DISCUSSION
Epidemiological evidences show that SARS-CoV-2 infection in children is
less frequent and severe than adults. Age-related ACE2 receptor
expression and maturation, lymphocyte count and trained immunity might
all be contributing factors to explain pediatric
superiority35 with respect to early infectivity and
disease severity. We can speculate that high ACE2 receptor
concentrations, trained immunity and a constitutional high lymphocyte
count in children may partially explain the mild disease observed in
this group of patients but this is not yet established by definitive
research. Real reasons will probably remain a mystery fortunately
because the number of infected children is too low to allow good-sized
immunological studies. This may be related to both exposure and host
factors as has been previously speculated.14 Likewise,
the age at which children appear similar to adults with respect to
disease progression is not firmly established. One study suggesting that
this may be true as early as 10 years of age will need to be challenged
by additional studies that include patients other than overly infected
and symptomatic pediatric patients.36 Children are
usually well cared for at home and might have relatively fewer
opportunities to expose themselves to pathogens and/or patients who are
sick. This observation is heavily skewed by the experience thus far and
will likely need to be re-evaluated as the virus moves to other
geographic areas particularly LMICs where care, proximity and infection
opportunities are likely very different.
Current risk assessment for pediatrics and pregnancy to COVID-19
treatment options suggests that the usual concerns for both these
populations are relevant for many of the repurposed agents currently
being evaluated. The disease itself does pose additional risks mostly
due to its extensive distribution and effect on the inflammatory system
particularly in later stages of duration. Unfortunately, the majority of
single agent and combination drug trials excludes pediatric patients and
pregnant women at present, though hopefully there will be an opportunity
for prospective testing in both populations as one or more therapeutic
options become viable. The same is true for vaccines of course. As has
been the case for other antiviral drug therapies, successful treatment
of SARS-CoV-2 likely involves drug combination, multimodal therapy.
Similar to the experience with HIV, effective treatment likely lies with
multiple mechanisms to kill the virus, stop the virus from entering
cells and stop the virus from replicating. Also like HIV hopefully,
choices of agents that represent the standard of care will be tailored
to limit side effects and drug interaction potential and will also be
tailored to the target population of interest which may present
different benefit:risk profiles different from mainstream patients
(i.e., pediatrics and pregnant women). Experience with HIV in the
populations may also shed light on timing of therapy
considerations37 or combination choices that may be
given to women during pregnancy, to reduce the risk of vertical
transmission to the child.38
Recent trends to share real world data (RWD) from COVID-19 patients is
very encouraging in addition to the collaborative events in general. It
provides a forum from which the available basic and clinical
pharmacology can be linked to more rapidly pressure-test repurposed
drugs and vaccines while providing a benchmark for new drugs and drug
combinations for the purpose of future readiness. The PEDIATRIC COVID-19
Registry
(https://www.pids.org/news/764-usa-pediatric-covid-19-registry.html)
similarly creates a repository of surveyed pediatric patients treated
for COVID-19. Under the umbrella of the Pediatric Infectious Diseases
Transplant Network (PIDTRAN) and through its Coordinating Center at St.
Jude Children’s Research Hospital, in collaboration with Children’s
Hospital of Philadelphia, Seattle Children’s and Chicago Children’s
Hospital survey data captures epidemiologic and clinical information
about all cases of pediatric COVID-19 infections in the United States.
Other efforts to accumulate COVID-19 RWD for evaluating real-time
clinical performance of therapies representing the current standard of
care and potentially guiding us on future pandemic readiness include the
ISPY-2 for COVID accelerator, the CURE-ID and the COVID-19 Diagnostics
Evidence Accelerator. CURE ID is an internet-based repository that lets
the clinical community report novel uses of existing drugs for
difficult-to-treat infectious diseases through a website, a smartphone
or other mobile device. The platform enables the crowdsourcing of
medical information from health care providers to facilitate the
development of new treatments for neglected diseases. CURE ID is a
collaboration between the FDA and the National Center for Advancing
Translational Sciences (NCATS), part of the National Institutes of
Health (NIH). FDA and NIH are also collaborating with the World Health
Organization and the Infectious Disease Society of America to assess the
global utility of the CURE ID. The Diagnostics Evidence Accelerator is
organized by the Reagan-Udall Foundation for the FDA in collaboration
with Friends of Cancer Research. The Diagnostics Evidence Accelerator is
the companion project to the previously announced Therapeutic Evidence
Accelerator, which brings together leading experts in health data
aggregation and analytics in a unified, collaborative effort to share
insights, compare results and answer key questions to inform the
collective COVID-19 response. In addition, less traditional RWD sources
such as patient-centric data39,40 and large-scale
twitter feed data are coming to bear on quantifying COVID-19 prevalence
and treatment response.5
On the vaccine front, as of July 2020, 205 vaccine candidates were in
development, with 17 in human testing: two in Phase II efficacy and
dose-testing studies in human subjects, five in Phase I–II safety and
efficacy trials, and ten in Phase I trials.34 Early
results are promising but still too preliminary to assess a viable
clinical candidate. The National Institute of Allergy and Infectious
Diseases (NIAID) has established a new clinical trials network that aims
to enroll thousands of volunteers in large-scale clinical trials testing
a variety of investigational vaccines and monoclonal antibodies intended
to protect people from COVID-19. The COVID-19 Prevention Trials Network
(COVPN)41 was established by merging four existing
NIAID-funded clinical trials networks: the HIV Vaccine Trials Network
(HVTN)42, based in Seattle; the HIV Prevention Trials
Network (HPTN)43, based in Durham, N.C.; the
Infectious Diseases Clinical Research Consortium
(IDCRC)44, based in Atlanta; and the AIDS Clinical
Trials Group, based in Los Angeles. The presumption that using
real-world data can provide actionable information about the prevalence
of SARS-CoV-2 in specific populations and highlight individual risk
factors for patients, helping to improve our understanding of the
disease, tailor public health interventions and strategies to mitigate
risks for individuals and communities, and help stop the spread of
SARS-CoV-2 is an important milestone for these efforts and may indeed
provide a roadmap to handle future crisis situations. The evidence
generated through the various RWD platforms is intended to be
complementary to actual clinical studies that have been conducted or are
underway as well as a mechanism to address questions not yet answered.
One can only hope that the spirit of collaboration continues despite a
devolving political landscape that makes collaboration and open science
policies more difficult, especially in the face of a global pandemic.