of inflammation, and has implications for treatment and cardiac investigations, leading to recommendations for both acute echocardiographic studies, as well as sequential follow up at 2 and 6 weeks, across the spectrum of PIMS-TS in both the acute and convalescent phases.

Interpretation of biomarkers of cardiac involvement

Cardiac troponins is the preferred biomarker of cardiomyocyte injury and is more sensitive and specific than CK MB isoenzyme10. Contemporary high sensitivity cardiac troponin assays now detect troponin in 50-90% healthy individuals10. International societies and expert groups recommend using gender-specific upper reference limits (URLs) for interpretation of high-sensitivity cardiac troponin I and T (hs-cTnI/T) assays. URLs represent a recommended diagnostic cut-off at the 99th percentile of a healthy reference population, and using them provides more accurate diagnosis.

Cardiac troponin rise is observed in conditions other than myocardial infarction (MI), without features of myocardial ischaemia, such as myocarditis, sepsis, pulmonary embolism, chronic hypertensive heart disease, aortic dissection, exposure to toxic agents and mechanical trauma. An increased Troponin concentration is not a diagnosis but an indicator of myocardial injury or stress. “Highly abnormal” hs-Tn defines values beyond 5-fold the upper reference limit10. The best method to detect unstable disease in patients with Troponin levels elevated at baseline may be to use the minimal change – a serial change of at least 20% relative to presentation, where on presentation there is a baseline increase above the 99th percentile. More data are needed to define how to best determine an increasing and/or decreasing pattern, and clinical judgement should always be applied to interpretation of results12.

In QEUH, cardiac Troponin is measured using the ARCHITECT high-sensitive troponin I assay (Abbott Laboratories, Abbott Park, IL). This assay has a limit of detection of between 1.2 ng/L and 1.9 ng/L, and the sex-specific 99th centile diagnostic thresholds for adults are 16 ng/L for women and 34 ng/L for men13. Cut-off levels may be higher in patients with renal dysfunction. Other assays used in Scotland are Siemens Atellica high-sensitivity cardiac Troponin I assay and Roche Elecsys high-sensitivity cardiac troponin T assays. For these assays, the limit of detection is 1.6 ng/L and 5 ng/L respectively, and the limit of blank for the cardiac troponin T assay is 3 ng/L. For all 3 assays, in adult patients requiring risk stratification for MI, threshold of 5 ng/L has been evaluated, as well as the lower threshold of <2 ng/L for cardiac troponin I, and <3 ng/L for cardiac troponin T, as these thresholds are equivalent to the limit of detection and limit of blank, respectively13. These values are always lower than the 99th percentile, given by the Laboratory as the URL, due to the detection of cTn in healthy individuals by these high sensitivity assays.

In healthy children, 99th and 97.5th percentiles for Abbott hs-cTnI and Roche hs-cTnT assays have been established by the Canadian Laboratory Initiative on Pediatric Reference Intervals (CALIPER) 14-15. The study of hs-cTnI assay14 demonstrated no age or sex difference in hs-cTnI concentrations in young children. Authors suggested that a common reference interval may be employed, but pointed out the limitations of the sample size and the exception of adolescent age group, where there are differences between males and females in common enzymes and in left ventricular mass14.  The same group (CALIPER) then studied the Roche hs-cTnT Generation 5 assay in a larger group of healthy children15, and found hs-cTnT concentrations markedly increased from 0 to <6 months and subsequently decreased and narrowed at 1 year. The gender-specific 99th percentiles from 1 to <19 years were 14 ng/L for boys and 11 ng/L for girls. The percent detectable was markedly higher in the hs-cTnI study comparing to hs-cTnT (Appendix 2). It therefore appears that gender-specific adult laboratory upper reference limits can be used when interpreting cTn levels in children older than 1.

The negative predictive value of Troponin in adults with MI has been shown to exceed 98% and thus a result at the detection threshold can be used to rule out myocardial damage. In the paediatric population, cardiac Troponin shows a good correlation with the extent of myocardial damage following cardiac surgery and cardiotoxic medication, and has diagnostic value in cases when cardiac contusion or inflammation is suspected16.

B-type natriuretic peptide (brain natriuretic peptide, BNP) is a cardiac neurohormone synthesized in cardiac ventricles as a result of increased wall stress, with diuretic, natriuretic and vasodilator properties. BNP is initially synthesized as a 134-amino-acid peptide called pre-pro BNP. The secondary cleaving results in formation of BNP, a biologically active hormone, and also of its inactive metabolite N-terminal BNP. Biological half-life of BNP is much shorter than that of NT-BNP (22 min vs 120 min) and day-to-day NT-BNP levels have been found to be more consistent. In a blood sample, NT-proBNP is more stable than BNP.  The cut-off level of BNP and NT-proBNP depends on age (increase with advancing age) and is also influenced by oestrogens (higher in post-pubertal girls) and obesity. In adults, heart failure is unlikely if the BNP value is less than 100 pg/mL and heart failure is very likely if the value is over 500 pg/mL. For NT-proBNP, heart failure in an adult is unlikely if the value is <300 pg/mL and likely if the value is >450 pg/mL. In healthy children, NT-proBNP levels are very high during the first days of life but decrease drastically thereafter. There is a mild gradual decline of normal levels with age throughout childhood18.

Brain Natriuretic Peptide (BNP) and NT-proBNP paediatric reference values, similar to cTn, have been established17, 18. The data suggests that determination of BNP levels improves the diagnostic accuracy in the assessment of heart disease in the pediatric population, correlates with the Echocardiographic variables and persistent severe elevation may predict adverse outcomes.

Grimaud et al6 described Troponin values ranging between 31 and 4607 ng/mL (type of assay not specified) and BNP between 179 and 19013 pmol/L. Details of cTn and BNP from the case series described by Whittaker et al7, are currently unavailable.

Whittaker et al found that children with PIMS-TS who developed shock, had higher CRP and higher Troponin and NT-proBNP concentrations compared with those without shock. No difference in clinical or laboratory markers between children who developed coronary artery dilatation or aneurysms and those who did not were identified, nor were laboratory marker different between groups who did and who did not meet KD criteria. In a series of 120 children with sepsis, the levels of plasma BNP and cTnI were demonstrated to be associated with the severity of sepsis and positively correlated with CRP and TNF-a levels19.

Treatment

The treatment of PIMS-TS consists of supportive management based on the type of clinical presentation, and specific treatment aiming to suppress inflammation, guided by Paediatric ID and Rheumatology. Aspirin and anticoagulation guidance is currently consensus-based and further studies are needed, as emerging evidence suggests that thrombotic complications in PIMS-TS are relatively rare, despite many patients demonstrating features of coagulopathy.

Referral MDT process and RHC GGC PIMS referral pathway

All stable children with PIMS-TS should be discussed with an MDT within 24 hours to aid risk stratification and decision making about transfer.

Escalation to level 3 care should be considered early for a child with single or multiple organ dysfunction who meets the criteria for PIMS-TS.

All children with evidence of cardiac involvement should be cared for in a Level 2/3 unit with availability of Cardiology on site21.

In RHC, urgent referrals of all new patients to Cardiology service should be made within the framework for the hyper-inflammatory MDT, including Paediatric Cardiologist Lead for this MDT (Dr Maria Ilina)

The agreed referral pathway contains criteria for involvement of Cardiology and PICU in urgent MDT discussion and logistics for urgent MDT discussions, which will be recorded in paper or electronic version of the proforma (Appendix 3) by the MDT chair, usually Paediatric ID or Rheumatology Consultant

RHC GGC PIMS referral pathway

Cardiology SOP for management of inpatients with PIMS-TS and cardiac involvement

Delphi process determined no UK consensus regarding indications and timeline of ECG or inpatient crossectional imaging (CT, MRI). Pragmatic approach below can be tailored on a patient-by-patient basis

  • 12 lead ECG, Echo, Troponin and NT-proBNP should be performed on admission to RHC Glasgow for all patients
    • For ECG features of PIMS-TS, see Appendix 4
    • For Echocardiography protocol, see Appendix 5
  • Rule out infective cause other than SARS-CoV-2
  • If clinically suspected myocarditis20 (Appendix 5), initiate Myocarditis investigations per protocol https://www.clinicalguidelines.scot.nhs.uk/ggc-paediatric-guidelines/ggc-guidelines/cardiovascular-diseases/cardiomyopathy-and-myocarditis-investigations-protocol/
  • All pharmacological treatment (IVIG, antiviral, antibiotic, corticosteroids and biological agents, anticoagulation, Aspirin, inotropic and vasopressor support) is directed by the MDT including Paediatric ID, Rheumatology, PICU, Cardiology, Haematology and others (not covered in this guidance)
  • Haemodynamically unstable patients will be managed on PICU and have daily 12 lead ECG, daily Echocardiograms21 and 12-24 hourly cardiac biomarkers (cTn and NT-pro-BNP) Low threshold for Milrinone infusion, consider Levosimendan or pressor agents, VA ECMO for refractory shock22
  • Haemodynamically stable patients will have a minimum of 2 inpatient ECG, 2 echocardiograms and 2 sets of cTn and NT-proBNP whilst inpatient. Consider continuous ECG monitoring during first 24-48 hours after admission
  • 24 hour ambulatory ECG recording is required if tachyarrhythmias or evidence of any degree of AV block (to be agreed/requested by Cardiology)

Aspirin and anticoagulation

In the UK consensus has been established21 that

  • Children with complete or incomplete Kawasaki Disease should follow the local Kawasaki guideline regarding Aspirin
  • Children who have a thrombotic event should follow the local protocol for management of it.
  • Children who are on high dose Aspirin who improve clinically with improvement of inflammatory markers, can be stepped down to low dose Aspirin

Despite lack of reports of thrombotic/thromboembolic complications of PIMS-TS and lack of clear UK consensus21, Evelina Children’s Hospital guideline suggests all teenagers presenting with PIMS-TS should start DVT prophylaxis: wear compression stockings and consider LMW heparin or IV UF heparin (check coagulation profile prior to starting)22.

Criteria for discharge for patients with evidence of cardiac involvement

In the UK consensus has been established21 that

  • Stable cardiac function is a criterion for discharge

Follow-up

Consensus in the UK has been established on the following

  • all children should be followed up before 6 weeks after discharge
  • in addition to this should also be followed up 6 weeks after discharge21.

Multidisciplinary follow-up arrangements should include a Paediatric Cardiologist21.

For patients who presented with TSS-PIMS-TS and had features of pancarditis (biventricular function impairment, mitral/tricuspid valve regurgitation, diastolic dysfunction, pericardial effusion, coronary artery dilatation/aneurysm), consider follow up

  • at 1-2 weeks post-discharge
  • at 2, 4 and 6 weeks, or until all investigations results normalise
  • consider early outpatient cross-sectional imaging (CT/MRI)22.

For patients with KD presentation of PIMS-TS, the published KD guidance8 should be used in order to determine follow-up:

  • if evidence of coronary involvement (ectasia/aneurysms/giant aneurysms) in any presentation, follow antiplatelet/anticoagulation recommendations for Kawasaki disease8, 22
  • if no evidence of coronary involvement (ectasia/aneurysms/giant aneurysms) in any presentation, discontinue low dose Aspirin at 6 weeks in discussion with ID/Rheumatology22.
Appendix 1: Case definitions for Emerging Inflammatory Condition During COVID-19 Pandemic From The World Health Organization, Royal College of Paediatrics and Child Health, and Centers for Disease Control and Prevention1

Appendix 2: Scatter plots of hs-cTnI and hs-cTnT results in healthy children14,15

Appendix 3: RHC GGC Hyperinflammatory MDT proforma
Appendix 4: ECG abnormalities in PIMS-TS

Appendix 5: Echocardiography protocol for assessment of patients with PIMS-TS
Appendix 6: Diagnostic criteria for clinically suspected myocarditis

References
  1. Royal College of Paediatrics and Child Health. Guidance: pediatric multisystem inflammatory syndrome temporally associated with COVID-19. Accessed June 22, 2020
  2. Hill K, Russell C, Clifford S et al. The index case of SARS-CoV-2 in Scotland. Journal of Infection, Published online March 21, 2020 
  3. European Centre for Disease Prevention and Control. Rapid risk assessment: pediatric inflammatory multisystem syndrome and SARS-CoV-2 infection in children. Published May 15, 2020. Accessed June 22, 2020. 
  4. Pain C, Felsenstein S, Cleary G et al. Novel paediatric presentation of COVID-19 with ARDS and cytokine storm syndrome without respiratory symptoms. Lancet Rheumatol Published online May 15, 2020. 
  5. Jones VG, Mills M, Suarez D, et al. COVID-19 and Kawasaki Disease : Novel Virus and Novel Case. Hosp Pediatr. 2020 Jun; 10(6): 537-540. Published online April 7, 2020 
  6. Grimaud M, Starck J, Levy M et al. Acute myocarditis and multisystem inflammatory emerging disease following SARS-CoV-2 infection in critically ill children. Intensive Care (2020) 10:69. Published online June 1, 2020
  7. Whittaker E et al for the PIMS-TS Study Group and EUCLIDS and PERFORM Consortia. Clinical Characteristics of 58 Children With a Pediatric Inflammatory Multisystem Syndrome Temporally Associated With SARS-CoV-2. Published online June 8, 2020. doi: 10.1001/jama.2020.10369
  8. McCrindle BW, Rowley AH, Newburger JW et al. American Heart Association Rheumatic Fever, Endocarditis and Kawasaki Disease Committee of the Council on Cardiovascular Disease in the Young: Council on Cardiovascular and Stroke Nursing; Council on Cardiovascular Surgery and Anesthesia; and Council on Epidemiology and Prevention. Diagnosis, treatment and long-term management of Kawasaki Disease:a scientific statement for health professionals from the American Heart Association. Circulation. 2017; 135(17): e927-e999. doi: 10.1161/CIR.0000000000000484
  9. World Health Organization. Multisystem inflammatory syndrome in children and adolescents with COVID-19. Published May 15, 2020. Accessed June 22, 2020
  10. Roffi M, Patrono C et al, on behalf of the Task Force of the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-segment Elevation of the European Society of Cardiology (ESC). 2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST segment elevation. European Heart Journal (2016) 37, 267-315 doi:10.1093/eurheartj/ehv320
  11. Thygesen K, Alpret JS, Jaffe AS, et al. Fourth universal definition of myocardial infarction. J Am Coll Cardiol 2018; 72: 2231-64
  12. Katus H, Giannitsis E, Jaffe A. Interpreting Changes in Troponin – Clinical Judgment Is Essential. Clinical Chemistry 58:1, 39-44 (2012)
  13. Bularga A, Lee K, Stewart S et al. on behalf of the High-STEACS Investigators. High-Sensitivity Troponin and the Application of Risk Stratification Thresholds in Patients With Suspected Acute Coronary Syndrome. Circulation 2019; 140: 1557-1568. Doi:10.1161/CIRCULATIONAHA.119.042866
  14. Kavsak P, Rezanpour A, Chen Y, Adeli K. Assessment of the 99th or 97.5th Percentile or Cardiac Troponin I in a Healthy Paediatric Cohort. Clinical Chemistry 60: 12 (2014) doi: 10.1373/clinchem.2014.228619
  15. Hohn M, Higgins V, Kavsak P. et al. High-Sensitivity Generations 5 Cardiac Troponin T Sex- and Age-Specific 99th Percentiles in the CALIPER Cohort of Healthy Children and Adolescents. Clinical Chemistry 65:4, 589-592 (2019)
  16. Neves A, Henriques-Coelho T, Leite-Moreira A, Areias J. Cardiac injury biomarkers in paediatric age : Are we there yet ? Heart Fail Rev 2016 Nov; 21 (6): 771-781. Doi: 10.1007/s10741-016-9567-2
  17. Neves A, Henriques-Coelho T, Leite-Moreira A, Areias J. The Utility of Brain Natriuretic Peptide in Pediatric Cardiology: A Review. Pediatr Crit Care Med. 2016 Nov; 17(11): e529-e538. Doi: 10.1097/PCC.0000000000000966
  18. Nir A, Lindinger A, Rauh M. et al. NT-Pro-B-type Natriuretic Peptide in Infants and Children: Reference Values Based on Combined Data from Four Studies. Pediatr Cardiol (2009) 30: 3-8. Doi 10.1007/s00246-008-9258-4
  19. Zhang Y, Luo Y, Nijiatijiang G et al. Correlations of changes in Brain Natriuretic Peptide (BNP) and Cardiac Troponin I (cTnI) with Levels of C-Reactive Protein (CRP) and TNF-a in Pediatric Patients with Sepsis. Med Sci Monit, 2019, 25: 2561-2566. doi: 10.12659/MSM.912318
  20. Caforio A, Pankuweit S, Arbustini E. et al. Current state of knowledge on aetiology, diagnosis, management and therapy of myocarditis: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J (2013) 34, 2636-2648 doi: 10.1093/eurheartj/eht210 
  21. Kenny S, et al. NHS England Delphi PIMS-TS survey summary.
  22. PIMS-TS Paediatric Multisystem Inflammatory Syndrome temporally associated with SARS-CoV2. Clinical Guidance by Evelina Children’s Hospital PICU, GSTT NHS Foundation Trust, and South Thames PICU Retrieval Service, effective from May 11, 2020, review by 11 November 2020
  23. Dallaire F, Dahdah N. New Equations and a Critical Appraisal of Coronary Artery Z scores in Healthy Children. JASE, published online November 15, 2010.
Editorial Information

Last reviewed: 30 June 2020

Next review: 14 December 2021

Author(s): Dr Maria Ilina

Version: 2

Approved By: Scottish Paediatric Cardiac Service