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Scottish Paediatric Consensus Treatment Guideline for Covid-19 and related conditions

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Objectives

This guideline summarises case definitions, referral pathway, and treatment options for children in Scotland admitted to hospital with acute Covid-19, or with symptoms consistent with Paediatric Inflammatory Multi-system Inflammatory Syndrome Temporally associated with SARS-CoV-2(PIMS-TS) or Kawasaki Disease (KD). It also outlines eligibility criteria for priority research studies open to children with acute Covid-19, PIMS-TS or KD.

Scope

This is a national consensus guidance document for paediatric units in Scotland produced by the Scottish Hyperinflammatory Multidisciplinary Team (MDT). It is informed by and designed to complement guidance produced by the RCPCH. Some additional guidance has been added based on the recent UK Delphi process[1]. Guidance will be updated as further evidence arises about best practice in the management of paediatric Covid-19 and related conditions. It is not intended as guidance for primary care. Children with symptoms of Covid-19 severe enough to require treatment, and children with a possible diagnosis of KD, should always be referred acutely to secondary care.

NOTE: Published after limited peer review. This message will be removed when review is complete and replaced with a What’s New message highlighting any changes should they be required

1. Case definitions

1.1 Acute Covid-19

The following pragmatic criteria are used to define this clinical patient group for the purposes of this guideline. Note, different case definitions/criteria will be used to indicate community based testing, and hospital testing for infection control purposes.

  1. SARS-CoV-2 PCR positive with symptoms consistent with COVID-19, but not meeting criteria for either PIMS-TS or KD. The most common symptom in children is fever, other symptoms include upper and lower respiratory symptoms, gastrointestinal symptoms, loss of sense of taste or smell, myalgia, fatigue and rash. Presentation in children is non-specific and highly similar to other febrile childhood illness. A high proportion of children may have asymptomatic infection, therefore in some PCR positive children, symptoms may be due to other infections or diseases. It is accepted that there may be some overlap in clinical features of acute Covid-19 and PIMS-TS, but for the purposes of this management pathway, all cases meeting PIMS-TS criteria should be discussed at MDT. Where there is doubt, discuss.
  2. SARS-CoV-2 PCR negative (or result unknown) where there is a high clinical suspicion of severe acute respiratory Covid-19. This would include children presenting with features consistent with acute respiratory distress syndrome without other known cause, particularly where there is a known contact with Covid-19.

1.2 Kawasaki Disease (KD) Criteria

 “Complete” KD is defined according to American Heart Association[2] criteria as :

Fever of at least five days in addition to 4 of 5 additional criteria:

  1. Conjunctivitis: bilateral, bulbar, conjunctival injection without exudate
  2. Lymphadenopathy: cervical, often >1.5cm, usually unilateral
  3. Rash: maculopapular, diffuse erythroderma or erythema multiforme
  4. Changes of lips or oral mucosa: red cracked lips, “strawberry” tongue, or diffuse erythema of oropharynx
  5. Changes of extremities: erythema, and oedema of palms and soles in acute phase; and periungual desquamation in subacute phase.

OR less than 5 days of fever but otherwise meeting all five AHA criteria.

OR less than 5 days of fever with coronary artery aneurysm or coronary dilatation.

1.3 Incomplete KD Criteria

The following definition is adapted from the AHA criteria and has been agreed for use in the KD-CAAP trial.

Children (>1 year old) with fever for ≥5 days AND at least 2 other compatible clinical criteria listed above; OR infants ≤ 1year with fever ≥7 days without other explanation AND (for both age groups) CRP≥30 mg/L or ESR ≥40 mm/h AND

  • EITHER the presence of any 3 or more of: anaemia for age (haemoglobin less than the lower limit of normal laboratory reference range for age); platelet count ≥ 450 x109/L or <140 x109/L; albumin < 30g/L; elevated ALT, WCC <15x 109/L; urine ≥10 WBC per high power field
  • OR abnormal echocardiogram compatible with KD but without established CAA, with ≥3 of the following suggestive features: decreased left ventricular function, mitral regurgitation, pericardial effusion, or dliated but non-aneurysmal coronary arteries

1.4 Paediatric Inflammatory Multisystem Syndrome Temporally associated with SARS-CoV-2 (PIMS-TS)

RCPCH case definition:

  1. A child presenting with persistent fever, inflammation (neutrophilia, elevated CRP and lymphopenia) and evidence of single or multi-organ dysfunction (shock, cardiac, respiratory, renal gastrointestinal or neurological disorder) with additional features (see below). This may include children fulfilling full or partial criteria for Kawasaki disease.
  2. Exclusion of any other microbial cause, including bacterial sepsis, staphylococcal or streptococcal shock syndromes, infections associated with myocarditis such as enterovirus (waiting for results of these investigations should not delay seeking expert advice).
  3. SARS-Cov-2 PCR testing may be positive or negative.

Additional Features in PIMS-TS

Clinical Features:

  • Persistent fever >38.5°C (ALL)
  • Oxygen requirement or hypotension (MOST)
  • Other features include: abdominal pain, confusion, conjunctivitis, cough, diarrhoea, headache, lymphadenopathy, mucus membrane changes, neck swelling, rash, resp symptoms, sore throat, swollen hands and feet, syncope, vomiting

Laboratory

  • abnormal fibrinogen, absence of potential causative organisms (other than SARS-CoV-2), high CRP, high D-Dimers, high ferritin, hypoalbuminaemia, lymphopenia (ALL)
  • neutrophilia in MOST– normal neutrophils in some
  • other features in some patients include: acute kidney injury, anaemia, coagulopathy, proteinuria, raised CK, raised LDH, raised triglycerides, raised troponin, thrombocytopenia, transaminitis

Imaging and ECG

  • Echo and ECG – myocarditis, valvulitis, pericardial effusion, coronary artery dilatation
  • CXR – patchy symmetrical infiltrates, pleural effusion
  • Abdo USS – colitis, ileitis, lymphadenopathy, ascites, hepatosplenomegaly
  • CT chest – as for CXR – may demonstrate coronary artery abnormalities if with contrast

Note: WHO refer to PIMS-TS as Multisystem Inflammatory Syndrome in Children (MIS-C). The WHO case definition is similar, but requires at least 3 days of fever and either evidence of COVID-19 on PCR or serology or a likely contact with COVID-19.

Case definitions are preliminary and subject to change. Check for updates here: RCPCH , WHO

2. Referral pathway

Figure 1: Referral Pathway for possible Hyperinflammatory syndrome 

This guidance outlines the referral pathway for children with signs/symptoms consistent with hyper-inflammatory conditions or PIMS-TS to the Hyperinflammatory Multi-disciplinary Team at the Royal Hospital for Children, Glasgow or Royal Hospital for Sick Children, Edinburgh from paediatric units throughout Scotland. Patients presenting with hyper-inflammatory conditions can be complex; there may be diagnostic difficulties and management can be challenging. These conditions are rare, there is limited trial data to support management decisions and therefore local MDT discussion about diagnostics and management is beneficial. With the recent emergence of a cohort of children, presenting acutely unwell with an inflammatory multisystem syndrome, with some features similar to Kawasaki disease, some similar to toxic shock syndrome and some with features in keeping with macrophage activation syndrome (MAS)/haemophagocytic lymphohistiocytosis (HLH), there is a need for multi-disciplinary team working to manage these children.

MDT referral or discussion should be considered for children presenting with features consistent with any of the case definitions above. Children do not need to fulfil the full case definition to be referred/discussed and discussion about children with pyrexia of unknown origin, Kawasaki disease or evidence of hyper-inflammation without clear cause is encouraged. The urgency of referral, and the members of MDT required for discussion should be determined by clinical status as follows:

2.1 Critically unwell children or children with cardiac features

In paediatric units without PICU on site, where the child is critically unwell and thought to need ScotSTAR transfer, or if there is anticipation that PICU may be required, of if there are cardiac features (any of: elevated troponin (above local lab reference range), abnormal ECG, abnormal echocardiogram or haemodynamic instability), the referral should be through the usual referral pathway to ScotSTAR (Tel 03333 990 222) who will then involve the wider MDT at an appropriate time. ScotSTAR will then decide if the child should be transferred by ScotSTAR or the Scottish Ambulance Service (SAS).

In paediatric units with PICU on site, direct referral to the PICU on call team should be made as per usual pathways and wider MDT discussion can be convened at an appropriate time.

Referral to PICU/ ScotSTAR should be considered when there is:

  • Need for critical care support including: escalating non-invasive respiratory support above that provided comfortably by referring ward/hospital, invasive respiratory support and/or inotropic support or advanced support e.g. renal support or extra-corporeal support (ECMO).
  • Cardiovascular shock not reversed by standard fluid resuscitation.
  • Any deteriorating patient where there is clinical concern that would normally trigger a discussion with PICU.
  • Significant cardiac findings on echocardiogram thought to increase the risk of acute deterioration for the patient.
  • Patients requiring transfer to RHC Glasgow or RHSC Edinburgh out with the above criteria where there is significant concern regarding safe transfer due to likely patient deterioration.

In children with raised troponin (above local lab reference range), abnormal ECG, abnormal ECHO or haemodynamic instability, discussion with the Paediatric Cardiology Consultant on call should also be considered. At the point of referral to cardiology, desired tests include CXR for evidence of cardiomegaly, Echocardiogram (if available), troponin, NT-pro BNP (if available), but this should not delay MDT discussion. Both RHSC Edinburgh and RHC Glasgow have cardiology services, including cardiologist input and echocardiography. Patients requiring specialist cardiac or cardiac ICU services (including ECMO) should be discussed with Glasgow if potential transport is required.

Further information on interpretation of troponin, ECG features of PIMS-TS and cardiology monitoring and management are detailed here:

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

Children with possible hyperinflammatory syndromes referred firstly to PICU/Scotstar should be discussed with the wider MDT as soon as this felt to be appropriate by the PICU/Scotstar team to discuss early treatment options. Specific treatments (for example steroids or IVIG) may be appropriate prior to transfer, and will be considered by the MDT on a case-by-case basis.

2.2 Initial referral discussions for children who are not critically unwell

The referring team should complete the electronic referral document which can be downloaded here:

(Referral xls will be here)

Please note that not all fields on the referral document need to be completed to make an initial referral. In particular, it is likely that not all investigations will be undertaken and some results may be unavailable. The proforma can be used to facilitate the initial referral telephone discussion and MDT. The report from the electronic proforma should be printed for the patient notes, used as part of a transfer letter and scanned into the electronic patient record. The completed form should be emailed to the receiving clinician following the initial referral discussion who can then share with the wider MDT if necessary. The data on the individual electronic proforma will automatically input into a master spreadsheet to facilitate the audit process.

Initial referral should be by telephone to the on-call consultant for either Infectious Diseases (ID) or Rheumatology via switchboard at RHC, Glasgow or RHSC, Edinburgh according to usual regional referral pathways. Broadly speaking, initial discussions should be with ID if differential diagnoses are thought to mainly include acute COVID-19 or other infections, or with Rheumatology if differential diagnoses are thought to mainly include systemic rheumatological or inflammatory conditions. However, given the overlap in differential diagnoses either service welcomes initial discussion.

Following this initial discussion, if there are any high risk features (detailed below), or if agreed by the referring and receiving consultant, a wider MDT is required, as per the flowchart above. This MDT will include the referring consultant, ID and Rheumatology, and may include PICU/Scotstar or cardiology as per guidance above.

High risk features which should prompt a wider urgent MDT include:

  • Kawasaki disease (KD) not responding to IVIG within 24hrs, with low platelets, or in infants< 1year or >6 years
  • Non KD presentation with unexplained high inflammation markers
  • Increasing oxygen requirement
  • SARS-COV-2 PCR positive
  • Evolving HLH/MAS picture, defined as fever and ferritin>500 with any 2 of:
    • Hb<90 or platelets <150
    • WCC <4.9 or >16, or Neut/Lymph <1.0
    • ALT >3x upper limit of normal (ULN) or Albumin<25
    • LDH or CK >1.5x ULN
    • Triglyceride >1.5x ULN
    • Low or falling fibrinogen
    • CRP or ESR >2x ULN
    • ESR disproportionately low or falling

The MDT discussion will be arranged via Microsoft teams by the consultant receiving the initial referral, or via Scotstar if the child is critically unwell.

Children who are stable and require transfer for specialty input/investigation do not require ScotSTAR and should be transferred by SAS.

3. Treatment options

Figure 2: Treatment algorithm for acute Covid-19, KD and PIMS-TS

Treatment options for acute Covid-19, KD and PIMS-TS are summarised in Figure 1.  Treatment should where possible be undertaken as part of a clinical trial, and discussed with a Paediatric Infectious Diseases specialist. For PIMS-TS and Incomplete KD in the context of the SARS-CoV-2 pandemic, treatment should be discussed with the Scottish Hyperinflamatory MDT (see details for referral pathway below). The options by age and clinical presentation are as follows:

3.1 Acute Paediatric Covid-19

Respiratory phenotype - Mild disease

Supportive care only.

Respiratory phenotype - Moderate disease

WHO criteria for steroid treatment includes patients with ANY of saturations <90% in air, tachypnoea (RR >30 in children >5 years, ≥40 in children 1-5 years, ≥50 in children 2-11 months or ≥60 in infants <2months), or signs of severe respiratory distress[3]. Although not all these patients would meet RCPCH criteria for severe disease, early steroid treatment can be considered in this group, particularly if they are deteriorating.

Respiratory phenotype - Severe or critical disease

On the basis of adult trial data, for severe or critical diseases (defined by RCPCH as >40% (5l/min) O2, high flow, non-invasive or invasive respiratory support), dexamethasone is now standard of care in infants and children over 44 weeks corrected gestational age.

For neonates and preterm infants <44 weeks corrected gestational age, it is considered there is still clinical equipoise for steroid use. These infants should ideally be recruited to the RECOVERY trial, 1st randomisation 1a low-dose hydrocortisone versus (vs) standard of care (SOC) with or without 1b convalescent plasma.

Older infants and children ≤12 years can be recruited to RECOVERY, 1st randomisation 1b convalescent plasma, vs SOC. Children over 12 can be randomised to RECOVERY 1st randomisation 1b convalescent plasma vs REGN-COV2 (monoclonal antibody) in participating sites. Note, REGN-COV2 cannot be given out of hours, including at weekends and availability is limited. Always check availability before randomising to this option. However, use of these novel treatments should be discussed with the Paediatric ID team (see additional notes on convalescent plasma and REGN-COV2 below)

Children over 1 year old recruited to RECOVERY, not improving after initial treatment, can be considered for the 2nd randomisation to Tocilizumab. Eligibility criteria for randomisation to Tocilizumab as part of the RECOVERY trial are:

  • Randomised into the trial no more than 21 days ago.
  • Clinical evidence of progressive Covid-19 : a. Oxygen saturation<93% in air or requiring oxygen (or in children <18 years significant systemic disease with persistent pyrexia , with or without evidence of respiratory involvement) AND CRP≥75 mg/L.

Remdesivir is licensed in hospitalised patients in oxygen, over 12 years and over 40kg. Remdesivir can also be given on a compassionate basis to younger children. Remdesivir should not be given without discussion with the Paediatric ID team (see notes below).

SARS-CoV-2 PCR negative children where there is a high clinical suspicion of acute severe respiratory Covid-19 should be treated in the same way as PCR positive children as above. They are also eligible for the RECOVERY trial.

Compression stockings and low molecular weight heparin (LMWH) prophylaxis should be considered in unwell children who are immobile or have other risk factors for thrombosis (eg obesity, known or family history of pro-thrombotic condition, teenagers). Follow local guidance for LMWH prophylaxis dosing and monitoring.

Additional notes on Remdesivir

Remdesivir is currently the only licensed anti-viral therapy for SARS-CoV-2 (license limited to >12 years and >40kg, with acute respiratory Covid-19 in oxygen). It appears to be safe and well tolerated. It is expensive (approx £2000 per course). Evidence of benefit of Remdesivir is limited. Initial randomised trial data from Gilead  (n=541 recieved remdesivir) suggested a slightly shorter median recovery time of 10 days (95% confidence interval [CI], 9 to 11) with Remdesivir, as compared with 15 days (95% CI, 13 to 18) with placebo[4]. However, recent data from the larger WHO Solidarity trial (n=2750 assigned remdesivir) found no evidence of benefit in progression of symptoms or duration of stay[5]. Neither study demonstrated any mortality benefit. Further studies of of remdesivir in early/mild disease or as prophylaxis are awaited. At present, we consider that given the lack of evidence of significant benefit, use of remdesivir in children should be restricted to children at high risk of severe disease (for example immunosuppression) and should only be considered after discussion with Paediatric ID. This recommendation may change as data emerge.

Additional notes on convalescent plasma and REGN-COV2

Convalescent plasma and REGN-COV2 ( a monoclonal antibody cocktail targeting the SARS-CoV-2 spike protein) are currently only available for the treatment of acute COVID-19 as part of the RECOVERY trial, and are not available in all trial sites. The safety profile of these treatments in children is unknown, although both appear safe in adults to date. REGN-COV2 is only available to children over 12 years old and weighing over 40kg. There are additional concerns regarding use of convalescent plasma in children, due to concerns that PIMS-TS may be antibody mediated. We would advise at present that use of these treatments should be discussed with Paediatric ID.

Non-respiratory phenotype

In children with non-respiratory Covid-19 symptoms, who do not meet criteria for PIMS-TS or KD, no specific treatment is indicated. The only exception is in neonates or preterm infants <44 weeks corrected gestational age with shock, sepsis like presentation, multi-system organ failure or encephalopathy, where treatment can be considered as part of the RECOVERY trial as above.

Table 1: Paediatric Drug Treatments for Acute Covid-19

Drug for treatment of acute Covid-19

Route of administration

Dose

Treatment duration

Remdesivir

IV

<40kg (compassionate use) 5mg/kg loading dose, then 2.5mg/kg od

≥ 40kg (licensed use if >12years)

200mg loading dose then 100mg od

Total 5 days

Hydrocortisone

IV

Neonates and infants with CGA<44weeks (ideally as part of RECOVERY trial)

0.5mg/kg bd for 7 days then od for 3 days

Total 10 days

Dexamethasone

IV/NG/oral

Infants with CGA ≥44 weeks and children

0.1 mg/kg (as base) up to a maximum of 6mg once daily

 

For 10 days or until discharge

Tocilizumab

IV

(2nd line only as part of RECOVERY trial, only in children >1 year old)

<30kg 12mg/kg single dose

≥30kg 8mg/kg single dose (max 800mg)

A second dose may be given ≥12 and ≤24 hours later if the patient’s condition has not improved

1-2 doses only

 

3.2 “Complete” Kawasaki disease

Children who meet full criteria for KD, as defined above, should be treated in accordance with standard KD guidelines with IVIG 2g/kg, high dose aspirin, and cardiac follow up. Children with KD admitted to RHC, Glasgow may be considered for the KD-CAAP trial (which randomises to IVIG with or without early steroid treatment). The paediatric sub-group of RECOVERY has advised that children with complete KD are not the target group for recruitment to the RECOVERY trial.

Consideration may be given to steroids, repeat IVIG or biologic treatments in certain high risk groups or in children failing to respond to initial treatment (https://adc.bmj.com/content/99/1/74)[6].

Various steroid regimes have been used in KD. For simplicity, we recommend the dosing in Table 2, which is the regime recommended in the KD-CAAP trial.

Biological treatment should be considered as third line in children not responding to treatment with IVIG and steroids, and the decision to give a biological treatment should be made by the MDT. Infliximab is generally the preferred 1st line biological therapy.

3.3 Incomplete Kawasaki Disease

Children who meet AHA criteria for incomplete KD as defined above should be treated with IVIG, high-dose aspirin and cardiac follow-up in accordance with standard KD guidelines. Given the overlap with non-specific PIMS-TS and other conditions, children with Incomplete KD should ideally be discussed at MDT to agree that criteria for this diagnosis are met. In Glasgow, they should be considered for the KD-CAAP trial.

In other centres, children with incomplete KD thought to be associated with SARS-CoV-2 (i.e contact history, positive serology) may be considered for recruitment to the RECOVERY-PIMS-TS trial (steroids versus standard of care) after IVIG has been given. Note that the methylprednisolone dose (10mg/kg once daily) used in the RECOVERY trial differs from the KD regime in Table 2. This dose has been used in KD and incomplete KD [6] but usually followed by a weaning dose of prednisolone. However, it should be noted that evidence for specific steroid regimes in KD is limited. In children recruited to RECOVERY additional treatments, such as a second dose of IVIG, or a longer course of steroids, can be given according to clinician preference, but must be recorded as “off protocol” treatments.

Biological treatment should be considered as third line in children not responding to treatment with IVIG and steroids, and the decision to give a biological treatment should be made by the MDT. Children recruited to RECOVERY who require biological treatment can be considered for the 2nd randomisation to Tocilizumab. For children not recruited to RECOVERY, Infliximab is the preferred 1st line biological therapy. Outside the RECOVERY trial, dosing of biological therapy should be follow existing local guidance and be agreed at MDT.

Table 2: Paediatric dosing for drug treatment for KD

Drug for treatment of KD

Route of administration

Dose

Treatment duration

Immunoglobulin

IV

2g/kg once only. See additional prescribing guidance in main text for obese children

Can be repeated if not improving after 48 hours after discussion with MDT

Single dose

Corticosteroids

IV/PO

Prednisolone 2mg/kg/day or IV methylprednisolone equivalent (1.6mg/kg/day) for 5 days

If afebrile and CRP≤10 mg/L by day 5 reduce to 1mg/kg prednisolone/ day for 5 days

Then 0.5mg/kg prednisolone/day for 5 days then stop

Minimum 15 days (wean according to response)

Aspirin

PO

High dose 7.5-12.5mg/kg/qds

then

Low dose 2-5mg/kg/day once daily

Until disease defervescence

For mininum 6 weeks

Tocilizumab

IV

(2nd line ideally as part of RECOVERY trial, only in children >1 year old)

<30kg 12mg/kg single dose

≥30kg 8mg/kg single dose (max 800mg)

A second dose may be given ≥12 and ≤24 hours later if the patient’s condition has not improved

1-2 doses only

 

3.4 Non-specific PIMS-TS

Given the overlap with other conditions, children with suspected non-specific PIMS-TS should be discussed at MDT to agree the diagnosis and treatment plan. Children with an agreed diagnosis of PIMS-TS should be considered for recruitment to the RECOVERY trial for 1st randomisation to IVIG/steroids/standard of care. In children with severe or critical disease, treatment can be considered prior to randomisation. First line treatment in severe/critical disease would be methylprednisolone. This has been chosen for pragmatic reasons as it is simpler and faster to administer prior to transfer in critical patients than IVIG and has less volume. Children given steroids prior to recruitment to RECOVERY should be randomised to IVIG/standard of care only. Any additional “off protocol” treatments given after randomisation should be recorded. Children should be given empiric broad spectrum antibiotic cover with ceftriaxone until severe bacterial infection can be excluded. Children with features of toxic shock syndrome should also be given clindamycin. IV fluid boluses should be used in increments with close assessment of response given the risk of cardiac complications. Compression stockings and Low molecular weight heparin (LMWH) prophylaxis should be considered in unwell children who are immobile or have other risk factors for thrombosis (eg obesity, known or family history of pro-thrombotic condition, teenagers). Low-dose aspirin should be given to all children with a diagnosis of PIMS-TS for at least 6 weeks.

In children failing to improve after 24 hours, additional treatment with IVIG or steroids may be considered. Biological treatment should be considered as third line in children not responding to treatment with IVIG and steroids, and the decision to give a biological treatment should be made by the MDT. Children recruited to RECOVERY who require biological treatment can be considered for the 2nd randomisation to Tocilizumab. There is clinical equipoise for the preferred biological treatment in children not recruited to RECOVERY – tocilizumab, anakinra, or infliximab may be considered. The MDT has some experience in the use of Anakinra, with dosing otlined in Table 3. Outside the RECOVERY trial, dosing of biological therapy should be follow existing local guidance and be agreed at MDT.

Table 3: Paediatric dosing for drug treatment for non-specific PIMS-TS

Drug for treatment of non-specific PIMS-TS

Route of administration

Dose

Treatment duration

Methylprednisolone

IV

Dose if randomised as part of RECOVERY trial: 10mg/kg once daily (max 1g). A maintenance/weaning dose of steroids is not recommended as part of the RECOVERY trial, but can be considered if felt clinically necessary by MDT (see below)

Consider higher dose of 30mg/kg/day for patients requiring inotropic support, followed by daily oral prednisolone 1mg/kg (max 4mg) to be weaned over 2-3 weeks. IV methylprednisolone can be given when concerned regarding GI absorption.

3 days

 

 

 

 

 

2-3 weeks

 

Immunoglobulin

IV

2g/kg once only. See additional prescribing guidance in main text for obese children

Can be repeated if not improving after 48 hours after discussion with MDT

Single dose

Tocilizumab

IV

(2nd line ideally as part of RECOVERY trial, only in children >1 year old)

<30kg 12mg/kg single dose

≥30kg 8mg/kg single dose (max 800mg)

A second dose may be given ≥12 and ≤24 hours later if the patient’s condition has not improved

1-2 doses only

Anakinra

SC

2nd line. Consider in severely ill children or those failing to respond to combination of steroids and IVIg particularly in conjunction with high or rapidly rising ferritin.

2mg/kg once daily dose. Can be increased to 4mg/kg or 2mg/kg BD. Short half life (4hrs).

If response appears good continue once daily dosing until clinically stable and ferritin <500. Then consider reducing daily dose to 1mg/kg for 3 days before stopping.

See note

Anakinra

IV

For patients on significant doses of vasoconstricting inotropes or with reduced cardiac function to the point where subcutaneous perfusion may be impaired Anakinra is best given as an IV infusion.

Commence with a loading dose of 2mg/kg followed by a continuous infusion of 2mg/kg/24hours. This can be increased to 4mg/kg/24hrs if required. If response appears good consider switching to SC route when concerns regarding peripheral perfusion have resolved.

Switch to SC route when peripheral perfusion normalised

Aspirin

oral

Low dose 2-5mg/kg once daily

For minimum 6 weeks

 

3.5 Special considerations in treatment dosing

3.5.1 Obesity

In children with severe obesity, dosing of IVIG should be based on the 91st centile weight for age from the WHO/RCPCH growth centile chart, rather than actual body weight (other methods to estimate ideal weight exist, but this pragmatic approach avoids the need to measure height in very unwell children). For other drugs, care should be taken to adhere to maximum dosing.

3.5.1 Renal and Hepatic Impairment

Aspirin should be used with caution in mild-moderate renal and hepatic impairment, and avoided in severe impairment. Tocilizumab should be used with caution in renal and hepatic impairment, and renal function should be monitored closely. Treatment in these cases should be discussed at MDT with input from a specialist paediatric pharmacist.

4. Follow-up

Discharge may be considered when children have been afebrile for at least 24 hours and have stable cardiac function. Children with KD and Incomplete KD should have follow-up as per standard guidelines. As a minimum, children with PIMS-TS should have follow-up 1-2 weeks post discharge, and further follow-up 6 weeks after discharge. Low-dose aspirin should be continued in children with PIMS-TS until the 6 week review. Cardiology follow-up is outlined in the guideline above. Longer term antiplatelet/anticoagulation in children with coronary artery abnormalities should be discussed with cardiology/haematology.

5. MDT Peer Review

A database of all referrals will be maintained by the Scottish Hyperinflammatory Syndrome MDT. All referred cases of PIMS-TS and complex cases of KD will be discussed for the purposes of peer review and sharing experiences at the Scottish Hyperinflammatory Syndrome MDT meeting. This is currently held monthly, but may be held more frequently if case number rise. To join the mailing list for this meeting, or to suggest cases or topics for discussion, please email mary.glen@nhs.scot

6. Recruitment to Research Studies

6.1 ISARIC-4C

All children hospitalised with confirmed Covid-19 or PIMS-TS should be ideally be recruited to the ISARIC-4C (https://isaric4c.net) study which is an international observational study aiming to characterise clinical features and outcomes of Covid-19[7]. The RCPCH strongly recommends all paediatric units contribute to this study which has been prioritised by Public Health Scotland. Data collected by ISARIC-4C is also shared with WHO surveillance projects, therefore data does not need to be submitted to both.

Tier 0 of this study (sometimes referred to as CO-CIN), which collects only anonymised routine clinical data, does not require consent. Any child with confirmed or clinically diagnosed Covid-19 is eligible for Tier 0. Data is collected in most centres by research nursing teams. Tier 0 data can be collected retrospectively.

Patients with PIMS-TS, patients with SARS-Cov-2 co-infection (eg with RSV or Influenza), and patients with confirmed re-infection with SARS-COV-2,  are eligible for ISARIC-4C Tier 1 and 2, which collects additional blood and bodily fluid samples for research purposes and requires consent. This should be obtained by the local study team.

PICU patients can also be recruited to a sister study, the ISARIC GenOMICC study looking for the genetic basis of severe Covid-19 disease. Each recruiting site should have guidance on their own recruitment pathway.

6.2 RECOVERY

The RECOVERY trial is the largest collaborative UK trial of treatment for Covid-19. It is a pragmatic, adaptive open-label randomised controlled trial. RCPCH recommends that at present treatment for children for Covid-19 should ideally be given as part of the RECOVERY trial. It is therefore recommended that all paediatric admission units in Scotland become sites for RECOVERY. Any clinician who completes the RECOVERY trial training videos (and confirms this by electronic form on the website) can consent for and recruit to RECOVERY (https://www.recoverytrial.net/for-site-staff). All consent and assent forms can be downloaded and a link to the online randomisation system is here: https://www.recoverytrial.net/for-site-staff/randomisation Medicines can be prescribed by any qualified practitioner (i.e nurse or pharmacist prescriber, doctor) and given by any qualified person. They do not need to be given by the research team. Neonates and children with acute Covid-19 may be recruited to RECOVERY within their local units if considered appropriate by the responsible Consultant Paediatrician. We would recommend use of convalescent plasma or REGN-COV2 in children is discussed with Paediatric ID. All children with possible KD/PIMS-TS in Scotland should be discussed with the Hyper-inflammatory MDT before recruitment to RECOVERY.

6.3 KD-CAAP

The KD-CAAP trial is a European multicentre, randomised, open-label, blinded endpoint assessed trial of corticosteroids plus IVIG and aspirin, versus IVIG and aspirin for prevention of coronary artery aneurysm in Kawasaki disease (https://www.ctu.mrc.ac.uk/studies/all-studies/k/kd-caap/). In Scotland, this trial is currently only recruiting in Glasgow, as there were limits to the number of centres within a single country which could recruit. Aberdeen is a reserve centre and may recruit at a later date. Children from other centres should not be transferred to Glasgow for the sole purpose of entering this trial, but if transferred there for other reasons may be eligible. Patients who may be eligible for KD-CAAP in Glasgow should be discussed with the ID or Rheumatology consultant on call.

References
  1. Harwood R, Allin B, Jones CE, et al. A national consensus management pathway for paediatric inflammatory multisystem syndrome temporally associated with COVID-19 (PIMS-TS): results of a national Delphi process. Lancet Child Adolesc Health 2020.
  2. McCrindle BW, Rowley AH, Newburger JW, et al. 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-e99.
  3. Lamontagne F, Agoritsas T, Macdonald H, et al. A living WHO guideline on drugs for covid-19. BMJ 2020; 370: m3379.
  4. Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the Treatment of Covid-19 - Final Report. The New England journal of medicine 2020.
  5. WHO SOLIDARITY Trial Consortium. Repurposed antiviral drugs for COVID-19; interim WHO SOLIDARITY trial results. The New England Journal of Medicine. 2020.
  6. Eleftheriou D, Levin M, Shingadia D, Tulloh R, Klein NJ, Brogan PA. Management of Kawasaki disease. Arch Dis Child 2014; 99(1): 74-83.
  7. Swann OV, Holden KA, Turtle L, et al. Clinical characteristics of children and young people admitted to hospital with covid-19 in United Kingdom: prospective multicentre observational cohort study. BMJ 2020; 370: m3249.
Editorial Information

Last reviewed: 30 October 2020

Next review: 30 October 2021

Author(s): Dr Louisa Pollock; Dr Kirsty McLellan

Version: 3