4 DISCUSSION
Pediatric patients have largely been overlooked during the COVID-19
pandemic, as the largest cohort of morbidity and mortality has come in
elderly adult populations.24 More recently, the
insidious connection between COVID-19 infections and a syndrome similar
to Kawasaki disease has been investigated as healthcare professionals
noticed outbreaks of the rare constellation of symptoms throughout the
United States and the world.25 The context of these
reports is essential as officials weigh the risks of reopening schools
with the pandemic ongoing, and physicians are treating pediatric
patients with severe inflammatory responses. The association of Kawasaki
disease to coronaviruses is still a continuous area of research, and the
COVID-19 pandemic provides a unique opportunity to investigate the
connection of coronavirus infection to a pediatric inflammatory response
that mimics Kawasaki disease.
The COVID-19-associated multisystem inflammatory syndrome patients
tended to be much older than typical Kawasaki disease patients. A large
sample of Korean Kawasaki disease patients showed a mean age of just
2.54 years compared to 9.10 in this meta-analysis.26This finding is especially important because children with onset of
Kawasaki disease aged nine or older are at a significantly higher risk
of developing coronary artery aneurysms and left ventricular
abnormalities; a feared outcome is up to 25% of untreated
children.27 Older age may be one of many factors in
Kawasaki-like disease that contributed to such high proportions of
patients experiencing shock and hypotension, along with elevated
troponin and BNP levels. Although the cardiac manifestations of Kawasaki
disease typically resolve within two years, the long-term effects of an
inflammatory response in Kawasaki disease are not fully known with
microvascular changes and intimal thickening proposed as possible
sequelae.28
Patients in this meta-analysis presented with many typical symptoms of
Kawasaki disease, as well as several atypical ones. A previous study on
Kawasaki disease risk factors for developing coronary artery aneurysms
showed that having more of the typical five symptoms is a protective
factor. At the same time, atypical presentations are a risk
factor.29 Although many of the patients in our
analysis who developed Kawasaki-like illness related to COVID-19 had a
polymorphous maculopapular exanthema, nearly half of patients lacked
oral mucosal changes and conjunctival injections, and over half lacked
cervical lymphadenopathy and peripheral edematous changes to
extremities. Atypical gastrointestinal and neurocognitive symptoms were
frequent and may have contributed to delayed recognition of the
children’s condition as an inflammatory disease similar to Kawasaki
disease, thus delaying intravenous immunoglobulin administration.
Abnormal electrocardiograms and chest X-rays were also common findings
on admission for the multisystem inflammatory syndrome. The differences
between this clinical picture and Kawasaki disease will likely lead to
delays in treatment that could be detrimental to patients. It will be
necessary for pediatric tertiary care centers to stay apprised to the
evolving presentation of this inflammatory illness. One postulation for
the protective association of a patient’s number of symptoms and lower
risk of coronary artery aneurysms is less delay in the administration of
treatments like intravenous immunoglobulin. Another is that
dysfunctional immune systems are less likely to produce as many classic
symptoms of the disease.29
The massive inflammatory response to infection with COVID-19 is a
significant point of focus for research, novel therapeutic developments,
and vaccine research trials. Pediatric patients in this meta-analysis
had markedly elevated inflammatory markers, including C-reactive protein
and procalcitonin, which have been previously associated with an
increased risk of coronary artery aneurysms in Kawasaki
disease.29 The pathophysiology of Kawasaki disease and
its complications are driven by an intense inflammatory cell response
primarily to medium-sized blood vessel walls.30Children who develop Kawasaki disease often have a viral illness that
precipitates this immune response. About 69.6% of the patients in this
meta-analysis tested positive for SARS-CoV-2 IgG antibodies, a higher
number than tested positive for the nasal swab polymerase chain
reaction, which suggests that a COVID-19 infection weeks earlier could
have triggered the multisystem inflammatory syndrome and hemodynamic
shock.
Many of the laboratory findings in this pediatric population were
consistent with findings in adult patients who developed severe
respiratory disease from SARS-CoV-2. Elevated lactate dehydrogenase,
d-dimer levels, procalcitonin levels, troponin I level, and lymphopenia
have been demonstrated as markers of worse outcomes in adult COVID-19
patients.31 Interleukin-6 (IL-6) has been associated
with the “cytokine storm”, or macrophage activation syndrome-like
disease thought to be a factor in the development of acute respiratory
distress syndrome in adult patients.32 IL-6 also plays
a role in the pathogenesis and, more recently, targeted therapy of
childhood inflammatory disorders like systemic juvenile idiopathic
arthritis.33 Similarly, children who developed
multisystem inflammatory syndrome in this meta-analysis had remarkably
high IL-6 levels with a mean of 189.67 pg/mL, exhibiting the role of
systemic inflammation. Further research could evaluate whether
immunomodulatory therapies like tocilizumab, in addition to intravenous
immunoglobulin, could be useful for pediatric patients at risk of
developing progressing to the multisystem inflammatory syndrome.
One of the limitations of this meta-analysis was that the studies were
conducted in the United States and Europe. East Asian countries, which
historically have higher rates of Kawasaki disease, have pediatric
populations that have had longer COVID-19 exposure times, and
retrospective studies could be helpful to assess differences in
prevalence and outcomes. This region is also known to have different
phylogenetic SARS-CoV-2 genomes, which could influence the inflammatory
response seen in multisystem inflammatory syndrome
patients.34