kawasaki disease: is the answer blowin in the wind? -...
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Kawasaki Disease: Is the answer blowin’ in the wind?
Jane C. Burns, M.D.
Director
Professor and Chief, Division of Allergy and Immunology
Dept. of Pediatrics Univ. of California San Diego School of Medicine
Kawasaki Disease (KD) Acute self-limited vasculitis of
unknown etiology Coronary artery aneurysms
develop in 25% of untreated children
Early treatment with IVIG reduces risk of aneurysms
Most common cause of acquired pediatric heart disease in developed countries
Genetics
Gene expression
mirRNA
Proteomics
Biomarker discovery
Epidemiology and risk factor analysis
Clinical trial of infliximab
Endothelial cell function
KD Climate Project
BENCH RESEARCH CLINICAL RESEARCH
Adult KD Collaborative
UCSD/RCHSD Kawasaki Disease Research Center
Burns Laboratory 2011
Kawasaki Disease incidence, RCHSD 2000-2010
KD
cas
es /
100,
000
< 5
yrs.
0
5
10
15
20
25
30
35
40
45
2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010
Race/ethnicity-specific rates of KD RCHSD, 2000-2010
KD
cas
es/ 1
00,0
00 <
5 yr
s.
0
10
20
30
40
50
60
70
80
90
2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010
Asian
African-American
Caucasian
Hispanic
Proposed KD Paradigm 2011 Infectious
trigger
Genetically susceptible host
Manifests immunologic reaction (clinical KD)
Genetically determined outcome (can be modified by treatment)
Genetically resistant host
Asymptomatic infection
Immunity
Attack rate: 215 cases/100,000 Children < 5yrs. Greater than 12,000 new cases/yr. One out of every 185 children in Japan will develop KD during the first ten years of life
Current status of KD in Japan
Kawasaki disease: A climate connection?
US Team
Hiroshi Yanagawa Yosikazu Nakamura Ritei Uehara Mayumi Yashiro Tomisaku Kawasaki
Japanese Team
Dan Cayan Emelia Bainto Jane C. Burns Marian Melish Ian Lipkin
Catalan Team Xavier Rodo Joan Ballester Jordi Anton
Hypothesis: Phase I
• KD cases cluster in time and space » KD has a seasonal occurrence
Methods: Seasonality for Japan
• 135,027 KD cases from 1979-1998 (19 yrs) » Determined average incidence (# cases/day) for
each month and each prefecture » Ranked each month for each prefecture on a
1-12 scale, red=highest, blue=lowest
1 2 3 4
9
75 8 6
11 10 12
Methods: Seasonality for California
• 3,677 KD cases from1990-1999 (10 yrs) » Divided data set into northern and southern CA » Graphed average # cases/day for each month
California KD Cases, 1990-99, average # cases/day by month
Aver
age
# ca
se/d
ay
Aver
age
# ca
se/d
ay
Summary of Phase I
• Clustering of cases and marked seasonality of KD in both Japan and California suggest the possibility of an environmental trigger
• Further exploration of climate variables was undertaken for the Japan, Hawaii, and Western U.S.
Burns et al. Epidemiology 2004
Hypothesis: Phase II
• Climate-related factors trigger KD » A regional-scale climate pattern
precedes the onset of a KD cluster
Phase II: KD Climate Analyses
Analysis of climate patterns found highly significant link between tropospheric winds and KD cases » Usual prevailing winds blow from the south across
Japan in a northwesterly direction » Twice a year, this wind pattern reverses and winds
blow from Central Asia across Japan and the Pacific Ocean
» Change in wind pattern is tightly linked to increases and decreases in KD cases
3 major KD epidemics in Japan associated with strong wind pattern from the northwest
Rodo et al. Nature Sci Rep 2011
Phase II: Major Peaks of KD in Japan
Average winter tropospheric winds (300hPa) crossing from Asia to North Pacific Climatological (many years averaged) January values are depicted in map b) for geopotential height at 300 hPa (m) and winds at 300 hPa (m/s). Wind scale is shown at the top-left corner in b).. Panel d) depicts the seasonal cycle of the Pacific Zonal Wind Index (P-WIND, m/s) from earth’s surface to the top of the troposphere.
. KD and surface winds in Japan (a), San Diego (b) and Hawaii (c).
Barcelona Hypotheses
The Barcelona meeting hosted by IC3 in September 2010 was attended by representatives from Japan, US and Western Europe
Hypothesis #1: Tropospheric winds carry an agent that when inhaled by
genetically susceptible infants and children causes KD Hypothesis #2: The KD agent is transmitted through aerosolized dust
particles that originate from the plains of Central Asia Hypothesis #3: The diversion of water from the Aral Sea in the 1940s
created a new source of aerosolized particles that include the KD agent and thus explain the new appearance of KD in Japan in the 1950s and 1960s
Collaboration with Hiroshi Tanimoto National Institute of Environmental Science Tsukuba, Japan
AIRCRAFT DUST SAMPLING MARCH 4, 2011
MAXIMUM ALTITUDE 3,000 M SAMPLING TIME 2H 20 MIN
0
50
100
150
200
250 N
o.of
pat
ient
s
Month of diagnosis
Web-based KD surveillance in Japan
2010 2011 Dec. Jan. Feb. March April May June
Air sample collection March 4th and 6th
Courtesy of Dr. Ritei Uehara
Handling of filters
Current research directions
Barcelona team performing back-tracing of wind
Ian Lipkin, Columbia University, NYC » Sequencing of biome of tropospheric dust
collected on filters » 18s and 16s rRNA PCR amplification for
bacteria, fungi, and yeast
WIND Study Western U.S. INvestigation of Kawasaki Disease
Consortium of Western U.S. Pediatric Hospitalists in California, Oregon, Washington, and Hawaii
Principal Investigators: » Jane C. Burns, San Diego » Keith Vaux, San Diego » Jennifer Daru, San Francisco
WIND Study
Goal: Real-time surveillance of KD » Analysis of case clustering in space and time » Correlation with large scale climate variables » Can we predict seasonal fluctuations in KD?
Methods » Weekly web-based reporting of new KD
patients with zip code of residence and date of fever onset » real-time graphing of results
Future research directions
Repeat air sampling during KD peak and non-peak seasons in Japan
Molecular analysis of dust samples WIND Study: Prediction of KD activity Immunologic studies with patient cells
challenged with selected antigens identified from dust samples
Antibody testing in acute and conv. sera