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      Clustering and climate associations of Kawasaki Disease in San Diego County suggest environmental triggers

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          Abstract

          Kawasaki Disease (KD) is the most common cause of pediatric acquired heart disease, but its etiology remains unknown. We examined 1164 cases of KD treated at a regional children’s hospital in San Diego over a period of 15 years and uncovered novel structure to disease incidence. KD cases showed a well-defined seasonal variability, but also clustered temporally at much shorter time scales (days to weeks), and spatiotemporally on time scales of up to 10 days and spatial scales of 10–100 km. Temporal clusters of KD cases were associated with strongly significant regional-scale air temperature anomalies and consistent larger-scale atmospheric circulation patterns. Gene expression analysis further revealed a natural partitioning of KD patients into distinct groups based on their gene expression pattern, and that the different groups were associated with certain clinical characteristics that also exhibit temporal autocorrelation. Our data suggest that one or more environmental triggers exist, and that episodic exposures are modulated at least in part by regional weather conditions. We propose that characterization of the environmental factors that trigger KD in genetically susceptible children should focus on aerosols inhaled by patients who share common disease characteristics.

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          A single intravenous infusion of gamma globulin as compared with four infusions in the treatment of acute Kawasaki syndrome.

          Treatment of acute Kawasaki syndrome with a four-day course of intravenous gamma globulin, together with aspirin, has been demonstrated to be safe and effective in preventing coronary-artery lesions and reducing systemic inflammation. We hypothesized that therapy with a single, very high dose of gamma globulin would be at least as effective as the standard regimen. We conducted a multicenter, randomized, controlled trial involving 549 children with acute Kawasaki syndrome. The children were assigned to receive gamma globulin either as a single infusion of 2 g per kilogram of body weight over 10 hours or as daily infusions of 400 mg per kilogram for four consecutive days. Both treatment groups received aspirin (100 mg per kilogram per day through the 14th day of illness, then 3 to 5 mg per kilogram per day). The relative prevalence of coronary abnormalities, adjusted for age and sex, among patients treated with the four-day regimen, as compared with those treated with the single-infusion regimen, was 1.94 (95 percent confidence limits, 1.01 and 3.71) two weeks after enrollment and 1.84 (95 percent confidence limits, 0.89 and 3.82) seven weeks after enrollment. Children treated with the single-infusion regimen had lower mean temperatures while hospitalized (day 2, P less than 0.001; day 3, P = 0.004), as well as a shorter mean duration of fever (P = 0.028). Furthermore, in the single-infusion group the laboratory indexes of acute inflammation moved more rapidly toward normal, including the adjusted serum albumin level (P = 0.004), alpha 1-antitrypsin level (P = 0.007), and C-reactive protein level (P = 0.017). Lower IgG levels on day 4 were associated with a higher prevalence of coronary lesions (P = 0.005) and with a greater degree of systemic inflammation. The two groups had a similar incidence of adverse effects (including new or worsening congestive heart failure in nine children), which occurred in 2.7 percent of the children overall. All the adverse effects were transient. In children with acute Kawasaki disease, a single large dose of intravenous gamma globulin is more effective than the conventional regimen of four smaller daily doses and is equally safe.
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            Seasonality of Kawasaki Disease: A Global Perspective

            Background Understanding global seasonal patterns of Kawasaki disease (KD) may provide insight into the etiology of this vasculitis that is now the most common cause of acquired heart disease in children in developed countries worldwide. Methods Data from 1970-2012 from 25 countries distributed over the globe were analyzed for seasonality. The number of KD cases from each location was normalized to minimize the influence of greater numbers from certain locations. The presence of seasonal variation of KD at the individual locations was evaluated using three different tests: time series modeling, spectral analysis, and a Monte Carlo technique. Results A defined seasonal structure emerged demonstrating broad coherence in fluctuations in KD cases across the Northern Hemisphere extra-tropical latitudes. In the extra-tropical latitudes of the Northern Hemisphere, KD case numbers were highest in January through March and approximately 40% higher than in the months of lowest case numbers from August through October. Datasets were much sparser in the tropics and the Southern Hemisphere extra-tropics and statistical significance of the seasonality tests was weak, but suggested a maximum in May through June, with approximately 30% higher number of cases than in the least active months of February, March and October. The seasonal pattern in the Northern Hemisphere extra-tropics was consistent across the first and second halves of the sample period. Conclusion Using the first global KD time series, analysis of sites located in the Northern Hemisphere extra-tropics revealed statistically significant and consistent seasonal fluctuations in KD case numbers with high numbers in winter and low numbers in late summer and fall. Neither the tropics nor the Southern Hemisphere extra-tropics registered a statistically significant aggregate seasonal cycle. These data suggest a seasonal exposure to a KD agent that operates over large geographic regions and is concentrated during winter months in the Northern Hemisphere extra-tropics.
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              Association of Kawasaki disease with tropospheric wind patterns

              The causal agent of Kawasaki disease (KD) remains unknown after more than 40 years of intensive research. The number of cases continues to rise in many parts of the world and KD is the most common cause of acquired heart disease in childhood in developed countries. Analyses of the three major KD epidemics in Japan, major non-epidemic interannual fluctuations of KD cases in Japan and San Diego, and the seasonal variation of KD in Japan, Hawaii, and San Diego, reveals a consistent pattern wherein KD cases are often linked to large-scale wind currents originating in central Asia and traversing the north Pacific. Results suggest that the environmental trigger for KD could be wind-borne. Efforts to isolate the causative agent of KD should focus on the microbiology of aerosols.
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                Author and article information

                Contributors
                jcburns@ucsd.edu
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                12 November 2018
                12 November 2018
                2018
                : 8
                : 16140
                Affiliations
                [1 ]ISNI 0000000122595234, GRID grid.10919.30, Department of Mathematics and Statistics, , UiT the Arctic University of Norway, ; Tromsø, 9037 Norway
                [2 ]Department of Pediatrics, University Hospital of North Norway, and Department of Clinical Medicine, UiT the Arctic, University of Norway, Tromsø, 9037 Norway
                [3 ]ISNI 0000 0001 2107 4242, GRID grid.266100.3, School of Global Policy and Strategy, , University of California San Diego, ; La Jolla, CA 92093 USA
                [4 ]ISNI 0000 0001 2107 4242, GRID grid.266100.3, Scripps Institution of Oceanography, , University of California San Diego, ; La Jolla, CA 92093 USA
                [5 ]ISNI 0000 0001 2107 4242, GRID grid.266100.3, Department of Pediatrics, , University of California San Diego, ; La Jolla, CA 92093 USA
                [6 ]ISNI 0000000096214564, GRID grid.266190.a, Cooperative Institute for Research in Environmental Sciences, , University of Colorado, ; Boulder, CO 80309 USA
                [7 ]ISNI 0000 0001 1266 2261, GRID grid.3532.7, Physical Sciences Division, , National Oceanic and Atmospheric Administration, ; Boulder, CO 80305 USA
                [8 ]ISNI 0000 0001 2107 4242, GRID grid.266100.3, Department of Biomedical Informatics, , University of California San Diego, ; La Jolla, CA 92093 USA
                Article
                33124
                10.1038/s41598-018-33124-4
                6232126
                30420674
                8bd25f6e-8dda-4a11-9ddc-02974672e348
                © The Author(s) 2018

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 29 June 2018
                : 20 September 2018
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