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