Drop in Kawasaki Disease During COVID-19 Provides Clues to Pathogenesis

Efforts to control spread of SARS-CoV-2 early on during the COVID-19 pandemic in Japan were accompanied by a big drop in Kawasaki disease cases among young children, according to nationwide data. That provides some hints as to what might be causing the hyperimmune reaction characteristic of the condition, which can, in a minority of cases, lead to serious cardiac complications.

The number of cases diagnosed in 2020 was 35.6% lower than the number recorded in 2019, with the largest drops seen during a “special mitigation period” that included closures of schools and day cares cross the country, Ryusuke Ae, MD, PhD (Jichi Medical University, Shimotsuke, Japan), and colleagues report in a study published online this week in JAMA Pediatrics.

There’s evidence to support the idea that the reduction was due to the pandemic restrictions lessening exposure to whatever is causing Kawasaki disease—which remains unknown—as opposed to avoidance of the healthcare system by families wary of being exposed to SARS-CoV-2.

First, the pattern of falls and rebounds in Kawasaki disease numbers in 2020 differed between younger and older children, suggesting variations in exposure to the pathogen or pathogens responsible for the condition based on age. And second, there were no differences between 2019 and 2020 in how long parents waited before bringing their children to the hospital.

“We believe that the findings may support the hypothesis of a potential Kawasaki disease pathogenesis that may transmit through human-to-human contact,” Ae told TCTMD via email, noting that prior research from his group has shown that the reduction in Kawasaki disease during the pandemic differed from patterns observed with other pediatric infectious diseases. “Based on these findings, Kawasaki disease pathogenesis may have multiple pathways, including the transmission of something through human-to-human contact as well as other additional triggers.”

That suggests, he noted, that “some children can prevent Kawasaki disease by standard infection control measures, but it may not be effective for all children.”

Bucking a Long-term Trend

Studies from around the world reported a decline in Kawasaki disease numbers after the start of the COVID-19 pandemic. In Korea, for instance, there was a roughly 40% drop in cases. “These studies suggest that the global pandemic and its accompanying mitigation measures may provide an important opportunity to explore the hypothesis of a potential Kawasaki disease pathogenesis involving transmission via human-to-human contact,” Ae et al write.

Japan is particularly well equipped to study this issue as the country has been conducting a biennial national survey of Kawasaki disease since 1970. Over the past 50-plus years, there has been a general upward trend in both patient numbers and incidence rates, Ae said.

To see what happened during the first year of the COVID-19 pandemic, the investigators examined the 26th national survey, which covered 2019 and 2020. They defined a special mitigation period covering March to May 2020, which included nationwide closures of schools and day cares starting on March 2 and a state of emergency spanning April 7 to May 25.

Overall, 28,520 children (median age 26 months; 56.9% male) were diagnosed with Kawasaki disease in 2019 and 2020. The number was substantially lower in 2020 compared with the prior year (11,173 vs 17,347), reversing the prior long-term trend. The number of cardiac complications including coronary artery aneurysms and valvular lesions were also lower in 2020 than in 2019, although the proportion of patients with acute or delayed cardiac sequelae was similar in both periods.

There was no difference between the years in terms of the number of days parents waited before bringing their children to the hospital, with 96% presenting by day 7 overall, “suggesting that the decrease in Kawasaki disease incidence likely was not associated with pandemic-related delays in seeking treatment,” Ae et al write.

Average patient age at diagnosis tended to be lower in 2020 than in 2019, with a larger proportion diagnosed before age 12 months in the pandemic year (21.6% vs 19.4%; P < 0.001).

After implementation of pandemic restrictions, Kawasaki disease cases dropped more swiftly in children 2 years and older than they did in their younger peers, with an earlier and faster rebound after the special mitigation period.

“One potential reason for such differences is mask wearing,” the authors propose. “Given the existing hypothesis that Kawasaki disease may be triggered by inhalation of an unidentified ubiquitous respiratory agent, mask wearing might help prevent triggering Kawasaki disease mostly in children 24 months or older, whereas younger children are discouraged from wearing masks because of suffocation risk.

“Another possible reason,” they continue, “is that younger children are much less likely to use day care centers in Japan. . . . Therefore, nationwide school closures may have suddenly reduced human contact (and potential risk of acquiring unidentified Kawasaki disease pathogens) more dominantly among children 12 months or older, meaning a more prompt response and greater percentage reduction compared with patients younger than 12 months.”

Lingering Questions

Jane Newburger, MD, who wrote an accompanying editorial with Mary Beth Son, MD (both Boston Children’s Hospital, MA), told TCTMD the study is aligned with others showing that during the COVID-19 pandemic, which saw children wearing masks and often not going to school, the incidence of Kawasaki disease fell. And that’s not likely related to families avoiding the healthcare system, she said, noting that Kawasaki disease is well recognized in Japan. “There’s no reason to think it’s because people didn’t take their children to the doctor because the children who did come in had had the same number of days of fever as in previous eras.”

It’s scientifically interesting, but I don’t think it translates to any policy changes. Jane Newburger

Instead, it’s likely the steps taken to mitigate the spread of SARS-CoV-2 had a similar effect on whatever is causing Kawasaki disease. It’s long been hypothesized, Newburger said, that Kawasaki disease is a postinfectious reaction, much like the multisystem inflammatory syndrome in children (MIS-C) is a response to COVID-19, but a decades-long search has not been able to uncover the pathogen or—more likely—pathogens responsible for the hyperimmune response.

The current study doesn’t help narrow down a potential cause or suggest changes to management, she said. “It’s scientifically interesting, but I don’t think it translates to any policy changes about how you would treat children or whether you would, for example, say all children should wear masks, even pandemic aside, on the basis of avoiding Kawasaki disease. It’s too rare for that.”

Major remaining research questions revolve around the infectious agents most likely to cause the immune response characteristic of Kawasaki disease; the potential impact of noninfectious environmental triggers; and genetic factors that might explain why some children are more susceptible.

“Acquired heart disease like Kawasaki disease is very deserving of research funding,” Newburger said. “It can be a devastating disease for the small percentage of children who develop giant coronary artery aneurysms, so I think understanding all the mechanisms by which it occurs should be a high health priority within pediatrics.”