Risk Factors of Enterovirus 71 Infection and Associated Hand, Foot, and Mouth Disease/Herpangina in Children During an Epidemic in Taiwan
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Risk Factors of Enterovirus 71 Infection and Associated Hand, Foot, and Mouth Disease/Herpangina in Children During an Epidemic in Taiwan Luan-Yin Chang, MD*; Chwan-Chuen King, DrPH‡; Kuang-Hung Hsu, PhD§; Hsiao-Chen Ning, MSʈ; Kuo-Chien Tsao, BSʈ; Chung-Chen Li, MD*; Yhu-Chering Huang, MD, PhD*; Shin-Ru Shih, PhDʈ; Shu-Ti Chiou, MD, MPH¶; Po-Yen Chen, MD#; Hong-Jen Chang, MD, MPH**; and Tzou-Yien Lin, MD* ABSTRACT. Objective. In 1998, an enterovirus 71 for the development of EV71-related HFMD/herpangina (EV71) epidemic in Taiwan was associated with hand, in these children. foot, and mouth disease (HFMD)/herpangina and in- Conclusions. An increased incidence of EV71 infec- volved 78 fatal cases. We measured EV71 seroprevalence tion in young children occurred more often in geographic rates before and after the epidemic and investigated risk areas with increased mortality rates. Intrafamilial and factors associated with EV71 infection and illness. kindergarten transmissions among preschool children Methods. Neutralizing antibodies to EV71 were as- were major modes of disease transmission during the sayed for 539 people before the epidemic and 4619 people widespread EV71 epidemic in Taiwan in 1998. Pediatrics of similar ages after the epidemic. Questionnaires, which 2002;109(6). URL: http://www.pediatrics.org/cgi/content/ were completed during household interviews after the full/109/6/e88; enterovirus 71; hand, foot, and mouth dis- epidemic, solicited demographic variables, exposure his- ease; seroprevalence; transmission; risk factors; symptom- tory, and clinical manifestations. atic ratio; reemerging infectious disease; Taiwan. Results. A total of 129 106 cases of HFMD were re- ported during the epidemic. Age-specific pre-epidemic EV71 seroprevalence rates were inversely related to age- ABBREVIATIONS. EV71, enterovirus 71; HFMD, hand, foot, and -؊0.82) or severe mouth disease; OR, odds ratio; CI, confidence interval; SD, stan؍ specific periepidemic mortality rates (r .؊0.93). Higher postepidemic EV71 sero- dard deviation؍ case rates (r positive rates among children who were younger than 3 years positively correlated with higher mortality rates in After the epidemic, 51 (56%) of nterovirus 71 (EV71) has been associated with .(0.88 ؍ different areas (r 91 younger siblings of elder siblings who were EV71- outbreaks in the United States, Europe, Aus- seropositive were EV71-seropositive; otherwise, 2.2% (4 tralia, Japan, Brazil, and Malaysia1–10 since it E 1 of 186) of younger siblings were EV71-seropositive was originally recognized in l969 in California. Be- (matched odds ratio [OR]: 10; 95% confidence interval fore 1998, 3 large outbreaks with dozens of fatal cases [CI]: 3.4–29). Stepwise multiple logistic regression re- occurred in Bulgaria in 1975, Hungary in 1978, and vealed other factors associated with EV71 infection to be Malaysia in 1997.3,5,10 However, few studies have older age (adjusted OR: 2.5; 95% CI: 1.9–3.4), attendance at kindergartens/child care centers (adjusted OR: 1.8; 95% investigated the mode of transmission, the protective CI: 1.3–2.5), contact with HFMD/herpangina (adjusted effect of preexisting EV71 antibodies, and the risk OR: 1.6; 95% CI: 1.2–2.1), greater number of children in a factors associated with EV71 infection as well as its family (adjusted OR: 1.4; 95% CI: 1.1–1.7), and rural res- clinical outcomes. idence (adjusted OR: 1.4; 95% CI: 1.2–1.6). Twenty-nine The largest and most severe EV71 epidemic to date percent of preschool children who were infected with occurred in Taiwan in 1998.11–16 At that time, a total EV71 developed HFMD/herpangina. Younger age and of 129 106 cases of hand, foot, and mouth disease contact with HFMD/herpangina were significant factors (HFMD)/herpangina were reported; 405 cases had severe neurologic complications and/or pulmonary From the *Division of Pediatric Infectious Diseases, Department of Pediat- edema, and 78 children died.15 A retrospective re- rics, Chang Gung Children’s Hospital, Chang Gung University, Taoyuan, view found that sporadic cases of EV71 had occurred Taiwan; ‡Institute of Epidemiology, College of Public Health, National 15 Taiwan University, Taipei and Takemi Program, School of Public Health, in Taiwan in 1980 and 1986. In addition, sequences Harvard University, Boston, Massachusetts; §Laboratory for Epidemiology of some EV71 isolates in 1998 showed a high degree and Department of Health Care Management, Chang Gung University, (92%) of identity in the VP-1 genomic region with ʈ Taoyuan, Taiwan; Department of Clinical Pathology, Chang Gung Memo- that of the EV71 strain isolated in 1986.17 Apparently, rial Hospital, Chang Gung University, Taoyuan, Taiwan; the ʈHealth Bu- reau, Ilan County, Taiwan; #Department of Pediatrics, Veteran General EV71 has circulated in Taiwan for at least 18 years; Hospital, Taichung, Taiwan; and **Center for Disease Control, the Depart- however, factors underlying the widespread increase ment of Health, Taipei, Taiwan. of EV71 infection in 1998 remained unknown. There- Dr Chiou’s current affiliation is the Health Bureau, Taipei City; Dr Chang’s fore, we initiated a community-based seroepidemio- current affiliation is the Bureau of National Health Insurance. Received for publication Sep 24, 2001; accepted Feb 14, 2002. logic study to assess pre- and postepidemic immu- Reprint requests to (T-Y.L.) Division of Pediatric Infectious Diseases, De- nity of Taiwanese populations to EV71. These partment of Pediatrics, Chang Gung Children’s Hospital, Chang Gung measurements permitted description of the inci- University, 5 Fu-Hsin St, Kwei-Shan Hsiang, Taoyuan County, Taiwan. dence of infection in the 1998 epidemic as well as the E-mail: [email protected] PEDIATRICS (ISSN 0031 4005). Copyright © 2002 by the American Acad- relationship between attack rates of severe or fatal emy of Pediatrics. cases and the EV71-seropositive rate, risk factors as- http://www.pediatrics.org/cgi/content/full/109/6/Downloaded from www.aappublications.org/newse88 by guestPEDIATRICS on September Vol.28, 2021 109 No. 6 June 2002 1of6 sociated with acquiring EV71 infection, and patterns HFMD/herpangina during the epidemic period. All interviewers of symptomatic EV71 infection. were trained, and contact history information was collected from several family members to minimize recall bias. EV71 infection was defined as EV71 seropositivity and symptomatic EV71 infec- METHODS tion as EV71 seropositivity plus a history of HFMD/herpangina. Surveillance and Definitions of Severe Enterovirus Cases During the Epidemic Laboratory Methods for the EV71 Neutralizing During the 1998 epidemic, we used our nationwide sentinel Antibody physician surveillance and hospital surveillance systems to report The neutralizing antibody test of EV71 followed the standard uncomplicated and hospitalized HFMD/herpangina cases to Tai- protocol of a plaque reduction neutralization test.18,19 Serum sam- wan’s Department of Health, according to a previously described ples were heat treated for 30 minutes at 56°C, serially diluted, method.13,15 Although 129 106 cases of uncomplicated HFMD/ mixed with 100 50% tissue culture-infective doses of EV71 TW/ herpangina were reported,15 only severe cases were reviewed and 2272/98 strain (GenBank accession number AF119795), and then verified by a committee established for that purpose. incubated for 2 hours at 37°C in microtiter plates seeded with Cases were defined as severe by the isolation of enterovirus or rhabdomyosarcoma cells. Each plate included a cell control, serum the presence of the symptoms/signs of HFMD/herpangina plus control, and virus back-titration. Cytopathic effect was monitored the occurrence of 1 or more complications such as aseptic menin- from 2 to 7 days after incubation, and the serotiter was determined gitis, encephalitis, poliomyelitis-like syndrome, encephalomyeli- when the cytopathic effect was observed in 1 50% tissue culture- tis, pulmonary edema/hemorrhage, or death.13,15 Herpangina in- infective dose of the virus back-titration. Cells were fixed with 5% cluded oral ulceration over anterior tonsillar pillars, the soft glutaraldehyde and stained with 0.1% crystal violet. Seropositivity palate, buccal mucosa, or uvula. HFMD cases involved mouth was defined as a reciprocal of the serotiter Ն8. ulcers plus a vesicular rash occurring on the hands, feet, knees, or buttocks. Aseptic meningitis was defined as a clinically compati- Statistical Analyses ble illness, with cerebrospinal fluid pleocytosis (Ͼ5 ϫ 106 leuko- cytes/L if the patient was older than 1 month, or Ͼ25 ϫ 106 We analyzed the data with the SAS statistical software (version leukocytes/L if the patient was a newborn) plus negative bacterial 6.12; SAS Institute, Cary, NC). We used the Student t test for 2 culture. Encephalitis showed an altered level of consciousness. continuous data and tests appropriate for categorical data. Poliomyelitis-like syndrome was the occurrence of acute limb Mortality rates and severe case rates used the 1998 census popu- weakness plus decreased reflex and muscle strength. Encephalo- lation as the denominator. Geographic difference in mortality 2 myelitis included both encephalitis and poliomyelitis-like syn- rates was analyzed by goodness-of-fit test. A simple linear drome. Pulmonary edema/hemorrhage was defined as alveolar regression was used to examine the strength and pattern of asso- congestion on chest radiographs plus pink frothy fluid or blood ciation for continuous outcome variables. The relationship of EV71 2 from the endotracheal tube. seropositivity in sibling pairs was assessed by McNemar test with Yates correction. Univariate analysis was done to screen statistically significant variables. Then, a stepwise multiple logistic Study Design, Selection of Study Areas, and Data regression analysis was performed to adjust confounders simul- Collection for the Serosurvey taneously and to calculate the multivariate-adjusted odds ratios 20 ␣ Cross-sectional studies before and after the 1998 EV71 epidemic (OR) for risk factors. The level of model selection was set to be P Ͻ were conducted. For pre-epidemic serum samples, we randomly 0.15 for in-and-out models.