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SARS-CoV-2 infection is generally milder in children than in adults and most children with acute COVID-19 will uncharacteristically require any specific therapy. However, severe outcomes occur, and the burden in children should not be minimized. Pediatric COVID-19 treatment decisions should be guided by patient-level risk status (age, underlying comorbidities, and immune status), disease severity, clinical progression, and diagnostic evaluations.

Since the appearance of Omicron as of December 2021, the number of infections, children included, have dramatically increased due to the variant’s high infectivity. This has translated to an increased number of hospital admission/patients admitted with COVID-19, but not necessarily due to COVID-19-related symptoms. Based on preliminary data from the Canadian Nosocomial Infection Surveillance Program (CNISP) estimates approximately 50% of pediatric patients (<18 years) who have been hospitalized with lab confirmed COVID-19 from January to August 2022, were admitted for reasons other than COVID-19 (Personal Communication CNISP preliminary data, Public Health Agency of Canada).

Moreover, co-infections have increased, especially with the lifting of masking mandates and other public health measures. Some of these co-infections could represent remote COVID-19 with acute infection from another respiratory virus (RSV, influenza, etc). Consideration should be given to testing for other viruses if the child is admitted and sick enough to warrant COVID-19-specific treatment.

Data on the treatment of acute COVID-19 in pediatrics are very limited. While some randomized controlled trials of COVID-19 therapeutics included a small proportion of adolescents ≥12 years old, none have reported results on younger children. Given the ever-changing evidence, the pediatric COVID-19 working group of AMMI Canada have adopted a question and answer format for this article for some of the more common questions/dilemmas that arise when treating children with acute COVID-19. The post-COVID-19 inflammatory syndromes (Multisystem Inflammatory Syndrome in Children [MIS-C]) will not be addressed in this article.

As of March 18, 2022, persons 0–19 years old accounted for 20.1% of COVID-19 cases but only 3.5% of hospitalizations and 2.0% of ICU admissions in Canada, while representing 21.1% of the total population (1,2). The emergence of the highly contagious Omicron variant has led to greater numbers of children acquiring infection, resulting in the highest incidence of pediatric COVID-19 hospital admissions to date, especially among those too young to have received a complete primary series of COVID-19 vaccination.

Risk factors for severe acute COVID-19 disease in children may differ across the pediatric age spectrum and from those identified in adults (35). A non-exhaustive list is presented in Figure 1. While children who have multiple (≥2) chronic comorbidities are at higher risk for severe outcomes, more than half of Canadian children with PCR-positive SARS-CoV-2 infection admitted for COVID-19 had no underlying medical condition (3,6).

Figure 1: Factors associated with COVID-19 hospitalization or severe outcomes in children

The management of COVID-19 is rapidly changing as new therapeutic agents are approved for use.

Management pathways are well defined in adults (7,8) and incorporate disease category and risk for severity applying a range of therapeutics aimed at (1) pre-exposure prophylaxis (PrEP) directed at active immunity and passive immunity, (2) post-exposure prophylaxis (PEP) utilizing monoclonal antibodies in high-risk populations, and finally (3) treatment of symptomatic individuals addressing the various pathophysiological processes that span the spectrum of acute COVID-19.

The main challenges in pediatrics relate to treatment in children <12 years, especially neonates and children <2 years old, where several of the current antiviral agents, monoclonal antibodies, and immunomodulatory agents available for treating infections in adults are not approved for use in children.

Individual pediatric hospital guidelines from children’s hospitals are available (9) and are mostly based on expert opinion and extrapolation from adult clinical trial data.

Management approaches will differ based on the severity category, timing of presentation and whether the child is deemed to be at high risk or not (Figure 2). While no therapeutic interventions are required for normal healthy children without risk factors who have mild infection, early initiation of antiviral agents, in those at high risk could prevent progression to severe disease. To this end, early diagnosis and discussion with a pediatric infectious disease expert is critical. Children admitted for COVID-19 who progress to moderate disease and have sustained oxygen requirements require first-line immunomodulation using steroids (dexamethasone). Based on risk status, clinical progression and diagnostic evaluation, decisions to add antibiotics or antiviral agents should be made. In addition to steroids, immunomodulation with anti–IL-6 or anti-Janus kinase agents may be necessary for children progressing to severe to critical disease. Monoclonal antibodies (short-acting anti-spike) are mainly for mild infection although in select high risk cases incorporating these into the management for moderate cases if available, and within the first 5–7days (some experts extend this to 10 days) may be considered on a case-by-case basis, especially if other modalities are contraindicated.

Figure 2: Management of acute COVID-19 in children with and without risk factors for progression to severe disease

Notes:
1Viral Co-infection: Exclude other viral co-infections, eg, influenza for which oseltamivir may be beneficial
2Steroids: Dexamethasone should be initiated in cases of acute COVID-19 with sustained new oxygen requirements Where possible, prior to commencing steroids consider screening for latent tuberculosis as well as strongyloides serology in immigrants from countries where these are prevalent
3Antiviral agents:
a) Remdesivir:
A 5-day course of remdesivir may be given to individuals with moderate to severe disease, before disease advances to critical, and may be initiated earlier in the immunocompromised or at-risk hosts, if within 7 to 10 days of symptom onset and no significant renal or hepatic dysfunction
A 3-day course has been shown to be effective in preventing progression in high-risk individuals with mild COVID-19 (17); however, given the burden (to the patient and to health care services) of 3 days of outpatient IV treatment, the much lower baseline risk of hospital admission in children, and the decreased risk of hospitalization with the currently circulating Omicron variant (compared to variants in the PINETREE study), the clinical utility of ambulatory treatment in children is very uncertain; dosing recommendations for children >3.5 kg are in Table 1. Data on use in neonates <3.5 kg (2.5 mg/kg iv then 1.25 mg/kg iv x 2–4 d) are very limited: (1820)
a) Nirmaltrevir/Ritonavir (Paxlovid): May be considered for children >12 years with mild COVID-19 who are at high risk of progressing to severe, provided there are no contraindications and within the first 5 days of symptoms
b) If respiratory viral testing confirms influenza, consider oseltamivir if no contraindication or concern for drug interaction
4Neutralizing antibodies (monoclonal anti-spike antibodies): Only short-acting anti-spike antibodies (aSa) have a role to play in the management of children with COVID-19 and should be restricted to children at high risk of progression early in their presentation before requirement of oxygen; the long acting aSa (tixagevimab/cilgavimab) has no role in the treatment of COVID-19; sotrovimab is the only short-acting aSa available in Canada with activity against the Omicron strain (BA.1, BA2,75, and to a lesser extent BA2.11, BA2.12, and BA4/5) and may be used in children who are ≥12 years old and ≥40kg with mild to moderate disease who are at high risk of disease progression and are either unvaccinated or unlikely to have mounted an optimal response and are still within ideally 5–7 days of symptom (this may be extended to 10 days) onset (7); although it is recommended for use in children with mild to moderate disease, the evidence is only available for mild disease as the trial did not enrol any individual with moderate disease (ie, on low flow oxygen). New data suggest the need for caution with its use where Omicron subvariant has not been determined or where subvariants other than BA1 or BA2.75 are dominant given the substantial reduction in in vitro neutralizing activity against non-BA1 subvariants; impact on clinical efficacy has not been determined) (11); some experts do not recommend use where subvariants r than BA1 and BA2.75 dominate; other experts recommend administering higher doses, for example, 1000 mg iv (21,22); in select high risk patients with moderate disease who are unable to mount an antibody response, some experts will consider short-acting aSa relevant to circulating strain on a case by case especially if other treatment options are contraindicated
There are no approved monoclonal anti-spike antibodies available that are highly active against the BA.2 subvariants in Canada, although a new agent bebtelovimab does retain activity against both Omicron subvariants BA.1, BA.2, and BA4/5 (11,15)
5Anticoagulation: Children with severe to critical COVID-19 may be at risk for thrombosis; those with underlying risk factors may need earlier consideration
6Biologics (anti-IL-6), eg tocilizumab, may be considered in patients with severe to critical disease within 14 days of onset who despite optimal steroid therapy for 24–48 hours, are demonstrating increasing oxygen or ventilatory requirements or have features of hyperinflammation suggesting Cytokine release syndrome (CRS) or related syndromes (eg, elevated CRP >75 mg/L, hyperferritinemia, persistent fever, or other evidence of CRS or related syndromes). JAK1/2 inhibitors, eg, baricitinib are recommended alternatives in adults, and dosing guides are available for children ≥2 years (7), but there is still limited experience with its use in children with acute COVID-19 who develop CRS and some expert groups do not recommend use of this agent (23); consider screening for latent tuberculosis and strongyloides prior to start if possible

Screening for latent tuberculosis and strongyloidiasis is encouraged prior to commencing corticosteroids or biologics, especially if there is risk of exposure, for example, when treating an immigrant population from a country of high prevalence.

Monoclonal antibody activity varies with each Omicron subvariant. Evusheld demonstrates 4–5-fold and 20-fold reduction in neutralization activity of against BA4/5 and BA2, respectively (15). Neutralization activity of sotrovimab is reduced over 20-fold for BA2.12 and reduced 2-fold for BA4/5 (16). Bebtelovimab retains activity against all Omicron subvariants (15).

Part A: What are the considerations and indications for the use of monoclonal antibodies in the pediatric population?
Treatment of mild to moderate COVID-19

Evidence shows that monoclonal antibodies reduce the risk of COVID-19-related hospitalization or death in non-hospitalized high-risk adults with a recent infection (0–7 days of symptoms) (2426). In Canada, sotrovimab and casirivimab/imdevimab are approved for the treatment of mild to moderate COVID-19 in adults and adolescents (≥12 years and ≥40 kg) who are at high risk for progressing to hospitalization and/or death. However, as of February 2022, only sotrovimab is recommended because of its conserved activity against Omicron (subvariant BA.1). There is, however, substantial decreased in vitro neutralization activity for BA.2 and BA4/5 subvariants with unknown impact on clinical efficacy (15,16). As such some experts recommend against its use where BA.2 is the dominant variant (21,22). Given that the course of COVID-19 is typically mild in children and adolescents, monoclonal antibodies should not be routinely administered in children.

Consensus of experts recommend that sotrovimab may be considered case by case, reserving for use in a highly select group of children who are at highest risk for severe disease meeting the following criteria, if sotrovimab retains neutralizing activity against the circulating variant:

  • ≥12 years and ≥40 kg

AND

  • Confirmed SARS-CoV-2 infection by RT-PCR

AND

  • Mild or moderate illness related to acute COVID-19 within 7 days of symptom onset

AND

  • Not fully vaccinated or expected to have insufficient immune response following vaccination (immunocompromised)

AND

  • Risk factors for severe acute COVID-19: such as severe immunosuppression or other factors. Please consult local expert re provincial and local guidelines, and availability of agents

Part B: For a child 12 years or older admitted because of COVID-19, should one consider monoclonal antibodies for treatment?

Prior to Omicron, casirivimab/imdevimab (REGEN-COV) had been associated with a reduced mortality in hospitalized patients (≥12 years and ≥40 kg) who were seronegative for SARS-CoV-2 (RECOVERY trial) (27). It is no longer a relevant option as it retains little neutralizing activity against Omicron subvariants.

Although some experts may still consider use of sotrovimab, at higher doses for use in high-risk outpatients with mild COVID-19, there is no data to support its use in hospitalized patients whose hospitalization is due to acute COVID-19 (28).

Bebtelovimab is a promising new anti-spike antibody that retains activity against Omicron and has a role in mild to moderate COVID-19 but has not been approved for clinical use and is not available in Canada (Table 1) (10,11).

Table

Table 1: Available drug interventions for pediatric population

Table 1: Available drug interventions for pediatric population

Drug Category Drug Treatment option Pediatric option Age group/ Weight restriction Approved or available under EUA in Canada for children Activity against Omicron Dosing for options relevant to children Comments
Long-acting anti-spike Tixagevimab/ cilgavimab
(Evusheld)
X
Pre-exposure prophylaxis
only
≥12 yrs
≥40 kg
x BA1 (active)
BA2 (less active)
BA4/5(4-5 reduced
150 mg tixagevimab: 150 mg cilgavimab
im x 1dose
Has no role in treatment of acute COVID-19
Reserved for select high risk populations
Short-acting anti-spike Sotrovimab
(Xevudy)

Mild–moderate
≥12 yrs
≥40 kg
BA.1 (active)
BA.2 (reduced)
BA4/5 (reduced)
500 mg iv x 1 dose Trial only enrolled outpatients with COVID-19
Data supports efficacy if initiated prior to requirement for oxygen
No data available for moderate COVID-19; cannot recommend use.
Suggest case by case discussion for with ID for select high risk hospitalized cases
Caution: Significantly reduced invitro neutralizing activity against BA.2 and later variants
ID guidance should be considered
Bebtelovimab (10,11) Mild to moderate ≥12 yrs
≥40 kg
X ✓BA.1
✓BA.2
✓BA4/5
175 mg IV x 1 In US use limited to clinical research
Antiviral Remdesivir
(Veklury)

Mild–severe
>3.5kg 3.5–<40 kg
5 mg/kg/dose x1 the 2.5 mg/kg iv
≥40 kg
200 mg iv x1 then 100 mg iv daily
Neonatal dosing in infants <3.5 kg limited to case reports
Contraindicated if significant hepatic or renal impairment
ID guidance recommended
Nirmaltrevir/ ritonavir
(Paxlovid)

Mild
≥12yrs
≥40kg
Nirmatrelvir 300 mg/ritonavir100 mg bid x 5 d Multiple drug-drug interactions
Pharmacy consult is encouraged in patients on polypharmacy
ID guidance recommended
Molnupiravir
(Lagevrio)

Mild
x Adult x N/A
Steroids Dexamethasone
Moderate-critical
>7 days N/A 0.15 mg/kg/dose iv/po od x10 d or to discharge Neonatal data limited to case reports;
No experience in infants <7 days; recommend ID involvement for neonatal cases
Biologics Tocilizumab
(Actemra)

Severe/critical
N/A <30 kg
12 mg/kg x1
≥30 kg
8 mg/kg iv
There is limited experience in pediatrics and immunocompromised hosts
Prolonged half-life (2–3 weeks) may pose challenges in sepsis
Screen for latent infections
Sepsis and severe liver dysfunction contraindicate use
Sarilumab
(Kevzara)

Severe/critical
x Adult x N/A N/A
Baricitinib (Olumiant )
Severe/critical
≥2 yrs N/A 2 yrs to < 9 yrs
2 mg od x14 d or discharge
≥9 yrs
4 mg od x14 d or to discharge
Limited experience in children and immunocompromised hosts
Neutropenia and significant transaminitis contraindicate use
May cause reactivation of HSV and other opportunistic infections
Some pediatric experts do not favour use

Notes:

Some experts still recommend administering sotrovimab in face of variants where neutralizing activity may be reduced; if used the dose should be doubled to 1000 mg as a single dose

Other biologics, for example, IL-1 inhibitors such as anakinra, are approved for treating cytokine release syndromes (CRS) caused by COVID-19 multi-inflammatory syndrome in children (12); although there are promising reports emerging (13,14), there is currently no evidence to recommend its use in the treatment of CRS associated with acute COVID-19; casirivimab/imdevimab and bamlanivimab/etesevimab are short-acting monoclonal COVID-19 antibodies that had a role to play in treating disease caused by pre-Omicron variants in children >12 years but are no longer recommended given that they have not retained neutralizing activity against Omicron variants

Discussion with an infectious diseases’ specialist is recommended if antiviral, biologics, or anti-spike antibody therapy is being considered; additionally, management of neonates with COVID-19 and children with severe to critical COVID-19 should be discussed with an infectious disease specialist

Part C: Is there any role for post-exposure prophylaxis?

Given that the dominant SARS-CoV-2 variants circulating are resistant to the monoclonal antibodies recommended for post-exposure prophylaxis (29), there are currently no COVID-19 mAb or antivirals authorized for use as post-exposure prophylaxis.

It is important to emphasize that monoclonal antibodies are not a substitute for vaccination against COVID-19 and vaccination is recommended in high risk and immunocompromised patients.

For most children, close daily monitoring of those at high risk of progression of illness and supportive care is the mainstay of management and can be done in remote/rural locations.

Specific therapeutics with monoclonal antibodies can be considered as outlined in Question 3. Currently no oral antiviral agents are licensed for use in children in Canada. In the future, if effective oral antiviral medication were authorized in children this could allow patients with risk factors for progression to stay in their communities while receiving these medications.

Factors such as inequitable distribution of specific therapeutics across the country, limited supply, administration via intravenous route, as well as monitoring during infusion and post-infusion are important considerations for the administration of these medications.

Health care providers should proactively become knowledgeable about access to therapeutics in their individual locations as well as any possible barriers or delays in access to these medications. Additionally, provinces or health authorities should determine criteria for which patients will require transfer to an area where they can receive outpatient therapy in a centre that has access to these medications (when not available locally) as well as determine the way by which these medications will be delivered (eg, outpatient, via home care with monitoring, etc).

Perinatal transmission or acquisition of SARS-CoV-2 in the first few days of life typically results in mild or asymptomatic disease. It is often difficult to determine whether respiratory distress is due to COVID-19 versus another etiology. Corticosteroids given to preterm infants in the first week of life to prevent chronic lung disease increase the risk of neurodevelopmental impairment, spontaneous intestinal perforation, and hypertrophic cardiomyopathy. Therefore, it is the opinion of this committee that dexamethasone is not recommended for term or preterm infants with COVID-19 in the first week life as it is not known to be beneficial and may be harmful.

For neonates who require oxygen because of COVID-19 and are minimum 7 days old, one may consider dexamethasone 0.15 mg/kg daily until they are off oxygen (maximum 10 days). However, there are no efficacy or safety data on dexamethasone for this indication in neonates, and most will have an uneventful course. On the other hand, if the neonate requires mechanical ventilation for respiratory distress attributed to COVID-19, the committee recommends that dexamethasone be given as the benefit likely outweighs the harm. Pending data, other anti-inflammatories such as tocilizumab might be considered if the neonate has critical disease attributed to COVID-19, is deteriorating despite dexamethasone, and has very high inflammatory markers (C-reactive protein).

Remdesivir has been used in neonates, but the efficacy and safety are not known so use is not routinely recommended at this time.

Underlying immunocompromise has not clearly been identified as a risk factor for severe COVID-19 disease in children but given the limited available evidence around SARS-CoV-2 and our experience with other respiratory viruses in this population, immunocompromised children should be considered at higher risk of severe COVID-19 than healthy children. Most reports of COVID-19 in immunocompromised children describe mild symptoms and full recovery. Registry data of children with solid organ transplants and cancer as well as observational studies evaluating risk factors for severe COVID-19 in children suggest that children with immunocompromising conditions are hospitalized with COVID-19 more frequently than are children without underlying medical conditions but do not appear to be at increased risk of ICU admission (3038).

There is extremely limited evidence to guide the treatment of COVID-19 in immunocompromised children. Consultation with a pediatric infectious diseases specialist is recommended. In general, the approach to treatment of COVID-19 should be similar to the approach in other children (see Question 2) with the following additional considerations (7,3942):

  1. The use of remdesivir should be considered in any immunocompromised child hospitalized with COVID-19 especially if they have a new or increasing oxygen requirement; a 5-day course of remdesivir is generally recommended, but the course can be extended to 10 days if the child has not recovered and is tolerating the medication well;

  2. The risks and benefits of using additional immunosuppressive medications including dexamethasone and biologic agents in immunocompromised children with COVID-19 are not clear; decisions to use these agents should be made with input from the teams primarily responsible for managing the immune suppression/immunocompromising condition (transplant teams, oncology, immunology, etc); children who are treated with these medications should be closely monitored for secondary infections including bacterial, fungal, and viral infections/reactivation of latent viruses;

  3. Immunocompromised children may be on multiple medications, including immunosuppressants and prophylactic antimicrobials; potential drug-drug interactions and overlapping toxicities should be carefully assessed when COVID-19 therapies are being considered and monitoring for drug levels and/or toxicities should be performed; and

  4. While COVID-19 mRNA vaccines are recommended for eligible immunocompromised children, it should be assumed that children with a significant immunocompromising condition may have a less robust response to COVID-19 vaccines and therapies normally recommended for unvaccinated or seronegative individuals, including monoclonal antibody therapies, should still be considered in this population even if they have been vaccinated against COVID-19 (41,42).

Conceptualization, J Autmizguine, M Barton, C Burton, D Dixit, J Papenburg, J Robinson, KA Top, E Rubin; Writing – Original Draft, J Autmizguine, M Barton, C Burton, D Dixit, J Papenburg, J Robinson, KA Top, E Rubin; Writing – Reviewing & Editing, J Autmizguine, M Barton, C Burton, D Dixit, J Papenburg, J Robinson, KA Top, E Rubin.

N/A

N/A

N/A

All data will not be made publicly available. Researchers who require access to the study data can contact the corresponding author for further information.

No funding was received for this work.

The authors have nothing to disclose.

This manuscript has been peer reviewed.

N/A

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