Effect of COVID-19 on Kawasaki Disease: Decrease Age of Onset and Increase Skin Manifestation

Kawasaki Disease (KD) is the most common form of vasculitis in childhood that predominantly affects children under 5 years of age. KD is an acute onset systemic vasculitis involving medium and small-sized arteries with a predilection toward the coronary arteries [1]. Cardiac manifestations in KD include coronary aneurysm/dilatation, aortic root dilatation, myocarditis, and rarely cardiogenic shock. KD is considered to be the most common cause of acquired heart disease in children in developed countries. The certain etiology of KD has not been determined yet, but viruses have been suspected to be a causal factor [2].

The Coronavirus disease 2019 (COVID-19) pandemic caused by a novel mutant coronavirus, also known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), rapidly spread throughout China, and later on throughout the world, resulting in a global health crisis affecting all ages. SARS-CoV-2 infection is usually responsible for mild to moderate respiratory symptoms in children. While COVID-19 appears to be less severe in children, there is a growing concern that the disease might present as post infection immune dysregulation, especially in young asymptomatic children. Post-viral immunological reactions are thought to play an important role in the pathogenesis of this phenomenon. This condition is called “pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 infection (PIMS-TS)” or multisystem inflammatory syndrome in children (MIS-C) that is hard to distinguish from KD [3‐6].

An increase in the incidence of KD and alterations in its clinical features have been observed during the COVID-19 pandemic. With the limited number of studies in this regard, and the existence of controversies among scientific societies being into consideration, the present study conducted to investigate the association between KD and COVID-19 and compare with same period of time before COVID-19 pandemic.

In adults, COVID-19 is typically characterised by pneumonia and respiratory symptoms as well as inflammatory cascade hyperactivation [9, 10], whereas in children the respiratory tract seems not to be the only system infected by SARS-CoV-2 infection [11‐13]. There is some evidence indicating that COVID-19 might present in children as a post-infection immune dysregulation. this condition is called “pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 infection (PIMS-TS)” or multisystem inflammatory syndrome in children (MIS-C) seems to be a post SARS-COV-2 infection immune reaction. It often appears few weeks after the SARS-COV-2 infection and only a proportion of patients, maybe 1/3 seems to have a positive PCR at diagnosis [14]. Some of those patients have overlapping features with KD. As mentioned earlier, KD is suspected to have correlation with COVID-19 infection since an increase in KD incidence and changes in its clinical features were observed during the COVID-19 pandemic; however, some controversies exist [15].

We performed this study to investigate possible association between KD and COVID-19. Demographic, clinical, laboratory and echocardiographic data of hospitalized children with established KD diagnosis during COVID-19 pandemic (February to September 2020) were compared with characteristics of KD patients at the same period of time in 2019.

Our study demonstrated that 68% of the total KD patients during the COVID-19 pandemic were COVID-19 positive which was significantly higher than previous literature conducted by Lio K et al. and Verdoni L et al. that reported 14%, and 30% of COVID-19 positive in KD patients [15, 16]. This difference might be due to the higher prevalence of COVID-19 in Iran; moreover, it might suggest that ethnicity and genetic factors may contribute. Our results showed that the demographic information, clinical presentations, laboratory findings, and echocardiographic characteristics of our patients were similar to previous literature in KD. The most common clinical presentation of KD was rash (seen in 62% of patients), oral mucosa and lip involvement (58%), and extremity changes (58%). Our findings were similar to the findings of Cheraghali F et al. [17] introducing skin rash (68.6%) and changes of the lip and oropharyngeal mucosa (60.8%) as the most common manifestations of KD, but were slightly different from Pilania R.K. et al. which showed oral cavity and lips’ changes as the most common manifestation (> 95%) of KD, and rash as the second (> 90%). Furthermore, our results showed that neck lymphadenopathy was the least common clinical finding that is compatible with Pilania R.K. et al. [18].

There was an apparent decrease in KD cases in our referral hospital’s admissions during the COVID-19 pandemic in comparison with the same period last year. Lio K et al. reported a similar drop in KD cases in Tokyo, Japan, in contrast with Verdoni L et al. who showed an increase in disease incidence in Bergamo, Italy. Epidemiological clusters of KD occurrence, seasonal changes and a very low risk of recurrent Kawasaki suggest that several factors can be triggers for KD like infectious agents [19]. Consequently, in our study, KD admission rate decrease was assumed to be a reflection of the decrease in other viral and bacterial infective diseases during the COVID-19 pandemic because of the quarantine and improvement of hygiene; therefore, SARS-CoV-2 infection is probably not an indicating factor for prevalence or incidence of KD and needs further investigation.

There was no significant difference between the demographic information, clinical presentations, laboratory findings, and echocardiographic characteristics between the two groups and between COVID-19 Positive and COVID-19 negative patients in the course of the COVID-19 pandemic; however, there was a significant decrease in the mean age of KD presentation comparing to last year. The results were similar to the ones of Verdoni L et al. that found a difference in the mean age of KD patients during and before the COVID-19 pandemic (3·0 vs 7·5 years). In contrast, Lio K et al. demonstrated that there was no significant difference in mean age of KD presentation. Accordingly, such results can suggest that at younger ages, SARS-CoV-2 infection may increase the prevalence of KD.

We only analysed CRP and ESR results of the patients as the predominant laboratory data for KD diagnosis. CRP and ESR results in KD patients during the pandemic (group 1) were compared to last year records of KD patients (group 2). Our results show no significant difference in laboratory data between the two groups. Our results (ESR = 75.79 mm/h in group 1 vs ESR = 57.5 mm/h in group 2 and CRP = 50.39 mg/L in group 1 vs CRP = 58.25 mg/L in group 2) are similar to Verdoni L et al. research that represent no significant change in ESR and CRP (Mean ESR: 72 mm/h, mean CRP: 25 mg/dL) during COVID-19 pandemic.

In European countries, the proportion of KD patients with coronary artery aneurysm reported were similar to that reported in North America, eg, in Ontario, Canada, during 2004–2006, approximately 4% of KD patients were reported to have developed coronary artery aneurysms and 4.6% with aneurysms in Ireland. Slightly higher proportions of KD patients with coronary artery aneurysm reported in recent studies in Northern France (18%) and Northern Italy (24%) [20, 21]. The incidence of coronary artery dilatations and aneurysms in our study was 43% with no significant difference between COVID-19 pandemic time and before (34% in group 1 and 26% in group 2) that is in contrast with Verdoni L, et al. research that represents an increase in cardiac involvement (2 of 19 vs 6 of 10). Incidence of coronary involvement is significantly higher in our research compared to mentioned literature that can be due to referral of our hospital and difference in ethnicity and genetics that need to be investigated.

In our study the incidence of coronary artery abnormalities was higher in COVID-19 negative cases compared to the ones who tested positive (40% vs 31.8%, p < 0.05). This is compatible with Verdoni L et al., in which 67% (4 of 6) of the patients who were tested negative for COVID-19 demonstrated abnormal coronary artery findings, versus 50% (2 of 4) of COVID-19 positive cases.

The limitation of our study is that the present report based on a retrospective study at a single tertiary referral center in Iran’s southwest. Further studies are needed to clarify the actual relationship between COVID-19 and KD. Since the current study focused only on patients with KD, the exact epidemiology and characteristics of PIMS-TS was not analysed and excluded.

Sixty-eight percent of KD patients were COVID-19 positive during the pandemic of COVID-19 and the age of onset for KD during the COVID-19 pandemic was lower than the same period of time before the pandemic. Skin rash was significantly higher in COVID-19 positive patients, but coronary involvement was more prevalent in COVID-19 negative patients. We did not find increasing in KD admission rate during the COVID-19 pandemic.

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.