Kawasaki disease was discovered by Tomisaku Kawasaki in Japan in 1967. He described a sample of 50 paediatric patients that were all suffering from an “acute febrile mucocutaneous syndrome with lymphoid involvement and specific desquamation of the fingers and toes” (Burns, 2017). This presentation gives the disease its other name, mucocutaneous lymph node syndrome. Recently, there have been an increase in cases of Kawasaki disease, specifically during the COVID-19 pandemic. This article will describe the general presentation of Kawasaki disease and how it could possibly relate to COVID-19.
Kawasaki disease is referred to as a systemic, febrile vasculitis. It is diagnosed by the presence of 4 positive symptoms in addition to a fever and abnormal laboratory values (Agarwal and Agrawal, 2017). The typical symptoms include: a strawberry tongue and fissured lips, bilateral conjunctivitis, cervical lymphadenopathy, limb changes (swelling of hands and feet), and multiple skin rashes over the body (table 1) (Agrawal and Agrawal, 2017; Hedrich et al., 2018). Although the disease is multisystemic, it has a predilection for small and medium sized arteries, especially the coronary arteries of the heart. If the disease is not treated then there is the risk of progression to coronary artery aneurysm, thrombosis, stenosis, and sudden death (Agrawal and Agrawal, 2017).
Kawasaki disease mainly affects children under the age of 5 years and over the age of 6 months (due to the presence of maternal antibodies). The highest annual incidence of Kawasaki was reported to be in Japan (239/100,000 affected children under the age of 5 years), Korea (113.2/100,000), and Taiwan (69/ 100,000). The United States has reported an annual incidence of 19/100,000 affected hospitalised children with Kawasaki disease, while Europe reports a minor 8.5/100,000 affected. The highest incidence of the disease seems to be in winter, which was the reason that scientists began to contemplate that the cause of Kawasaki may be viral (Agrawal and Agrawal, 2017).
The cause of Kawasaki has never been determined. There has been a general consensus that the aetiology is an interplay between genetic susceptibility and an infectious trigger. Specifically, the infectious trigger is believed to activate those that are susceptible. There are many supportive reasons for the hypothesis that a viral infection causes Kawasaki, which includes: (1) the incidence of Kawasaki increases in the winter seasons when majority of viral infections predominate, (2) the epidemics of Kawasaki are clustered similarly to infections, (3) the disease is self-resolving within 1 - 3 weeks, (4) the common age is 6 months to 5 years, a period where children are highly susceptible to viral infections (Agrawal and Agrawal, 2017). Electron microscopy was used to examine tissue taken from the bronchial during autopsy, this showed the presence of aggregates of RNA and viral protein, which suggests that Kawasaki disease could be initially due to an acute viral infection of the upper respiratory tract later leading to a dysregulated immune response. No infectious agent has been found despite intensive efforts to characterise such a virus (Hedrich et al., 2018).
Rowley et al. (2019) proposed the RNA Virus Theory for Kawasaki. This theory was formed after a postmortem examination of Kawasaki patients revealed the invasion of many macrophages, CD8 T-cells, and IgA producing plasma cells in the lung tissue. These specific immune cells are usually present in viral diseases, and the location supports the theory of a respiratory origin. Recent studies have shown that respiratory viruses are detected by polymerase chain reaction (PCR) in more than 50% of Kawasaki patients. Interestingly, this study by Rowley et al. suggested that there needs to be more research into novel viruses as the causative agent and Nakamura et al. (2019) suspected Human Coronavirus HCoV-NL63, which was closely matched to the RNA found in Kawasaki disease but not an exact match.
On the 7th April this year, Hospital Paediatrics published a case report describing an infant who was diagnosed and treated for Kawasaki disease. This patient also tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19. On April 26, an alert was sent to general practitioners in London advising them of rising numbers of inflammatory conditions affecting multiple organs in children, which looked very similar to Kawasaki disease. In Italy, Kawasaki was diagnosed in 20 children over a few days, equivalent to the total number of cases normally seen over a time span of 3 years. The French health minister reported that 15 children were admitted to hospital with symptoms of Kawasaki disease and comorbid COVID-19. On May 4th, the New York health department issued a health alert describing another 15 cases of Kawasaki-like disease with the novel coronavirus (Schroeder et al., 2020).
The evidence above is suggestive of a link between Kawasaki disease and COVID-19, or other respiratory viruses. It should be noted that although a link appears likely, we should avoid committing a causal fallacy. Before an attempt at a definitive answer is made, it is vital that more epidemiological observation and research is conducted.
References
Agarwal, S. and Agrawal, D., 2017. Kawasaki disease: etiopathogenesis and novel treatment strategies. Expert Review of Clinical Immunology, [online] 13(3), pp.247-258. Available at: <https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5542821/> [Accessed 23 May 2020].
Burns, J., 2017. History of the worldwide emergence of Kawasaki disease. International Journal of Rheumatic Diseases, [online] 21(1), pp.13-15. Available at: <https://escholarship.org/uc/item/6vx3n630> [Accessed 23 May 2020].
Hedrich, C., Schnabel, A. and Hospach, T., 2018. Kawasaki Disease. Frontiers in Pediatrics, [online] 6(198). Available at: <https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6048561/> [Accessed 23 May 2020].
Nagata, S., 2019. Causes of Kawasaki Disease—From Past to Present. Frontiers in Pediatrics, [online] 7(18). Available at: <https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6371652/> [Accessed 23 May 2020].
Nakamura, A., Ikeda, K. and Hamaoka, K., 2019. Aetiological Significance of Infectious Stimuli in Kawasaki Disease. Frontiers in Pediatrics, [online] 7(244). Available at: <https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6611380/#B28> [Accessed 23 May 2020].
.Rowley AH, Wylie KM, Kim KY, Pink AJ, Yang A, Reindel R, Baker SC, Shulman ST, Orenstein JM, Lingen MW, Weinstock GM, Wylie TN. BMC Genomics. 2015 Dec 18. The transcriptional profile of coronary arteritis in Kawasaki disease; (16):1076.
Schroeder, A., Wilson, K. and Ralston, S., 2020. COVID-19 And Kawasaki Disease: Finding The Signal In The Noise. [online] American Academy of Pediatrics. Available at: <https://hosppeds.aappublications.org/content/early/2020/05/11/hpeds.2020-000356.long> [Accessed 23 May 2020].
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