EV71 isolate TW/2086/98 was amplified and purified as an antigen for µ-capture ELISA. In comparison with standard method of conventional virus culture, sensitivity and specificity for µ-capture ELISA were 91.5% and 93.1%, respectively.18
Statistical Analysis
Data were analyzed with the SAS Statistical Package (Version 8.2, SAS Institute, Cary, North Carolina). We used Student’s t test for continuous variables and χ 2 test for categorical data. After univariate analysis screened statistically significant variables, forward stepwise multiple logistic regression analysis was performed to adjust confounders simultaneously and to calculate multivariate-adjusted odds ratios for risk factors of EV71 infection and an unfavorable outcome in children. Corrected risk ratio was measured by using the formula of Zhang J and Yu KF to correct the adjusted odds ratios obtained from logistic regression if the incidence of an outcome was over 10%
in the study subjects.21 The α level of model selection was set at 0.15 for in-and-out models. P<.05 was considered statistically significant.
Results
Demography, Source of Infection, and Transmission Rates
One hundred and seventy-three suspected cases of EV71 and their household member (343 children and 441 adults) were surveyed from February 2001 to August 2002. The flowchart describing the selection of 94 families with positive EV71
isolation and the source of EV71 infection are shown in Figure. The source of infection to the 94 families was only identified in 47% (44/94): 19% from relatives, 13% from schoolmates, 11% from neighbors and 4% from friends. Because of the difficulties in identifying the source of EV71 infection to the families, we failed to find the source of infection to 53% (50/94) of the families (Figure).
The EV71 infection transmission interval ranged from 1 to 15 days. Median transmission interval was 3 days and mean (SD) interval was 3.7 (2.6) days.
Table 1 shows demographic data and the rates for isolating EV71, detecting EV71 IgM and demonstrating seropositive neutralizing antibodies among index cases and household contacts. The 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. The transmission rate was 84%
(89/106) among household children, and 37% (87/233) among household adults (P<.001). The 39% (41/106) EV71 isolation rate from children household contacts was also significantly higher than the 4.3% (10/233) EV71 isolation rate from adult
household contacts (P<.001).
EV71 infection rates declined as age increased (Table 2). Furthermore, 100%
(71/71) of children younger than 2 years were infected with EV71. Among children, no significant difference in the infection rate existed between siblings and cousins. Among adults, parents had a higher infection rate (41%, 72/175) than other adults (26%, 15/58) (P =.05). Infection rate for mothers (43%, 40/92) was similar to that for fathers (39%, 32/83) (P =.61). EV71 seropositive rates for all family members were as high as 93%
(401/429).
Factors Associated with EV71 Infection in Children
Table 3 shows factors associated with EV71 infection in children. Male sex and age less than 6 years of age were associated with increased risk of EV71 infection.
Children attending kindergarten or school had a lower incidence of EV71 infection.
More household members, more children in the household and having a more crowded household did not significantly increase the risk of infection. Forward stepwise
multiple logistic regression analysis indicated that the most significant factors
associated with infection in children were age less than 6 years (adjusted OR=9.11, 95% confidence interval=2.90-28.65, P<.001; corrected risk ratio=2.37, 95%
CI=1.74-2.68) and male gender (adjusted OR=4.11, 95% confidence interval=1.19-14.15, P=.03; corrected risk ratio=1.13, 95% CI=1.02-1.19).
Clinical Syndromes and Outcomes in Children
Clinical syndromes and outcomes for infected children and adults are shown in Table 4. Children had significantly higher rates than adults for complications (21% vs.
0%, P<.001), long-term sequelae and fatalities (13% vs. 0%, P=.001).
Ten children (5%, 10/183) died: 6 patients died within 24 hours of hospitalization due to brainstem encephalitis plus fulminant cardiopulmonary failure, 3 patients died within 2 to 7 weeks of hospitalization due to brainstem encephalitis plus deep coma, and 1 with sequelae of dysphagia plus central hypoventilation died at home due to ventilator dysfunction 4 months after onset of illness.
At 6 months of follow-up, thirteen (7%, 13/183) children suffered from long-term sequelae that involved the CNS. Magnetic resonance imaging findings revealed
abnormal signal intensity in the brainstem and/or the spinal cord on T2-weighted images. Five patients had limb weakness/atrophy, 5 patients had swallowing dysfunction plus central hypoventilation plus limb weakness/atrophy, 1 patient had swallowing dysfunction plus central hypoventilation, 1 patient had limb
weakness/atrophy plus abducens palsy, and 1 patient had abducens palsy alone.
Unfavorable outcomes including sequelae or deaths occurred in 23 (13%, 23/183) children. Table 5 shows factors associated with unfavorable outcomes in infected children based on univariate analyses. Age less than 3 years was the most significant factor. The clinical outcome of the secondary cases was not significantly different from that of the index cases (P=.09). Contact history with HFMD/HA, more household members, more children in the household and crowded household were not associated with a significantly higher unfavorable outcome rate. Children in kindergarten and school had lower unfavorable outcome rates. Forward stepwise multiple logistic regression analysis indicated that the most significant factor associated with an
unfavorable outcome in infected children was age less than 3 years (adjusted OR=6.19, 95% confidence interval=1.77-21.6, P=.004; corrected risk ratio=5.18, corrected 95%
CI=1.72-12.2). However, in the less-than-3-year-old age group, we did not find any fatal cases in young infants less than 3 months of age.
Clinical Syndromes and Outcomes in Adults
Of 87 EV71-infected adults, 53% (46/87) were asymptomatic. All symptomatic adults recovered completely from uncomplicated illnesses, which included HFMD, herpangina, fever, upper respiratory tract infection and viral exanthema.
COMMENT
In this prospective family cohort study, we found that EV71 infections in young children to be associated with serious diseases; we also found a high household
transmission rate for children and a high ratio of asymptomatic adults. Long periods of viral shedding may account for widespread transmission of enteroviral diseases, which is certainly the case for polio and coxsackievirus infections.14 In a previous study, we found EV71 to be present in the stool of infected patients for up to 5 weeks.22 Previous research has demonstrated a higher rate of EV71 isolation from throat swabs than from rectal swabs or stool: 90% vs. 32%, respectively.23 We speculate that respiratory transmission by large droplet from the oral cavity may explain the high secondary infection rate within households in Taiwan, despite hand washing precautions in practice since 1998.24 Therefore, isolation of infected patients within single rooms and masks for the patients and the close contacts may be recommended for the prevention of respiratory droplet transmission of EV71.
New York Virus Watch data indicate that secondary coxsackievirus infections are more frequent in mothers (78%) than fathers (47%).15 However, the EV71 infection rates in the mothers and fathers in this study were similar: 43% and 39%, respectively (Table 1). EV71 infection rates for parents (41%, 72/175) were higher than for other adults (26%, 15/58), suggesting that close or longer contact facilitated EV71
transmission.
EV71 seropositive rates for all family members were as high as 93% (Table 1), which were significantly higher than those (57% to 67%) for the general population in a previous seroepidemiological study,11 therefore, it is likely that almost all the
susceptible family members were infected once EV71 had been introduced. Table 3 shows that EV71 infection rate increases as age decreases, so the most susceptible households have the highest EV71 infection rates. The high infectivity of EV71 is similar to that of poliovirus.14
Among children, household transmission produced a higher rate of clinical symptoms (94%) compared to extra-household transmission (29%) in our previous EV71 seroepidemiological study.11 Viral load or host genetic factors may account for this difference. Because the rate of asymptomatic infection with EV71 after social contact is high (about 71%),11 it was difficult to identify the source of primary
infections to the family. We were successful in determining the sources in only 47% of the cases.
EV71 infections in adults were less serious than those in children. Although EV71 infection is a differential consideration in cases of adult encephalitis, unexplained pulmonary edema or cardiopulmonary failure and although two deaths have occurred in adults,2,17 most infected adults in the present study were asymptomatic or suffered mild
upper respiratory tract infections. Why adults or older children have less severe
illnesses needs further study. One possible reason for the reduced severity might be that most adults and older children have antibody to this virus or a related virus, whereas younger children may incur primary infections. Another possible reason is that inadequate hygiene of younger children may increase a higher viral load and subsequently more severe diseases. EV71 transmission by infected adults who are asymptomatic or mildly symptomatic is a likely source of many infections. In some families whose source of infection could not be identified, we speculate that EV71 infections might be introduced into the family by an asymptomatic adult.
In conclusion, EV71 household transmission rates are high for children, medium for parents and low for other household adults. EV71 infections in children, especially those younger than 3 years old, are associated with serious complications, long-term sequelae and death. Adult EV71 infection can be characterized as having a high ratio of asymptomatic adults or nonspecific mild illnesses.
Author Contributions:
Study concept and design: Chang, Lin.
Acquisition of data: Chang, Tsao, Hsia, Shih, CG Huang, Hsu, Fang, YC Huang.
Analysis and interpretation of data: Chang, Tsao, Hsia, Chan, Hsu, Lin Drafting of the manuscript: Chang, Lin.
Critical revision of the manuscript for important intellectualcontent: Chang, Tsao, Hsia, Shih, CG Huang, Chan, Hsu, Fang, YC Huang, Lin.
Statistical expertise: Chang, Hsu.
Obtained funding: Chang, Lin.
Administrative, technical, or material support: Tsao, Shih, Huang, Lin.
Study supervision: Lin.
Funding/Support: This study was supported by grants from the Chang Gung Memorial Hospital (CMRP1089) and National Science Council (NSC 90-2314-B-002-463 and NSC 91-3112-B-002-029).
Acknowledgement: We thank Mr. James Steed for his critical review on this manuscript.
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Table 1. Demographic Data and Rates for Isolating EV71, Detecting EV71 IgM, Demonstrating Seropositivity for Neutralizing Antibodies and Infection Among the Index Cases and Household Contacts
Subjects Number Age, mean (SD), y Sex
(Male/ Female)
Positive EV71 Isolation Rate
Positive EV71 IgM Rate
EV71 Seropositivity Rate†
Infection Rate‡
Total subjects* 433 20.9 (18.4) 223/210 28% (119/433) 47% (201/425) 93% (401/429) 62% (270/433)
Index case 94 3.1 (2.1) 56/38 72% (68/94) 94% (85/90) 98% (90/92) 100% (94/94)
Household contacts 339 25.8 (17.8) 167/172 15% (51/339) 35% (116/335) 92% (311/337) 52% (176/339) Children household
contacts 106 4.5 (4.6) 60/46 39% (41/106) 76% (79/104) 95% (99/104) 84% (89/106)
Siblings 83 4.4 (3.8) 46/37 40% (33/83) 78% (63/81) 96% (78/81) 84% (70/83) Cousins 23 5.0 (6.8) 14/9 35% (8/23) 70% (16/23) 91% (21/23) 83% (19/23) Adults household
contacts
233 35.7 (12.0) 107/126 4.3% (10/233) 16% (37/231) 91% (212/233) 37% (87/233) Parents 175 31.5 (5.4) 83/92 5% (9/175) 17% (29/175) 91% (159/175) 41% (72/175) Grandparents 36 59.3 (10.4) 14/22 0% (0/36) 15% (5/34) 94% (34/36) 28% (10/36) Uncles/aunts 19 27.4 (8.7) 10/9 5% (1/19) 16% (3/19) 84% (16/19) 26% (5/19)
Babysitters 3 36.6 (7.7) 0/3 0% (0/3) 0% (0/3) 100% (3/3) 0% (0/3) Abbreviation: EV71, enterovirus 71; SD, standard deviation.
*Total subjects included index cases and household contacts.
† EV71 seropositivity was defined as an EV71 neutralizing antibody titer ≥8 .
‡EV71 infection was defined as either positive EV71 isolation, a four-fold change in EV71 neutralizing antibody titers or presence of EV71 IgM.
Table 2. EV71 Infection Rates in Different Age Groups
Age Group, y EV71 Infection Rates Adjusted Odds Ratio*
(95% CI)
Corrected Risk Ratio†
(95% CI)
P Value*
<6 96% (159/165) 1.0 1.0 － 7-18 72% (26/36) 0.10 (0.03-0.3) 0.74 (0.46-0.91) <.001 19-40 39% (71/181) 0.025 (0.01-0.06) 0.39 (0.20-0.61) <.001
>40 27% (14/51) 0.014 (0.005-0.04) 0.26 (0.11-0.51) <.001 Abbreviation: EV71, enterovirus 71; CI, confidence interval.
*Adjusted odds ratio and P value were calculated by using the age≤6 group as the reference group and adjusted by sex.
†Corrected risk ratio was measured by using the formula of Zhang J and Yu KF to correct the adjusted odds ratio obtained from logistic regression.21
Table 3. Factors Associated With EV71 Infection in Children
Factors Infected (n=183)
Not Infected (n=17)
P Value
Male/female ratio 1.57 (112/71) 0.31 (4/13) <.01 Age, mean (SD), y 3.3 (2.4) 10.0 (7.6) <.01 Age<6 years 86% (158/183) 35% (6/17) <.01 No. of household members>6 52% (95/183) 53% (9/17) .94 No. of children>3* 45% (82/183) 59% (10/17) .27
Crowded household† 64% (118/183) 53% (9/17) .34 Kindergarten or school attendance 34% (62/183) 71% (12/17) <.01 Abbreviation: EV71, enterovirus 71; SD, standard deviation.
*No. of children was the number of children in the same household.
†Crowded household was defined as the ratio of the number of household members to the number of bedrooms over 1.5.
Table 4. Clinical Syndromes and Outcomes of EV71-infected Children and Adults
Children (n=183)
Adults (n=87)
P Value
Clinical Syndromes
Asymptomatic 11 (6%) 46 (53%) －
Symptomatic 172 (94%) 41 (47%) <.001*
Uncomplicated symptomatic 133 (73%) 41 (47%) －
HFMD 90 (49%) 7 (8%) －
Herpangina 19 (10%) 8 (9%) － Nonspecific febrile illness 4 (2%) 1 (1%) － Upper respiratory tract infection 16 (9%) 18 (21%) － Enteritis 2 (1%) 2 (2%) － Viral exanthema 2 (1%) 5 (6%) －
Complicated symptomatic† 39 (21%) 0 <.001†
HFMD plus meningitis 9 (5%) 0 － HFMD plus encephalitis 11 (6%) 0 － HFMD plus polio-like syndrome 5 (3%) 0 － HFMD plus encephalomyelitis and
cardiopulmonary failure 14 (8%) 0 －
Outcomes
Unfavorable outcomes (sequelae or deaths) 23 (13%)‡ 0 .001 Abbreviation: EV71, enterovirus 71; HFMD, hand, foot, and mouth disease.
* P Value was measured with Pearson χ2test to compare the rates of symptomatic cases between infected children and infected adults.
† P Value was measured with Pearson χ2 test to compare the rates of complications between infected children and infected adults.
‡ These 23 included 13 sequelae and 10 deaths.
Table 5. Factors Associated With Unfavorable Outcomes in EV71-infected Children
Factors Children With
Unfavorable Outcomes*
(n=23)
Children With Favorable Outcomes (n=160)
P Value
Age<3 years 87% (20/23) 52% (83/160) <.01 Males 65% (15/23) 61% (97/160) .67 Secondary case in family 26% (6/23) 46% (68/149) † .09 Contact history with HFMD/HA 52% (12/23) 71% (110/160) .11 No. of household members>6 48% (11/23) 53% (84/160) .68 No. of children>3‡ 43% (10/23) 45% (72/160) .89 Crowded household§ 65% (15/23) 64% (103/160) .94
Kindergarten or school attendance 9% (2/23) 38% (60/160) .01 Abbreviation: EV71, enterovirus 71; HFMD/HA, hand, foot, and mouth disease or herpangina.
*Unfavorable outcomes were defined as death or having log-term sequelae, and favorable outcomes as complete recovery.
† Because 11 out of 160 infected children with favorable outcomes were asymptomatic, these 11 cases could not be defined as primary or secondary.
‡No. of children was the number of children in the same household.
§Crowded household was defined as the ratio of the number of household members to the number of bedrooms over 1.5.
Figure. Flowchart of Family Surveillance Study and Identified Sources of EV71 Infection to the Family
Virus isolation
1st blood sample for EV71 antibodies Questionnaire-based investigation Telephone interview +/– clinical assessment
94/173 (54%) families (200 children and 233 adults) (+) for EV71 isolation
50/173 (29%) families (88 children and 136 adults) (–) for EV71 isolation
29/173 (17%) families (55 children and 72 adults) (+) for non-71 enterovirus
Excluded from study 2nd blood sample for EV71 antibodies
Clinical outcome assessment Data analysis
The first EV71-infected cases in 44/94 (47%) families had identified source of infection
Source of infection was not identified in 50/94 (53%) families
Identified source of infection
Relatives 19% (18/94) Schoolmates 13% (12/94) Neighbors 11% (10/94) Friends 4% (4/94)
Outcome of Enterovirus 71 Infections with or without Stage-based Management, 1998 -
2002
Luan-Yin Chang, MD, PhD; Shao-Hsuan Hsia, MD; Chang-Teng Wu, MD; Yhu-Chering Huang, MD, PhD; Kuang-Lin Lin, MD; Tsui-Yen Fang, BS; Tzou-Yien Lin, MD
Division of Pediatric Infectious Diseases (LYC, YCH, TYF, TYL), Division of Pediatric Critical Care and Emergency Medicine (SHH, CTW), Divison of Pediatric Neurology (KLL), Department of Pediatrics, Chang Gung Children’s Hospital, Chang Gung University, Taoyuan, Taiwan
*Dr. Chang’s current affiliation is Department of Pediatrics, National Taiwan University Hospital, College of Medicine, National Taiwan University.
Running Title: Outcome of EV71 Infection
Correspondence and Reprint Requests to: Dr. Tzou-Yien Lin
Division of Pediatric Infectious Diseases, Department of Pediatrics, Chang Gung Children’s Hospital, Chang Gung University,
5, Fu-Hsing Street, Kweishan, Taoyuan, Taiwan Tel: 886-3-3281200 ext 8002; Fax: 886-3-3288957;
E-mail: [email protected]
Abstract
Background: Enterovirus 71 (EV71) infection may progress through four stages, one of which is cardiopulmonary failure. In Taiwan in 1998, almost all the EV71 patients with cardiopulmonary failure died. To improve clinical outcome of EV71 patients, we developed a stage-based management program in 2000.
Methods: The medical records of 196 EV71 patients who did not have stage-based management (1998-1999) and of 331 EV71 patients who did (2000-2002) at Chang Gung Children’s Hospital were reviewed for demographic characteristics, clinical syndromes, case-fatality rates and sequelae. We compared and analyzed the results for the two groups.
Results: Of the patients who did not receive stage-based management, 83% (15/18) of cases with both central nervous system (CNS) involvement and cardiopulmonary failure died during the acute stage of the infection. Two patients died at convalescence and one had sequelae of dysphagia and limb weakness. By contrast, of the patients who received stage-based management, 33% (12/36) of cases with CNS and
cardiopulmonary failure died during the acute stage, 8% (3/36) died at convalescence, 14% (5/36) recovered completely and 43% (16/36) had severe sequelae of central hypoventilation, dysphagia, and limb weakness (p<0.001). For cases with CNS and cardiopulmonary failure, multivariate analysis showed that age older than 2 years and cerebrospinal fluid white cell count over 100/uL were associated with a increase in acute mortality (95% CI 1.9 to 105.3, p=0.001; 95% CI 1.1 to 66.6, p=0.04,
respectively) but stage-based management was significantly associated with a reduction in acute mortality (95% CI 0.007 to 0.24; p=0.0004). Stage-based management did not affect the outcome of cases with CNS involvement alone.
Conclusions: Stage-based management reduced the case-fatality rate of EV71-related cardiopulmonary failure, but two-thirds of the survivors had severe sequelae.
Key words: enterovirus 71; pulmonary edema; stage; management; fatality; sequel
Introduction
There were large outbreaks of enterovirus 71 (EV71) infection resulting in dozens of deaths in Bulgaria in 1975,1 Hungary in 1978,2 and Malaysia in 1997,3 and in the largest and most severe EV71 epidemic, to date, in Taiwan in 1998.4 During the 1998 Taiwan
There were large outbreaks of enterovirus 71 (EV71) infection resulting in dozens of deaths in Bulgaria in 1975,1 Hungary in 1978,2 and Malaysia in 1997,3 and in the largest and most severe EV71 epidemic, to date, in Taiwan in 1998.4 During the 1998 Taiwan