HomeDiseases, Conditions, SyndromesMay 19, 2014
Possible cause, source of Kawasaki disease found—condition linked to winds from China
Possible cause, source of Kawasaki disease found—condition may be triggered by airborne aerosols from China
An international team of scientists, including researchers from the University of California, San Diego, report that the likely causative agent of Kawasaki disease (KD) in Japan is a windborne agent originating from a source in northeast China. KD is a mysterious childhood ailment that can permanently damage coronary arteries.
The findings are published in the May 19, 2014 online early edition of issue of PNAS (Proceedings of the National Academy of Sciences).
KD is the most common cause of acquired heart disease in children. It is difficult to diagnose and, without treatment, 25 percent of children with KD develop coronary artery aneurysms – balloon-like bulges of heart vessels – that may eventually result in heart attacks, congestive heart failure or sudden death. Prevalence rates of KD are rising among children in Asia, the United States and Western Europe. Predictive models estimate that by 2020 one in every 1,600 adults in the U.S. will be affected by the disease.
First described in Japan in 1967 and named after its discoverer, Tomisaku Kawasaki, MD, the cause of KD has eluded two generations of researchers. Jane C. Burns, MD, professor and director of the Kawasaki Disease Research Center at UC San Diego School of Medicine and Rady Children's Hospital-San Diego, assembled an international team to help decipher the distinct seasonality of this devastating childhood illness.
Noting that the timing of KD outbreaks in Japan coincides with certain wind patterns from Asia, climate scientist Xavier Rodó, PhD, and colleagues at the Catalan Institution for Research and Advanced Studies and the Catalan Institute of Climate Sciences, both in Barcelona, used computer models to simulate air currents and airborne particle transport for all days since 1977 with high numbers of KD cases in Japan, based on data compiled by Yoshikazu Nakamura, MD, and colleagues at Jichi Medical University in Japan. The modeling indicated that KD cases in many Japanese locations, both in and out of epidemic years, peaked only when winds originated from a densely-cultivated region in northeastern China characterized by vast cereal croplands.
In 2011, the Barcelona researchers equipped an aircraft based in Japan with a newly designed large-volume air-filtering device to collect aerosol samples. With help from Hiroshi Tanimoto, PhD, and colleagues at the National Institute of Environmental Science in Tsukuba, Japan, the plane sampled at altitudes between two and three kilometers above Japan to avoid surface contaminants, and on days during the KD season when air currents originated only from northeastern China. Detailed microbiome analyses of the samples by Brent Williams, PhD, and Ian Lipkin, MD, at Columbia University in New York City identified Candida species as the dominant airborne fungus, a finding not previously reported from other aerosol sampling campaigns in other regions of the globe. Candida is a genus of yeasts and the most common cause of diverse human fungal infections worldwide.
In their current PNAS paper, the multidisciplinary team of Rodó, Burns, Dan Cayan, PhD, a climate researcher at UC San Diego Scripps Institution of Oceanography and co-authors in New York, Barcelona and Japan, say the new evidence suggests that the most likely cause of KD is a "preformed toxin or environmental molecule" originating from northeastern China, possibly related to Candida, which has been linked to Kawasaki-like coronary artery vasculitis in mouse models.
Burns summarized the major findings:
Prevailing wind patterns associated with KD cases in Japan track back to northeastern China, which is the country's main cereal grain-growing region.
KD has a short incubation time (less than 24 hours between exposure and fever onset), suggesting the cause is not a traditional infectious organism, but more likely a toxin, perhaps fungal in origin, that readily triggers a host immune response in genetically susceptible children.
Air sampling in Japan during the winter KD season found unexpectedly high levels of Candida species within the rich microbiome of tropospheric winds.
Burns, who has published extensively on KD, said these combined factors point to a pathogenic airborne toxin or molecule associated with areas of intensive agriculture, which is lofted into the winds and causes idiosyncratic immune reactions in genetically susceptible children.
"This is a Sherlock Holmes situation," said Burns. "The data suggest that people are doing something new (since World War II) in northeastern China. Could they be burning a biomass fuel in winter that carries the agent on aerosolized ash to Japan? Could there be some agricultural practice or crop or activity that is new since the 1960s when KD first started to appear in Japan? Could it be that the aerosolized particle is chemically altered to become pathogenic as it travels through clouds on its way to Japan?
"We need to figure out what the activity or condition is that creates these aerosols carried by the winds. There are certainly other source regions around the globe, but focusing on the link between northeastern China, Japan, Hawaii, and the west coast of North America is our best bet for figuring this out."
Burns said rising KD cases elsewhere in the world, notably in the Philippines and India, may involve the same agent originating from different source regions. She said the findings have broader implications as well.
"I think that KD represents a new disease paradigm," she said. In years of searching for its source, "we kept trying to shove a round peg into a square hole. Now I think the door has been opened to thinking about this disease in a new way that may well liberate our thinking about other diseases as well."
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More information: Tropospheric winds from northeastern China carry the etiologic agent of Kawasaki disease from its source to Japan, Proceedings of the National Academy of Sciences, www.pnas.org/cgi/doi/10.1073/pnas.1400380111
Journal reference: Proceedings of the National Academy of Sciences
Provided by University of California - San Diego
Xavier Rodó, doi: 10.1073/pnas.1400380111
Tropospheric winds from northeastern China carry the etiologic agent of Kawasaki disease from its source to Japan
Xavier Rodóa,b,1, Roger Curcollb, Marguerite Robinsonb, Joan Ballesterb,c, Jane C. Burnsd, Daniel R. Cayane,f, W. Ian Lipking, Brent L. Williamsg, Mara Couto-Rodriguezg, Yosikazu Nakamurah, Ritei Ueharah, Hiroshi Tanimotoi, and Josep-Anton Morguíb
Author Affiliations
Edited* by Mark H. Thiemens, University of California, San Diego, La Jolla, CA, and approved April 4, 2014 (received for review January 9, 2014)
AbstractAuthors & InfoSIMetricsPDFPDF + SI
Significance
Kawasaki disease (KD), the leading cause of acquired heart disease in children worldwide, has remained a mystery for more than 40 y. No etiological agent has yet been identified. By using simulations with the flexible particle dispersion model from different Japanese cities from each single high (low) KD incidence day, the source region KD is retrieved in cereal croplands in northeastern China. We infer the incubation time for KD ranges from 6 h to 2 d, thus favoring an antigenic or toxic exposure as the trigger. Candida sp. is reported as the dominant fungal species collected aloft (54% of all fungal DNA clones) demonstrating the potential for human disease in aerosols transported by wind currents traveling long distances.
Abstract
Evidence indicates that the densely cultivated region of northeastern China acts as a source for the wind-borne agent of Kawasaki disease (KD). KD is an acute, coronary artery vasculitis of young children, and still a medical mystery after more than 40 y. We used residence times from simulations with the flexible particle dispersion model to pinpoint the source region for KD. Simulations were generated from locations spanning Japan from days with either high or low KD incidence. The postepidemic interval (1987–2010) and the extreme epidemics (1979, 1982, and 1986) pointed to the same source region. Results suggest a very short incubation period (<24 h) from exposure, thus making an infectious agent unlikely. Sampling campaigns over Japan during the KD season detected major differences in the microbiota of the tropospheric aerosols compared with ground aerosols, with the unexpected finding of the Candida species as the dominant fungus from aloft samples (54% of all fungal strains). These results, consistent with the Candida animal model for KD, provide support for the concept and feasibility of a windborne pathogen. A fungal toxin could be pursued as a possible etiologic agent of KD, consistent with an agricultural source, a short incubation time and synchronized outbreaks. Our study suggests that the causative agent of KD is a preformed toxin or environmental agent rather than an organism requiring replication. We propose a new paradigm whereby an idiosyncratic immune response, influenced by host genetics triggered by an environmental exposure carried on winds, results in the clinical syndrome known as acute KD.
northeastern China source agriculture heart disease FLEXPART cereal croplands
Footnotes
1To whom correspondence should be addressed. E-mail: xavier.rodo@ic3.cat.
Author contributions: X.R., J.C.B., D.R.C., W.I.L., Y.N., H.T., and J.-A.M. designed research; X.R., R.C., M.R., J.B., W.I.L., B.L.W., M.C.-R., Y.N., R.U., H.T., and J.-A.M. performed research; X.R., R.C., B.L.W., M.C.-R., R.U., H.T., and J.-A.M. contributed new reagents/analytic tools; X.R., M.R., J.B., W.I.L., B.L.W., Y.N., and R.U. analyzed data; and X.R., J.C.B., D.R.C., W.I.L., B.L.W., and J.-A.M. wrote the paper.
The authors declare no conflict of interest.
*This Direct Submission article had a prearranged editor.
†Kang H-Y, Ryu Y-W, Xylitol production by flocculating yeast, Candida sp. HY200. 25th Symposium on Biotechnology for fuels and chemicals, National Renewable Energy Laboratory, May 4–7, 2003, Breckenridge, CO, poster presentation 2-23.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1400380111/-/DCSupplemental.