In late 2019, a new virus, SARS-CoV-2 (Severe Acute Respiratory Syndrome coronavirus
strain 2), was reported in Wuhan, China [1]. The resulting COVID-19 disease has become
a global pandemic, with 4.5 million cases reported worldwide as of May 16, 2020, which
without universal COVID-19 viral testing almost certainly represents the tip of the
iceberg [2]. When assessing SARS-CoV-2 infection, clinicians initially focused on
symptoms in adults; however, emerging anecdotes, pre-prints, letters, and peer-reviewed
reports suggest that children are also affected. Parents and clinicians have watched
how, despite the incredible toll of COVID-19 on adults, the new coronavirus generally
seemed to spare children [3,4]. As the outbreak spread to the US, data from Chinese
health officials showed that children did not become infected in the same numbers
as adults [5]. Diagnostic and therapeutic guidelines used for children are commonly
extrapolated from studies conducted in adults. However, there are potential dangers
in assuming that children are small adults and will have the same clinical presentation,
course, and response to disease or therapy as adults, given many important physiological
differences.
1
COVID-19 epidemiology
Children are a small fraction of confirmed COVID-19 cases—in China, Italy, and the
United States, less than 2% of reported infections have been in children and adolescents
less than 18 years old [6]. Researchers agree, however, that children tend to respond
with COVID-19 better than adults do. Initial data suggested that children can transmit
the virus but were far less likely to experience coronavirus-related complications
[7].
Emerging evidence in the UK and US confirms that, although severe illness is less
frequent in children, COVID-19 can have a marked disease burden in children and that
existing comorbidities appear to be important in determining which children become
infected [8]. Additional cases of children presenting with severe inflammatory syndrome
with cardiovascular symptoms, and a laboratory-confirmed case of COVID-19 and an epidemiological
link to a COVID-19 case have been reported [9].
Cardiovascular diseases in children related to viral illnesses and their therapies
have been a focus of our research for decades and have resulted in several lessons
that may be relevant to understanding the cardiovascular manifestations of COVID-19
in children. We need to determine the course, risk factors, and biomarkers that can
predict outcomes for these children [10]. Some cardiovascular manifestations may be
the result of direct viral infection of cardiomyocytes [11], but indirect effects
from inflammation, coinfections, existing medical conditions, therapies, and genetic
predispositions must also be considered [[12], [13], [14], [15], [16], [17], [18],
[19]].
Recently, 8 cases, including 1 death, have been reported in the UK [20]. In the 8
children, 6 were of Afro-Caribbean descent and 5 were boys. Antibody testing established
that all 8 were positive for SARS-CoV-2. Notably, respiratory symptoms were not present
in all cases. In Bergamo province, Italy, 10 cases of a Kawasaki-like disease were
identified during the SARS-CoV-2 epidemic; this was a monthly incidence of at least
30 times greater than the average of 3 per month over the previous 5 years, an increase
that clearly began after the first case of COVID-19 was diagnosed in the Bergamo area
[21]. The researchers suggested that one of the coronaviruses might trigger Kawasaki
disease because SARS-CoV-2 is a particularly virulent strain that can elicit a powerful
immune response in the host. Among 48 children from 46 pediatric intensive care units
in North America, in the US (none in Canada) enrolled in a 2-week study, 40 (83%)
had preexisting underlying medical conditions, 35 (73%) presented with respiratory
symptoms, and 18 (38%) required invasive ventilation. Hospital mortality was 4.2%
(2 of 48) [22].
In a March 2020 study of households with confirmed COVID-19 cases in Shenzhen, China,
[23] children younger than 10 years were just as likely as adults to become infected
but were much less likely to have severe symptoms. However, other media reports, including
some from South Korea, Italy, and Iceland, where testing has been more widespread,
mentioned lower infection rates among children than among adults. Some Chinese studies
also support the possibility that children are less susceptible to infection. One
analyzed data from contact tracing in the Province of Hunan, China [24]. For every
infected child under the age of 15 years, almost 3 adults between the ages of 20 and
64 were infected (odds ratio, 0.34; 95% CI, 0.24 to 0.49). A preliminary analysis
of 300 infected children found that they produced much lower concentrations of cytokines
than did infected adults. Cytokines are proteins released by the immune system; a
fact consistent with Kawasaki disease as a condition associated with acquired immune
dysfunction. Cytokines depress heart function through direct immune activation which
can be associated with myocytolysis.
Increasing evidence suggests that bodily tissue damage in COVID-19 is mostly mediated
by the host's innate immunity [25,26]. The disease is characterized by a cytokine
storm resembling that of macrophage activation seen in viral-induced hemophagocytic
lymphohistiocytosis [27]. In 2020, 102 children in New York State have had virus-related
heart symptoms similar to those of Kawasaki disease and a toxic-shock-like syndrome,
and 3 have died [28]. This new condition associated with COVID-19 has been named Pediatric
Multi-System Inflammatory Syndrome, whose primary symptoms consist of persistent fever,
extreme systemic inflammation, and evidence that one or more organs are not functioning
properly, but the mechanisms of the syndrome remain unclear.
Laboratory evidence of inflammation includes, but is not limited to, one or more of
the following: an elevated erythrocyte sedimentation rate and elevated concentrations
of C-reactive protein, fibrinogen, procalcitonin, d-dimer, ferritin, lactic acid dehydrogenase,
interleukin 6, or neutrophils and lower concentrations of lymphocytes and albumin.
Notably, these cases begin to appear about a month after related adults become symptomatic
for COVID-19 [29].
Some symptoms can resemble those of Kawasaki Disease Shock Syndrome [30]. Kawasaki
disease [31] is an acute and usually self-limiting vasculitis of the medium-caliber
vessels, which almost exclusively affects children. In serious cases, COVID-19 can
cause heart swelling and damage; fever with many symptoms, including rash; conjunctivitis;
redness in the lips, tongue, and mucous membranes of the mouth and throat; swollen
hands or feet; and sometimes enlarged lymph nodes on one side of the neck. In some
children with COVID-19 disease, enlarged coronary arteries and aneurysms may contribute
to blood clots [32]. Some children have had coronary artery aneurysms. The number
of similar cases—including several deaths—has been increasing in other parts of Europe,
although the cause of these aneurysms is not well-understood [33]. Reports also commonly
describe elevated serum biomarker concentrations for inflammation [34]. Cytokines
depress heart function through direct immune activation that can be associated with
myocytolysis. Most children have responded to high doses of aspirin, intravenous immunoglobulin,
steroids, and cytokine blockers [35]. Evidence from Europe suggests most children
will recover with evidence-based critical and supportive care, although at least one
14-year-old boy in London has died [20].
2
Myocardial damage
Clinical myocarditis is uncommon in infants and children, but most cases in children
are caused by a viral infection. The most common pathogens are Coxsackievirus B [36],
but other enteroviruses [37], influenza [38], rubella [39], adenoviruses, and a host
of other agents have also been implicated. The offending agents trigger an immune
response, resulting in myocardial edema that eventually impairs systolic and diastolic
ventricular function. Although Coxsackie B disease is not usually fatal, the reoccurrence
rate is 20%, and heart damage is typically permanent [40]. Newborns and infants are
more severely affected because the immature myocardium is less able to adapt to an
acute insult.
The cardiovascular findings in COVID-19 are similar to those of Kawasaki disease,
[[41], [42], [43]] a well characterized cardiovascular condition in children. Kawasaki
disease is sometimes proposed as a model for all pediatric viral cardiovascular diseases
by generalizing its course, risk factors, validated surrogate markers of outcome,
and therapies are generalized to other viral cardiovascular diseases. We have not
found this model useful in other pediatric viral cardiovascular diseases, as detailed
below [44].
Children may present with sinus tachycardia and a gallop on auscultation, cardiomegaly
on radiographs, and small voltages on electrocardiograms [45]. Several studies have
reported that myocarditis can affect cardiac function for life [[46], [47], [48]].
One study found that 2 (9%) of 21 children with presumed to have viral-induced myocarditis
had dead and dying heart muscle similar to that found after an acute infarction that
responded to repeated, high doses of intravenous immunoglobulin [49]. Nonspecific
biomarkers of inflammation (white blood cell count, C-reactive protein, and erythrocyte
sedimentation rate) are often elevated in viral myocarditis [50]. Elevated blood concentrations
of cardiac troponins T and I are markers of cardiomyocyte damage or death and have
been reported in substantial numbers of children with myocarditis [[51], [52], [53]].
When symptoms repeated over several clinical episodes, many children show a “burned
out” myocardium with end-stage dilated cardiomyopathy [54]; nevertheless, myocarditis
can have an ominous prognosis in newborns. Mortality when Coxsackievirus B is the
suspected pathogen can be as high as 75% [55]. Mortality is less than 25% in older
children, and another 25% will have chronic symptoms of heart failure. Recovery is
complete in half of children with myocarditis [56].
Sudden death in children is commonly associated with myocarditis. Sudden death occurred
in 57% of autopsied patients with a diagnosis of myocarditis at a single pediatric
center in children over 12 years with a median age of 10 months (range, 10 days to
16 years) [57]. Studies of sudden infant death syndrome have linked infection with
viruses such as enterovirus, adenovirus, parvovirus B19, Epstein-Barr virus, and to
myocarditis [58,59].
3
Treatment
First-line treatments COVID-19 myocarditis include rest, oxygen, and diuretics. Inotropic
agents are useful for treating moderate-to-severe heart failure. Most children have
responded to anti-viral agents [60,61], intravenous immunoglobulin, steroids, and
cytokine blockers [47]. Registry studies show improvements in systolic ventricular
performance in viral heart diseases treated with cause-specific antiviral therapy
[62]. We found that monthly immunomodulatory treatment with IVIG markedly improved
cardiovascular structure and function in these virus-infected children [63]. Further,
we have found that some of these infected children have progressive cardiovascular
abnormalities that are strongly associated with chronic inflammation [64]. Acute and
chronic immune activation also affects vasculitis in these children [65,66].
However, from longitudinal follow-ups of other virus-exposed or infected children,
we have learned that viral-associated cardiovascular diseases in children are much
more complicated than indicated by the mere assessment of systolic ventricular performance
[67]. Assessing the global risk of developing symptomatic cardiovascular disease by
using Pathobiological Determinants of Atherosclerosis in Youth coronary arteries and
abdominal aorta risk scores calculated by measuring a combination of modifiable risk
factors, along with other surrogate markers of symptomatic cardiovascular disease,
are more informative than assessing systolic ventricular performance alone [67]. For
example, although antiviral therapy increases LV systolic performance in virus-exposed
or infected children, it can also result in long-term diastolic dysfunction [68],
as well as other major persistent or progressive cardiovascular issues. One of the
remarkable outcomes is that these hearts often remain too small for the body as these
children grow, perhaps because of the stunting effects of viral replication leading
to stunting of cardiac growth [69,70], which may eventually be associated with premature
symptomatic cardiovascular diseases.
Children with myocarditis who have a swollen endothelium and depressed heart function
are particularly vulnerable to cardiotoxic medications, such as hydroxychloroquine
alone or in combination with azithromycin [71]. This vulnerability is secondary to
genetic susceptibility and variability and is associated with mitochondria mutations
[72]. Antiviral therapy-associated cardiotoxicity in these children is not a class
effect. Rather, specific antiviral therapies can have more deleterious effects on
cardiovascular structure and function [73], allowing antiviral therapy to be tailored
to achieve the greatest efficacy while minimizing cardiovascular toxicity. Several
over-the-counter medications have been removed from the market, because they can increase
the risk of QT-prolongation, which is associated with sudden death in children with
myocarditis and other heart damage [74]. For example, the US FDA issued a “Black Box”
warning that long-acting stimulant therapy for children with underlying cardiovascular
disease should be carefully assessed, given a possible association with sudden death
[75,76].
4
The importance of patient registries
Multicenter, pediatric cardiovascular disease registries comprised of prospectively
collected data have supported treatments that have reduced the failure of medical
management of cardiomyopathy by 50% at participating centers [77], emphasizing the
importance of registry-based research that may lend itself to COVID-19 cardiovascular
diseases. With data from a registry, we recently developed a new classification system
for pediatric myocardial diseases [78] by identifying differences in the course and
outcomes specific to the causes of several cardiomyopathies [79]. Competing-risk analyses
established that children with suspected myocarditis have outcomes similar to those
in children with histologically proven myocarditis, a finding that can avoid the risks
of biopsy. Although echocardiograms of children with myocarditis may be similar to
those with dilated cardiomyopathy, their course and outcomes differ, which may help
manage COVID-10 cardiac disease [54].
A final note here about the how to ensure the safety of the providers caring for children
with COVID-19. In the current climate with the COVID-19 pandemic there is significant
concern among all clinicians around the potential consequences of being infected,
including history of immune suppression, diabetes, heart disease, and also seems to
have an increased effect in the Black, Asian and Minority Ethnic (BAME) community
due to the excess deaths faced by this cohort [80,81]. Several groups around the world
are recommending to risk stratify healthcare workers as a way to best protect healthcare
workers that are most at risk of getting infected [82]. Related, the coronavirus pandemic
has greatly affected how echocardiograms are acquired in the intensive care unit and
perioperative settings. Careful consideration of the indications, venues, and approaches
for echocardiographic imaging will protect healthcare providers, and preserve the
operational integrity of health systems [83]. Echocardiography personnel can be further
protected by carefully reassigning those at increased risk for infection, such as
advanced age, chronic conditions, immunosuppression, and pregnancy [84].
5
The need for immunology research strategies
COVID-19-associated cardiovascular disease is thought to be associated with both immune
activation and viral effects in some affected children. This immune vulnerability
makes it imperative to determine whether this Kawasaki disease-like illness is causally
associated with COVID-19 and, if so, to identify the biological and immunological
processes involved.
Tomisaku Kawasaki first reported his 50 cases in Japan a half-century ago, but the
definitive causes of Kawasaki disease remain unknown [31]. Serum cardiac troponin
concentrations are consistent with active cardiomyocyte injury that goes beyond the
often-reversible myocardial depressant effects of certain cytokines that are activated
or that “storm” in some of these children. These conditions suggest that children
are likely to experience long-term cardiovascular effects because cardiomyocyte death
or mitochondrial damage are often irreversible.
Some investigators have suggested that the coronavirus family might be one of the
triggers of Kawasaki disease, SARS-CoV-2 being a particularly virulent strain able
to elicit a powerful immune response in the host [85]. Intriguing questions have been
raised about the affinity of the coronavirus and the Angiotensin Converting Enzyme
2 (ACE2) receptor for cell entry, which is also associated with Kawasaki disease [86].
A recent study examined upper and lower airway cells for the expression of ACE2, the
gene that codes for the receptor that the coronavirus uses to infect cells [87]. Preliminary
evidence suggests that an allergy paradoxically may reduce the susceptibility to SARS-CoV-2
infection and severe COVID-19 disease. In both children and adults, respiratory allergy,
asthma, and controlled allergen exposure were associated with greatly reduced ACE2
expression. The expression of ACE2 was lowest in people with more severe asthma and
a higher sensitivity to allergens.
We have found that some children acutely treated for cancer can have a similar pattern
of dead and dying cardiomyocytes and irreversible mitochondrial injury [88]. In these
children, one of the leading mechanisms is free-radical injury to cardiomyocytes and
their mitochondria from the cancer and its treatment. In high-risk children with a
genetic predisposition [89] or exposure to certain risk factors and cancer therapies,
treatment that reduces free-radical injury results in substantially fewer damaged
cardiomyocytes and mitochondria with less cardiac injury [[90], [91], [92], [93]]
even years later. These results indicate the need to understand the course, risk factors,
and biomarkers of pediatric cardiovascular diseases to support the development of
cause-specific therapies and to prevent toxicity and late effects. Many lessons are
to be learned, but targeted discovery is key. We have suggested a research agenda
and funding strategies that may lead to better clinical outcomes for children at risk
of cardiovascular diseases [[94], [95], [96]].
6
Clinical testing
Children are currently not tested for COVID-19 as often as are adults because they
have no or only mild symptoms. We need to know whether the rates of SARS-CoV-2 infection
differ between children who have asthma or other allergic conditions and children
who do not [97].
For children with presumed acute-onset viral disease, detecting active myocardial
involvement is critical because its symptoms can be wrongly attributed to respiratory
or infectious complications, delaying appropriate therapy [98,99]. We found that nearly
10% of children presenting to the emergency department of a major children's hospital
with presumptive viral febrile illnesses had active myocardial injury, characterized
with dead and dying cardiomyocytes, and about 2% had serum concentrations of cardiac
troponin T similar to those found in adults with acute myocardial infarctions. Yet
for these young children, cardiac involvement was clinically unsuspected [100]. “If
you don't look for it, you may not find it.” Further, some of these cardiac biomarkers
are validated predictors of long-term cardiovascular health or disease in children,
which better informs treatment decisions in high-risk groups [101]. The possibility
of unsuspected myocardial injury suggests that children with symptoms of COVID-19
infection should also be screened for cardiac involvement by measuring serum concentrations
of cardiac troponin and NT-proBNP, both of which have low costs in time and money
and would not delay potentially more appropriate therapy.
7
Conclusions and recommendations
We believe the growing threat to children from COVID-19 supports the following recommendations
for policymakers and clinicians.
1.
Organizational learning must be a top priority
The COVID-19 pandemic has seriously tested the reliability of social, learning, and
governance systems [102]. Peer to peer, “horizontal learning” that brings researchers,
clinicians, and policy makers together to create a “community of practice” is an innovative
and comprehensive approach to pediatric multidisciplinary “action research.” The resulting
learning collaboration can be powerful tool to improve COVID-19 learning [103]. Multi-stakeholder
collaborations and authentic learning partnerships can address the tempo of learning
from the widespread care of all children with COVID-19 while reducing harmful and
unscientific variations in COVID-19 cardiac care [104]. Evidence has shown that creating
this “community of practice” builds trust, shares knowledge, and generates empirical
evidence to use and disseminate innovative quality-improvement initiatives to improve
communication, coordination, and clinical teamwork [105]. The approach represents
a fundamental paradigm shift in that it actively seeks to bridge disciplinary silos
and to address knowledge gaps within and across COVID-19 care delivery system [106].
Such an approach can support the creation of an integrated research and implementation
continuum, stretching from prehospital care to long-term wellness that can transform
the care delivery services and spread innovation and uptake [107].
a.
Agree on Definitions and Data Collection. We need to obtain consensus on common diagnostic
definitions and to ensure their widespread and consistent use by providers, public
health officials, and policymakers [108,109].
b.
Identify and Validate Surrogate Endpoints. Conducting trials in children with heart
failure is challenging because selecting and interpreting study endpoints to evaluate
policy and service interventions remain contested [110]. Many studies of these children
have tested the utility of serum biomarkers, imaging studies, and disease severity
as surrogate endpoints. Although such endpoints have been proven useful for risk stratification,
none have been validated as predictors of “hard” clinical endpoints in this population
[111,112].
c.
Fund and Support Cardiac Registries. A global pediatric COVID-19 cardiac registry
of patient characteristics and outcomes [113], modeled, for example, after the Pediatric
Cardiomyopathy Registry, should be established as soon as possible. Similar pediatric
registries have proven their value in understanding and treating diseases in children
[114].
2.
Health Policy Funding Priorities. Funding needs to be increased substantially for
pediatric public health; test development, supplies, and personal protective equipment;
and for the routine application of serological testing, once available and well-validated,
in the diagnosis and management of COVID-19 patients. At the same time, targeted funding
for COVID-19 pediatric cardiac injury research is needed to support longitudinal studies
of immune response and risk of re-infection [115,116].
3.
Better Child Screening. Large, high-quality population studies are needed. Symptomatic
children should be tested for COVID-19 infection and for serum concentrations of cardiac
troponin and NT-proBNP to screen for occult cardiac involvement.
4.
Protecting Health Care Workers. The safety and wellness of health-care workers must
be ensured. Data from China [117], Italy, Spain, Italy, UK [118], Mexico, and the
US show that tens of thousands of responding health-care workers have been infected
and hundreds have died [119]. In the UK and the US, most healthcare workers who have
died have come from black, Hispanic and Asian backgrounds [81]. Reports from medical
staff describe physical and mental exhaustion, the torment of difficult triage decisions,
and the pain of losing patients and colleagues, all in addition to the ever-present
risk of potentially fatal infection. Assuring adequate availability of personal protective
equipment is just the first step; other measures must be considered, including cancelling
of non-essential medical care and group events to concentrate resources and providing
food, rest, and personal and family psychological support [120]. In any pandemic,
health-care workers are every country's most valuable resource.
5.
Virtual Care is the Future. The movement toward virtual visits aims to protect children,
their families, and healthcare workers from exposure to COVID-19, so eliminating as
much in-person traffic and contact as possible at hospital and clinics is essential.
Telemedicine is not new, but the urgency of the COVID-19 crisis has forced most healthcare
organizations to make radical shifts to telehealth within a few weeks, transitioning
most appointments to a telemedicine platform. Using appropriately software, clinicians
can carefully triage upcoming appointments to select children most appropriate for
telemedicine visits and those who should be seen in person, such as patients who need
to come in for chemotherapy infusions. We need to better understand how and when to
best use patient-facing digital health technologies and how these technologies influence
the quality, safety, and satisfaction of children and their families [121].
6.
Inequity. Pediatricians, health service researchers, and policy makers are not at
all surprised to read headlines about the disproportionately high numbers of COVID-19
deaths among the poor, underrepresented minorities (black and minority ethnic backgrounds)
and people who are in nursing homes, marginalized and homeless, incarcerated, highly
religious, and indigenous. Unfortunately, the number of minority healthcare providers
and social workers that have been infected and died is also disproportionally high
[81]. It is time to commit the resources and political will to address inequalities
in care, especially among children.
Declaration of competing interest
The authors have no conflicts of interest to declare.