Should children with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection receive antiviral therapy? If so, what should we give, to which children, and for what disease severity?

Despite brisk scientific progress elucidating the biology and transmission of SARS-CoV-2, and numerous adult trials testing antiviral therapies, we may pass the formative stages of this pandemic without defining antiviral agents’ appropriate role in pediatric management. We urgently need pediatric clinical trials to establish the efficacy, safety, and pharmacokinetics of the most promising experimental and repurposed coronavirus disease 2019 (COVID-19) therapies proposed to date.1 

Researchers of early reports show that pediatric SARS-CoV-2 infection tends to be mild but that some children develop severe disease.2  In these reports, researchers highlight differences between pediatric and adult COVID-19 and argue that risk/benefit calculations of therapies derived from adult trials cannot be readily extrapolated to children. Gaps in our knowledge of pediatric COVID-19 further complicate assessments of risk and benefit. To date, we have a limited understanding of viral kinetics or immune responses in children, what factors predispose some children to severe disease, or how these variables affect responses to therapies. We have equally limited comprehension of how SARS-CoV-2 affects children with primary immunodeficiencies, illnesses requiring immune-compromising therapies, or other complex conditions. Nonetheless, treatment planning for severe pediatric cases, even if they will be few, has spurred children’s hospitals to develop algorithms that include antiviral agents, such as remdesivir, chloroquine (CQ), and hydroxychloroquine (HCQ). Pediatricians have been forced to make these consequential decisions about therapies in an evidence vacuum.

The struggle to repurpose CQ and HCQ for pediatric COVID-19 provides a potent example of the need for controlled therapy trials in children. To date, reports of pediatric use of these agents for COVID-19 are limited to anecdote. Doses and durations are inferred from conflicting in vitro studies, regimens for other diseases, and unpublished, underpowered, and conflicting adult clinical studies.1  Although both drugs have been used for years in children, their efficacy in COVID-19 is not assured. Studies of CQ use to prevent viral infections in animal models have yielded mixed results, with some revealing similar or inferior virological, immunologic, and clinical outcomes compared with no therapy.3  In studies of CQ and HCQ to treat a range of viral infections in adults, researchers have failed to show benefit, despite encouraging in vitro data.4  Although many children’s hospitals are already using CQ and HCQ for COVID-19, appropriate dosing, efficacy, and safety of these drugs in pediatric COVID-19 patients remain unknown.

Equipoise over safety and effectiveness of antiviral agents like CQ and HCQ to treat COVID-19 has led to a wave of adult clinical trials. This development has been slow to take hold in pediatrics. In a preprint systematic review, researchers identified 63 trials of conventional therapy targeting COVID-19 in China, only 3 of which enrolled patients <16 years old.5  As of April 18, 2020, clinicaltrials.gov listed 26 conventional therapy trials that do not exclude children outright. All of these also recruit adults. As discussed below, combined pediatric–adult trials may be a strategy to gather drug efficacy data in children, but it is not clear that these existing trials will have sufficient power to analyze efficacy in children specifically. If researchers of trials continue to sideline children, we will ultimately be unable to tell if antiviral agents used to treat ill pediatric patients helped, harmed, or did nothing.

In absence of a vaccine, antiviral agents have been proposed as a strategy to prevent SARS-CoV-2 infection. Because most children experience mild infection, pediatric prophylaxis theoretically would serve to reduce viral reservoirs and mitigate spread from children to individuals at higher risk for severe COVID-19. We must be confident that any treatment provided for this purpose is explicitly safe and effective in pediatric populations. Trials studying prophylaxis in children face a number of hurdles, such as challenges with measurement of secondary public health benefits of treating asymptomatic children. The pediatric community may decide that the ethical and scientific dilemmas inherent to preventive antiviral therapy supersede their potential utility. However, if antiviral agents do show promise in preventing SARS-CoV-2 infection, use in children should be predicated on robust pediatric trials.

Admittedly, there may be several impediments to antiviral clinical trials in SARS-CoV-2–infected children. These include uncertainty over which outcomes to use (such as improvements in oxygenation, inflammation, or virological clearance) and concerns about low recruitment, given the typically mild course of pediatric infection and public misconceptions of antiviral agents’ efficacy. Additionally, heterogeneity of conditions predisposing to severe disease may complicate trial analysis. Conducting trials during a pandemic also raises unique ethical challenges, such as balancing research versus clinical care and titrating tolerance of experimental therapies’ risks to an evolving understanding of disease.

To address these concerns and others, and to promote development of trial protocols, we offer 6 recommendations.

  • Trials should be conducted with central coordination. The multiplicity of studies in China ultimately prompted the government to issue guidelines to harmonize new trials. In the United States, government or professional organizations like the National Institutes of Health, American Academy of Pediatrics, or Pediatric Infectious Diseases Society could issue such guidance proactively. Central coordination could reduce redundant research efforts and promote synergistic trials. Adherence to standardized endpoints would enable effective comparisons between trials and ultimately produce speedier, more robust conclusions.

  • Multicenter trials should be prioritized. These would support sufficiently powered studies to test therapies for sicker, hospitalized children and facilitate analyses among subgroups with specific predisposing conditions. Existing trial networks like the Pediatric Trial Network could be enlisted.

  • Some therapeutics trials in adults could be extended to include children, as a small number of studies are already doing. Although divergent clinical courses of COVID-19 in adults and children may make many joint studies untenable, some research questions, such as efficacy of preventive antiviral agents, may be answerable by studies that include both adults and children. Joint studies also would enable resource sharing, alleviating pragmatic barriers to pediatric trials.

  • Although randomized controlled trials should be conducted whenever possible, children receiving drugs for COVID-19 should at least be offered the opportunity to participate in prospective observational studies. Although these studies are limited in their ability to establish efficacy, they would allow prospective data collection on clinical and virological trajectories and drug-associated adverse effects. It would also permit comparative subgroup analyses between groups of children with varying risks for adverse outcomes.

  • Endpoints should be used that consider both the pediatric COVID-19 clinical trajectory and the role of children in the pandemic at large. For example, trials in children could assess both symptom resolution and reduction of viral shedding, which may have implications for transmission. Jin et al6  published a clinical outcomes set for COVID-19 using Core Outcome Measures in Effectiveness Trials Initiative methods. These measures capture virological clearance, outcomes, and endpoints that reflect clinical trajectory and resource use.

  • Researchers in pediatric clinical trials should be sensitive to the unique ethical challenges associated with conducting trials during a pandemic. Guidance developed during previous epidemics proposes ways to ensure ethical trial conduct while facilitating rapid results.7  Examples include use of adaptive trials, prioritizing investigation of the most promising agents, and ensuring provision of standard care.

As pediatric researchers and health care providers, we must decide if we will rigorously study drug efficacy for children with COVID-19, or administer these agents on the unproven hope that giving anything at all is better than giving supportive care alone. We know that COVID-19 follows a different course in children than adults, so we cannot rely on results that trickle down from adult trials. Conducting controlled, coordinated pediatric trials is the only way to learn whether the potential benefits of these drugs outweigh their risks. The urgency with which we pursue robust studies now will determine if we know what to do, or if we will continue to guess, should this pandemic persist.

We thank Dr Amy Sherman for her insights on this Perspective.

Dr Campbell conceived of this perspective and drafted the manuscript; Drs Ocwieja and Nakamura conceived of this perspective and provided critical revisions; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

FUNDING: No external funding.

     
  • COVID-19

    coronavirus disease 2019

  •  
  • CQ

    chloroquine

  •  
  • HCQ

    hydroxychloroquine

  •  
  • SARS-CoV-2

    severe acute respiratory syndrome coronavirus 2

1
McCreary
EK
,
Pogue
JM
.
Coronavirus disease 2019 treatment: a review of early and emerging options
.
Open Forum Infect Dis
.
2020
;
7
(
4
):
ofaa105
2
Dong
Y
,
Mo
X
,
Hu
Y
, et al
.
Epidemiology of COVID-19 among children in China
.
Pediatrics
.
2020
;
145
(
6
):
20200702e
3
Roques
P
,
Thiberville
SD
,
Dupuis-Maguiraga
L
, et al
.
Paradoxical effect of chloroquine treatment in enhancing chikungunya virus infection
.
Viruses
.
2018
;
10
(
5
):
E268
4
Touret
F
,
de Lamballerie
X
.
Of chloroquine and COVID-19
.
Antiviral Res
.
2020
;
177
:
104762
5
Qiu
R
,
Wei
X
,
Zhao
M
, et al
Outcome reporting from protocols of clinical trials of Coronavirus Disease 2019 (COVID-19): a review.
March 8,
2020
.
medRxiv
. doi:
6
Jin
X
,
Pang
B
,
Zhang
J
, et al
.
Core outcome set for clinical trials on coronavirus disease 2019 (COS-COVID) [published online ahead of print March 18, 2020]
.
Engineering (Beijing)
.
doi: 10.1016/j.eng.2020.03.002
7
Keusch
G
,
McAdam
KPWJ
,
Cuff
PA
,
Mancher
M
,
Busta
ER
.
Integrating Clinical Research into Epidemic Response: The Ebola Experience
.
Wasington, DC
:
The National Academies Press
;
2017

Competing Interests

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.