Kawasaki disease and the environmental agent hypothesis

People | Human Health

By Isabel Rowbotham, Co-Editor in Chief

Published October 5th, 2022

The story of a rare heart disease in children shows us that a better understanding of the relationship between climate and disease is more important than ever. The cause of Kawasaki disease has remained a mystery, however researchers believe a causative environmental agent may be carried in the wind after being picked up from croplands in northeast Asia—through Japan and all the way to the West Coast of the United States.

Kawasaki disease (KD) is a condition known to cause fever, swelling of neck lymph nodes, conjunctivitis, skin rash and heart disease. KD was first identified in Japan in the 1960s and the causative agent has since eluded scientists. Despite this mystery, KD epidemics seem to be triggered by an environmental agent or toxin of unknown origin.

Japan has the highest incidence of Kawasaki disease in the world. | Cyril Bèle / Flickr

Researchers have discovered the possibility that the environmental agent responsible for causing KD may be transported in the wind by North Pacific atmospheric circulations. This was observed during an increase of KD cases in Japan—during peak epidemic years (from 1979 to 1986)—which was associated with stronger northwesterly winds originating from an area between Russia and China.

Through the study of atmospheric simulations, a strong North Pacific wind current was observed to be associated with an increased number of Kawasaki cases. Moreover, the study demonstrated that understanding KD activity might help predict a change in the number of cases all across the Pacific Ocean, and even through to the West Coast of the United States.

‘The environmental agent responsible for causing Kawasaki disease may be transported in the wind by North Pacific atmospheric circulations.’

A more recent study looked closely at onset cases of KD in Japanese prefectures, from 1970 to 2010. This is a very valuable dataset since Japan has the highest incidence of KD in the world. The research combines these clinical data points with a particle dispersion model in order to assess the trajectory of the wind 10 days before the day of the onset of disease and to locate the possible origin of the causal agent of KD.

Did North Pacific winds pick up the environmental agent of KD?

The particle dispersion simulation FLEXPART—which can also be used to measure air pollution through 3D atmospheric data—pointed to the southern regions in northeastern China as the area where winds picked up or lifted particles into the air 10 to 15 days before the epidemics reached its peak (95% threshold of cases).

Through the use of a NASA land database, the team was able to discern that half of this land in northeastern China was used for croplands and farms, with the main crops being maize, rice and spring wheat.

A satellite image of China (left) and particle model (right) shows the location of particles (in yellow) for the dates within the three epidemics and brown dots represent crops according to NASA land images. | NASA WorldWind via eutrophication&hypoxia, Flickr / Rodó X. (2014) / PNAS

Could this environmental agent originate from farming?

After analysing the results from the particle dispersion simulations and data from the biggest KD epidemics in Japan, we can clearly start to see a pattern and identify this intensely cultivated cropland and farm area as a possible source of environmental pollutants.

Researchers identified this area as a high-residence time region, referring to the time a parcel of fluid spends in a region of interest. The more time spent in a region, the higher chance there is to pick up particles into the air. The results associated with a high KD incidence point to this cropland region in northeast China.

‘The team was able to discern that half of this land, in northeastern China, was used for croplands and farms.’

China has been self-sufficient in grain agriculture due to an impressive economic growth, high labour rates and the use of fertilisers and pesticides. Harbin, in Heilongjiang province, is a region with fertile black soil and for decades has cultivated mostly maize, but also soybean, wheat, rice, potato, vegetables and sunflower.

Most of the land is ploughed and uses fertilisers, but only 29% of land is used with pesticides; the latter was considered extremely low compared to the rest of the country, according to studies in the 1990s. A closer look into activities between the 1970s and 1980s—a period during which a high KD incidence was observed in Japan—may help elucidate if there is a connection or not.

Farmers working the land in Heilongjiang, China, taken in November 2015. | Jay Fang / Wikimedia Commons

What about any connection to climate change? Meteorological data from northeast China, from 1970 to 2009, suggests an increase of an average of 0.34°C in daily temperatures, which led to the extension of croplands northward by 80 kilometres over a period of 40 years. However, any connection between these events to the incidence of KD has not yet been confirmed.

The problem with connecting the environmental agent of KD to farming is that during this period of wind transference, KD is most common in the winter months, often resulting in the ground being frozen; creating new possibilities of what such an agent could be.

There is also a possibility that KD may be caused by an environmental agent or toxin linked to crops or plant decay, such as a bacterial or fungal toxin, researchers speculated. Many types of crops can harbour fungal toxins or spores, which, if inhaled, can cause a variety of symptoms affecting the liver, kidney and brain.

‘There is also a possibility KD may be caused by an environmental agent or toxin linked to crops or plant decay, such as a bacterial or fungal toxin.’

The study included sampling tropospheric level air over Japan for a period of one week, in order to assess the microbiome carried by winds exclusively from the region suspected as the source. They detected a fungus in the air known as Candida species. The finding of 54% Candida supports the feasibility of a wind borne pathogen.

maize in Harbin. | Jay Fang / Wikimedia Commons

Even though Candida species has not been officially declared as the environmental agent responsible for causing KD, it may be another piece to the puzzle when trying to comprehend a disease characterised in fatal cases by damage to coronary arteries. Separate animal studies found extracts secreted by the fungus may cause disruption of the blood vessel wall leading to arteritis, another common feature in KD.

Why specifically China?

There is nothing in these results that point to any specific activity on behalf of China. Researchers investigated this region first due to its proximity to Japan, the country with the highest incidence of KD. Secondly, the FLEXPART model highlights winds blowing west and passing through this cropland, an area most likely to be the source of lifted particles.

Evidence pointing to an environmental agent or toxin

If in fact, winds are carrying an environmental agent; fungal mycotoxins or others, the study’s simulation results suggest there was a short time—two to three days—between winds picking up an agent in northeast China and the onset of disease in Japan.

Locals enjoying the fresh air in Tokyo, Japani. The study published in 2014 discussed the possibility of wind currents carrying the potential environmental agent of KD, as evidence shows epidemics rising simultaneously across nearby cities in a short period of time. | Mike Sutherland / Flickr

Another clue pointing to wind currents and not a disease spread from person to person is the short incubation time seen across neighbouring cities at the time of epidemics. For example, there was a correlation between rising cases in Tokyo and Yokohama—28 kilometres apart—and Tokyo and Saitama—32 kilometres apart. This suggests that there would not be enough time for a community spread to occur if the causative agent for KD was of infectious nature.

The simulation analysis showed that within two days of the winds picking up from the source area and reaching these cities, patients rapidly developed a sudden fever, which is a characteristic symptom of KD.

‘Results suggested there was a short time—two to three days—between winds picking up an agent in northeast China and the onset of disease in Japan.’

The synchronisation of epidemics and the rapid development of symptoms may suggest a short incubation period—the time between exposure to a causative agent and the onset of fever. Results revealed that between six hours to 2.5 days was the period in which winds picked up the potential agent from the area of origin in northeast China and the onset of fever in patients across Japan.

Evidence pointing to a respiratory infectious disease

One thing seems to be the case, whatever causes KD is entering the body through the upper respiratory tract. Antibodies found in the trachea, lungs and various organs (in fatal cases) serve as evidence of this being an infection. Additionally, the seasonality factor—the wintertime predominance—also points to a respiratory illness.

A lot has happened since the 1980s, when the data from this study was used to identify a potential source of KD. However, this data is useful because the epidemics showed the highest number of cases in Japan.

A recent epidemiological study on KD hospital admission found that 2018 was the year with the highest number of cases since the famous epidemics, which shows how this disease has been slowly increasing in incidence through the decades. In 2020, with the start of the COVID-19 pandemic, KD decreased by 50% alongside other infectious diseases, making research more difficult in the years to come and ultimately making it more challenging to solve the mystery of what causes KD.

Harbin, China. | Brian Jeffery Beggerly / Flickr

The risk of farming-related organic toxins and their effects on the incidence of KD is intriguing. On the one hand, fungal toxins have been found to cause damage to arteries in small animals developing similar pathological findings as KD, such as arteritis. On the other hand, there is the possibility of herbicides, fungicides, and/or fertilisers being responsible, all of which have widespread use in agricultural settings.

The question of whether KD is caused by infectious organisms or an environmental agent, unfortunately, remains unanswered. However, the evidence in this research suggests that environmental factors may have influenced the increase in KD incidence in Japan, and air sampling results have shown that a further look into fungal toxins and their role in arteritis may still be worth pursuing.

Featured Image: Mage Rui Xu | Unsplash

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