Research ArticleEffect of Meteorological and Geographical Factors onthe Epidemics of Hand Foot and Mouth Disease inIsland-Type Territory East Asia

Chang-Chun David Lee1 Jia-Hong Tang2 Jing-Shiang Hwang2

Mika Shigematsu3 and Ta-Chien Chan4

1Genomics Research Center Academia Sinica Taipei 115 Taiwan2Institute of Statistical Science Academia Sinica Taipei 115 Taiwan3National Institute of Infectious Diseases Tokyo 162-8640 Japan4Research Center for Humanities and Social Sciences Academia Sinica Taipei 115 Taiwan

Correspondence should be addressed to Ta-Chien Chan dachianpiggmailcom

Received 28 August 2014 Revised 16 September 2014 Accepted 17 September 2014

Academic Editor Shih-Bin Su

Copyright copy 2015 Chang-Chun David Lee et alThis is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in anymedium provided the originalwork is properly cited

Hand foot and mouth disease (HFMD) has threatened East Asia for more than three decades and has become an importantpublic health issue owing to its severe sequelae and mortality among children The lack of effective treatment and vaccine forHFMD highlights the urgent need for efficiently integrated early warning surveillance systems in the region In this study we tryto integrate the available surveillance and weather data in East Asia to elucidate possible spatiotemporal correlations and weatherconditions among different areas from low to high latitude The general additive model (GAM) was applied to understand theassociation between HFMD and latitude as well as meteorological factors for islands in East Asia namely Japan Taiwan HongKong and Singapore from 2012 to 2014The results revealed that latitudewas themost important explanatory factor associatedwiththe timing and amplitude of HFMD epidemics (119875 lt 00001) Meteorological factors including higher dew point lower visibilityand lower wind speed were significantly associated with the rise of epidemics (119875 lt 001) In summary weather conditions andgeographic location could play some role in affecting HFMD epidemics Regional integrated surveillance of HFMD in East Asia isneeded for mitigating the disease risk

1 Introduction

Hand foot and mouth disease (HFMD) is a syndromewhich usually affects children below the age of five [1ndash3]The causal agents are various enteroviruses especially humanenterovirus 71 (EV71) and coxsackie virus A16 (CVA16)responsible for 50 to 90 of HFMD in many episodes [14 5] Some cases develop into severe clinical manifestationssuch as encephalitis aseptic meningitis acute flaccid paral-ysis (AFP) neurogenic pulmonary edema cardiopulmonaryfailure and even death in the case of EV71 infection [6ndash9]

In the 1960s both the Netherlands and USA recordedcases of EV71 [7 10] Afterward severe cases with about a 10case fatality rate occurred in Bulgaria and Hungary in 1975

and 1978 respectively [11 12] Meanwhile cases with HFMDCNS manifestations and death were associated with EV71in Japan in 1973 and 1978 [9 13] In the late 20th centurya vast death toll related to HFMD occurred in SoutheastAsia In 1997 29 fatal cases were attributed to EV71 infectionin Malaysia [14] One year later an outbreak of around 15million estimatedHFMD cases occurred in Taiwan and led to405 severe cases and 78 dead children [1] Since then HFMDhas become endemic in Southeast andEastAsia In particularapproximately 72 million probable cases of HFMD werereported in China during 2008 to 2012 [15] To date HFMDand enterovirus-derived severe syndromes have resultedin a heavy disease burden especially to children in thisarea

Hindawi Publishing CorporationBioMed Research InternationalVolume 2015 Article ID 805039 8 pageshttpdxdoiorg1011552015805039

2 BioMed Research International

Surveillance systems for example sentinel physiciansurveillance and national communicable disease networkshave been initiated for HFMD in these countries after thelarge scale outbreaks [16ndash18] These surveillance systemsprovide timely disease information yet HFMD still cannotbe well controlled Several studies have proposed integratedsurveillance comprising disease surveillance andmeteorolog-ical data to provide signals for early warning and predictionof this disease [15 18ndash20] Nevertheless some factors havestill not been closely studied East Asia is composed of acontinental land mass peninsulas and several island-typecountries The effects of meteorological factors on HFMDmay not be universal across these areas Thus this studyaims (1) to determine whether the known meteorologicalfactors associated with HFMD are appropriate to island-typecountries and (2) to examine whether different geographicalzones and latitudinal ranges are associated with the incidenceof HFMD within or between those island countries

With a better understanding of the effects that thelandform and meteorological factors may have public healthagencies will have a better system for early warning andcontrol of HFMD and subsequent severe sequelae

2 Methods

21 Data Hand foot and mouth disease (HFMD)surveillance data were collected online from the NationalInstitute of Infectious Diseases (NIID) in Japan (httpwwwnihgojpniidensurvaillance-data-table-englishhtml) Tai-wan CDC (httpnidsscdcgovtwRODS 5aspx) Depart-ment of Health in Hong Kong (httpwwwchpgovhkensentinel2644292html) and Ministry of Health in Singa-pore (httpwwwmohgovsgcontentmoh webhomestat-isticsinfectiousDiseasesStatisticsweekly infectiousdiseases-bulletinhtml) The studied period started from week 31 of2012 to week 27 of 2014 The length of the studied period was101 weeks

There were 55 spatial areas including 47 prefectures inJapan six surveillance areas in Taiwan which belonged to sixcontrol centers of Taiwanrsquos CDC one area in Hong Kongand one area in Singapore The spatial extent ranged from135∘N to 4338∘N in latitude and from 10381∘E to 14257∘Ein longitude (Figure 1) However the statistical units ofHFMD surveillance in different countries were differentJapan used the HFMD cases per sentinel clinics andhospitals (httpidscnihgojpiasr20230de2309html)Taiwan used the HFMD cases per 1000 emergency roomvisits and Hong Kong used two sources including generalpractitioners (GPs) and general practice outpatient clinics(GOPCs) from the sentinel surveillance systems [21]In Singapore we used HFMD incidence which dividedthe HFMD cases by their population each week Theclinical definitions of HFMD are similar among thedifferent countries and indicate a contagious enterovirusinfectious disease mainly found among toddlers withvesicles present on hands feet and lower limbs insidethe oral cavity (buccal mucous membrane) andor on lips(httpwwwmhlwgojpbunyakenkoukekkaku-kansensh-

ou1101-05-20html) However the reporting mechanismsare different due to the different surveillance systems andregulations in different countries Japan and Hong Kongrsquosdata are from sentinel hospitals and clinic surveillanceTaiwanrsquos data are from syndromic surveillance in emergencyroom settings And Singaporersquos data are from notifiableinfectious disease surveillance since October 2000 Due tothe diversity of the statistical units we then standardizedthe HFMD statistics (Z rate) separately by 55 areas whichbecame the scale-free units for pooling analysis Theweather data were collected from the National Climatic DataCenter (NCDC) of the National Oceanic and AtmosphericAdministration (NOAA) The daily mean temperature(degrees Celsius ∘C) mean dew point (degrees Celsius ∘C)mean visibility (kilometer km)meanwind speed (meters persecond ms) and precipitation amount (millimeters mm)were calculated as the average values for the correspondingweeks in each areaThere were 209 weather stations includedin this study after excluding the stations located at over1000 meters altitude and stations located on the ocean Thespatial distributions of the climate stations used are shownin Figures 2(a)ndash2(d)

22 Statistical Analysis The analysis used a semiparametricgeneralized additive model (GAM) to examine the associa-tion between weekly standardized HFMD cases and mete-orological factors [18] We assumed a GAM with Gaussiandistribution and used both cubic smoothing spline methodfor meteorological variables and linear term for the latitudeto fit the model [22] All GAM parameters were estimated bySAS software (SAS Institute Cary NC) The spatiotemporaldistribution of HFMD standardized values (Z rate) wasanalyzed using the fishnet toolbox in ArcGIS (ArcMapversion102 ESRI Inc Redlands CA USA)

3 Results

31 Temporal and Spatial Distribution of HFMD in Islandsin East Asia All areas with HFMD Z rates among the 101weeks are shown in the spatiotemporal map (Figure 3) Zrates in each area were standardized by all observed valuesduring the studied periodThey reflect the relative amplitudeand severity of HFMD epidemic for each area HFMD wasendemic in all four areas especially in 2013 In Japan severeHFMD outbreaks occurred from week 25 to 38 in 2013 inalmost all prefectures Okinawa was the exception reachingthe peak earlier from week 15 to 17 in 2013 Most of thoseprefectures demonstrated high Z rates of HFMD around 4 to5 weeks long In Taiwan early outbreaks of HFMD showedup in southern Taiwan compared to the rest of Taiwan in2013TheHFMDcontinued for at least fourweeks in the threemetropolitan areas (Taipei Central Taiwan and Kaohsiung-Pingtung (KKP)) and the highest Z rate level stopped atweek 27 Compared to Japan and Taiwan only two weeksof the highest Z rate of HFMD occurred in Hong Kongin 2013 Notably although no Z rate was larger than 3 inSingapore there were 6 weeks of moderate to high Z rateHFMD from week 38 to 43 in 2013 These results suggest that

BioMed Research International 3

100∘09984000998400998400E 110

∘09984000998400998400E 120

∘09984000998400998400E 130

∘09984000998400998400E 140

∘09984000998400998400E 150

∘09984000998400998400E

50∘09984000998400998400N

40∘09984000998400998400N

30∘09984000998400998400N

20∘09984000998400998400N

10∘09984000998400998400N

0∘09984000998400998400

10∘09984000998400998400S

Japan

N

TaiwanHong Kong

Singapore

0 340 680 1360 2040 2720(km)

Studied areas

Figure 1 Studied areas

the epidemic timing peaks and durations of HFMDnot onlywere different between countries or regions but also variedwithin individual areas in every country or region Overallthe timing of the HFMD peaks was delayed with the increasein latitude

32 Descriptive Statistics ofMeteorological Factors Fivemete-orological factors in those areas during the study period aresummarized in Table 1 Singapore had the highest 101-week

mean temperature with standard deviation (283 plusmn 094∘C)and mean dew point (238 plusmn 081∘C) while those itemswere lowest in Japan with 151 plusmn 879∘C and 885 plusmn 928∘Crespectively Similarly these values in Taiwanwere lower thanthose in Hong Kong Other measurements had no obviousorder between Singapore Hong Kong Taiwan and Japan Inaddition the temperature-relatedmeasurements also showedhigher deviation in Japan than in other areas which indicatedthe variations which occurred within Japan Together with

4 BioMed Research International

China

Russia

North Korea

South Korea

0

50∘09984000998400998400N

40∘09984000998400998400N

30∘09984000998400998400N

20∘09984000998400998400N

130∘09984000998400998400E 140

∘09984000998400998400E

StationsJapan

480240 720 960120(km)

N

(a)

China

Central Area

Eastern Area

KKP Area

Taipei AreaNorth Area

Southern Area

StationsTaiwan

26∘09984000998400998400N

24∘09984000998400998400N

22∘09984000998400998400N

20∘09984000998400998400N

118∘09984000998400998400E 120

∘09984000998400998400E 122

∘09984000998400998400E

0 30 60 120 180 240

(km)

N

(b)

Hong Kong

0 8 16 24 324(km)

N

113∘50

9984000998400998400E 114

∘09984000998400998400E 114

∘10

9984000998400998400E 114

∘20

9984000998400998400E

22∘40

9984000998400998400N

22∘30

9984000998400998400N

22∘20

9984000998400998400N

22∘10

9984000998400998400N

22∘09984000998400998400N

StationsSingapore

(c)

Malaysia

Indonesia

Singapore

StationsSingapore

0 4 8 12 162

(km)

N103

∘40

9984000998400998400E 103

∘50

9984000998400998400E 104

∘09984000998400998400E

1∘30

9984000998400998400N

1∘20

9984000998400998400N

1∘10

9984000998400998400N

(d)

Figure 2 Meteorological stations in four areas in study (a) Japan (b) Taiwan (c) Hong Kong and (d) Singapore

the decreasing trend of mean temperature from south tonorth we inferred that latitude played an important role inchange in temperature and would be associated with the Zrate of HFMD Therefore this factor was incorporated intothe following GAM analysis

33 GAM Analysis of HFMD Standardized Value To under-stand the roles which latitude and meteorological factors

played the GAM analysis was performed The final model ofZ rate incorporates latitude dew point visibility wind speedmean temperature and total precipitation All estimates andsignificance levels are listed in Table 2 Based on the linearestimation of each explanatory variable fromGAM the coef-ficientsrsquo estimations of latitude and weekly dew point weresignificantly positively associated with increasing HFMD Zrate (119875 lt 00001) The coefficientsrsquo estimations of visibility

BioMed Research International 5

HFMD (standardized value for each area)

Mie

Oita

Gifu

Nara

Saga

IwateAkita

Aichi

Shiga

Fukui

Chiba

Kochi

Osaka

Kyoto

Tokyo

Ehime

Tottori

Hyogo

Ibaraki

Miyagi

Niigata

Gunma

Tochigi

Nagano

Aomori

Toyama

Saitama

Kagawa

Shimane

Fukuoka

Okinawa

Ishikawa

Nagasaki

Shizuoka

Miyazaki

Okayama

Hokkaido

Yamagata

Singapore

Kanagawa

Hiroshima

Yamanashi

WakayamaTokushima

Fukushima

Kumamoto

Yamaguchi

Kagoshima

Hong Kong

73986431 9865421752 1134 38 1314 16 18 2021 23 2526 2930282724221917151210 11 1314 16 18 2021 23 252627242219171512103940414243444546474849505152 4443424140 4546474849505152373533 363231 34 3839373533 363231

Taiwan east

Taiwan TPE

Taiwan KKP

Taiwan north

Taiwan southTaiwan central

N

W

S

E

001ndash100

101ndash200201ndash300301ndash586

minus145ndashminus043minus042ndash000

Figure 3 Spatiotemporal map of HFMD Z rate from week 31 of 2012 to week 27 of 2014

Table 1 Mean standard deviation coefficient of variation and quantiles of meteorological factors among four regions in study

Factors Regions(size 119899)

Japan(119899 = 47)

Taiwan(119899 = 6)

Hong Kong(119899 = 1)

Singapore(119899 = 1)

Temperature(∘C)

Mean plusmn SD 151 plusmn 879 239 plusmn 447 230 plusmn 528 283 plusmn 094CV () 582 187 230 33111987611198763 727 227 201 280 187 277 276 289

Dew point(∘C)

Mean plusmn SD 885 plusmn 928 187 plusmn 473 181 plusmn 623 238 plusmn 081CV () 1048 253 344 34011987611198763 064 176 148 232 144 240 236 243

Visibility(km)

Mean plusmn SD 143 plusmn 490 897 plusmn 502 706 plusmn 367 707 plusmn 359CV () 341 560 520 50811987611198763 126 168 532 121 196 974 188 959

Wind speed(ms)

Mean plusmn SD 305 plusmn 086 323 plusmn 158 314 plusmn 051 250 plusmn 086CV () 281 490 162 34511987611198763 245 353 211 380 279 339 190 275

Totalprecipitation(mm)

Mean plusmn SD 399 plusmn 506 411 plusmn 864 520 plusmn 840 420 plusmn 488CV () 1269 2104 1616 116211987611198763 080 506 000 404 000 635 076 573

CV indicates coefficient of variation (standard deviationmean lowast 100)

6 BioMed Research International

Table 2 Parameter estimates of linear terms in general additivemodel (GAM)

Variable Estimate Standard error 119875 valueLatitude 00465 00020 lt00001lowast

Mean temperature 00031 00063 05917Dew point 00566 00060 lt00001lowast

Visibility minus00066 00023 00037lowast

Wind speed minus00514 00118 lt00001lowast

Total precipitation 00018 00021 04100lowast

119875 value lt 005

(119875 = 00037) and wind speed (119875 lt 00001) were inverselyassociated with increasing HFMD Z rate However meantemperature and total precipitation were not significantlycorrelated with the Z rate

In addition the smoothing components plot (Figure 4)demonstrated the estimated smoothing spline functions withthe linear effect subtracted out The significant smoothersindicated that the correlations between Z rate and explana-tory variables were nonlinear The plot showed that holdingall linear and the other nonlinear terms fixed temperaturetended to increase gradually with Z rate (119875 lt 00001) andin addition there was a kind of turning point for a positiveeffect of dew point at around of 20∘C (119875 lt 00001) with aslight positive effect overall The Z rate tended to be lowerwhen the total precipitation increased (119875 = 00003) Thenonlinear effects of the visibility and thewind speed could notbe estimated because their corresponding degrees of freedom(DF) were too small

4 Discussion

HFMD is a common disease caused by enteroviruses thatmainly attack children below the age of six in East Asia Fur-ther clinical progress results in severe sequelae or even leadsto death Thus HFMD is a great public health issue in thisregion including mainland China (on the continent) SouthKorea (a peninsula) Japan Taiwan and Hong Kong (islands)[1 15 23ndash25] This study incorporates meteorological dataHFMD data and spatiotemporal analysis to reshape theepidemiological features of this disease occurring in islandsduring the study period Dynamic changes and duration ofHFMD severity among different parts of study sites weredemonstrated clearly through the integrated surveillance Forthose four epidemic islands including Japan Taiwan HongKong and Singapore in this study dew point was a keymeteorological factor associated with HFMD Neverthelesslatitude difference plays an important role that even surpassesthe impact of dew point onHFMDWhy this factor affects thedisease rate so much is still an enigma However East Asia ismore than 3500 km from south to north and covers tropicalsubtropical and temperate climate zones which are definedby climate factors and latitudeThis results in different climatefeatures in the different climate zones including temperaturevariations and ranges directions of monsoon in differentseasons among climate zones and rainfallThose phenomenabring direct effects to the islands in East Asia for example

typhoons strike Japan Taiwan and Hong Kong in summerand autumn with high-intensity rainfall that causes floodsand disease outbreaks [4 26] Of note HFMD is not anexception to the rule that the relative risk of enterovirusinfection will increase after extreme precipitation in Taiwan[19]

In contrast mainland China represents the continentallandform which can be divided into several regions accord-ing to both meteorological factors and latitude In a long-term population-based study of HFMD in China increasingamplitude of HFMD outbreaks was shown to accompanythe increase of latitude in southern China [15] Studies alsomentioned that seasonal variations in China of HFMD wereassociated with precipitation sunshine temperature and airpressure consistent with other studies in China [18 2027 28] In our study only higher dew point (a predictorfor humidity) was found to be positively associated withincreasing HFMD Z rate This factor is in accord withthe previous findings from other studies [15 28] Althoughtemperature overall did not show a linear positive effect onHFMD Z rate the results in the smoothing componentsshowed that temperature above 28∘C had a persistent positiveeffect on Z rate and temperature below 5∘C had a negativeeffect on Z rate These findings might result from theenvironmental niche condition of HFMD epidemic beingduring the hot season However findings for precipitationdiffered between our study and previous ones [15 19 28]A possible reason is that for our study site the mean totalprecipitation only differed by 004 inches (016 to 020) or10mmThis tiny differencewould not affect the Z rate amongthe island type landforms in East Asia From the GAM resultlow visibility and low wind speed were significantly related tothe elevation of Z rate of HFMD Although low wind speedwas also found in a transmission modeling study there wereno direct mechanisms for these negatively associated factorsA possible implication would be that higher wind speedcreates good airflow which may shorten how long the virusparticles remain somewhere Visibility was highly correlatedwith sunshine which was inversely correlated with HFMD[29]

This study has some limitations First HFMD is causedby several enteroviruses In this study there was no detailedinformation on causal agents for example EV71 or CVA16are responsible for the outbreaks among islands during thestudy period This may affect the disease duration or peak ofoutbreaks Second the transmission chain of HFMD amongareas defined in this study was not taken into considerationThis also impacts the spread of HFMD between or withinthe study areas Finally the studied period was too short tomake strong conclusions and extended data are needed forvalidating the association found in this study

5 Conclusion

In conclusion we found out that latitude is a major riskfactor for increasing the Z rate of HFMD in islands inEast Asia In addition only some meteorological factors(dew point low visibility and low wind speed) were foundin previous mainland China studies to be associated with

BioMed Research International 7

15

10

05

00

minus05

minus10

minus10 0 10 20 30

Temperature

Splin

e (te

mpe

ratu

re) 2

1

0

minus1

minus10 0 10 20 0 10 20 30

04

03

02

01

00

minus01

02

01

00

minus01

2 4 6 8 10

000

minus025

minus050

minus075

minus100

0 20 40 60 80

DF = 1239

P = 00003P =

P = DF = 4455 DF = 0P lt 00001P lt 00001

Splin

e (de

w p

oint

)

Splin

e (vi

sibili

ty)

Visibility

Splin

e (w

ind

spee

d)

Splin

e (pr

ecip

itatio

n)

Precipitation

DF = 0336 DF = 0969

Smoothing components for Z ratewith 95 confidence limits

Wind speed

Dew point

Figure 4 Smoothing component plots for standardized HFMD rate (Z rate)

the outbreaks This indicates that island-type geographicalareas have intrinsic differences from continental areas bothin climate impact and in causes of HFMD Since HFMDstrikes East Asia every year and there are no effective phar-maceutical treatments for this disease integrated surveillancewith timely multiple surveillance sources and meteorologicalinformation in different countries can assist in the control andmitigation of the impacts of HFMD in East Asia Also theseresults can be applied to islands in other oceans for predictingHFMD or other infectious diseases

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

Acknowledgments

This research was supported by a grant from the Ministryof Science and Technology Taiwan (MOST 103-2621-M-001-002) The authors also wish to express their sincere gratitudeto Mr Kent M Suarez for his English editing

References

[1] MHo E-R Chen K-HHsu et al ldquoAn epidemic of enterovirus71 infection in Taiwanrdquo The New England Journal of Medicinevol 341 no 13 pp 929ndash935 1999

[2] F-C Tseng H-C Huang C-Y Chi et al ldquoEpidemiologicalsurvey of enterovirus infections occurring in Taiwan between2000 and 2005 analysis of sentinel physician surveillance datardquoJournal of Medical Virology vol 79 no 12 pp 1850ndash1860 2007

[3] S-C Chen H-L Chang T-R Yan Y-T Cheng and K-T Chen ldquoAn eight-year study of epidemiologic features ofenterovirus 71 infection in Taiwanrdquo The American Journal ofTropical Medicine and Hygiene vol 77 no 1 pp 188ndash191 2007

[4] W De K Changwen L Wei et al ldquoA large outbreak ofhand foot and mouth disease caused by EV71 and CAV16 inGuangdong China 2009rdquo Archives of Virology vol 156 no 6pp 945ndash953 2011

[5] H Ni B Yi J Yin et al ldquoEpidemiological and etiologicalcharacteristics of hand foot and mouth disease in NingboChina 2008ndash2011rdquo Journal of Clinical Virology vol 54 no 4pp 342ndash348 2012

[6] L-Y Chang Y-CHuang andT-Y Lin ldquoFulminant neurogenicpulmonary oedema with hand foot and mouth diseaserdquo TheLancet vol 352 no 9125 pp 367ndash368 1998

8 BioMed Research International

[7] N J Schmidt E H Lennette andHH Ho ldquoAn apparently newenterovirus isolated from patients with disease of the centralnervous systemrdquo Journal of Infectious Diseases vol 129 no 3pp 304ndash309 1974

[8] J Blomberg E Lycke K Ahlfors T Johnsson S Wolontis andG von Zeipel ldquoLetter new enterovirus type associated withepidemic of aseptic meningitis and-or hand foot and mouthdiseaserdquoThe Lancet vol 2 no 7872 article 112 1974

[9] Y Ishimaru S Nakano K Yamaoka and S Takami ldquoOutbreaksof hand foot and mouth disease by enterovirus 71 Highincidence of complication disorders of central nervous systemrdquoArchives of Disease in Childhood vol 55 no 8 pp 583ndash5881980

[10] S Van Der Sanden M Koopmans G Uslu and H Van DerAvoort ldquoEpidemiology of enterovirus 71 in the Netherlands1963 to 2008rdquo Journal of Clinical Microbiology vol 47 no 9 pp2826ndash2833 2009

[11] M ChumakovM Voroshilova L Shindarov et al ldquoEnterovirus71 isolated from cases of epidemic poliomyelitis-like disease inBulgariardquo Archives of Virology vol 60 no 3-4 pp 329ndash3401979

[12] G Nagy S Takatsy E Kukan I Mihaly and I Domok ldquoViro-logical diagnosis of enterovirus type 71 infections experiencesgained during an epidemic of acute CNS diseases in Hungaryin 1978rdquo Archives of Virology vol 71 no 3 pp 217ndash227 1982

[13] I Tagaya R Takayama and A Hagiwara ldquoA large-scaleepidemic of hand foot and mouth disease associated withenterovirus 71 infection in Japan in 1978rdquo Japanese Journal ofMedical Science and Biology vol 34 no 3 pp 191ndash196 1981

[14] L G Chan U D Parashar M S Lye et al ldquoDeaths ofchildren during an outbreak of hand foot and mouth diseasein SarawakMalaysia clinical and pathological characteristics ofthe diseaserdquo Clinical Infectious Diseases vol 31 no 3 pp 678ndash683 2000

[15] W Xing Q Liao C Viboud et al ldquoHand foot and mouthdisease in China 2008-12 an epidemiological studyrdquoTheLancetInfectious Diseases vol 14 no 4 pp 308ndash318 2014

[16] T-N Wu S-F Tsai S-F Li et al ldquoSentinel surveillance forenterovirus 71 Taiwan 1998rdquo Emerging Infectious Diseases vol5 no 3 pp 458ndash460 1999

[17] Y Podin E L M Gias F Ong et al ldquoSentinel surveillance forhuman enterovirus 71 in Sarawak Malaysia Lessons from thefirst 7 yearsrdquo BMC Public Health vol 6 article 180 2006

[18] Y Huang T Deng S Yu et al ldquoEffect of meteorologicalvariables on the incidence of hand foot and mouth diseasein children a time-series analysis in Guangzhou Chinardquo BMCInfectious Diseases vol 13 no 1 article 134 2013

[19] M J Chen C Y Lin Y T Wu et al ldquoEffects of extremeprecipitation to the distribution of infectious diseases inTaiwan1994ndash2008rdquo PLoS ONE vol 7 no 6 Article ID e34651 2012

[20] M Urashima N Shindo and N Okabe ldquoSeasonal models ofherpangina and hand-foot-mouth disease to simulate annualfluctuations in urban warming in Tokyordquo Japanese Journal ofInfectious Diseases vol 56 no 2 pp 48ndash53 2003

[21] M EdmondCWong and SKChuang ldquoEvaluation of sentinelsurveillance system for monitoring hand foot and mouthdisease in Hong Kongrdquo Public Health vol 125 no 11 pp 777ndash783 2011

[22] D JMuscatello A T Newall D E Dwyer and C RMacIntyreldquoMortality attributable to seasonal and pandemic influenzaAustralia 2003 to 2009 using a novel time series smoothingapproachrdquo PLoS ONE vol 8 no 6 Article ID e64734 2013

[23] K Park B Lee K Baek et al ldquoEnteroviruses isolated from her-pangina and hand-foot-and-mouth disease inKorean childrenrdquoVirology Journal vol 9 article 205 2012

[24] M Kobayashi T Makino N Hanaoka et al ldquoClinical manifes-tations of coxsackievirus A6 infection associated with a majoroutbreak of hand foot and mouth disease in Japanrdquo JapaneseJournal of Infectious Diseases vol 66 no 3 pp 260ndash261 2013

[25] C C Yip S K Lau J Y Lo K-H Chan P C Woo and K-Y Yuen ldquoGenetic characterization of EV71 isolates from 2004to 2010 reveals predominance and persistent circulation of thenewly proposed genotype D and recent emergence of a distinctlineage of subgenotype C2 inHong KongrdquoVirology Journal vol10 article 222 2013

[26] H-P Su T-C Chan and C-C Chang ldquoTyphoon-related lep-tospirosis and melioidosis Taiwan 2009rdquo Emerging InfectiousDiseases vol 17 no 7 pp 1322ndash1324 2011

[27] F Qiaoyun J Xiongfei L lihuan and X Angao ldquoEpidemiologyand etiological characteristics of hand foot and mouth diseasein Huizhou City between 2008 and 2011rdquo Archives of Virologyvol 158 no 4 pp 895ndash899 2013

[28] Y Wang Z Feng and Y Yang ldquoHand foot and mouth diseasein China patterns of spread and transmissibilityrdquo Epidemiologyvol 22 no 6 pp 781ndash792 2011

[29] H Wu H Wang Q Wang et al ldquoThe effect of meteorologicalfactors on adolescent hand foot and mouth disease andassociated effect modifiersrdquo Global Health Action vol 7 ArticleID 24664 2014

BioMed Research International 3

100∘09984000998400998400E 110

∘09984000998400998400E 120

∘09984000998400998400E 130

∘09984000998400998400E 140

∘09984000998400998400E 150

∘09984000998400998400E

50∘09984000998400998400N

40∘09984000998400998400N

30∘09984000998400998400N

20∘09984000998400998400N

10∘09984000998400998400N

0∘09984000998400998400

10∘09984000998400998400S

Japan

N

TaiwanHong Kong

Singapore

0 340 680 1360 2040 2720(km)

Studied areas

Figure 1 Studied areas

the epidemic timing peaks and durations of HFMDnot onlywere different between countries or regions but also variedwithin individual areas in every country or region Overallthe timing of the HFMD peaks was delayed with the increasein latitude

32 Descriptive Statistics ofMeteorological Factors Fivemete-orological factors in those areas during the study period aresummarized in Table 1 Singapore had the highest 101-week

mean temperature with standard deviation (283 plusmn 094∘C)and mean dew point (238 plusmn 081∘C) while those itemswere lowest in Japan with 151 plusmn 879∘C and 885 plusmn 928∘Crespectively Similarly these values in Taiwanwere lower thanthose in Hong Kong Other measurements had no obviousorder between Singapore Hong Kong Taiwan and Japan Inaddition the temperature-relatedmeasurements also showedhigher deviation in Japan than in other areas which indicatedthe variations which occurred within Japan Together with

4 BioMed Research International

China

Russia

North Korea

South Korea

0

50∘09984000998400998400N

40∘09984000998400998400N

30∘09984000998400998400N

20∘09984000998400998400N

130∘09984000998400998400E 140

∘09984000998400998400E

StationsJapan

480240 720 960120(km)

N

(a)

China

Central Area

Eastern Area

KKP Area

Taipei AreaNorth Area

Southern Area

StationsTaiwan

26∘09984000998400998400N

24∘09984000998400998400N

22∘09984000998400998400N

20∘09984000998400998400N

118∘09984000998400998400E 120

∘09984000998400998400E 122

∘09984000998400998400E

0 30 60 120 180 240

(km)

N

(b)

Hong Kong

0 8 16 24 324(km)

N

113∘50

9984000998400998400E 114

∘09984000998400998400E 114

∘10

9984000998400998400E 114

∘20

9984000998400998400E

22∘40

9984000998400998400N

22∘30

9984000998400998400N

22∘20

9984000998400998400N

22∘10

9984000998400998400N

22∘09984000998400998400N

StationsSingapore

(c)

Malaysia

Indonesia

Singapore

StationsSingapore

0 4 8 12 162

(km)

N103

∘40

9984000998400998400E 103

∘50

9984000998400998400E 104

∘09984000998400998400E

1∘30

9984000998400998400N

1∘20

9984000998400998400N

1∘10

9984000998400998400N

(d)

Figure 2 Meteorological stations in four areas in study (a) Japan (b) Taiwan (c) Hong Kong and (d) Singapore

the decreasing trend of mean temperature from south tonorth we inferred that latitude played an important role inchange in temperature and would be associated with the Zrate of HFMD Therefore this factor was incorporated intothe following GAM analysis

33 GAM Analysis of HFMD Standardized Value To under-stand the roles which latitude and meteorological factors

played the GAM analysis was performed The final model ofZ rate incorporates latitude dew point visibility wind speedmean temperature and total precipitation All estimates andsignificance levels are listed in Table 2 Based on the linearestimation of each explanatory variable fromGAM the coef-ficientsrsquo estimations of latitude and weekly dew point weresignificantly positively associated with increasing HFMD Zrate (119875 lt 00001) The coefficientsrsquo estimations of visibility

BioMed Research International 5

HFMD (standardized value for each area)

Mie

Oita

Gifu

Nara

Saga

IwateAkita

Aichi

Shiga

Fukui

Chiba

Kochi

Osaka

Kyoto

Tokyo

Ehime

Tottori

Hyogo

Ibaraki

Miyagi

Niigata

Gunma

Tochigi

Nagano

Aomori

Toyama

Saitama

Kagawa

Shimane

Fukuoka

Okinawa

Ishikawa

Nagasaki

Shizuoka

Miyazaki

Okayama

Hokkaido

Yamagata

Singapore

Kanagawa

Hiroshima

Yamanashi

WakayamaTokushima

Fukushima

Kumamoto

Yamaguchi

Kagoshima

Hong Kong

73986431 9865421752 1134 38 1314 16 18 2021 23 2526 2930282724221917151210 11 1314 16 18 2021 23 252627242219171512103940414243444546474849505152 4443424140 4546474849505152373533 363231 34 3839373533 363231

Taiwan east

Taiwan TPE

Taiwan KKP

Taiwan north

Taiwan southTaiwan central

N

W

S

E

001ndash100

101ndash200201ndash300301ndash586

minus145ndashminus043minus042ndash000

Figure 3 Spatiotemporal map of HFMD Z rate from week 31 of 2012 to week 27 of 2014

Table 1 Mean standard deviation coefficient of variation and quantiles of meteorological factors among four regions in study

Factors Regions(size 119899)

Japan(119899 = 47)

Taiwan(119899 = 6)

Hong Kong(119899 = 1)

Singapore(119899 = 1)

Temperature(∘C)

Mean plusmn SD 151 plusmn 879 239 plusmn 447 230 plusmn 528 283 plusmn 094CV () 582 187 230 33111987611198763 727 227 201 280 187 277 276 289

Dew point(∘C)

Mean plusmn SD 885 plusmn 928 187 plusmn 473 181 plusmn 623 238 plusmn 081CV () 1048 253 344 34011987611198763 064 176 148 232 144 240 236 243

Visibility(km)

Mean plusmn SD 143 plusmn 490 897 plusmn 502 706 plusmn 367 707 plusmn 359CV () 341 560 520 50811987611198763 126 168 532 121 196 974 188 959

Wind speed(ms)

Mean plusmn SD 305 plusmn 086 323 plusmn 158 314 plusmn 051 250 plusmn 086CV () 281 490 162 34511987611198763 245 353 211 380 279 339 190 275

Totalprecipitation(mm)

Mean plusmn SD 399 plusmn 506 411 plusmn 864 520 plusmn 840 420 plusmn 488CV () 1269 2104 1616 116211987611198763 080 506 000 404 000 635 076 573

CV indicates coefficient of variation (standard deviationmean lowast 100)

6 BioMed Research International

Table 2 Parameter estimates of linear terms in general additivemodel (GAM)

Variable Estimate Standard error 119875 valueLatitude 00465 00020 lt00001lowast

Mean temperature 00031 00063 05917Dew point 00566 00060 lt00001lowast

Visibility minus00066 00023 00037lowast

Wind speed minus00514 00118 lt00001lowast

Total precipitation 00018 00021 04100lowast

119875 value lt 005

(119875 = 00037) and wind speed (119875 lt 00001) were inverselyassociated with increasing HFMD Z rate However meantemperature and total precipitation were not significantlycorrelated with the Z rate

In addition the smoothing components plot (Figure 4)demonstrated the estimated smoothing spline functions withthe linear effect subtracted out The significant smoothersindicated that the correlations between Z rate and explana-tory variables were nonlinear The plot showed that holdingall linear and the other nonlinear terms fixed temperaturetended to increase gradually with Z rate (119875 lt 00001) andin addition there was a kind of turning point for a positiveeffect of dew point at around of 20∘C (119875 lt 00001) with aslight positive effect overall The Z rate tended to be lowerwhen the total precipitation increased (119875 = 00003) Thenonlinear effects of the visibility and thewind speed could notbe estimated because their corresponding degrees of freedom(DF) were too small

4 Discussion

HFMD is a common disease caused by enteroviruses thatmainly attack children below the age of six in East Asia Fur-ther clinical progress results in severe sequelae or even leadsto death Thus HFMD is a great public health issue in thisregion including mainland China (on the continent) SouthKorea (a peninsula) Japan Taiwan and Hong Kong (islands)[1 15 23ndash25] This study incorporates meteorological dataHFMD data and spatiotemporal analysis to reshape theepidemiological features of this disease occurring in islandsduring the study period Dynamic changes and duration ofHFMD severity among different parts of study sites weredemonstrated clearly through the integrated surveillance Forthose four epidemic islands including Japan Taiwan HongKong and Singapore in this study dew point was a keymeteorological factor associated with HFMD Neverthelesslatitude difference plays an important role that even surpassesthe impact of dew point onHFMDWhy this factor affects thedisease rate so much is still an enigma However East Asia ismore than 3500 km from south to north and covers tropicalsubtropical and temperate climate zones which are definedby climate factors and latitudeThis results in different climatefeatures in the different climate zones including temperaturevariations and ranges directions of monsoon in differentseasons among climate zones and rainfallThose phenomenabring direct effects to the islands in East Asia for example

typhoons strike Japan Taiwan and Hong Kong in summerand autumn with high-intensity rainfall that causes floodsand disease outbreaks [4 26] Of note HFMD is not anexception to the rule that the relative risk of enterovirusinfection will increase after extreme precipitation in Taiwan[19]

In contrast mainland China represents the continentallandform which can be divided into several regions accord-ing to both meteorological factors and latitude In a long-term population-based study of HFMD in China increasingamplitude of HFMD outbreaks was shown to accompanythe increase of latitude in southern China [15] Studies alsomentioned that seasonal variations in China of HFMD wereassociated with precipitation sunshine temperature and airpressure consistent with other studies in China [18 2027 28] In our study only higher dew point (a predictorfor humidity) was found to be positively associated withincreasing HFMD Z rate This factor is in accord withthe previous findings from other studies [15 28] Althoughtemperature overall did not show a linear positive effect onHFMD Z rate the results in the smoothing componentsshowed that temperature above 28∘C had a persistent positiveeffect on Z rate and temperature below 5∘C had a negativeeffect on Z rate These findings might result from theenvironmental niche condition of HFMD epidemic beingduring the hot season However findings for precipitationdiffered between our study and previous ones [15 19 28]A possible reason is that for our study site the mean totalprecipitation only differed by 004 inches (016 to 020) or10mmThis tiny differencewould not affect the Z rate amongthe island type landforms in East Asia From the GAM resultlow visibility and low wind speed were significantly related tothe elevation of Z rate of HFMD Although low wind speedwas also found in a transmission modeling study there wereno direct mechanisms for these negatively associated factorsA possible implication would be that higher wind speedcreates good airflow which may shorten how long the virusparticles remain somewhere Visibility was highly correlatedwith sunshine which was inversely correlated with HFMD[29]

This study has some limitations First HFMD is causedby several enteroviruses In this study there was no detailedinformation on causal agents for example EV71 or CVA16are responsible for the outbreaks among islands during thestudy period This may affect the disease duration or peak ofoutbreaks Second the transmission chain of HFMD amongareas defined in this study was not taken into considerationThis also impacts the spread of HFMD between or withinthe study areas Finally the studied period was too short tomake strong conclusions and extended data are needed forvalidating the association found in this study

5 Conclusion

In conclusion we found out that latitude is a major riskfactor for increasing the Z rate of HFMD in islands inEast Asia In addition only some meteorological factors(dew point low visibility and low wind speed) were foundin previous mainland China studies to be associated with

BioMed Research International 7

15

10

05

00

minus05

minus10

minus10 0 10 20 30

Temperature

Splin

e (te

mpe

ratu

re) 2

1

0

minus1

minus10 0 10 20 0 10 20 30

04

03

02

01

00

minus01

02

01

00

minus01

2 4 6 8 10

000

minus025

minus050

minus075

minus100

0 20 40 60 80

DF = 1239

P = 00003P =

P = DF = 4455 DF = 0P lt 00001P lt 00001

Splin

e (de

w p

oint

)

Splin

e (vi

sibili

ty)

Visibility

Splin

e (w

ind

spee

d)

Splin

e (pr

ecip

itatio

n)

Precipitation

DF = 0336 DF = 0969

Smoothing components for Z ratewith 95 confidence limits

Wind speed

Dew point

Figure 4 Smoothing component plots for standardized HFMD rate (Z rate)

the outbreaks This indicates that island-type geographicalareas have intrinsic differences from continental areas bothin climate impact and in causes of HFMD Since HFMDstrikes East Asia every year and there are no effective phar-maceutical treatments for this disease integrated surveillancewith timely multiple surveillance sources and meteorologicalinformation in different countries can assist in the control andmitigation of the impacts of HFMD in East Asia Also theseresults can be applied to islands in other oceans for predictingHFMD or other infectious diseases

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

Acknowledgments

This research was supported by a grant from the Ministryof Science and Technology Taiwan (MOST 103-2621-M-001-002) The authors also wish to express their sincere gratitudeto Mr Kent M Suarez for his English editing

References

[1] MHo E-R Chen K-HHsu et al ldquoAn epidemic of enterovirus71 infection in Taiwanrdquo The New England Journal of Medicinevol 341 no 13 pp 929ndash935 1999

[2] F-C Tseng H-C Huang C-Y Chi et al ldquoEpidemiologicalsurvey of enterovirus infections occurring in Taiwan between2000 and 2005 analysis of sentinel physician surveillance datardquoJournal of Medical Virology vol 79 no 12 pp 1850ndash1860 2007

[3] S-C Chen H-L Chang T-R Yan Y-T Cheng and K-T Chen ldquoAn eight-year study of epidemiologic features ofenterovirus 71 infection in Taiwanrdquo The American Journal ofTropical Medicine and Hygiene vol 77 no 1 pp 188ndash191 2007

[4] W De K Changwen L Wei et al ldquoA large outbreak ofhand foot and mouth disease caused by EV71 and CAV16 inGuangdong China 2009rdquo Archives of Virology vol 156 no 6pp 945ndash953 2011

[5] H Ni B Yi J Yin et al ldquoEpidemiological and etiologicalcharacteristics of hand foot and mouth disease in NingboChina 2008ndash2011rdquo Journal of Clinical Virology vol 54 no 4pp 342ndash348 2012

[6] L-Y Chang Y-CHuang andT-Y Lin ldquoFulminant neurogenicpulmonary oedema with hand foot and mouth diseaserdquo TheLancet vol 352 no 9125 pp 367ndash368 1998

8 BioMed Research International

[7] N J Schmidt E H Lennette andHH Ho ldquoAn apparently newenterovirus isolated from patients with disease of the centralnervous systemrdquo Journal of Infectious Diseases vol 129 no 3pp 304ndash309 1974

[8] J Blomberg E Lycke K Ahlfors T Johnsson S Wolontis andG von Zeipel ldquoLetter new enterovirus type associated withepidemic of aseptic meningitis and-or hand foot and mouthdiseaserdquoThe Lancet vol 2 no 7872 article 112 1974

[9] Y Ishimaru S Nakano K Yamaoka and S Takami ldquoOutbreaksof hand foot and mouth disease by enterovirus 71 Highincidence of complication disorders of central nervous systemrdquoArchives of Disease in Childhood vol 55 no 8 pp 583ndash5881980

[10] S Van Der Sanden M Koopmans G Uslu and H Van DerAvoort ldquoEpidemiology of enterovirus 71 in the Netherlands1963 to 2008rdquo Journal of Clinical Microbiology vol 47 no 9 pp2826ndash2833 2009

[11] M ChumakovM Voroshilova L Shindarov et al ldquoEnterovirus71 isolated from cases of epidemic poliomyelitis-like disease inBulgariardquo Archives of Virology vol 60 no 3-4 pp 329ndash3401979

[12] G Nagy S Takatsy E Kukan I Mihaly and I Domok ldquoViro-logical diagnosis of enterovirus type 71 infections experiencesgained during an epidemic of acute CNS diseases in Hungaryin 1978rdquo Archives of Virology vol 71 no 3 pp 217ndash227 1982

[13] I Tagaya R Takayama and A Hagiwara ldquoA large-scaleepidemic of hand foot and mouth disease associated withenterovirus 71 infection in Japan in 1978rdquo Japanese Journal ofMedical Science and Biology vol 34 no 3 pp 191ndash196 1981

[14] L G Chan U D Parashar M S Lye et al ldquoDeaths ofchildren during an outbreak of hand foot and mouth diseasein SarawakMalaysia clinical and pathological characteristics ofthe diseaserdquo Clinical Infectious Diseases vol 31 no 3 pp 678ndash683 2000

[15] W Xing Q Liao C Viboud et al ldquoHand foot and mouthdisease in China 2008-12 an epidemiological studyrdquoTheLancetInfectious Diseases vol 14 no 4 pp 308ndash318 2014

[16] T-N Wu S-F Tsai S-F Li et al ldquoSentinel surveillance forenterovirus 71 Taiwan 1998rdquo Emerging Infectious Diseases vol5 no 3 pp 458ndash460 1999

[17] Y Podin E L M Gias F Ong et al ldquoSentinel surveillance forhuman enterovirus 71 in Sarawak Malaysia Lessons from thefirst 7 yearsrdquo BMC Public Health vol 6 article 180 2006

[18] Y Huang T Deng S Yu et al ldquoEffect of meteorologicalvariables on the incidence of hand foot and mouth diseasein children a time-series analysis in Guangzhou Chinardquo BMCInfectious Diseases vol 13 no 1 article 134 2013

[19] M J Chen C Y Lin Y T Wu et al ldquoEffects of extremeprecipitation to the distribution of infectious diseases inTaiwan1994ndash2008rdquo PLoS ONE vol 7 no 6 Article ID e34651 2012

[20] M Urashima N Shindo and N Okabe ldquoSeasonal models ofherpangina and hand-foot-mouth disease to simulate annualfluctuations in urban warming in Tokyordquo Japanese Journal ofInfectious Diseases vol 56 no 2 pp 48ndash53 2003

[21] M EdmondCWong and SKChuang ldquoEvaluation of sentinelsurveillance system for monitoring hand foot and mouthdisease in Hong Kongrdquo Public Health vol 125 no 11 pp 777ndash783 2011

[22] D JMuscatello A T Newall D E Dwyer and C RMacIntyreldquoMortality attributable to seasonal and pandemic influenzaAustralia 2003 to 2009 using a novel time series smoothingapproachrdquo PLoS ONE vol 8 no 6 Article ID e64734 2013

[23] K Park B Lee K Baek et al ldquoEnteroviruses isolated from her-pangina and hand-foot-and-mouth disease inKorean childrenrdquoVirology Journal vol 9 article 205 2012

[24] M Kobayashi T Makino N Hanaoka et al ldquoClinical manifes-tations of coxsackievirus A6 infection associated with a majoroutbreak of hand foot and mouth disease in Japanrdquo JapaneseJournal of Infectious Diseases vol 66 no 3 pp 260ndash261 2013

[25] C C Yip S K Lau J Y Lo K-H Chan P C Woo and K-Y Yuen ldquoGenetic characterization of EV71 isolates from 2004to 2010 reveals predominance and persistent circulation of thenewly proposed genotype D and recent emergence of a distinctlineage of subgenotype C2 inHong KongrdquoVirology Journal vol10 article 222 2013

[26] H-P Su T-C Chan and C-C Chang ldquoTyphoon-related lep-tospirosis and melioidosis Taiwan 2009rdquo Emerging InfectiousDiseases vol 17 no 7 pp 1322ndash1324 2011

[27] F Qiaoyun J Xiongfei L lihuan and X Angao ldquoEpidemiologyand etiological characteristics of hand foot and mouth diseasein Huizhou City between 2008 and 2011rdquo Archives of Virologyvol 158 no 4 pp 895ndash899 2013

[28] Y Wang Z Feng and Y Yang ldquoHand foot and mouth diseasein China patterns of spread and transmissibilityrdquo Epidemiologyvol 22 no 6 pp 781ndash792 2011

[29] H Wu H Wang Q Wang et al ldquoThe effect of meteorologicalfactors on adolescent hand foot and mouth disease andassociated effect modifiersrdquo Global Health Action vol 7 ArticleID 24664 2014

4 BioMed Research International

China

Russia

North Korea

South Korea

0

50∘09984000998400998400N

40∘09984000998400998400N

30∘09984000998400998400N

20∘09984000998400998400N

130∘09984000998400998400E 140

∘09984000998400998400E

StationsJapan

480240 720 960120(km)

N

(a)

China

Central Area

Eastern Area

KKP Area

Taipei AreaNorth Area

Southern Area

StationsTaiwan

26∘09984000998400998400N

24∘09984000998400998400N

22∘09984000998400998400N

20∘09984000998400998400N

118∘09984000998400998400E 120

∘09984000998400998400E 122

∘09984000998400998400E

0 30 60 120 180 240

(km)

N

(b)

Hong Kong

0 8 16 24 324(km)

N

113∘50

9984000998400998400E 114

∘09984000998400998400E 114

∘10

9984000998400998400E 114

∘20

9984000998400998400E

22∘40

9984000998400998400N

22∘30

9984000998400998400N

22∘20

9984000998400998400N

22∘10

9984000998400998400N

22∘09984000998400998400N

StationsSingapore

(c)

Malaysia

Indonesia

Singapore

StationsSingapore

0 4 8 12 162

(km)

N103

∘40

9984000998400998400E 103

∘50

9984000998400998400E 104

∘09984000998400998400E

1∘30

9984000998400998400N

1∘20

9984000998400998400N

1∘10

9984000998400998400N

(d)

Figure 2 Meteorological stations in four areas in study (a) Japan (b) Taiwan (c) Hong Kong and (d) Singapore

the decreasing trend of mean temperature from south tonorth we inferred that latitude played an important role inchange in temperature and would be associated with the Zrate of HFMD Therefore this factor was incorporated intothe following GAM analysis

33 GAM Analysis of HFMD Standardized Value To under-stand the roles which latitude and meteorological factors

played the GAM analysis was performed The final model ofZ rate incorporates latitude dew point visibility wind speedmean temperature and total precipitation All estimates andsignificance levels are listed in Table 2 Based on the linearestimation of each explanatory variable fromGAM the coef-ficientsrsquo estimations of latitude and weekly dew point weresignificantly positively associated with increasing HFMD Zrate (119875 lt 00001) The coefficientsrsquo estimations of visibility

BioMed Research International 5

HFMD (standardized value for each area)

Mie

Oita

Gifu

Nara

Saga

IwateAkita

Aichi

Shiga

Fukui

Chiba

Kochi

Osaka

Kyoto

Tokyo

Ehime

Tottori

Hyogo

Ibaraki

Miyagi

Niigata

Gunma

Tochigi

Nagano

Aomori

Toyama

Saitama

Kagawa

Shimane

Fukuoka

Okinawa

Ishikawa

Nagasaki

Shizuoka

Miyazaki

Okayama

Hokkaido

Yamagata

Singapore

Kanagawa

Hiroshima

Yamanashi

WakayamaTokushima

Fukushima

Kumamoto

Yamaguchi

Kagoshima

Hong Kong

73986431 9865421752 1134 38 1314 16 18 2021 23 2526 2930282724221917151210 11 1314 16 18 2021 23 252627242219171512103940414243444546474849505152 4443424140 4546474849505152373533 363231 34 3839373533 363231

Taiwan east

Taiwan TPE

Taiwan KKP

Taiwan north

Taiwan southTaiwan central

N

W

S

E

001ndash100

101ndash200201ndash300301ndash586

minus145ndashminus043minus042ndash000

Figure 3 Spatiotemporal map of HFMD Z rate from week 31 of 2012 to week 27 of 2014

Table 1 Mean standard deviation coefficient of variation and quantiles of meteorological factors among four regions in study

Factors Regions(size 119899)

Japan(119899 = 47)

Taiwan(119899 = 6)

Hong Kong(119899 = 1)

Singapore(119899 = 1)

Temperature(∘C)

Mean plusmn SD 151 plusmn 879 239 plusmn 447 230 plusmn 528 283 plusmn 094CV () 582 187 230 33111987611198763 727 227 201 280 187 277 276 289

Dew point(∘C)

Mean plusmn SD 885 plusmn 928 187 plusmn 473 181 plusmn 623 238 plusmn 081CV () 1048 253 344 34011987611198763 064 176 148 232 144 240 236 243

Visibility(km)

Mean plusmn SD 143 plusmn 490 897 plusmn 502 706 plusmn 367 707 plusmn 359CV () 341 560 520 50811987611198763 126 168 532 121 196 974 188 959

Wind speed(ms)

Mean plusmn SD 305 plusmn 086 323 plusmn 158 314 plusmn 051 250 plusmn 086CV () 281 490 162 34511987611198763 245 353 211 380 279 339 190 275

Totalprecipitation(mm)

Mean plusmn SD 399 plusmn 506 411 plusmn 864 520 plusmn 840 420 plusmn 488CV () 1269 2104 1616 116211987611198763 080 506 000 404 000 635 076 573

CV indicates coefficient of variation (standard deviationmean lowast 100)

6 BioMed Research International

Table 2 Parameter estimates of linear terms in general additivemodel (GAM)

Variable Estimate Standard error 119875 valueLatitude 00465 00020 lt00001lowast

Mean temperature 00031 00063 05917Dew point 00566 00060 lt00001lowast

Visibility minus00066 00023 00037lowast

Wind speed minus00514 00118 lt00001lowast

Total precipitation 00018 00021 04100lowast

119875 value lt 005

(119875 = 00037) and wind speed (119875 lt 00001) were inverselyassociated with increasing HFMD Z rate However meantemperature and total precipitation were not significantlycorrelated with the Z rate

In addition the smoothing components plot (Figure 4)demonstrated the estimated smoothing spline functions withthe linear effect subtracted out The significant smoothersindicated that the correlations between Z rate and explana-tory variables were nonlinear The plot showed that holdingall linear and the other nonlinear terms fixed temperaturetended to increase gradually with Z rate (119875 lt 00001) andin addition there was a kind of turning point for a positiveeffect of dew point at around of 20∘C (119875 lt 00001) with aslight positive effect overall The Z rate tended to be lowerwhen the total precipitation increased (119875 = 00003) Thenonlinear effects of the visibility and thewind speed could notbe estimated because their corresponding degrees of freedom(DF) were too small

4 Discussion

HFMD is a common disease caused by enteroviruses thatmainly attack children below the age of six in East Asia Fur-ther clinical progress results in severe sequelae or even leadsto death Thus HFMD is a great public health issue in thisregion including mainland China (on the continent) SouthKorea (a peninsula) Japan Taiwan and Hong Kong (islands)[1 15 23ndash25] This study incorporates meteorological dataHFMD data and spatiotemporal analysis to reshape theepidemiological features of this disease occurring in islandsduring the study period Dynamic changes and duration ofHFMD severity among different parts of study sites weredemonstrated clearly through the integrated surveillance Forthose four epidemic islands including Japan Taiwan HongKong and Singapore in this study dew point was a keymeteorological factor associated with HFMD Neverthelesslatitude difference plays an important role that even surpassesthe impact of dew point onHFMDWhy this factor affects thedisease rate so much is still an enigma However East Asia ismore than 3500 km from south to north and covers tropicalsubtropical and temperate climate zones which are definedby climate factors and latitudeThis results in different climatefeatures in the different climate zones including temperaturevariations and ranges directions of monsoon in differentseasons among climate zones and rainfallThose phenomenabring direct effects to the islands in East Asia for example

typhoons strike Japan Taiwan and Hong Kong in summerand autumn with high-intensity rainfall that causes floodsand disease outbreaks [4 26] Of note HFMD is not anexception to the rule that the relative risk of enterovirusinfection will increase after extreme precipitation in Taiwan[19]

In contrast mainland China represents the continentallandform which can be divided into several regions accord-ing to both meteorological factors and latitude In a long-term population-based study of HFMD in China increasingamplitude of HFMD outbreaks was shown to accompanythe increase of latitude in southern China [15] Studies alsomentioned that seasonal variations in China of HFMD wereassociated with precipitation sunshine temperature and airpressure consistent with other studies in China [18 2027 28] In our study only higher dew point (a predictorfor humidity) was found to be positively associated withincreasing HFMD Z rate This factor is in accord withthe previous findings from other studies [15 28] Althoughtemperature overall did not show a linear positive effect onHFMD Z rate the results in the smoothing componentsshowed that temperature above 28∘C had a persistent positiveeffect on Z rate and temperature below 5∘C had a negativeeffect on Z rate These findings might result from theenvironmental niche condition of HFMD epidemic beingduring the hot season However findings for precipitationdiffered between our study and previous ones [15 19 28]A possible reason is that for our study site the mean totalprecipitation only differed by 004 inches (016 to 020) or10mmThis tiny differencewould not affect the Z rate amongthe island type landforms in East Asia From the GAM resultlow visibility and low wind speed were significantly related tothe elevation of Z rate of HFMD Although low wind speedwas also found in a transmission modeling study there wereno direct mechanisms for these negatively associated factorsA possible implication would be that higher wind speedcreates good airflow which may shorten how long the virusparticles remain somewhere Visibility was highly correlatedwith sunshine which was inversely correlated with HFMD[29]

This study has some limitations First HFMD is causedby several enteroviruses In this study there was no detailedinformation on causal agents for example EV71 or CVA16are responsible for the outbreaks among islands during thestudy period This may affect the disease duration or peak ofoutbreaks Second the transmission chain of HFMD amongareas defined in this study was not taken into considerationThis also impacts the spread of HFMD between or withinthe study areas Finally the studied period was too short tomake strong conclusions and extended data are needed forvalidating the association found in this study

5 Conclusion

In conclusion we found out that latitude is a major riskfactor for increasing the Z rate of HFMD in islands inEast Asia In addition only some meteorological factors(dew point low visibility and low wind speed) were foundin previous mainland China studies to be associated with

BioMed Research International 7

15

10

05

00

minus05

minus10

minus10 0 10 20 30

Temperature

Splin

e (te

mpe

ratu

re) 2

1

0

minus1

minus10 0 10 20 0 10 20 30

04

03

02

01

00

minus01

02

01

00

minus01

2 4 6 8 10

000

minus025

minus050

minus075

minus100

0 20 40 60 80

DF = 1239

P = 00003P =

P = DF = 4455 DF = 0P lt 00001P lt 00001

Splin

e (de

w p

oint

)

Splin

e (vi

sibili

ty)

Visibility

Splin

e (w

ind

spee

d)

Splin

e (pr

ecip

itatio

n)

Precipitation

DF = 0336 DF = 0969

Smoothing components for Z ratewith 95 confidence limits

Wind speed

Dew point

Figure 4 Smoothing component plots for standardized HFMD rate (Z rate)

the outbreaks This indicates that island-type geographicalareas have intrinsic differences from continental areas bothin climate impact and in causes of HFMD Since HFMDstrikes East Asia every year and there are no effective phar-maceutical treatments for this disease integrated surveillancewith timely multiple surveillance sources and meteorologicalinformation in different countries can assist in the control andmitigation of the impacts of HFMD in East Asia Also theseresults can be applied to islands in other oceans for predictingHFMD or other infectious diseases

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

Acknowledgments

This research was supported by a grant from the Ministryof Science and Technology Taiwan (MOST 103-2621-M-001-002) The authors also wish to express their sincere gratitudeto Mr Kent M Suarez for his English editing

References

[1] MHo E-R Chen K-HHsu et al ldquoAn epidemic of enterovirus71 infection in Taiwanrdquo The New England Journal of Medicinevol 341 no 13 pp 929ndash935 1999

[2] F-C Tseng H-C Huang C-Y Chi et al ldquoEpidemiologicalsurvey of enterovirus infections occurring in Taiwan between2000 and 2005 analysis of sentinel physician surveillance datardquoJournal of Medical Virology vol 79 no 12 pp 1850ndash1860 2007

[3] S-C Chen H-L Chang T-R Yan Y-T Cheng and K-T Chen ldquoAn eight-year study of epidemiologic features ofenterovirus 71 infection in Taiwanrdquo The American Journal ofTropical Medicine and Hygiene vol 77 no 1 pp 188ndash191 2007

[4] W De K Changwen L Wei et al ldquoA large outbreak ofhand foot and mouth disease caused by EV71 and CAV16 inGuangdong China 2009rdquo Archives of Virology vol 156 no 6pp 945ndash953 2011

[5] H Ni B Yi J Yin et al ldquoEpidemiological and etiologicalcharacteristics of hand foot and mouth disease in NingboChina 2008ndash2011rdquo Journal of Clinical Virology vol 54 no 4pp 342ndash348 2012

[6] L-Y Chang Y-CHuang andT-Y Lin ldquoFulminant neurogenicpulmonary oedema with hand foot and mouth diseaserdquo TheLancet vol 352 no 9125 pp 367ndash368 1998

8 BioMed Research International

[7] N J Schmidt E H Lennette andHH Ho ldquoAn apparently newenterovirus isolated from patients with disease of the centralnervous systemrdquo Journal of Infectious Diseases vol 129 no 3pp 304ndash309 1974

[8] J Blomberg E Lycke K Ahlfors T Johnsson S Wolontis andG von Zeipel ldquoLetter new enterovirus type associated withepidemic of aseptic meningitis and-or hand foot and mouthdiseaserdquoThe Lancet vol 2 no 7872 article 112 1974

[9] Y Ishimaru S Nakano K Yamaoka and S Takami ldquoOutbreaksof hand foot and mouth disease by enterovirus 71 Highincidence of complication disorders of central nervous systemrdquoArchives of Disease in Childhood vol 55 no 8 pp 583ndash5881980

[10] S Van Der Sanden M Koopmans G Uslu and H Van DerAvoort ldquoEpidemiology of enterovirus 71 in the Netherlands1963 to 2008rdquo Journal of Clinical Microbiology vol 47 no 9 pp2826ndash2833 2009

[11] M ChumakovM Voroshilova L Shindarov et al ldquoEnterovirus71 isolated from cases of epidemic poliomyelitis-like disease inBulgariardquo Archives of Virology vol 60 no 3-4 pp 329ndash3401979

[12] G Nagy S Takatsy E Kukan I Mihaly and I Domok ldquoViro-logical diagnosis of enterovirus type 71 infections experiencesgained during an epidemic of acute CNS diseases in Hungaryin 1978rdquo Archives of Virology vol 71 no 3 pp 217ndash227 1982

[13] I Tagaya R Takayama and A Hagiwara ldquoA large-scaleepidemic of hand foot and mouth disease associated withenterovirus 71 infection in Japan in 1978rdquo Japanese Journal ofMedical Science and Biology vol 34 no 3 pp 191ndash196 1981

[14] L G Chan U D Parashar M S Lye et al ldquoDeaths ofchildren during an outbreak of hand foot and mouth diseasein SarawakMalaysia clinical and pathological characteristics ofthe diseaserdquo Clinical Infectious Diseases vol 31 no 3 pp 678ndash683 2000

[15] W Xing Q Liao C Viboud et al ldquoHand foot and mouthdisease in China 2008-12 an epidemiological studyrdquoTheLancetInfectious Diseases vol 14 no 4 pp 308ndash318 2014

[16] T-N Wu S-F Tsai S-F Li et al ldquoSentinel surveillance forenterovirus 71 Taiwan 1998rdquo Emerging Infectious Diseases vol5 no 3 pp 458ndash460 1999

[17] Y Podin E L M Gias F Ong et al ldquoSentinel surveillance forhuman enterovirus 71 in Sarawak Malaysia Lessons from thefirst 7 yearsrdquo BMC Public Health vol 6 article 180 2006

[18] Y Huang T Deng S Yu et al ldquoEffect of meteorologicalvariables on the incidence of hand foot and mouth diseasein children a time-series analysis in Guangzhou Chinardquo BMCInfectious Diseases vol 13 no 1 article 134 2013

[19] M J Chen C Y Lin Y T Wu et al ldquoEffects of extremeprecipitation to the distribution of infectious diseases inTaiwan1994ndash2008rdquo PLoS ONE vol 7 no 6 Article ID e34651 2012

[20] M Urashima N Shindo and N Okabe ldquoSeasonal models ofherpangina and hand-foot-mouth disease to simulate annualfluctuations in urban warming in Tokyordquo Japanese Journal ofInfectious Diseases vol 56 no 2 pp 48ndash53 2003

[21] M EdmondCWong and SKChuang ldquoEvaluation of sentinelsurveillance system for monitoring hand foot and mouthdisease in Hong Kongrdquo Public Health vol 125 no 11 pp 777ndash783 2011

[22] D JMuscatello A T Newall D E Dwyer and C RMacIntyreldquoMortality attributable to seasonal and pandemic influenzaAustralia 2003 to 2009 using a novel time series smoothingapproachrdquo PLoS ONE vol 8 no 6 Article ID e64734 2013

[23] K Park B Lee K Baek et al ldquoEnteroviruses isolated from her-pangina and hand-foot-and-mouth disease inKorean childrenrdquoVirology Journal vol 9 article 205 2012

[24] M Kobayashi T Makino N Hanaoka et al ldquoClinical manifes-tations of coxsackievirus A6 infection associated with a majoroutbreak of hand foot and mouth disease in Japanrdquo JapaneseJournal of Infectious Diseases vol 66 no 3 pp 260ndash261 2013

[25] C C Yip S K Lau J Y Lo K-H Chan P C Woo and K-Y Yuen ldquoGenetic characterization of EV71 isolates from 2004to 2010 reveals predominance and persistent circulation of thenewly proposed genotype D and recent emergence of a distinctlineage of subgenotype C2 inHong KongrdquoVirology Journal vol10 article 222 2013

[26] H-P Su T-C Chan and C-C Chang ldquoTyphoon-related lep-tospirosis and melioidosis Taiwan 2009rdquo Emerging InfectiousDiseases vol 17 no 7 pp 1322ndash1324 2011

[27] F Qiaoyun J Xiongfei L lihuan and X Angao ldquoEpidemiologyand etiological characteristics of hand foot and mouth diseasein Huizhou City between 2008 and 2011rdquo Archives of Virologyvol 158 no 4 pp 895ndash899 2013

[28] Y Wang Z Feng and Y Yang ldquoHand foot and mouth diseasein China patterns of spread and transmissibilityrdquo Epidemiologyvol 22 no 6 pp 781ndash792 2011

[29] H Wu H Wang Q Wang et al ldquoThe effect of meteorologicalfactors on adolescent hand foot and mouth disease andassociated effect modifiersrdquo Global Health Action vol 7 ArticleID 24664 2014

BioMed Research International 5

HFMD (standardized value for each area)

Mie

Oita

Gifu

Nara

Saga

IwateAkita

Aichi

Shiga

Fukui

Chiba

Kochi

Osaka

Kyoto

Tokyo

Ehime

Tottori

Hyogo

Ibaraki

Miyagi

Niigata

Gunma

Tochigi

Nagano

Aomori

Toyama

Saitama

Kagawa

Shimane

Fukuoka

Okinawa

Ishikawa

Nagasaki

Shizuoka

Miyazaki

Okayama

Hokkaido

Yamagata

Singapore

Kanagawa

Hiroshima

Yamanashi

WakayamaTokushima

Fukushima

Kumamoto

Yamaguchi

Kagoshima

Hong Kong

73986431 9865421752 1134 38 1314 16 18 2021 23 2526 2930282724221917151210 11 1314 16 18 2021 23 252627242219171512103940414243444546474849505152 4443424140 4546474849505152373533 363231 34 3839373533 363231

Taiwan east

Taiwan TPE

Taiwan KKP

Taiwan north

Taiwan southTaiwan central

N

W

S

E

001ndash100

101ndash200201ndash300301ndash586

minus145ndashminus043minus042ndash000

Figure 3 Spatiotemporal map of HFMD Z rate from week 31 of 2012 to week 27 of 2014

Table 1 Mean standard deviation coefficient of variation and quantiles of meteorological factors among four regions in study

Factors Regions(size 119899)

Japan(119899 = 47)

Taiwan(119899 = 6)

Hong Kong(119899 = 1)

Singapore(119899 = 1)

Temperature(∘C)

Mean plusmn SD 151 plusmn 879 239 plusmn 447 230 plusmn 528 283 plusmn 094CV () 582 187 230 33111987611198763 727 227 201 280 187 277 276 289

Dew point(∘C)

Mean plusmn SD 885 plusmn 928 187 plusmn 473 181 plusmn 623 238 plusmn 081CV () 1048 253 344 34011987611198763 064 176 148 232 144 240 236 243

Visibility(km)

Mean plusmn SD 143 plusmn 490 897 plusmn 502 706 plusmn 367 707 plusmn 359CV () 341 560 520 50811987611198763 126 168 532 121 196 974 188 959

Wind speed(ms)

Mean plusmn SD 305 plusmn 086 323 plusmn 158 314 plusmn 051 250 plusmn 086CV () 281 490 162 34511987611198763 245 353 211 380 279 339 190 275

Totalprecipitation(mm)

Mean plusmn SD 399 plusmn 506 411 plusmn 864 520 plusmn 840 420 plusmn 488CV () 1269 2104 1616 116211987611198763 080 506 000 404 000 635 076 573

CV indicates coefficient of variation (standard deviationmean lowast 100)

6 BioMed Research International

Table 2 Parameter estimates of linear terms in general additivemodel (GAM)

Variable Estimate Standard error 119875 valueLatitude 00465 00020 lt00001lowast

Mean temperature 00031 00063 05917Dew point 00566 00060 lt00001lowast

Visibility minus00066 00023 00037lowast

Wind speed minus00514 00118 lt00001lowast

Total precipitation 00018 00021 04100lowast

119875 value lt 005

(119875 = 00037) and wind speed (119875 lt 00001) were inverselyassociated with increasing HFMD Z rate However meantemperature and total precipitation were not significantlycorrelated with the Z rate

In addition the smoothing components plot (Figure 4)demonstrated the estimated smoothing spline functions withthe linear effect subtracted out The significant smoothersindicated that the correlations between Z rate and explana-tory variables were nonlinear The plot showed that holdingall linear and the other nonlinear terms fixed temperaturetended to increase gradually with Z rate (119875 lt 00001) andin addition there was a kind of turning point for a positiveeffect of dew point at around of 20∘C (119875 lt 00001) with aslight positive effect overall The Z rate tended to be lowerwhen the total precipitation increased (119875 = 00003) Thenonlinear effects of the visibility and thewind speed could notbe estimated because their corresponding degrees of freedom(DF) were too small

4 Discussion

HFMD is a common disease caused by enteroviruses thatmainly attack children below the age of six in East Asia Fur-ther clinical progress results in severe sequelae or even leadsto death Thus HFMD is a great public health issue in thisregion including mainland China (on the continent) SouthKorea (a peninsula) Japan Taiwan and Hong Kong (islands)[1 15 23ndash25] This study incorporates meteorological dataHFMD data and spatiotemporal analysis to reshape theepidemiological features of this disease occurring in islandsduring the study period Dynamic changes and duration ofHFMD severity among different parts of study sites weredemonstrated clearly through the integrated surveillance Forthose four epidemic islands including Japan Taiwan HongKong and Singapore in this study dew point was a keymeteorological factor associated with HFMD Neverthelesslatitude difference plays an important role that even surpassesthe impact of dew point onHFMDWhy this factor affects thedisease rate so much is still an enigma However East Asia ismore than 3500 km from south to north and covers tropicalsubtropical and temperate climate zones which are definedby climate factors and latitudeThis results in different climatefeatures in the different climate zones including temperaturevariations and ranges directions of monsoon in differentseasons among climate zones and rainfallThose phenomenabring direct effects to the islands in East Asia for example

typhoons strike Japan Taiwan and Hong Kong in summerand autumn with high-intensity rainfall that causes floodsand disease outbreaks [4 26] Of note HFMD is not anexception to the rule that the relative risk of enterovirusinfection will increase after extreme precipitation in Taiwan[19]

In contrast mainland China represents the continentallandform which can be divided into several regions accord-ing to both meteorological factors and latitude In a long-term population-based study of HFMD in China increasingamplitude of HFMD outbreaks was shown to accompanythe increase of latitude in southern China [15] Studies alsomentioned that seasonal variations in China of HFMD wereassociated with precipitation sunshine temperature and airpressure consistent with other studies in China [18 2027 28] In our study only higher dew point (a predictorfor humidity) was found to be positively associated withincreasing HFMD Z rate This factor is in accord withthe previous findings from other studies [15 28] Althoughtemperature overall did not show a linear positive effect onHFMD Z rate the results in the smoothing componentsshowed that temperature above 28∘C had a persistent positiveeffect on Z rate and temperature below 5∘C had a negativeeffect on Z rate These findings might result from theenvironmental niche condition of HFMD epidemic beingduring the hot season However findings for precipitationdiffered between our study and previous ones [15 19 28]A possible reason is that for our study site the mean totalprecipitation only differed by 004 inches (016 to 020) or10mmThis tiny differencewould not affect the Z rate amongthe island type landforms in East Asia From the GAM resultlow visibility and low wind speed were significantly related tothe elevation of Z rate of HFMD Although low wind speedwas also found in a transmission modeling study there wereno direct mechanisms for these negatively associated factorsA possible implication would be that higher wind speedcreates good airflow which may shorten how long the virusparticles remain somewhere Visibility was highly correlatedwith sunshine which was inversely correlated with HFMD[29]

This study has some limitations First HFMD is causedby several enteroviruses In this study there was no detailedinformation on causal agents for example EV71 or CVA16are responsible for the outbreaks among islands during thestudy period This may affect the disease duration or peak ofoutbreaks Second the transmission chain of HFMD amongareas defined in this study was not taken into considerationThis also impacts the spread of HFMD between or withinthe study areas Finally the studied period was too short tomake strong conclusions and extended data are needed forvalidating the association found in this study

5 Conclusion

In conclusion we found out that latitude is a major riskfactor for increasing the Z rate of HFMD in islands inEast Asia In addition only some meteorological factors(dew point low visibility and low wind speed) were foundin previous mainland China studies to be associated with

BioMed Research International 7

15

10

05

00

minus05

minus10

minus10 0 10 20 30

Temperature

Splin

e (te

mpe

ratu

re) 2

1

0

minus1

minus10 0 10 20 0 10 20 30

04

03

02

01

00

minus01

02

01

00

minus01

2 4 6 8 10

000

minus025

minus050

minus075

minus100

0 20 40 60 80

DF = 1239

P = 00003P =

P = DF = 4455 DF = 0P lt 00001P lt 00001

Splin

e (de

w p

oint

)

Splin

e (vi

sibili

ty)

Visibility

Splin

e (w

ind

spee

d)

Splin

e (pr

ecip

itatio

n)

Precipitation

DF = 0336 DF = 0969

Smoothing components for Z ratewith 95 confidence limits

Wind speed

Dew point

Figure 4 Smoothing component plots for standardized HFMD rate (Z rate)

the outbreaks This indicates that island-type geographicalareas have intrinsic differences from continental areas bothin climate impact and in causes of HFMD Since HFMDstrikes East Asia every year and there are no effective phar-maceutical treatments for this disease integrated surveillancewith timely multiple surveillance sources and meteorologicalinformation in different countries can assist in the control andmitigation of the impacts of HFMD in East Asia Also theseresults can be applied to islands in other oceans for predictingHFMD or other infectious diseases

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

Acknowledgments

This research was supported by a grant from the Ministryof Science and Technology Taiwan (MOST 103-2621-M-001-002) The authors also wish to express their sincere gratitudeto Mr Kent M Suarez for his English editing

References

[1] MHo E-R Chen K-HHsu et al ldquoAn epidemic of enterovirus71 infection in Taiwanrdquo The New England Journal of Medicinevol 341 no 13 pp 929ndash935 1999

[2] F-C Tseng H-C Huang C-Y Chi et al ldquoEpidemiologicalsurvey of enterovirus infections occurring in Taiwan between2000 and 2005 analysis of sentinel physician surveillance datardquoJournal of Medical Virology vol 79 no 12 pp 1850ndash1860 2007

[3] S-C Chen H-L Chang T-R Yan Y-T Cheng and K-T Chen ldquoAn eight-year study of epidemiologic features ofenterovirus 71 infection in Taiwanrdquo The American Journal ofTropical Medicine and Hygiene vol 77 no 1 pp 188ndash191 2007

[4] W De K Changwen L Wei et al ldquoA large outbreak ofhand foot and mouth disease caused by EV71 and CAV16 inGuangdong China 2009rdquo Archives of Virology vol 156 no 6pp 945ndash953 2011

[5] H Ni B Yi J Yin et al ldquoEpidemiological and etiologicalcharacteristics of hand foot and mouth disease in NingboChina 2008ndash2011rdquo Journal of Clinical Virology vol 54 no 4pp 342ndash348 2012

[6] L-Y Chang Y-CHuang andT-Y Lin ldquoFulminant neurogenicpulmonary oedema with hand foot and mouth diseaserdquo TheLancet vol 352 no 9125 pp 367ndash368 1998

8 BioMed Research International

[7] N J Schmidt E H Lennette andHH Ho ldquoAn apparently newenterovirus isolated from patients with disease of the centralnervous systemrdquo Journal of Infectious Diseases vol 129 no 3pp 304ndash309 1974

[8] J Blomberg E Lycke K Ahlfors T Johnsson S Wolontis andG von Zeipel ldquoLetter new enterovirus type associated withepidemic of aseptic meningitis and-or hand foot and mouthdiseaserdquoThe Lancet vol 2 no 7872 article 112 1974

[9] Y Ishimaru S Nakano K Yamaoka and S Takami ldquoOutbreaksof hand foot and mouth disease by enterovirus 71 Highincidence of complication disorders of central nervous systemrdquoArchives of Disease in Childhood vol 55 no 8 pp 583ndash5881980

[10] S Van Der Sanden M Koopmans G Uslu and H Van DerAvoort ldquoEpidemiology of enterovirus 71 in the Netherlands1963 to 2008rdquo Journal of Clinical Microbiology vol 47 no 9 pp2826ndash2833 2009

[11] M ChumakovM Voroshilova L Shindarov et al ldquoEnterovirus71 isolated from cases of epidemic poliomyelitis-like disease inBulgariardquo Archives of Virology vol 60 no 3-4 pp 329ndash3401979

[12] G Nagy S Takatsy E Kukan I Mihaly and I Domok ldquoViro-logical diagnosis of enterovirus type 71 infections experiencesgained during an epidemic of acute CNS diseases in Hungaryin 1978rdquo Archives of Virology vol 71 no 3 pp 217ndash227 1982

[13] I Tagaya R Takayama and A Hagiwara ldquoA large-scaleepidemic of hand foot and mouth disease associated withenterovirus 71 infection in Japan in 1978rdquo Japanese Journal ofMedical Science and Biology vol 34 no 3 pp 191ndash196 1981

[14] L G Chan U D Parashar M S Lye et al ldquoDeaths ofchildren during an outbreak of hand foot and mouth diseasein SarawakMalaysia clinical and pathological characteristics ofthe diseaserdquo Clinical Infectious Diseases vol 31 no 3 pp 678ndash683 2000

[15] W Xing Q Liao C Viboud et al ldquoHand foot and mouthdisease in China 2008-12 an epidemiological studyrdquoTheLancetInfectious Diseases vol 14 no 4 pp 308ndash318 2014

[16] T-N Wu S-F Tsai S-F Li et al ldquoSentinel surveillance forenterovirus 71 Taiwan 1998rdquo Emerging Infectious Diseases vol5 no 3 pp 458ndash460 1999

[17] Y Podin E L M Gias F Ong et al ldquoSentinel surveillance forhuman enterovirus 71 in Sarawak Malaysia Lessons from thefirst 7 yearsrdquo BMC Public Health vol 6 article 180 2006

[18] Y Huang T Deng S Yu et al ldquoEffect of meteorologicalvariables on the incidence of hand foot and mouth diseasein children a time-series analysis in Guangzhou Chinardquo BMCInfectious Diseases vol 13 no 1 article 134 2013

[19] M J Chen C Y Lin Y T Wu et al ldquoEffects of extremeprecipitation to the distribution of infectious diseases inTaiwan1994ndash2008rdquo PLoS ONE vol 7 no 6 Article ID e34651 2012

[20] M Urashima N Shindo and N Okabe ldquoSeasonal models ofherpangina and hand-foot-mouth disease to simulate annualfluctuations in urban warming in Tokyordquo Japanese Journal ofInfectious Diseases vol 56 no 2 pp 48ndash53 2003

[21] M EdmondCWong and SKChuang ldquoEvaluation of sentinelsurveillance system for monitoring hand foot and mouthdisease in Hong Kongrdquo Public Health vol 125 no 11 pp 777ndash783 2011

[22] D JMuscatello A T Newall D E Dwyer and C RMacIntyreldquoMortality attributable to seasonal and pandemic influenzaAustralia 2003 to 2009 using a novel time series smoothingapproachrdquo PLoS ONE vol 8 no 6 Article ID e64734 2013

[23] K Park B Lee K Baek et al ldquoEnteroviruses isolated from her-pangina and hand-foot-and-mouth disease inKorean childrenrdquoVirology Journal vol 9 article 205 2012

[24] M Kobayashi T Makino N Hanaoka et al ldquoClinical manifes-tations of coxsackievirus A6 infection associated with a majoroutbreak of hand foot and mouth disease in Japanrdquo JapaneseJournal of Infectious Diseases vol 66 no 3 pp 260ndash261 2013

[25] C C Yip S K Lau J Y Lo K-H Chan P C Woo and K-Y Yuen ldquoGenetic characterization of EV71 isolates from 2004to 2010 reveals predominance and persistent circulation of thenewly proposed genotype D and recent emergence of a distinctlineage of subgenotype C2 inHong KongrdquoVirology Journal vol10 article 222 2013

[26] H-P Su T-C Chan and C-C Chang ldquoTyphoon-related lep-tospirosis and melioidosis Taiwan 2009rdquo Emerging InfectiousDiseases vol 17 no 7 pp 1322ndash1324 2011

[27] F Qiaoyun J Xiongfei L lihuan and X Angao ldquoEpidemiologyand etiological characteristics of hand foot and mouth diseasein Huizhou City between 2008 and 2011rdquo Archives of Virologyvol 158 no 4 pp 895ndash899 2013

[28] Y Wang Z Feng and Y Yang ldquoHand foot and mouth diseasein China patterns of spread and transmissibilityrdquo Epidemiologyvol 22 no 6 pp 781ndash792 2011

[29] H Wu H Wang Q Wang et al ldquoThe effect of meteorologicalfactors on adolescent hand foot and mouth disease andassociated effect modifiersrdquo Global Health Action vol 7 ArticleID 24664 2014

6 BioMed Research International

Table 2 Parameter estimates of linear terms in general additivemodel (GAM)

Variable Estimate Standard error 119875 valueLatitude 00465 00020 lt00001lowast

Mean temperature 00031 00063 05917Dew point 00566 00060 lt00001lowast

Visibility minus00066 00023 00037lowast

Wind speed minus00514 00118 lt00001lowast

Total precipitation 00018 00021 04100lowast

119875 value lt 005

(119875 = 00037) and wind speed (119875 lt 00001) were inverselyassociated with increasing HFMD Z rate However meantemperature and total precipitation were not significantlycorrelated with the Z rate

In addition the smoothing components plot (Figure 4)demonstrated the estimated smoothing spline functions withthe linear effect subtracted out The significant smoothersindicated that the correlations between Z rate and explana-tory variables were nonlinear The plot showed that holdingall linear and the other nonlinear terms fixed temperaturetended to increase gradually with Z rate (119875 lt 00001) andin addition there was a kind of turning point for a positiveeffect of dew point at around of 20∘C (119875 lt 00001) with aslight positive effect overall The Z rate tended to be lowerwhen the total precipitation increased (119875 = 00003) Thenonlinear effects of the visibility and thewind speed could notbe estimated because their corresponding degrees of freedom(DF) were too small

4 Discussion

HFMD is a common disease caused by enteroviruses thatmainly attack children below the age of six in East Asia Fur-ther clinical progress results in severe sequelae or even leadsto death Thus HFMD is a great public health issue in thisregion including mainland China (on the continent) SouthKorea (a peninsula) Japan Taiwan and Hong Kong (islands)[1 15 23ndash25] This study incorporates meteorological dataHFMD data and spatiotemporal analysis to reshape theepidemiological features of this disease occurring in islandsduring the study period Dynamic changes and duration ofHFMD severity among different parts of study sites weredemonstrated clearly through the integrated surveillance Forthose four epidemic islands including Japan Taiwan HongKong and Singapore in this study dew point was a keymeteorological factor associated with HFMD Neverthelesslatitude difference plays an important role that even surpassesthe impact of dew point onHFMDWhy this factor affects thedisease rate so much is still an enigma However East Asia ismore than 3500 km from south to north and covers tropicalsubtropical and temperate climate zones which are definedby climate factors and latitudeThis results in different climatefeatures in the different climate zones including temperaturevariations and ranges directions of monsoon in differentseasons among climate zones and rainfallThose phenomenabring direct effects to the islands in East Asia for example

typhoons strike Japan Taiwan and Hong Kong in summerand autumn with high-intensity rainfall that causes floodsand disease outbreaks [4 26] Of note HFMD is not anexception to the rule that the relative risk of enterovirusinfection will increase after extreme precipitation in Taiwan[19]

In contrast mainland China represents the continentallandform which can be divided into several regions accord-ing to both meteorological factors and latitude In a long-term population-based study of HFMD in China increasingamplitude of HFMD outbreaks was shown to accompanythe increase of latitude in southern China [15] Studies alsomentioned that seasonal variations in China of HFMD wereassociated with precipitation sunshine temperature and airpressure consistent with other studies in China [18 2027 28] In our study only higher dew point (a predictorfor humidity) was found to be positively associated withincreasing HFMD Z rate This factor is in accord withthe previous findings from other studies [15 28] Althoughtemperature overall did not show a linear positive effect onHFMD Z rate the results in the smoothing componentsshowed that temperature above 28∘C had a persistent positiveeffect on Z rate and temperature below 5∘C had a negativeeffect on Z rate These findings might result from theenvironmental niche condition of HFMD epidemic beingduring the hot season However findings for precipitationdiffered between our study and previous ones [15 19 28]A possible reason is that for our study site the mean totalprecipitation only differed by 004 inches (016 to 020) or10mmThis tiny differencewould not affect the Z rate amongthe island type landforms in East Asia From the GAM resultlow visibility and low wind speed were significantly related tothe elevation of Z rate of HFMD Although low wind speedwas also found in a transmission modeling study there wereno direct mechanisms for these negatively associated factorsA possible implication would be that higher wind speedcreates good airflow which may shorten how long the virusparticles remain somewhere Visibility was highly correlatedwith sunshine which was inversely correlated with HFMD[29]

This study has some limitations First HFMD is causedby several enteroviruses In this study there was no detailedinformation on causal agents for example EV71 or CVA16are responsible for the outbreaks among islands during thestudy period This may affect the disease duration or peak ofoutbreaks Second the transmission chain of HFMD amongareas defined in this study was not taken into considerationThis also impacts the spread of HFMD between or withinthe study areas Finally the studied period was too short tomake strong conclusions and extended data are needed forvalidating the association found in this study

5 Conclusion

In conclusion we found out that latitude is a major riskfactor for increasing the Z rate of HFMD in islands inEast Asia In addition only some meteorological factors(dew point low visibility and low wind speed) were foundin previous mainland China studies to be associated with

BioMed Research International 7

15

10

05

00

minus05

minus10

minus10 0 10 20 30

Temperature

Splin

e (te

mpe

ratu

re) 2

1

0

minus1

minus10 0 10 20 0 10 20 30

04

03

02

01

00

minus01

02

01

00

minus01

2 4 6 8 10

000

minus025

minus050

minus075

minus100

0 20 40 60 80

DF = 1239

P = 00003P =

P = DF = 4455 DF = 0P lt 00001P lt 00001

Splin

e (de

w p

oint

)

Splin

e (vi

sibili

ty)

Visibility

Splin

e (w

ind

spee

d)

Splin

e (pr

ecip

itatio

n)

Precipitation

DF = 0336 DF = 0969

Smoothing components for Z ratewith 95 confidence limits

Wind speed

Dew point

Figure 4 Smoothing component plots for standardized HFMD rate (Z rate)

the outbreaks This indicates that island-type geographicalareas have intrinsic differences from continental areas bothin climate impact and in causes of HFMD Since HFMDstrikes East Asia every year and there are no effective phar-maceutical treatments for this disease integrated surveillancewith timely multiple surveillance sources and meteorologicalinformation in different countries can assist in the control andmitigation of the impacts of HFMD in East Asia Also theseresults can be applied to islands in other oceans for predictingHFMD or other infectious diseases

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

Acknowledgments

This research was supported by a grant from the Ministryof Science and Technology Taiwan (MOST 103-2621-M-001-002) The authors also wish to express their sincere gratitudeto Mr Kent M Suarez for his English editing

References

[1] MHo E-R Chen K-HHsu et al ldquoAn epidemic of enterovirus71 infection in Taiwanrdquo The New England Journal of Medicinevol 341 no 13 pp 929ndash935 1999

[2] F-C Tseng H-C Huang C-Y Chi et al ldquoEpidemiologicalsurvey of enterovirus infections occurring in Taiwan between2000 and 2005 analysis of sentinel physician surveillance datardquoJournal of Medical Virology vol 79 no 12 pp 1850ndash1860 2007

[3] S-C Chen H-L Chang T-R Yan Y-T Cheng and K-T Chen ldquoAn eight-year study of epidemiologic features ofenterovirus 71 infection in Taiwanrdquo The American Journal ofTropical Medicine and Hygiene vol 77 no 1 pp 188ndash191 2007

[4] W De K Changwen L Wei et al ldquoA large outbreak ofhand foot and mouth disease caused by EV71 and CAV16 inGuangdong China 2009rdquo Archives of Virology vol 156 no 6pp 945ndash953 2011

[5] H Ni B Yi J Yin et al ldquoEpidemiological and etiologicalcharacteristics of hand foot and mouth disease in NingboChina 2008ndash2011rdquo Journal of Clinical Virology vol 54 no 4pp 342ndash348 2012

[6] L-Y Chang Y-CHuang andT-Y Lin ldquoFulminant neurogenicpulmonary oedema with hand foot and mouth diseaserdquo TheLancet vol 352 no 9125 pp 367ndash368 1998

8 BioMed Research International

[7] N J Schmidt E H Lennette andHH Ho ldquoAn apparently newenterovirus isolated from patients with disease of the centralnervous systemrdquo Journal of Infectious Diseases vol 129 no 3pp 304ndash309 1974

[8] J Blomberg E Lycke K Ahlfors T Johnsson S Wolontis andG von Zeipel ldquoLetter new enterovirus type associated withepidemic of aseptic meningitis and-or hand foot and mouthdiseaserdquoThe Lancet vol 2 no 7872 article 112 1974

[9] Y Ishimaru S Nakano K Yamaoka and S Takami ldquoOutbreaksof hand foot and mouth disease by enterovirus 71 Highincidence of complication disorders of central nervous systemrdquoArchives of Disease in Childhood vol 55 no 8 pp 583ndash5881980

[10] S Van Der Sanden M Koopmans G Uslu and H Van DerAvoort ldquoEpidemiology of enterovirus 71 in the Netherlands1963 to 2008rdquo Journal of Clinical Microbiology vol 47 no 9 pp2826ndash2833 2009

[11] M ChumakovM Voroshilova L Shindarov et al ldquoEnterovirus71 isolated from cases of epidemic poliomyelitis-like disease inBulgariardquo Archives of Virology vol 60 no 3-4 pp 329ndash3401979

[12] G Nagy S Takatsy E Kukan I Mihaly and I Domok ldquoViro-logical diagnosis of enterovirus type 71 infections experiencesgained during an epidemic of acute CNS diseases in Hungaryin 1978rdquo Archives of Virology vol 71 no 3 pp 217ndash227 1982

[13] I Tagaya R Takayama and A Hagiwara ldquoA large-scaleepidemic of hand foot and mouth disease associated withenterovirus 71 infection in Japan in 1978rdquo Japanese Journal ofMedical Science and Biology vol 34 no 3 pp 191ndash196 1981

[14] L G Chan U D Parashar M S Lye et al ldquoDeaths ofchildren during an outbreak of hand foot and mouth diseasein SarawakMalaysia clinical and pathological characteristics ofthe diseaserdquo Clinical Infectious Diseases vol 31 no 3 pp 678ndash683 2000

[15] W Xing Q Liao C Viboud et al ldquoHand foot and mouthdisease in China 2008-12 an epidemiological studyrdquoTheLancetInfectious Diseases vol 14 no 4 pp 308ndash318 2014

[16] T-N Wu S-F Tsai S-F Li et al ldquoSentinel surveillance forenterovirus 71 Taiwan 1998rdquo Emerging Infectious Diseases vol5 no 3 pp 458ndash460 1999

[17] Y Podin E L M Gias F Ong et al ldquoSentinel surveillance forhuman enterovirus 71 in Sarawak Malaysia Lessons from thefirst 7 yearsrdquo BMC Public Health vol 6 article 180 2006

[18] Y Huang T Deng S Yu et al ldquoEffect of meteorologicalvariables on the incidence of hand foot and mouth diseasein children a time-series analysis in Guangzhou Chinardquo BMCInfectious Diseases vol 13 no 1 article 134 2013

[19] M J Chen C Y Lin Y T Wu et al ldquoEffects of extremeprecipitation to the distribution of infectious diseases inTaiwan1994ndash2008rdquo PLoS ONE vol 7 no 6 Article ID e34651 2012

[20] M Urashima N Shindo and N Okabe ldquoSeasonal models ofherpangina and hand-foot-mouth disease to simulate annualfluctuations in urban warming in Tokyordquo Japanese Journal ofInfectious Diseases vol 56 no 2 pp 48ndash53 2003

[21] M EdmondCWong and SKChuang ldquoEvaluation of sentinelsurveillance system for monitoring hand foot and mouthdisease in Hong Kongrdquo Public Health vol 125 no 11 pp 777ndash783 2011

[22] D JMuscatello A T Newall D E Dwyer and C RMacIntyreldquoMortality attributable to seasonal and pandemic influenzaAustralia 2003 to 2009 using a novel time series smoothingapproachrdquo PLoS ONE vol 8 no 6 Article ID e64734 2013

[23] K Park B Lee K Baek et al ldquoEnteroviruses isolated from her-pangina and hand-foot-and-mouth disease inKorean childrenrdquoVirology Journal vol 9 article 205 2012

[24] M Kobayashi T Makino N Hanaoka et al ldquoClinical manifes-tations of coxsackievirus A6 infection associated with a majoroutbreak of hand foot and mouth disease in Japanrdquo JapaneseJournal of Infectious Diseases vol 66 no 3 pp 260ndash261 2013

[25] C C Yip S K Lau J Y Lo K-H Chan P C Woo and K-Y Yuen ldquoGenetic characterization of EV71 isolates from 2004to 2010 reveals predominance and persistent circulation of thenewly proposed genotype D and recent emergence of a distinctlineage of subgenotype C2 inHong KongrdquoVirology Journal vol10 article 222 2013

[26] H-P Su T-C Chan and C-C Chang ldquoTyphoon-related lep-tospirosis and melioidosis Taiwan 2009rdquo Emerging InfectiousDiseases vol 17 no 7 pp 1322ndash1324 2011

[27] F Qiaoyun J Xiongfei L lihuan and X Angao ldquoEpidemiologyand etiological characteristics of hand foot and mouth diseasein Huizhou City between 2008 and 2011rdquo Archives of Virologyvol 158 no 4 pp 895ndash899 2013

[28] Y Wang Z Feng and Y Yang ldquoHand foot and mouth diseasein China patterns of spread and transmissibilityrdquo Epidemiologyvol 22 no 6 pp 781ndash792 2011

[29] H Wu H Wang Q Wang et al ldquoThe effect of meteorologicalfactors on adolescent hand foot and mouth disease andassociated effect modifiersrdquo Global Health Action vol 7 ArticleID 24664 2014

BioMed Research International 7

15

10

05

00

minus05

minus10

minus10 0 10 20 30

Temperature

Splin

e (te

mpe

ratu

re) 2

1

0

minus1

minus10 0 10 20 0 10 20 30

04

03

02

01

00

minus01

02

01

00

minus01

2 4 6 8 10

000

minus025

minus050

minus075

minus100

0 20 40 60 80

DF = 1239

P = 00003P =

P = DF = 4455 DF = 0P lt 00001P lt 00001

Splin

e (de

w p

oint

)

Splin

e (vi

sibili

ty)

Visibility

Splin

e (w

ind

spee

d)

Splin

e (pr

ecip

itatio

n)

Precipitation

DF = 0336 DF = 0969

Smoothing components for Z ratewith 95 confidence limits

Wind speed

Dew point

Figure 4 Smoothing component plots for standardized HFMD rate (Z rate)

the outbreaks This indicates that island-type geographicalareas have intrinsic differences from continental areas bothin climate impact and in causes of HFMD Since HFMDstrikes East Asia every year and there are no effective phar-maceutical treatments for this disease integrated surveillancewith timely multiple surveillance sources and meteorologicalinformation in different countries can assist in the control andmitigation of the impacts of HFMD in East Asia Also theseresults can be applied to islands in other oceans for predictingHFMD or other infectious diseases

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

Acknowledgments

This research was supported by a grant from the Ministryof Science and Technology Taiwan (MOST 103-2621-M-001-002) The authors also wish to express their sincere gratitudeto Mr Kent M Suarez for his English editing

References

[1] MHo E-R Chen K-HHsu et al ldquoAn epidemic of enterovirus71 infection in Taiwanrdquo The New England Journal of Medicinevol 341 no 13 pp 929ndash935 1999

[2] F-C Tseng H-C Huang C-Y Chi et al ldquoEpidemiologicalsurvey of enterovirus infections occurring in Taiwan between2000 and 2005 analysis of sentinel physician surveillance datardquoJournal of Medical Virology vol 79 no 12 pp 1850ndash1860 2007

[3] S-C Chen H-L Chang T-R Yan Y-T Cheng and K-T Chen ldquoAn eight-year study of epidemiologic features ofenterovirus 71 infection in Taiwanrdquo The American Journal ofTropical Medicine and Hygiene vol 77 no 1 pp 188ndash191 2007

[4] W De K Changwen L Wei et al ldquoA large outbreak ofhand foot and mouth disease caused by EV71 and CAV16 inGuangdong China 2009rdquo Archives of Virology vol 156 no 6pp 945ndash953 2011

[5] H Ni B Yi J Yin et al ldquoEpidemiological and etiologicalcharacteristics of hand foot and mouth disease in NingboChina 2008ndash2011rdquo Journal of Clinical Virology vol 54 no 4pp 342ndash348 2012

[6] L-Y Chang Y-CHuang andT-Y Lin ldquoFulminant neurogenicpulmonary oedema with hand foot and mouth diseaserdquo TheLancet vol 352 no 9125 pp 367ndash368 1998

8 BioMed Research International

[7] N J Schmidt E H Lennette andHH Ho ldquoAn apparently newenterovirus isolated from patients with disease of the centralnervous systemrdquo Journal of Infectious Diseases vol 129 no 3pp 304ndash309 1974

[8] J Blomberg E Lycke K Ahlfors T Johnsson S Wolontis andG von Zeipel ldquoLetter new enterovirus type associated withepidemic of aseptic meningitis and-or hand foot and mouthdiseaserdquoThe Lancet vol 2 no 7872 article 112 1974

[9] Y Ishimaru S Nakano K Yamaoka and S Takami ldquoOutbreaksof hand foot and mouth disease by enterovirus 71 Highincidence of complication disorders of central nervous systemrdquoArchives of Disease in Childhood vol 55 no 8 pp 583ndash5881980

[10] S Van Der Sanden M Koopmans G Uslu and H Van DerAvoort ldquoEpidemiology of enterovirus 71 in the Netherlands1963 to 2008rdquo Journal of Clinical Microbiology vol 47 no 9 pp2826ndash2833 2009

[11] M ChumakovM Voroshilova L Shindarov et al ldquoEnterovirus71 isolated from cases of epidemic poliomyelitis-like disease inBulgariardquo Archives of Virology vol 60 no 3-4 pp 329ndash3401979

[12] G Nagy S Takatsy E Kukan I Mihaly and I Domok ldquoViro-logical diagnosis of enterovirus type 71 infections experiencesgained during an epidemic of acute CNS diseases in Hungaryin 1978rdquo Archives of Virology vol 71 no 3 pp 217ndash227 1982

[13] I Tagaya R Takayama and A Hagiwara ldquoA large-scaleepidemic of hand foot and mouth disease associated withenterovirus 71 infection in Japan in 1978rdquo Japanese Journal ofMedical Science and Biology vol 34 no 3 pp 191ndash196 1981

[14] L G Chan U D Parashar M S Lye et al ldquoDeaths ofchildren during an outbreak of hand foot and mouth diseasein SarawakMalaysia clinical and pathological characteristics ofthe diseaserdquo Clinical Infectious Diseases vol 31 no 3 pp 678ndash683 2000

[15] W Xing Q Liao C Viboud et al ldquoHand foot and mouthdisease in China 2008-12 an epidemiological studyrdquoTheLancetInfectious Diseases vol 14 no 4 pp 308ndash318 2014

[16] T-N Wu S-F Tsai S-F Li et al ldquoSentinel surveillance forenterovirus 71 Taiwan 1998rdquo Emerging Infectious Diseases vol5 no 3 pp 458ndash460 1999

[17] Y Podin E L M Gias F Ong et al ldquoSentinel surveillance forhuman enterovirus 71 in Sarawak Malaysia Lessons from thefirst 7 yearsrdquo BMC Public Health vol 6 article 180 2006

[18] Y Huang T Deng S Yu et al ldquoEffect of meteorologicalvariables on the incidence of hand foot and mouth diseasein children a time-series analysis in Guangzhou Chinardquo BMCInfectious Diseases vol 13 no 1 article 134 2013

[19] M J Chen C Y Lin Y T Wu et al ldquoEffects of extremeprecipitation to the distribution of infectious diseases inTaiwan1994ndash2008rdquo PLoS ONE vol 7 no 6 Article ID e34651 2012

[20] M Urashima N Shindo and N Okabe ldquoSeasonal models ofherpangina and hand-foot-mouth disease to simulate annualfluctuations in urban warming in Tokyordquo Japanese Journal ofInfectious Diseases vol 56 no 2 pp 48ndash53 2003

[21] M EdmondCWong and SKChuang ldquoEvaluation of sentinelsurveillance system for monitoring hand foot and mouthdisease in Hong Kongrdquo Public Health vol 125 no 11 pp 777ndash783 2011

[22] D JMuscatello A T Newall D E Dwyer and C RMacIntyreldquoMortality attributable to seasonal and pandemic influenzaAustralia 2003 to 2009 using a novel time series smoothingapproachrdquo PLoS ONE vol 8 no 6 Article ID e64734 2013

[23] K Park B Lee K Baek et al ldquoEnteroviruses isolated from her-pangina and hand-foot-and-mouth disease inKorean childrenrdquoVirology Journal vol 9 article 205 2012

[24] M Kobayashi T Makino N Hanaoka et al ldquoClinical manifes-tations of coxsackievirus A6 infection associated with a majoroutbreak of hand foot and mouth disease in Japanrdquo JapaneseJournal of Infectious Diseases vol 66 no 3 pp 260ndash261 2013

[25] C C Yip S K Lau J Y Lo K-H Chan P C Woo and K-Y Yuen ldquoGenetic characterization of EV71 isolates from 2004to 2010 reveals predominance and persistent circulation of thenewly proposed genotype D and recent emergence of a distinctlineage of subgenotype C2 inHong KongrdquoVirology Journal vol10 article 222 2013

[26] H-P Su T-C Chan and C-C Chang ldquoTyphoon-related lep-tospirosis and melioidosis Taiwan 2009rdquo Emerging InfectiousDiseases vol 17 no 7 pp 1322ndash1324 2011

[27] F Qiaoyun J Xiongfei L lihuan and X Angao ldquoEpidemiologyand etiological characteristics of hand foot and mouth diseasein Huizhou City between 2008 and 2011rdquo Archives of Virologyvol 158 no 4 pp 895ndash899 2013

[28] Y Wang Z Feng and Y Yang ldquoHand foot and mouth diseasein China patterns of spread and transmissibilityrdquo Epidemiologyvol 22 no 6 pp 781ndash792 2011

[29] H Wu H Wang Q Wang et al ldquoThe effect of meteorologicalfactors on adolescent hand foot and mouth disease andassociated effect modifiersrdquo Global Health Action vol 7 ArticleID 24664 2014

8 BioMed Research International

[7] N J Schmidt E H Lennette andHH Ho ldquoAn apparently newenterovirus isolated from patients with disease of the centralnervous systemrdquo Journal of Infectious Diseases vol 129 no 3pp 304ndash309 1974

[8] J Blomberg E Lycke K Ahlfors T Johnsson S Wolontis andG von Zeipel ldquoLetter new enterovirus type associated withepidemic of aseptic meningitis and-or hand foot and mouthdiseaserdquoThe Lancet vol 2 no 7872 article 112 1974

[9] Y Ishimaru S Nakano K Yamaoka and S Takami ldquoOutbreaksof hand foot and mouth disease by enterovirus 71 Highincidence of complication disorders of central nervous systemrdquoArchives of Disease in Childhood vol 55 no 8 pp 583ndash5881980

[10] S Van Der Sanden M Koopmans G Uslu and H Van DerAvoort ldquoEpidemiology of enterovirus 71 in the Netherlands1963 to 2008rdquo Journal of Clinical Microbiology vol 47 no 9 pp2826ndash2833 2009

[11] M ChumakovM Voroshilova L Shindarov et al ldquoEnterovirus71 isolated from cases of epidemic poliomyelitis-like disease inBulgariardquo Archives of Virology vol 60 no 3-4 pp 329ndash3401979

[12] G Nagy S Takatsy E Kukan I Mihaly and I Domok ldquoViro-logical diagnosis of enterovirus type 71 infections experiencesgained during an epidemic of acute CNS diseases in Hungaryin 1978rdquo Archives of Virology vol 71 no 3 pp 217ndash227 1982

[13] I Tagaya R Takayama and A Hagiwara ldquoA large-scaleepidemic of hand foot and mouth disease associated withenterovirus 71 infection in Japan in 1978rdquo Japanese Journal ofMedical Science and Biology vol 34 no 3 pp 191ndash196 1981

[14] L G Chan U D Parashar M S Lye et al ldquoDeaths ofchildren during an outbreak of hand foot and mouth diseasein SarawakMalaysia clinical and pathological characteristics ofthe diseaserdquo Clinical Infectious Diseases vol 31 no 3 pp 678ndash683 2000

[15] W Xing Q Liao C Viboud et al ldquoHand foot and mouthdisease in China 2008-12 an epidemiological studyrdquoTheLancetInfectious Diseases vol 14 no 4 pp 308ndash318 2014

[16] T-N Wu S-F Tsai S-F Li et al ldquoSentinel surveillance forenterovirus 71 Taiwan 1998rdquo Emerging Infectious Diseases vol5 no 3 pp 458ndash460 1999

[17] Y Podin E L M Gias F Ong et al ldquoSentinel surveillance forhuman enterovirus 71 in Sarawak Malaysia Lessons from thefirst 7 yearsrdquo BMC Public Health vol 6 article 180 2006

[18] Y Huang T Deng S Yu et al ldquoEffect of meteorologicalvariables on the incidence of hand foot and mouth diseasein children a time-series analysis in Guangzhou Chinardquo BMCInfectious Diseases vol 13 no 1 article 134 2013

[19] M J Chen C Y Lin Y T Wu et al ldquoEffects of extremeprecipitation to the distribution of infectious diseases inTaiwan1994ndash2008rdquo PLoS ONE vol 7 no 6 Article ID e34651 2012

[20] M Urashima N Shindo and N Okabe ldquoSeasonal models ofherpangina and hand-foot-mouth disease to simulate annualfluctuations in urban warming in Tokyordquo Japanese Journal ofInfectious Diseases vol 56 no 2 pp 48ndash53 2003

[21] M EdmondCWong and SKChuang ldquoEvaluation of sentinelsurveillance system for monitoring hand foot and mouthdisease in Hong Kongrdquo Public Health vol 125 no 11 pp 777ndash783 2011

[22] D JMuscatello A T Newall D E Dwyer and C RMacIntyreldquoMortality attributable to seasonal and pandemic influenzaAustralia 2003 to 2009 using a novel time series smoothingapproachrdquo PLoS ONE vol 8 no 6 Article ID e64734 2013

[23] K Park B Lee K Baek et al ldquoEnteroviruses isolated from her-pangina and hand-foot-and-mouth disease inKorean childrenrdquoVirology Journal vol 9 article 205 2012

[24] M Kobayashi T Makino N Hanaoka et al ldquoClinical manifes-tations of coxsackievirus A6 infection associated with a majoroutbreak of hand foot and mouth disease in Japanrdquo JapaneseJournal of Infectious Diseases vol 66 no 3 pp 260ndash261 2013

[25] C C Yip S K Lau J Y Lo K-H Chan P C Woo and K-Y Yuen ldquoGenetic characterization of EV71 isolates from 2004to 2010 reveals predominance and persistent circulation of thenewly proposed genotype D and recent emergence of a distinctlineage of subgenotype C2 inHong KongrdquoVirology Journal vol10 article 222 2013

[26] H-P Su T-C Chan and C-C Chang ldquoTyphoon-related lep-tospirosis and melioidosis Taiwan 2009rdquo Emerging InfectiousDiseases vol 17 no 7 pp 1322ndash1324 2011

[27] F Qiaoyun J Xiongfei L lihuan and X Angao ldquoEpidemiologyand etiological characteristics of hand foot and mouth diseasein Huizhou City between 2008 and 2011rdquo Archives of Virologyvol 158 no 4 pp 895ndash899 2013

[28] Y Wang Z Feng and Y Yang ldquoHand foot and mouth diseasein China patterns of spread and transmissibilityrdquo Epidemiologyvol 22 no 6 pp 781ndash792 2011

[29] H Wu H Wang Q Wang et al ldquoThe effect of meteorologicalfactors on adolescent hand foot and mouth disease andassociated effect modifiersrdquo Global Health Action vol 7 ArticleID 24664 2014