The COVID-19 pandemic has already reached over 80.8 million infections and caused over 1,760,000 deaths till December 2020. While the exactly prevalence of COVID-19 in children is still unknown, mounting evidence has highlighted that the clinical severity of COVID-19 in children and young adults appears significantly milder compared to older individuals with comorbidities. (20, 21) COVID-19 was also reported to induced the Kawasaki-like disease, the multisystem inflammatory syndrome in children (MIS-C), a novel syndrome linked to SARS-CoV-2. In this study, we compared the difference between children patients with COVID-19 (not MIS-C) and KD (not including KD shock syndrome, KDSS) and demonstrated that higher WBC, platelet, procalcitonin, and AST provide laboratory markers for distinguishing COVID-19 from KD. We further revealed that KD patients have lower age and higher characteristics of fever than COVID-19 children. Other laboratory data including lactate dehydrogenase (LDH), D-dimer, creatine kinase (CK) and serum creatinine were also increased in children with COVID-19. According to the statement of American Heart Association (AHA) (13, 22), LDH, D-dimer, CK and serum creatinine didn't in the list of supplementary criteria of suspected incomplete KD. However, LDH, CK, serum creatinine and D-dimer levels were reported to be higher in KD patients and associated with IVIG resistance or coronary artery lesions formation. (23-26)
The golden period for IVIG treatment in KD patients is around five to nine days after disease onset; therefore, early awareness of KD is very important both for clinicians and parents. However, the challenge for clinicians in pediatric emergency departments is early identification of KD because KD shares many clinical signs with other febrile illnesses in childhood. (27) Furthermore, with “stay at home” orders and trepidation related to COVID-19 infection, many parents now hesitate or fear seeking in-person consultation for their children. Harahsheh et al., raised the concern of a future surge in the prevalence of CAAs caused by the potential for missed or late diagnosis and treatment of KD in children. (28)
In 1974, Tomisaku Kawasaki first described 50 cases of KD in English language. (29) The etiopathogenesis of KD remains unknown even today, and many studies have failed to identify a pathogen responsible for KD or any identified pathogens could not be repeated between studies. (30) Furthermore, growing evidence has demonstrated that KD may be the result of a combination of infection, genetics, environment and immunity. (31) In addition to standard diagnostic criteria, KD patients may experience a variety of nonspecific clinical features, including uveitis, aseptic meningitis, gastrointestinal symptoms, maculopapular rash, impaired liver function, and anemia. (7, 32, 33) Hepcidin-induced iron deficiency was reported to be related with transient anemia and disease outcomes in KD patients but anemia was not found in children with COVID-19. Neutrophil percentage was higher in KD patients than COVID-19 while lymphocyte percentage showed higher in COVID-19 children than KD indicating viral immune response in COVID-19.
In the most severe cases of KD, patients may develop hemodynamic instability, known as KD shock syndrome (KDSS), and secondary hemophagocytic lymphohistiocytosis fulfilled the criteria of macrophage activation syndrome (MAS). (34) Surprisingly, several lines of study have suggested that COVID-19 children have presented significantly unwell across Europe and the US with a novel syndrome linked to SARS-CoV-2 (MIS-C). (35, 36) This rare syndrome of COVID-19, children shares common features with other pediatric inflammatory conditions, including KD, staphylococcal/streptococcal toxic shock, macrophage activation syndrome, and sepsis. (36)
In 2005, Esper et al. identified a novel human coronavirus tested by RT-PCR, designated New Haven coronavirus (HCoV-NH), in the respiratory secretions of eight of 11 children with KD versus one of 22 controls. (37) Notably, Jones et al., reported a six-month-old infant diagnosed with KD and treated with IVIG and aspirin and positive screening of COVID-19 in Italy. (38) Thereafter, Verdoni et al., reported a case series of a 30-fold increased incidence of Kawasaki-like disease at the Italian epicenter of the COVID-19 epidemic. (39) The patients who showed evidence of an immune response to the COVID-19 virus were older, had a higher rate of cardiac involvement, and macrophage activation syndrome features. (39) Consistently, in Whittaker et al.’s study, pediatric MIS-C patients were generally older than those with KD or KDSS and had higher WBC, and CRP, as well as more profound lymphopenia and anemia. (40) The COVID-19 epidemic has also been associated with a high incidence of a severe form of KD (41). They also identified that the Kawasaki-like disease described here remains a rare condition, probably affecting no more than one in 1000 children exposed to COVID-19. (39) The very limited COVID-19 children (N=24) included in this study is the limitation and weakness of this study. However, the association between KD and COVID-19 still warrants further investigation. In the era of the COVID-19 pandemic, multisystem inflammatory presentations of COVID-19 children and typical KD patients will be more challenging for clinicians and pediatricians in the future.