Since December 2019, the world has faced the most significant pandemic for over a century. As of September 2021, severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) has infected more than 230 million people worldwide, resulting in more than 4.7 million deaths.1 In Australia, strict isolation and quarantine measures have resulted in a comparatively low incidence of infections by global standards. Nonetheless, subsequent waves are requiring substantial additional lockdown measures to control viral spread. To date, there have been more than 100 000 confirmed SARS‐CoV‐2 infections and more than 1200 related deaths in Australia.2 There have been over 25 000 children and adolescents aged less than 19 years infected with SARS‐CoV‐2 in Australia (a quarter of all cases of SARS‐CoV‐2 infection). The infection rate in 0–19‐year‐old children was 434 per 100 000, with one death reported in this age group in Australia, compared with 420 per 100 000 in adults.2
Although the recent deployment of vaccines internationally provides grounds for optimism, SARS‐CoV‐2 and its variants appear likely to remain threats to human health for years to come.3 Researchers, clinicians and governments have quickly realised that establishing evidence for treatment and prevention is key to guiding patient care, not only in the coronavirus disease 2019 (COVID‐19) pandemic but also in future pandemics. Clinical guidelines in the context of rapidly emerging evidence must be continually updated and tailored to specific populations, including children and adolescents.
COVID‐19 in children and adolescents
Initial reports on the incidence of COVID‐19 in China noted a limited number of severe cases and hospitalisations in children.4 Larger international cohorts have confirmed that, in general, children have a much less severe acute form of the disease compared with adults, especially older adults.5,6 However, SARS‐CoV‐2 infection can cause severe respiratory complications in children, especially in neonates and infants.5,6 Other groups who appear disproportionately affected include children from minority ethnic groups in the United Kingdom and the United States5,7 and children with comorbidities.5 A review of COVID‐19 mortality in children (> 8700 deaths worldwide as of May 2021)8 showed larger fatality rates in lower and middle‐income countries compared with higher income countries. The prevalence and severity of the disease for children and adolescents is likely to increase with the emergence of SARS‐CoV‐2 variants that affect younger people, such as the Delta strain.9
In early 2020, in addition to descriptions of acute COVID‐19 in children, researchers in France10 and the UK11 reported a sudden increase in cases of apparent Kawasaki disease, including atypical presentations. This increase in paediatric inflammatory syndromes, later reported in the US and elsewhere, has now been recognised as temporally and causally associated with SARS‐CoV‐2 infection.12 It has been termed paediatric inflammatory multisystem syndrome (PIMS‐TS) or multisystem inflammatory syndrome in children (MIS‐C).13,14 Although it has certain similarities with Kawasaki disease, differences in epidemiology and clinical features have cemented its current status as a distinct syndrome.15,16
The Australian response: the formation of a national taskforce
The Australian Living Evidence Consortium is a world leader in the development of living guidelines.17 In March 2020, during the first wave of infection in Australia, the National COVID‐19 Clinical Evidence Taskforce was established to produce living recommendations on the clinical care of people with COVID‐19 in Australia, bringing together representatives from the peak health professional bodies whose members are providing clinical care to people with COVID‐19. The Taskforce employs over 20 dedicated staff and involves more than 250 experts across all spheres of health care (average 360 volunteer hours per week). To develop recommendations specific to paediatric COVID‐19 care, the Taskforce established a Paediatric and Adolescent Care (PAC) Panel. This Panel currently comprises 15 paediatric experts (53% women) from New South Wales, Victoria, Queensland, South Australia, Western Australia and the Northern Territory, including an Indigenous representative supported by the National Aboriginal Community Controlled Health Organisation, and representation from urban, rural and remote areas.
Methods
The living guidelines have been developed according to the Australian National Health and Medical Research Council (NHMRC) standards, including the use of Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. The Taskforce uses the MAGICapp platform (https://magicevidence.org/) and its Evidence to Decision framework.18 The guidelines were first approved by the NHMRC on 23 November 2020. Complete guideline methods are available online.19,20 No primary data from human subjects were collected and, therefore, formal ethics approval was not sought.
Methodology issues specific to children and adolescents
Specific challenges to the provision of reliable guidance for the management of children and adolescents arise from the fact that this population is not routinely included in clinical trials.21 Given the paucity of paediatric data, it was decided to include trial evidence from the adult population when considering paediatric recommendations. The PAC Panel noted that clinicians providing care for children and adolescents are familiar with this approach, including reviewing literature for safety and pharmacokinetic data in children, and extrapolating efficacy data from adult populations. Importantly, the resultant recommendations emphasise that rigorous clinical trials in paediatric populations are needed to establish strong evidence for interventions.22
As the guidelines used GRADE23 methods, the Panel downgraded the certainty of the evidence for the outcomes of interest by one step (due to serious indirectness) if the studies being considered did not include children or adolescents. When no trial evidence in adults was available, the Panel decided to produce consensus recommendations based on best practice, data from similar conditions or treatments, and expert consensus.
As living guidelines, these recommendations are updated as new evidence, either from adults or children and adolescents, becomes available. The Taskforce’s evidence team conducts daily searches for relevant population, intervention, comparison and outcomes (PICO) questions, constructed by and reviewed with the relevant panels meeting regularly to consider their findings.
For the development of PIMS‐TS‐specific recommendations, the Taskforce convened an expert advisory group to provide additional expertise to the PAC Panel. Experts in Kawasaki disease and related conditions advised the panel on this novel syndrome. As there was no evidence from clinical trials available for this condition, the Panel considered additional sources, including international, peer‐reviewed guidelines and large, multicentre cohort studies reporting on PIMS‐TS or MIS‐C. The Panel then formulated consensus recommendations pending new, higher quality evidence, which will be reviewed as it becomes available.
Consumer input
The Taskforce, in collaboration with the Consumers Health Forum of Australia, convened a consumer panel beginning in June 2020, including members who were parents (including of children with health care needs) and/or involved in child advocacy, but no children or adolescents. This panel reviewed all PAC Panel recommendations, provided feedback and advised on the preferences and values of children, adolescents and their families and carers when formulating recommendations for the care of children and adolescents.
Pregnancy and perinatal care
For those recommendations involving newborn care and pregnancy and perinatal health care, collaborative discussions were held between the PAC Panel and the Pregnancy and Perinatal Care Panel to reach consensus. Recommendations for pregnancy and perinatal care have been recently published.24
Governance and review
Draft recommendations from the PAC Panel are reviewed and approved sequentially by the National Guidelines Leadership Group and the Steering Committee, which include representatives from the 32 Australian stakeholder organisations endorsing the guidelines.25 The structure of the National COVID‐19 Clinical Evidence Taskforce is shown in the online Supporting Information (figure 1).
Recommendations
Overarching principles
The overarching principles are detailed in the online Supporting Information (table 1). In general, our recommendations are aimed towards children under 16 years of age. The decision to apply paediatric or adult recommendations should be guided by consideration of the physical and developmental maturity of individual patients. The term “child” also includes infants and neonates unless otherwise specified. The following recommendations are current as of 20 August 2021; any updates since publication are available at https://covid19evidence.net.au/.
Definition of disease severity
Box 1 provides the definitions of COVID‐19 severity in children and adolescents (consensus recommendation). Cardiorespiratory and vital parameters must be considered within the normal age‐appropriate ranges for neonates and children, and/or any pre‐existing illness.
Disease‐modifying treatments for COVID‐19
Disease‐modifying treatment recommendations for children and adolescents are shown in Box 2 and in the online Supporting Information (table 2), and the supporting evidence is summarised below.
Corticosteroids
Evidence informing these recommendations comes from a recent meta‐analysis28 of seven randomised controlled trials of patients with critical COVID‐19;29,30,31,32,33,34,35,36 one study of patients with moderate, severe and critical COVID‐19;26 and one study of patients with severe COVID‐19.36
Evidence indicates that corticosteroids reduce deaths in adult patients with critical or severe COVID‐19, but may increase deaths in adult patients with moderate COVID‐19. Although these trials did not include children, due to a reduction in death along with no important resource implications and the likely acceptability of these drugs, we recommend considering using corticosteroids in children and adolescents with COVID‐19 who are receiving oxygen, including mechanically ventilated children.
Remdesivir
Evidence supporting this recommendation comes from four randomised controlled trials that compared remdesivir with standard care in over 7300 adults hospitalised with COVID‐19.37,38,39,40
Given the absence of children or adolescents in any of these trials, as well as concerns about how applicable this evidence is for the paediatric population (low certainty of the evidence due to serious indirectness), the PAC Panel considered that the potential benefits of remdesivir may not outweigh the harms, and that more research is needed in children and adolescents.
Tocilizumab
The evidence supporting the use of tocilizumab comes from ten randomised trials that compared tocilizumab with standard care in 6570 adults hospitalised with COVID‐19. The majority of data are from the RECOVERY trial, which included 4116 adults hospitalised with moderate to critical COVID‐19.26Evidence indicates that tocilizumab probably reduces the risk of death in hospitalised adults who require supplemental oxygen, as well as reducing the need for invasive mechanical ventilation and admission to the intensive care unit. Given this evidence, the previous experience on using tocilizumab in children plus the absence of trials in children and adolescents, the PAC Panel formulated a conditional recommendation supporting the use of tocilizumab in children and adolescents.
Treatments not recommended (strong recommendations against) and/or only recommended in trials
The Taskforce has issued a further 45 recommendations on a wide range of disease‐modifying treatments (Box 2 and online Supporting Information, table 2). Full evidence summaries are available at https://app.magicapp.org/#/guideline/L4Q5An/section/L0OPkj.
Other treatments recommendations: venous thromboembolism prophylaxis
In the adult population, there has been concern of an increased risk for venous thromboembolism.41 Paediatric guidelines published in the US in 2020 recommended a modified approach to thromboprophylaxis in children.42 The PAC Panel currently considers that the evidence is insufficient to modify well established protocols of thromboprophylaxis in children and adolescents (Box 2 and online Supporting Information, table 2).
Respiratory support in neonates, children and adolescents
The paediatric population is particularly vulnerable to respiratory failure due to viral infection.43 At the commencement of the COVID‐19 pandemic, the roles of many established and evidence‐based critical care respiratory support approaches were questioned due to the risk of infection of staff, patients and carers from aerosol generation. The Taskforce evaluated a diverse range of respiratory therapies, including non‐invasive ventilation, management of the deteriorating child (including intubation and approaches to intubation), prone positioning, mechanical ventilation strategies and the use of high frequency oscillatory ventilation and extracorporeal membrane oxygenation.
The Taskforce has formulated ten recommendations on the management of respiratory support in children and adolescents (Box 3). There is currently no primary evidence on the benefits and harms of any of the respiratory support approaches in children and adolescents with COVID‐19. Therefore, the PAC Panel relied on consensus and previous experience to issue these recommendations, noting that many of these therapies have established evidence, or are considered best practice, in other conditions with similar pathophysiology to COVID‐19, or are designed for disease processes that are known complications of COVID‐19 (such as acute respiratory distress syndrome). Recommendations for the use of neuromuscular blockers and videolaryngoscopy were adapted from the evidence used in recommendations for adults, with specific commentary to reflect the equity, access and training limitations for these therapies in children.
Paediatric inflammatory multisystem syndrome
The panel reviewed all available definitions and reached consensus on endorsing the provisional case definition for PIMS‐TS from the UK Royal College of Paediatrics and Child Health,13 but also reviewed published articles using other common definitions, including MIS‐C in the US.12,44 This approach was considered suitable for reviewing global evidence and translating it to an Australian context. The panel also noted the initial definition and advice produced in the Australian context by the Paediatric Active Enhanced Disease Surveillance (PAEDS) network and the Royal Australasian College of Physicians.45 The defining features of PIMS‐TS are summarised in the online Supporting Information (table 3).13 The recommendations for PIMS‐TS management are informed by an ongoing living systematic review and evidence surveillance that includes observational studies, systematic reviews and meta‐analyses as well as international guidance. Box 4 provides specific recommendations for the management and treatment of PIMS‐TS.
Discussion
Developing paediatric evidence‐based recommendations during a global pandemic has proven difficult and has produced unique challenges compared with other population groups. Traditionally, children have been excluded from clinical trials and this has remained the case for many COVID‐19 therapies.54 The Taskforce needed to rely on trial data from adults to formulate recommendations for children, with the well known limitations and risks of extrapolation this brings.55 The need to consider certain paediatric subpopulations separately, such as neonates and adolescents, amplified this problem. Pragmatic adaptive trials such as RECOVERY26 and WHO Solidarity38 have proven to be successful methods of providing timely evidence; these trial designs could be applied to children and adolescents. Where high quality trial data do not exist, robust observational data are needed. Several established, and newly formed, prospective, multinational collaborations focusing on paediatric populations are providing rapid and useful information, especially when managing less frequent conditions such as PIMS‐TS. In the Australian context, this includes initiatives such as the PAEDS network and the Australian and New Zealand Paediatric Infectious Diseases Group of the Australasian Society of Infectious Diseases.
Balancing the importance of providing the best therapy to a patient against the risks that it may pose to health care workers has been problematic during the COVID‐19 pandemic. This was particularly relevant for the development of respiratory recommendations for children and adolescents. Non‐invasive therapies were well established before the COVID‐19 pandemic and were based on a sound evidence base in paediatric critical care. Due to the high aerosol‐generating potential of non‐invasive therapies, this was questioned at the start of the pandemic, despite the higher morbidity profile associated with invasive therapies. These considerations, together with the lower total oxygen flow rates delivered to children compared with adults, were important in the recommendation to use non‐invasive ventilation and high flow cannulae when appropriate infection control measures could be applied. Another important consideration is that dedicated paediatric critical care, especially invasive respiratory support, is highly centralised in Australia. This creates greater inequity in resource allocation (equipment and airway expertise) in rural and remote areas compared with adult populations.
Although it is not the primary objective of the Taskforce, concerns were raised by the PAC Panel regarding the impact that COVID‐19 measures could have on wellbeing and psychosocial and developmental factors in children and adolescents, such as closures of schools and childcare services.56 The potential impact of emerging aspects of the COVID‐19 pandemic, such as “long COVID‐19” and SARS‐CoV‐2‐specific vaccinations, also need to be considered in children and adolescents. Development and psychosocial wellbeing of children affected by COVID‐19 should be included as outcome measures in future research.
Conclusion
The Taskforce has successfully produced timely, evidence‐based living guidelines for Australian clinicians (and beyond) managing COVID‐19 in children and adolescents. The strength of diverse representative voices with the inclusion of different Australian health care and consumer stakeholders has enabled a values‐driven and evidence‐based approach. The evidence landscape is changing rapidly, and the guidelines will continue to adapt to this change. We encourage those who care for infants, children and adolescents affected by COVID‐19 to keep up‐to‐date at https://covid19evidence.net.au/.
Box 1 – Definitions of disease severity for children and adolescents with acute coronavirus disease 2019 (COVID‐19)*
|
Disease severity |
Feeding, hydration, conscious state |
Respiratory and vital signs |
Oxygen requirement† |
||||||||||||
|
|
|||||||||||||||
|
Mild |
|
|
|
||||||||||||
|
Moderate |
|
|
|
||||||||||||
|
Severe |
|
|
|
||||||||||||
|
Critical |
|
|
|
||||||||||||
|
|
|||||||||||||||
|
MET = medical emergency team; SpO2 = peripheral oxygen saturation. * Depending on the physical size and/or developmental status of the patient, either the paediatric or adult severity grading can be applied. † Oxygen saturation targets should be modified for patients with cyanotic heart disease. ‡ Temperature instability should be considered an abnormal vital sign in infants. Fever is common in children and does not contribute to determination of illness severity in isolation. § Infants and neonates < 4 kg may be managed on high flow nasal cannula oxygen at 2–8 L/min irrespective of weight. Comorbidities (eg, preterm infants, oncology, immunosuppressed etc) may increase the risk of more severe disease. |
|||||||||||||||
Box 2 – Disease‐modifying treatment recommendations for children and adolescents
|
Treatment |
Recommendations |
||||||||||||||
|
|
|||||||||||||||
|
Corticosteroids |
Consider using dexamethasone daily intravenously or orally for up to 10 days (or acceptable alternative regimen) in children and adolescents with acute COVID‐19 who are receiving oxygen (including mechanically ventilated patients) (GRADE: low certainty; conditional recommendation) |
||||||||||||||
|
A dose of 6 mg daily is recommended in adults. The RECOVERY trial protocol recommended a dose of 0.15 mg/kg/day to a maximum of 6 mg/day for children, but it is not stated whether any children were included in the trial. If dexamethasone is not available, an acceptable alternative regimen would be:
|
|||||||||||||||
|
Do not routinely use dexamethasone (or other corticosteroids) to treat COVID‐19 in children or adolescents who do not require oxygen (GRADE: low certainty; conditional recommendation against) |
|||||||||||||||
|
Dexamethasone and other corticosteroids should still be used for other evidence‐based indications in children or adolescents who have COVID‐19 |
|||||||||||||||
|
Specific recommendations on the use of corticosteroids for PIMS‐TS available at https://app.magicapp.org/#/guideline/L4Q5An/section/nVp73j |
|||||||||||||||
|
Tocilizumab |
Consider using tocilizumab for the treatment of COVID‐19 in children and adolescents who require supplemental oxygen, particularly where there is evidence of systemic inflammation (GRADE: low certainty; conditional recommendation) |
||||||||||||||
|
There is no established dose for tocilizumab for the treatment of acute COVID‐19 in children and adolescents (the Taskforce notes that RECOVERY is recruiting children and adolescents with PIMS‐TS for their trial of tocilizumab26). Tocilizumab should be administered as a single intravenous infusion over 60 minutes, with the potential for a second dose to be administered either 12 or 24 hours later if the patient’s condition has not improved |
|||||||||||||||
|
Following protocol information in the RECOVERY trial, as well as previous literature on the use of tocilizumab for other indications, the suggested dose is dependent on body weight:
|
|||||||||||||||
|
In the RECOVERY trial, 29% of patients received a second dose 12–24 hours after the first dose, although results were not reported separately for this population. The decision to administer a second dose of tocilizumab should take into consideration the availability of tocilizumab |
|||||||||||||||
|
In addition, the RECOVERY and REMAP‐CAP trials have demonstrated a significant benefit when using corticosteroids in conjunction with tocilizumab in adults. Use of combined tocilizumab and corticosteroids should be considered in children and adolescents hospitalised with COVID‐19 who require oxygen; however, the optimal sequencing of tocilizumab and corticosteroid use is unclear in all populations |
|||||||||||||||
|
As tocilizumab inhibits the production of CRP, a reduction in CRP should not be used as a marker of clinical improvement |
|||||||||||||||
|
Remdesivir |
Use of remdesivir for children or adolescents with COVID‐19 outside a trial setting should not be routinely considered (GRADE: low certainty; conditional recommendation against) |
||||||||||||||
|
|||||||||||||||
|
Other treatments not recommended |
Do not use aspirin, azithromycin, colchicine, convalescent plasma, hydroxychloroquine, hydroxychloroquine plus azithromycin, interferon‐β‐1a, lopinavir‐ritonavir or interferon‐β‐1a plus lopinavir‐ritonavir, for the treatment of COVID‐19 (GRADE: high certainty; strong recommendation)* |
||||||||||||||
|
|||||||||||||||
|
Venous thromboembolism prophylaxis for children and adolescents |
For children and adolescents admitted to hospital with COVID‐19, refer to local thromboprophylaxis protocols and seek expert advice (Consensus recommendation) |
||||||||||||||
|
|||||||||||||||
|
|
|||||||||||||||
|
ANZPID = Australia and New Zealand Paediatric Infectious Diseases Group; COVID‐19 = coronavirus disease 2019; CRP = C‐reactive protein; GRADE = Grading of Recommendations Assessment Development and Evaluation; PIMS‐TS = paediatric inflammatory multisystem syndrome; RECOVERY = Randomised Evaluation of COVID‐19 Therapy; REMAP‐CAP = Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community‐Acquired Pneumonia study. * Text adapted from current recommendations. |
|||||||||||||||
Box 3 – Respiratory support in neonates, children and adolescents
|
|
Type of respiratory support |
||||||||||||||
|
|
|||||||||||||||
|
Non‐invasive respiratory support |
|
||||||||||||||
|
Patients requiring invasive mechanical ventilation |
|
||||||||||||||
|
|
|||||||||||||||
|
ARDS = acute respiratory distress syndrome; COVID‐19 = coronavirus disease 2019; GRADE = Grading of Recommendations Assessment, Development and Evaluation. * Non‐invasive ventilation modes include any mode of applied pressure support delivered without an endotracheal tube during spontaneous breathing, such as continuous positive applied pressure, bilevel positive applied pressure, non‐invasive intermittent positive pressure ventilation via mask or nasal prongs. |
|||||||||||||||
Box 4 – Paediatric inflammatory multisystem syndrome (PIMS‐TS) recommendations
|
Management of children with PIMS‐TS* |
Recommendation |
Remarks |
Rationale |
||||||||||||
|
|
|||||||||||||||
|
IVIg plus corticosteroids |
Consider using IVIg (2 g/kg per dose) in combination with methylprednisolone in children and adolescents who meet PIMS‐TS criteria (Conditional recommendation) |
IVIg should be considered for all children with complete or incomplete Kawasaki disease, irrespective of whether it may be related to COVID‐19. Depending on the age and the phenotype expression of PIMS‐TS, combination therapy of IVIg and corticosteroids should be considered as a first line therapy.46,47,48 This is particularly relevant for older children with myocardial dysfunction, as opposed to younger children with a more Kawasaki disease‐like phenotype |
Three Observational studies on the management of PIMS‐TS have been identified:46,47,48
|
||||||||||||
|
Note that the oncotic load from a large IVIg dose should be considered when administering this agent to children with myocardial dysfunction.49 For selected cases of PIMS‐TS with severe myocardial dysfunction, corticosteroid treatment alone and/or delayed use of IVIg may be beneficial |
|||||||||||||||
|
Further details on the evidence underpinning this recommendation available at https://app.magicapp.org/#/guideline/L4Q5An/rec/jmPNAE |
|||||||||||||||
|
Corticosteroids |
Consider using corticosteroids (irrespective of oxygen status) as adjuvant therapy for children and adolescents diagnosed with PIMS‐TS (Consensus recommendation) |
Intravenous corticosteroids (eg, methylprednisolone) may be given before, or in combination with, IVIg.47 Corticosteroids should be considered as the next treatment option for children who remain unwell (tachycardia, need for vasoactive support) 24 hours after infusion of IVIg, particularly if they have ongoing pyrexia or have not received corticosteroids as a first line treatment |
Corticosteroids are used for the treatment of several conditions and, in particular, in high risk refractory cases of Kawasaki disease50 |
||||||||||||
|
For selected cases of PIMS‐TS with severe myocardial dysfunction, corticosteroid treatment alone and/or delayed use of IVIg may be beneficial50 |
|
||||||||||||||
|
Other immunomodulatory agents |
Additional immunomodulatory agents for PIMS‐TS (anti‐IL‐1, anti‐IL‐6 or anti‐TNF) should be considered as a third‐line option in children and adolescents with PIMS‐TS who do not respond to IVIg and corticosteroids (Consensus recommendation) |
Before initiating additional immunomodulatory therapies, all patients with PIMS‐TS need to be discussed with a multidisciplinary team and interventions carefully considered. Immunomodulatory agents previously used that have an acceptable risk–benefit ratio include: anakinra (IL‐1 receptor antagonist), infliximab (TNF inhibitor), and tocilizumab (IL‐6 receptor antagonist). Consider testing for infections that may be unmasked by the use of these agents |
Immunomodulatory agents are routinely used to treat a range of rheumatological conditions in children and adolescents and may limit the hyperinflammatory state associated with this syndrome. Given the partial characterisation of PIMS‐TS, immunomodulatory agents have occasionally been used for its treatment in international cohorts51,52 |
||||||||||||
|
Aspirin and other antithrombotic agents |
Children who are treated for PIMS‐TS with IVIg or other agents should also be prescribed low‐dose aspirin (3–5 mg/kg once daily for at least 6 weeks) (Consensus recommendation) |
Additional measures to be considered to prevent venous thrombosis associated with PIMS‐TS include anticoagulation therapy and compression stockings (in children older than 12 years of age) |
Aspirin is used as an antithrombotic to prevent coronary artery thrombosis in Kawasaki disease53 |
||||||||||||
|
|
|||||||||||||||
|
COVID‐19 = coronavirus disease 2019; IL = interleukin; IVIg = intravenous immunoglobulin; OR = odds ratio; RR = risk ratio; TNF = tumour necrosis factor. * Children and adolescents who have suspected or confirmed PIMS‐TS should be managed by and discussed with a multidisciplinary team. Because of the potential for rapid deterioration, early consultation with experts and consideration of early transfer to a paediatric hospital with intensive care facilities to manage children are recommended for patients with suspected or confirmed PIMS‐TS (Consensus recommendation). |
|||||||||||||||
Provenance: Not commissioned; externally peer reviewed.
- David Fraile Navarro1,2
- Britta Tendal1
- David Tingay3,4
- Nan Vasilunas5
- Lorraine Anderson6,7
- James Best7
- Penelope Burns8,9,10
- Saskia Cheyne1,11
- Simon S Craig12,13
- Simon J Erickson14
- Nicholas SS Fancourt15,16
- Zoy Goff14
- Vimbai Kapuya15,17
- Catherine Keyte18,19
- Lorelle Malyon20
- Steve McDonald1
- Heath White1
- Danielle Wurzel3,4
- Asha C Bowen14,21
- Brendan McMullan22,23
- Clinical care of children and adolescents with COVID-19: recommendations from the National COVID-19 Clinical Evidence Taskforce
- 1 Cochrane Australia, Monash University, Melbourne, VIC
- 2 Centre for Health Informatics, Australian Institute of Health Innovation, Macquarie University, Sydney, NSW
- 3 Murdoch Children’s Research Institute, Melbourne, VIC
- 4 Royal Children’s Hospital Melbourne, Melbourne, VIC
- 5 Women’s and Children’s Health Network, Women’s and Children’s Hospital Adelaide, Adelaide, SA
- 6 Kimberley Aboriginal Medical Services Council, Broome, WA
- 7 Junction Street Family Practice, Sydney, NSW
- 8 Australian National University, Canberra, ACT
- 9 Northern Beaches Hospital, Sydney, NSW
- 10 Western Sydney University, Sydney, NSW
- 11 NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW
- 12 Monash University, Melbourne, VIC
- 13 Monash Medical Centre, Monash Health, Melbourne, VIC
- 14 Perth Children’s Hospital, Perth, WA
- 15 Charles Darwin University, Darwin, NT
- 16 Royal Darwin Hospital, Darwin, NT
- 17 Australian College of Rural and Remote Medicine, Brisbane, QLD
- 18 Queensland Children’s Hospital, Brisbane, QLD
- 19 Australian College of Nursing, Canberra, ACT
- 20 College of Emergency Nursing Australasia, Melbourne, VIC
- 21 Wesfarmers Centre for Vaccines and Infectious Diseases, Telethon Kids Institute, Perth, WA
- 22 Sydney Children’s Hospital, Randwick, Sydney, NSW
- 23 University of New South Wales, Sydney, NSW
The National COVID-19 Clinical Evidence Taskforce acknowledges the member organisations, partners, governments and funders that support the initiative (online Supporting Information). These guidelines have received funding from the Australian Government Department of Health, the Victorian Government Department of Health and Human Services, the Ian Potter Foundation, the Walter Cottman Endowment Fund managed by Equity Trustees, the Lord Mayor’s Charitable Foundation, and the Victorian Government Operational Infrastructure Support Program. David Tingay was supported by a National Health and Medical Research Council Clinical Research Fellowship (Grant ID 1053889).
No relevant disclosures.
- 1. Dong E, Du H, Gardner L. An interactive web‐based dashboard to track COVID‐19 in real time. Lancet Infect Dis 2020; 20: 533–534.
- 2. Australian Government. COVID‐19 cases by age group and sex. https://www.health.gov.au/resources/covid‐19‐cases‐by‐age‐group‐and‐sex (viewed Aug 2021).
- 3. Murdock J. Virus expert says COVID will “not go away” and could be around for “rest of our lives”. Newsweek 2020; 26 Nov. https://www.newsweek.com/dr‐ian‐lipkin‐columbia‐university‐expert‐warns‐coronavirus‐covid19‐rest‐lives‐1550585 (viewed May 2021).
- 4. Dong Y, Mo X, Hu Y, et al. Epidemiology of COVID‐19 among children in China. Pediatrics 2020; 145: e20200702.
- 5. 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.
- 6. Götzinger F, Santiago‐García B, Noguera‐Julián A, et al. COVID‐19 in children and adolescents in Europe: a multinational, multicentre cohort study. Lancet Child Adolesc Heal 2020; 4: 653–661.
- 7. Kim L, Whitaker M, O’Halloran A, et al. Hospitalization rates and characteristics of children aged < 18 years hospitalized with laboratory‐confirmed COVID‐19 — COVID‐NET, 14 states, March 1 – July 25, 2020. Morb Mortal Wkly Rep 2020; 69: 1081.
- 8. UNICEF. Children mortality and COVID‐19, May 2021. https://data.unicef.org/topic/child‐survival/covid‐19/ (viewed Sept 2021).
- 9. McLaws M. COVID‐19 in children: time for a new strategy. Med J Aust 2021; 215: 212–213. https://www.mja.com.au/journal/2021/215/5/covid‐19‐children‐time‐new‐strategy
- 10. Toubiana J, Poirault C, Corsia A, et al. Kawasaki‐like multisystem inflammatory syndrome in children during the covid‐19 pandemic in Paris, France: prospective observational study. BMJ 2020; 369: m2094.
- 11. Viner RM, Whittaker E. Kawasaki‐like disease: emerging complication during the COVID‐19 pandemic. Lancet 2020; 395: 1741–1743.
- 12. Ouldali N, Pouletty M, Mariani P, et al. Emergence of Kawasaki disease related to SARS‐CoV‐2 infection in an epicentre of the French COVID‐19 epidemic: a time‐series analysis. Lancet Child Adolesc Heal 2020; 4: 662–668.
- 13. World Health Organization. Multisystem inflammatory syndrome in children and adolescents with COVID‐19: scientific brief, 15 May 2020. https://apps.who.int/iris/handle/10665/332095 (viewed May 2021).
- 14. Royal College of Paediatrics and Child Health. Guidance: paediatric multisystem inflammatory syndrome temporally associated with COVID‐19. London: RCPCH, 2020. https://www.rcpch.ac.uk/sites/default/files/2020‐05/COVID‐19‐Paediatric‐multisystem‐%20inflammatory%20syndrome‐20200501.pdf (viewed Aug 2021).
- 15. Godfred‐Cato S, Bryant B, Leung J, et al. COVID‐19‐associated multisystem inflammatory syndrome in children — United States, March–July 2020. Morb Mortal Wkly Rep 2020; 69: 1074–1080.
- 16. Abrams JY, Godfred‐Cato SE, Oster ME, Chow EJ, Koumans EH, Bryant B, et al. Multisystem inflammatory syndrome in children associated with severe acute respiratory syndrome coronavirus 2: a systematic review. J Pediatr 2020; 226: 45–54.
- 17. White H, Tendal B, Elliott J, et al. Breathing life into Australian diabetes clinical guidelines. Med J Aust 2020; 212: 250–251. https://www.mja.com.au/journal/2020/212/6/breathing‐life‐australian‐diabetes‐clinical‐guidelines
- 18. Alonso‐Coello P, Schünemann HJ, Moberg J, et al. GRADE Evidence to Decision (EtD) frameworks: a systematic and transparent approach to making well informed healthcare choices. 1: Introduction. BMJ 2016; 353: i2016.
- 19. Tendal B, Vogel JP, McDonald S, et al. Weekly updates of national living evidence‐based guidelines: Methods for the Australian Living Guidelines for Care of People with COVID‐19. J Clin Epidemiol 2021; 131: 11–21.
- 20. National COVID‐19 Clinical Evidence Taskforce. About the guidelines. https://covid19evidence.net.au/more‐about‐the‐guidelines/ (viewed May 2021).
- 21. Caldwell PHY, Murphy SB, Butow PN, Craig JC. Clinical trials in children. Lancet 2004; 364: 803–811.
- 22. Campbell JI, Ocwieja KE, Nakamura MM. A call for pediatric COVID‐19 clinical trials. Pediatrics 2020; 146: e20201081.
- 23. Schünemann HJ. [GRADE: from grading the evidence to developing recommendations. A description of the system and a proposal regarding the transferability of the results of clinical research to clinical practice] [German]. Z Evid Fortbild Qual Gesundhwes 2009; 103: 391–400.
- 24. Vogel JP, Tendal B, Giles M, et al. Clinical care of pregnant and postpartum women with COVID‐19: living recommendations from the National COVID‐19 Clinical Evidence Taskforce. Aust New Zeal J Obstet Gynaecol 2020; 60: 840–851.
- 25. National COVID‐19 Clinical Evidence Taskforce. About the taskforce. https://covid19evidence.net.au/about‐the‐taskforce/ (viewed May 2021).
- 26. RECOVERY Trial. Randomised evaluation of COVID‐19 Therapy (RECOVERY); protocol version 14, 2021. https://www.recoverytrial.net/files/recovery‐protocol‐v14‐0‐2021‐02‐15.pdf (viewed August 2021).
- 27. US Food and Drug Administration. COVID‐19 update: FDA broadens emergency use authorization for Veklury (remdesivir) to include all hospitalized patients for treatment of COVID‐19 [media release]. 28 Aug 2020. https://www.fda.gov/news‐events/press‐announcements/covid‐19‐update‐fda‐broadens‐emergency‐use‐authorization‐veklury‐remdesivir‐include‐all‐hospitalized (viewed May 2021).
- 28. World Health Organization. Corticosteroids for COVID‐19: living guidance, 2 September 2020. https://www.who.int/publications/i/item/WHO‐2019‐nCoV‐Corticosteroids‐2020.1 (viewed May 2021).
- 29. Dequin PF, Heming N, Meziani F, et al. Effect of hydrocortisone on 21‐day mortality or respiratory support among critically ill patients with COVID‐19: a randomized clinical trial. JAMA 2020; 324: 1298–1306.
- 30. Glucocorticoid therapy for COVID‐19 critically ill patients with severe acute respiratory failure. ClinicalTrials.gov; 2020. https://clinicaltrials.gov/ct2/show/NCT04244591 (viewed May 2021).
- 31. Angus DC, Derde L, Al‐Beidh F, et al. Effect of hydrocortisone on mortality and organ support in patients with severe COVID‐19: the REMAP‐CAP COVID‐19 Corticosteroid Domain Randomized Clinical Trial. JAMA 2020; 324: 1317–1329.
- 32. Tomazini BM, Maia IS, Cavalcanti AB, et al. Effect of dexamethasone on days alive and ventilator‐free in patients with moderate or severe acute respiratory distress syndrome and COVID‐19: The CoDEX randomized clinical trial. J Am Med Assoc 2020; 324: 1307–1316.
- 33. Petersen MW, Meyhoff TS, Helleberg M, et al. Low‐dose hydrocortisone in patients with COVID‐19 and severe hypoxia (COVID STEROID) trial — protocol and statistical analysis plan. Acta Anaesthesiol Scand 2020; 64: 1365–1375.
- 34. Villar J, Añón JM, Ferrando C, et al. Efficacy of dexamethasone treatment for patients with the acute respiratory distress syndrome caused by COVID‐19: study protocol for a randomized controlled superiority trial. Trials 2020; 21: 1–10.
- 35. Jeronimo CM, Farias ME, Val FF, et al. Methylprednisolone as adjunctive therapy for patients hospitalized with coronavirus disease 2019 (COVID‐19; Metcovid): a randomized, double‐blind, phase IIb, placebo‐controlled trial. Clin Infect Dis 2021; 72: e373–e381.
- 36. Edalatifard M, Akhtari M, Salehi M, et al. Intravenous methylprednisolone pulse as a treatment for hospitalised severe COVID‐19 patients: results from a randomised controlled clinical trial. Eur Respir J 2020; 56: 2002808.
- 37. Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the treatment of COVID‐19 — preliminary report. N Engl J Med 2020; 383: 1813–1826.
- 38. WHO Solidarity Trial Consortium. Repurposed antiviral drugs for COVID‐19 — interim WHO Solidarity trial results. N Engl J Med 2021; 384: 497–511.
- 39. Spinner CD, Gottlieb RL, Criner GJ, et al. Effect of remdesivir vs standard care on clinical status at 11 days in patients with moderate COVID‐19: a randomized clinical trial. JAMA 2020; 324: 1048–1057.
- 40. Wang Y, Zhang D, Du G, et al. Remdesivir in adults with severe COVID‐19: a randomised, double‐blind, placebo‐controlled, multicentre trial. Lancet 2020; 395: 1569–1578.
- 41. Wichmann D, Sperhake JP, Lütgehetmann M, et al. Autopsy findings and venous thromboembolism in patients with COVID‐19: a prospective cohort study. Ann Intern Med 2020; 173: 268–277.
- 42. Goldenberg NA, Sochet A, Albisetti M, et al. Consensus‐based clinical recommendations and research priorities for anticoagulant thromboprophylaxis in children hospitalized for COVID‐19–related illness. J Thromb Haemost 2020; 18: 3099–3105.
- 43. Nye S, Whitley RJ, Kong M. Viral infection in the development and progression of pediatric acute respiratory distress syndrome. Front Pediatr 2016; 4: 128.
- 44. Centers for Disease Control and Prevention. Multisystem inflammatory syndrome in children (MIS‐C) associated with coronavirus disease 2019 (COVID‐19) [CDCHAN‐00432]. https://emergency.cdc.gov/han/2020/han00432.asp (viewed May 2021).
- 45. Paediatric Active Enhanced Disease Surveillance (PAEDS) Network. Advice for clinicians: paediatric inflammatory multisystem syndrome temporally associated with SARS‐CoV‐2 (PIMS‐TS). Sydney: National Centre for Immunisation Research and Surveillance, 2020. https://www.ncirs.org.au/advice‐for‐clinicians‐PIMS‐TS (viewed May 2021).
- 46. Ouldali N, Toubiana J, Antona D, et al. Association of intravenous immunoglobulins plus methylprednisolone vs immunoglobulins alone with course of fever in multisystem inflammatory syndrome in children. JAMA 2021; 325: 855–864.
- 47. McArdle AJ, Vito O, Patel H, et al. Treatment of multisystem inflammatory syndrome in children. N Engl J Med 2021; 385: 11–22.
- 48. Son MBF, Murray N, Friedman K, et al. Multisystem inflammatory syndrome in children — initial therapy and outcomes. N Engl J Med 2021; 385: 23–34.
- 49. Tacke CE, Burgner D, Kuipers IM, Kuijpers TW. Management of acute and refractory Kawasaki disease. Expert Rev Anti Infect Ther 2012; 10: 1203–1215.
- 50. Wardle AJ, Connolly GM, Seager MJ, Tulloh RM. Corticosteroids for the treatment of Kawasaki disease in children. Cochrane Database Syst Rev 2017; (1): CD011188.
- 51. Sperotto F, Friedman KG, Son MBF, et al. Cardiac manifestations in SARS‐CoV‐2‐associated multisystem inflammatory syndrome in children: a comprehensive review and proposed clinical approach. Eur J Pediatr 2021; 180: 307–322.
- 52. Ahmed M, Advani S, Moreira A, et al. Multisystem inflammatory syndrome in children: a systematic review. EClinicalMedicine 2020; 26: 100527.
- 53. Dallaire F, Fortier‐Morissette Z, Blais S, et al. Aspirin dose and prevention of coronary abnormalities in Kawasaki disease. Pediatrics 2017; 139: e20170098.
- 54. Malhotra A, Kumar A, Roehr CC, den Boer MC. Inclusion of children and pregnant women in COVID‐19 intervention trials. Pediatr Res 2021; 89: 1063–1064.
- 55. Klassen TP, Hartling L, Craig JC, Offringa M. Children are not just small adults: the urgent need for high‐quality trial evidence in children. PLoS Med 2008; 5: e172.
- 56. Hoffman JA, Miller EA. Addressing the consequences of school closure due to COVID‐19 on children’s physical and mental well‐being. World Med Health Policy 2020; 12: 300–310.
Abstract
Introduction: The epidemiology and clinical manifestations of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection are different in children and adolescents compared with adults. Although coronavirus disease 2019 (COVID‐19) appears to be less common in children, with milder disease overall, severe complications may occur, including paediatric inflammatory multisystem syndrome (PIMS‐TS). Recognising the distinct needs of this population, the National COVID‐19 Clinical Evidence Taskforce formed a Paediatric and Adolescent Care Panel to provide living guidelines for Australian clinicians to manage children and adolescents with COVID‐19 and COVID‐19 complications. Living guidelines mean that these evidence‐based recommendations are updated in near real time to give reliable, contemporaneous advice to Australian clinicians providing paediatric care.
Main recommendations: To date, the Taskforce has made 20 specific recommendations for children and adolescents, including definitions of disease severity, recommendations for therapy, respiratory support, and venous thromboembolism prophylaxis for COVID‐19 and for the management of PIMS‐TS.
Changes in management as a result of the guidelines: The Taskforce currently recommends corticosteroids as first line treatment for acute COVID‐19 in children and adolescents who require oxygen. Tocilizumab could be considered, and remdesivir should not be administered routinely in this population. Non‐invasive ventilation or high flow nasal cannulae should be considered in children and adolescents with hypoxaemia or respiratory distress unresponsive to low flow oxygen if appropriate infection control measures can be used. Children and adolescents with PIMS‐TS should be managed by a multidisciplinary team. Intravenous immunoglobulin and corticosteroids, with concomitant aspirin and thromboprophylaxis, should be considered for the treatment of PIMS‐TS.
The latest updates and full recommendations are available at www.covid19evidence.net.au.