Transmission and Clinical Features of EV71 Infections in Household Contacts in Taiwan (JAMA, 2004;291, in press, SCI, IF 16.783)

2. Outcome of Enterovirus 71 Infections with or without Stage-based Management, 1998 – 2002 (Ped Infect Dis J, accepted, SCI, IF 2.376)

Transmission and Clinical Features of EV71 Infections in Household Contacts in Taiwan

Luan-Yin Chang, MD, PhD, Kou-Chien Tsao, BS, Shao-Hsuan Hsia, MD, Shin-Ru Shih, PhD, Chung-Guei Huang, MS, Wing-Kai Chan, MD, Kuang-Hung Hsu, PhD, Tsui-Yen Fang, RN, Yhu-Chering Huang, MD, PhD, Tzou-Yien Lin, MD

Division of Pediatric Infectious Diseases (Drs Chang, Huang and Lin, Rn Fang), and Division of Pediatric Critical Care and Emergency Medicine (Dr Hsia), Department of Pediatrics, Chang Gung Children’s Hospital; Clinical Virology Laboratory, Chang Gung Memorial Hospital (Bs Tsao and Ms Huang); School of Medical Technology (Dr Shih), Laboratory for Epidemiology and Department of Health Care Management (Dr Hsu), Chang Gung University; Department of Medical Research (Dr Chan), National Taiwan University Hospital

Dr Chang is now with Department of Pediatrics, National Taiwan University Hospital, College of Medicine, National Taiwan University.

Corresponding Author and Reprints: Tzou-Yien Lin, MD,

Department of Pediatrics, Chang Gung Children’s Hospital, Chang Gung University, 5, Fu-Hsing Street, Kweishan, Taoyuan 333, Taiwan

Tel: 886-3-3281200 ext 8002; Fax: 886-3-3288957;

E-mail: [email protected]

Short title: Household Transmission of Enterovirus 71 Word count: 2995.

Abstract

Context Although enterovirus 71 has caused epidemics associated with significant morbidity and mortality, its transmission has not been thoroughly investigated.

Objective To evaluate enterovirus 71 transmission and clinical outcomes within households.

Design, Setting, and Subjects From February 2001 to August 2002, we performed a prospective family cohort study to investigate patients and family members of patients who had signs and symptoms suggestive of enterovirus 71. These patients and

household members underwent clinical evaluations, virologic studies and questionnaire-based interviews.

Main Outcome Measures Enterovirus 71 infection was defined as positive viral isolation, IgM or four-fold change of neutralizing antibody; clinical syndromes defined as asymptomatic, uncomplicated symptomatic and complicated; unfavorable outcome of sequelae or death.

Results We studied 433 family members from 94 families with positive enterovirus 71 isolation. The overall enterovirus 71 transmission rate of household contacts was 52%

(176/339): 84% (70/83) siblings, 83% (19/23) cousins, 41% (72/175) parents, 28%

(10/36) grandparents and 26% (5/19) uncles/aunts. Of 183 infected children, 6%

(11/183) were asymptomatic, 73% (133/183) had uncomplicated illnesses of hand, foot and mouth disease, herpangina or nonspecific febrile illness and 21% (39/183) suffered from complications of central nervous system involvement and/or cardiopulmonary failure. During the 6-month follow-up, 10 died and 13 had sequelae of dysfunction in swallowing, cranial nerve palsies, central hypoventilation or limb weakness/atrophy.

Age younger than 3 years was the most significant factor associated with unfavorable outcomes in children (P=.004). Among 87 infected adults, 53% (46/87) were

asymptomatic, 39% (34/87) had nonspecific illnesses of fever, sore throat or gastrointestinal discomfort and only 8% (7/87) had hand, foot and mouth disease.

Conclusions Enterovirus 71 household transmission rates are high for children, medium for parents and low for other adults. Serious complications, sequelae and death are associated with young children.

Key words: enterovirus 71; hand, foot and mouth disease; herpangina; household transmission; risk factors; outcomes

INTRODUCTION

Outbreaks of enterovirus 71 (EV71) have been documented since it was recognized in California in l969.¹ Forty-four fatalities have been reported in Bulgaria (1975), 47 in Hungary (1978) and 30 in Malaysia (1997).^2-4 The largest and most severe EV71 epidemic occurred in Taiwan in 1998.^5-10 During the 1998 epidemic in Taiwan, out of over hundred thousands cases of hand, foot, and mouth disease or herpangina (HFMD/HA), 405 suffered severe neurologic complications such as encephalitis, meningitis, polio-like syndrome, encephalomyelitis and/or pulmonary edema. ⁹ Among the 405, 78 children died.⁹

In a seroepidemiological study before and after the 1998 outbreak, we found that pre-epidemic and post-epidemic EV71 seroprevalence rates in adults and children older than 6 years ranged from 57% to 67%.¹¹ The post-epidemic EV71-seropositive rates among children below 3 years old ranged from 0% to 36%.¹¹ An increased incidence of EV71 infection in young children occurred more often in geographic areas with increased mortality rates.¹¹ For the 3 to 6-year-old children, the seropositive rates were between 26% and 51%. Interestingly, only 29% of preschool children infected with EV71 developed HFMD/HA. Combining the information of the clinical and seroepidemiological studies together, 1-6,8,9,11 we found that the clinical syndromes and severity of EV71 infection are very diverse, ranging from asymptomatic to fatal diseases.

In another Taiwanese seroepidemiological study, Lu CY et al. examined serial serum antibody titers to EV71 in blood samples from 81 children born in 1988.¹² Samples were obtained yearly from 1989 to 1994 and from 1997 to 1999. EV71 seroconversion occurred with a yearly incidence of 3% to 11% between 1989 and 1997.

By 1997, 68% of the 81 children at the age of 9 had serologic evidence of EV71 infection.¹² A seroepidemiological study in Singapore also demonstrated that the EV71 seroprevalence rate in the general population was as high as 60% to 70%.¹³ It is evident that EV71 infection is not uncommon and that documented cases do not accurately reflect the actual number of infections.

Why the 1998 EV71 outbreak in Taiwan was so large is not clear.^9,10 EV71 seropositivity was found to be concordant among siblings in our previous seroepidemiological study, suggesting that household transmission plays an important role on EV71 spread.¹¹ The secondary household transmission rates of enteroviruses vary, including those for poliovirus, enterovirus 70 and coxsackievirus A24.^14-16 The two adult fatalities that have been reported in Bulgaria and Singapore indicate that adults can also suffer serious complications from EV71 infections.^2,17 However, the impact and outcomes of EV71 infections in adults and disease transmission among household family members need further investigation.

Since vaccination programs have almost eliminated poliovirus infection, EV71 infections may become one of the most important enteroviral diseases associated with significant sequelae and mortalities among young children. To date, EV71 transmission and outcomes within households of EV71 infection have not been studied. Data on household transmission of EV71 are necessary to help control, manage and prevent future EV71 infections. Therefore, the objective of this study is to investigate EV71 transmission and clinical outcomes within households of EV71-infected patients.

METHODS

Patient Selection and Family Surveillance

At Chang Gung Children’s Hospital in Taiwan, we studied patients who were suspected of having EV71 illnesses, such as HFMD or herpangina, and their household family members from February 2001 to August 2002. Institutional Review Board approval was obtained for this study and informed consents were obtained from all subjects or their parents.

Study flowchart is shown in Figure. If patients at the emergent service, outpatient clinic or inpatient ward had clinical syndromes suggestive of EV71 infection, they and their household family members were asked to participate in the study. Throat and rectal swabs for virus isolation, and the first blood sample for EV71 IgM, tested by µ-capture enzyme-linked immunoassay (ELISA),¹⁸ and neutralizing antibodies were obtained from the suspected cases of EV71 treated at Chang Gung Children’s Hospital.

Clinical manifestations, courses and outcomes were recorded. If at any point the patients suspected of infection displayed clinical symptoms, the other family members in the same household were asked to undergo screening by virus isolation of throat swabs, and received the first blood sample for EV71 IgM and neutralizing antibodies.

Questionnaire-based interviews were used to collect information including demographic data, the number of bedrooms in the households, contact time, pattern and presence of current/recent signs and symptoms (ulcers, sore throat, rash, fever, abdominal pain and diarrhea) and preceding contact history with extra-household people who had clinical syndromes suggestive of EV71 infection. Follow-up telephone interviews repeated questions about signs and symptoms at 2, 4 and 8-week intervals. If any household family member reported experiencing signs or symptoms suggesting of EV71 infection during the follow-up period, clinical assessment and repeated laboratory investigation for EV71 were performed.

If the suspected case or any household family member tested positive for EV71 isolation, a second blood sample was obtained from the suspected cases and all their household family members 4 weeks after the first blood sample obtained. Household EV71 transmission rates and clinical outcomes were analyzed only for families with at

least a member for positive EV71 isolation.

Definitions of EV71 Infection, Clinical Syndromes, Outcomes and Identified

Source of Infection

Laboratory evidence of EV71 infection was defined as the isolation of EV71, the presence of EV71 IgM or a four-fold change in EV71 neutralizing antibody serotiters between acute and convalescent sera. EV71 seropositivity was defined as a serotiter ≥ 8.

In uncomplicated cases, evidence of HFMD infections included oral ulcers on the tongue and buccal mucosa and a vesicular rash on the hands, feet, knees or buttocks.

Evidence of herpangina included oral ulcerations on anterior tonsillar pillars, soft palate, buccal mucosa or uvula. Nonspecific febrile illness was defined as rectal temperature greater than 38^oC without other symptoms. Enteritis was defined as diarrhea with or without abdominal pain. Upper respiratory tract infection was defined as sore throat, coryza or cough without herpangina or rash.

In complicated cases, aseptic meningitis was defined as a clinically compatible illness with cerebrospinal fluid (CSF) pleocytosis (>5 leukocytes/mm³ in patients older than one month or >25 leukocytes/mm³ in neonates) and negative bacterial cultures.

Encephalitis was characterized by an altered level of consciousness accompanied by CSF pleocytosis. Evidence of a poliomyelitis-like syndrome included acute limb weakness with diminished reflexes and muscular strength. A diagnosis of encephalomyelitis was made when there was evidence of encephalitis and poliomyelitis-like syndrome. Cardiopulmonary failure was defined as pulmonary edema/hemorrhage with left ventricle failure requiring inotropic support. Unfavorable outcome was defined as death or sequelae, and favorable outcome was defined as complete recovery after 6 months of follow-up.

The index cases were the first members of the household to have clinically apparent illness confirmed by laboratory EV71 diagnosis. The secondary cases were defined as other family members whose EV71 symptoms occurred later than the index cases’

illness. Identified source of EV71 infection to the household was defined as “the first case in the household who displayed clinical apparent disease and who had had clear contact history with extra-household people who had illnesses suggestive of EV71 infection, such as HFMD or herpangina”. The infection transmission interval was defined as the time between the onset of disease for the first case in the household and the onset of disease in secondary case. Crowded household was defined as the ratio of the number of household members to the number of bedrooms over 1.5.