Paediatric Inflammatory Multisystem Syndrome (PIMS-TS) following SARS-CoV-2 Infection: Diagnosis and Management

Aim

To provide guidance for clinicians on the diagnostic features and management of Paediatric Inflammatory Multisystem Syndrome (PIMS-TS) temporally related to SARS-CoV-2 infection.

Background

• PIMS-TS [also known as Multisystem Inflammatory Syndrome in Children associated with COVID-19 (MIS-C)] is a rare but severe complication that occurred in around 1 in 3000 children 2-6 weeks following infection with previously circulating variants of SARS-CoV-2.¹ Observed PIMS-TS incidence has been lower following Omicron infection compared with earlier waves.^{2, 3}
• Consider PIMS-TS in the differential diagnosis in children presenting with fever, rash, conjunctival injection, abdominal pain, vomiting/diarrhoea, or shock if they have had proven or suspected COVID-19 in the 2 - 6 weeks prior.
• Some features overlap with Kawasaki disease, toxic shock syndrome and sepsis.¹
• Clinical condition can deteriorate rapidly; early recognition and timely initiation of appropriate therapy is important.
• Most cases of PIMS-TS occur in previously healthy children over the age of 5 years.
• Vaccinated children are significantly less likely to develop PIMS-TS.^{4, 5}

Definitions

There is no international consensus definition for PIMS-TS. The current case definition for PIMS-TS as per the Paediatric Active Enhanced Disease Surveillance (PAEDS) network in Australia is as follows and applies to children and adolescents up to the age of 18 years⁶:

Investigations

Children and adolescents with fever persisting for ≥ 3 days, an epidemiological link to SARS-CoV-2 and clinical features suggestive of PIMS-TS should be investigated as follows:

Figure 1: Suggested approach to the investigation of PIMS-TS

Note: PIMS-TS has overlapping clinical features with other fever and rash syndromes; assessment for and exclusion of other diagnoses is essential

Management Principles

• Because of the potential for rapid deterioration, consultation with and consideration of early transfer to a paediatric hospital with intensive care facilities is recommended for patients with suspected or confirmed PIMS-TS.
• Appropriate supportive management should be commenced and specific measures for hypotension or shock started urgently if required. Early referral to intensive care for institution of monitoring and supportive measures (including respiratory support, inotropes and mechanical cardiovascular support) is essential as deterioration may occur rapidly.
• Collect blood culture(s) and administer empiric antibiotics if features of sepsis are present. Refer to the ChAMP guideline Sepsis and Bacteraemia: Paediatric for empiric antibiotic recommendations.
• Children and adolescents who have suspected PIMS-TS should be discussed and managed by a multidisciplinary team that may consist of members from the following departments including, but not limited to:
  • General Paediatrics
  • Paediatric Cardiology
  • Paediatric Rheumatology
  • Paediatric Infectious Diseases
  • Paediatric Critical Care
• A formal Infectious Diseases consult for all patients with suspected PIMS-TS is strongly recommended to assist with evaluation of other infectious causes of systemic inflammation and to provide advice on treatment where PIMS-TS appears likely.
• Given that Kawasaki disease-like features are more common in patients < 5 years of age, treatment recommendations for PIMS-TS are divided into 2 groups by age⁷:

In children < 5 years of age with PIMS-TS:

In children ≥ 5 years of age with PIMS-TS:

• In all ages, following 3 days of IV methylprednisolone, continue with oral prednisolone 2mg/kg/day (maximum 60mg/day) and wean over 2-3 weeks to reduce the risk of rebound symptoms.
  • Children with mild disease who respond quickly to therapy may be able to cease therapy after 3 days rather than continuing with an oral prednisolone wean.
• Children with a mild illness who can tolerate oral prednisolone can commence therapy with oral prednisolone at 2mg/kg/day (maximum 60mg/day) instead of intravenous methylprednisolone.
• Cardiac follow-up:⁸
  • Children with abnormal troponin at diagnosis should have this laboratory parameter monitored until normalisation.
  • All children should receive baseline 12 lead ECG; continuous monitoring (pulse oximetry) is recommended for all hospitalised children; cardiac telemetry should be used in those with conduction abnormalities or on the advice of Cardiology.
  • Echocardiograms should be repeated (at a minimum) 7-14 days after presentation and at 4-6 weeks. This should include an evaluation of ventricular/valvular function, pericardial effusion and coronary artery dimensions (according to Z-scores). Earlier repeat echocardiogram should be performed in patients with persistently elevated/rising troponins.
  • Consider cardiac MRI in children with significant transient left ventricle dysfunction (ejection fraction <50%) during the acute illness, persistently elevated/rising troponin, or persistent LV dysfunction.
  • Cardiac CT should be considered in patients with suspected distal coronary artery aneurysms that may not be easily observed on echocardiogram.
• Follow up of these children following their admission is recommended to ensure full resolution of symptoms, and that an alternative diagnosis has not emerged.
• Children who have received intravenous immunoglobulin (IVIG) should not receive live vaccines for 11 months after the administration of IVIG due to possible decreased immunogenicity of vaccines.⁹ Vaccination for people who have recently received normal human immunoglobulin and other blood products | The Australian Immunisation Handbook (health.gov.au)A vaccine medical exemption through the Australian Immunisation Register should be completed for relevant patients.

Surveillance

• Surveillance for COVID-19 and PIMS-TS occurs nationally through the Paediatric Active Enhanced Surveillance (PAEDS; RGS0000000960) network https://paeds.org.au/covid-19-kawasaki-disease-kd-and-pims-ts-children.

• To report cases at PCH, contact the Infectious Diseases registrar who will progress the notification.

References and related external legislation, policies and guidelines

1. National Centre for Immunisation Research and Surveillance, Advice for clinicians: PIMS-TS, June 2020, Available from https://www.ncirs.org.au/sites/default/files/2020-06/PIMS-TS%20statement_Final_June%202020.docx.pdf
2. Jonathan M Cohen, Michael J Carter, C Ronny Cheung, Shamez Ladhani, for the Evelina Paediatric Inflammatory Multisystem Syndrome Temporally related to SARS-CoV-2 (PIMS-TS) Study Group, Lower Risk of Multisystem Inflammatory Syndrome in Children With the Delta and Omicron Variants of Severe Acute Respiratory Syndrome Coronavirus 2, Clinical Infectious Diseases, 2022;, ciac553, https://doi.org/10.1093/cid/ciac553
3. Holm M, Espenhain L, Glenthøj J, et al. Risk and Phenotype of Multisystem Inflammatory Syndrome in Vaccinated and Unvaccinated Danish Children Before and During the Omicron Wave. JAMA Pediatr. 2022;176(8):821–823. doi:10.1001/jamapediatrics.2022.22
4. Zambrano LD, Newhams MM, Olson SM, et al. Effectiveness of BNT162b2 (Pfizer-BioNTech) mRNA Vaccination Against Multisystem Inflammatory Syndrome in Children Among Persons Aged 12-18 Years – United States, July-December 2021. MMWR Morb Mortal Wkly Rep 2022;71:52, DOI:http://dx.doi.org/10.15585/mmwr.mm7102e1
5. Levy M, Recher M, Hubert H, et al. Multisystem Inflammatory Syndrome in Children by COVID-19 Vaccination Status of Adolescents in France. JAMA. 2022;327(3):281–283. doi:10.1001/jama.2021.23262
6. Paediatric Active Enhanced Disease Surveillance (PAEDS). Paediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2 (PIMS-TS). December 2022. URL: https://paeds.org.au/surveillance-and-research/pims-ts
7. National COVID-19 Clinical Evidence Taskforce. Australian guidelines for the clinical care of people with COVID-19. 2022 [version 64]. Available from: https://clinicalevidence.net.au
8. Henderson L, American College of Rheumatology Clinical Guidance for multi system inflammatory syndrome in children associated with SARS-CoV-2 and hyper inflammation in paediatric COVID-19 version 3. Arthritis and Rheumatology. 2022. 74, ppe1-20.
9. Australian Technical Advisory Group on Immunisation (ATAGI). Australian Immunisation Handbook, Australian Government Department of Health and Aged Care, Canberra, 2022, immunisationhandbook.health.gov.au

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