Author of summary: Lanfranco Pellesi; Reviewer: Francesca Bardi
Current data suggest that COVID-19 is less frequent in children, with a milder course. However, an increase in the number of children with a phenotype resembling Kawasaki disease has been observed over the past weeks. The aim of the current minireview is to recapitulate the current discoveries on children and adolescents affected by the recent outbreak of Kawasaki disease and to evaluate a potential association with SARS-CoV-2 infection.
The rapid spread of Coronavirus disease 2019 (COVID-2019) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to a global pandemic, with infected individuals of all ages. Pediatric patients appear to be affected in much smaller proportion compared to adults, with almost no fatalities reported. An epidemiologic report described over 90% of pediatric patients as asymptomatic, mild, or moderate cases . Little is currently known on co-incidence with other clinical conditions, including Kawasaki disease (KD), an acute vasculitis of childhood.
KD is a medium and small-sized vessel vasculitis occurring mainly in children under the age of 5 years. The pathogenesis is currently unknown. The current consensus is that KD is a result of an aberrant immunologic response to one or more unidentified pathogens in genetically susceptible children . The immunologic cascade leads to a systemic inflammation in medium sized arteries and multiple organs. Coronary aneurysms are the main complications, representing the primary cause of acquired heart disease in developed countries. As the incidence of KD peaks during winter and spring seasons, some evidence suggests an infectious trigger. Various studies have described an association between viral respiratory infections and KD [3,4,5]. However, the search for the infectious trigger has been unsatisfactory.
Viruses of the coronavirus family have been proposed as possibly implicated in the KD pathogenesis. In 2005, a novel human coronavirus, designated as New Haven coronavirus (HCoV-NH), was identified in the respiratory secretions of 8 out of 11 children with KD, versus 1 out of 22 controls tested by RT-PCR . However, a subsequent Japanese study found no RNA sequences of HCoV-NH in 19 children with KD, compared to 5 out of 208 controls (2%) . Another group from Japan explored the association between two coronaviruses (HCoV-NL63 and HCoV-229E) and KD by serological tests. No difference was detected regarding HCoV-NL63, whereas HCoV-229E antibody positivity was higher in KD patients . Following associations between coronaviruses and KD have been inconsistent or not replicated [9,10].
A relationship between COVID-19 and late manifestations of a Multisystem Inflammatory Syndrome (MIS) and KD-like features in pediatric patients has been increasingly suspected [11,12,13,14,15,16]. The temporal association between the onset of the COVID-19 pandemic and the results of tests (RT-PCR and antibodies) for SARS-CoV-2 suggests a causal link [13,15,16]. In a tertiary pediatric referral centre in Italy, the monthly incidence of KD-like disease was at least 30 times greater than the monthly incidence of KD in the previous 5 years . The development of KD-like features in these patients is more likely to be the result of a post-viral immunological reaction.
Post-infective MIS associated with COVID-19 is a novel disease in children, resembling KD. Common features include fever and gastrointestinal symtpoms, including abdominal pain, diarrhea and vomiting, with or without a rash [14,15,17,18]. Presentations of mucocutaneous inflammation (e.g., conjunctivitis, cervical lymphadenopathy) and systemic inflammation with organ involvement can also be seen. Moreover, they were described with a major pro-inflammatory state, along with leucopenia with marked lymphopenia, neutrophilia, thrombocytopenia, and increased ferritin [14,15,17,18,19]. Overall, the emerging phenotype is a combination of typical/atypical KD, Kawasaki shock syndrome, toxic shock syndrome, and macrophage activation syndrome/hemophagocytic lymphohistiocytosis.
KD-like features in pediatric patients were also associated with a high frequency of severe myocarditis and/or pericarditis. MRI findings revealed acute myocarditis with signs of diffuse myocardial edema and hyperemia, without evidence of focal myocardial necrosis/fibrosis and coronary artery abnormalities [20,21]. Increased levels of brain natriuretic peptide and troponin I were also found, with a transient systolic dysfunction. The time of occurrence of the acute myocarditis and the high rate of IgG and IgA identification strongly suggest a post-viral immunological reaction impacting the myocardium. Besides, the cardiac function improvement as well as the decrease in inflammatory biomarkers following treatment reinforces the hypothesis of a SARS-CoV-2 post-infective disease.
It is unclear whether COVID-19 causes KD or a syndrome that mimics KD. All these results support the hypothesis that the immune response to SARS-CoV-2 is responsible for KD-like features in susceptible patients. This phenomenon appears to result from an uninhibited immune response to a prior COVID-19 infection rather than a direct injury resulting from the acute viral infection. This is observed from the surge of cases presented around 2 to 3 weeks after the infection and the majority of children having a negative RT-PCR, but positive viral serology. Further research on the cause of KD and similar syndromes should focus on immune response to viral triggers.
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