Clinical features of echovirus 6 and 9 infections in children.

BACKGROUND: Clinical features of echovirus 6 and 9 infections in children have not been comprehensively evaluated, particularly for sporadic cases. OBJECTIVE: To describe the clinical features of children with echovirus 6 or 9 infections. STUDY DESIGNS: From 2000 to 2008, 199 children with culture-proven echovirus 6 or 9 infections identified in a university-affiliated hospital were included. Data extracted from 174 inpatients were further analyzed. RESULTS: Age ranged from 4 days to 15 years with a mean of 4.7 years. 123 (62%) were male. The disease spectrums were similar for echovirus 6 (n=100) and 9 (n=74) infections, with aseptic meningitis (49% and 51%, respectively) being the most common syndrome, followed by meningismus, upper respiratory tract infection, pneumonia, and herpangina. All 174 inpatients had fever but the duration of fever was significantly longer in patient with echovirus 9 infection than those with echovirus 6 infections (6.0 days vs. 3.8 days, p<0.001). The rate of leukocytosis (leukocyte count>15,000/µL) were significantly higher in patients with echovirus 6 infections than those with echovirus 9 infection (p<0.001). One neonate with echovirus 6 infection died from hepatic necrosis with coagulopathy, and one infant with echovirus 6 infection and one child with echovirus 9 infection died from brain involvement. Two children had long-term sequelae of seizure disorder. The remaining 169 children (97%) recovered uneventfully. CONCLUSION: For children with echovirus 6 or 9 infections requiring hospitalization, aseptic meningitis was the most common manifestation and fatal outcome or long-term sequel, though rare, might occur.

Outcome of enterovirus 71 infections with or without stage-based management: 1998 to 2002.

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 to 1999) and of 331 EV71 patients who did (2000 to 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 2 groups. RESULTS: Of the patients who did not receive stage-based management, 83% (15 of 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 1 had sequelae of dysphagia and limb weakness. By contrast of the patients who received stage-based management, 33% (12 of 36) of patients with CNS and cardiopulmonary failure died during the acute stage, 8% (3 of 36) died at convalescence, 14% (5 of 36) recovered and 43% (16 of 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 cerebro-spinal fluid white blood cell count >100/microl were associated with a increase in acute mortality [95% confidence interval (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.

Risk factors of enterovirus 71 infection and associated hand, foot, and mouth disease/herpangina in children during an epidemic in Taiwan.

OBJECTIVE: In 1998, an enterovirus 71 (EV71) epidemic in Taiwan was associated with hand, foot, and mouth disease (HFMD)/herpangina and involved 78 fatal cases. We measured EV71 seroprevalence rates before and after the epidemic and investigated risk factors associated with EV71 infection and illness. METHODS: Neutralizing antibodies to EV71 were assayed for 539 people before the epidemic and 4619 people of similar ages after the epidemic. Questionnaires, which were completed during household interviews after the epidemic, solicited demographic variables, exposure history, and clinical manifestations. RESULTS: A total of 129 106 cases of HFMD were reported during the epidemic. Age-specific pre-epidemic EV71 seroprevalence rates were inversely related to age-specific periepidemic mortality rates (r = -0.82) or severe case rates (r = -0.93). Higher postepidemic EV71 seropositive rates among children who were younger than 3 years positively correlated with higher mortality rates in different areas (r = 0.88). After the epidemic, 51 (56%) of 91 younger siblings of elder siblings who were EV71-seropositive were EV71-seropositive; otherwise, 2.2% (4 of 186) of younger siblings were EV71-seropositive (matched odds ratio [OR]: 10; 95% confidence interval [CI]: 3.4-29). Stepwise multiple logistic regression revealed other factors associated with EV71 infection to be older age (adjusted OR: 2.5; 95% CI: 1.9-3.4), attendance at kindergartens/child care centers (adjusted OR: 1.8; 95% CI: 1.3-2.5), contact with HFMD/herpangina (adjusted OR: 1.6; 95% CI: 1.2-2.1), greater number of children in a family (adjusted OR: 1.4; 95% CI: 1.1-1.7), and rural residence (adjusted OR: 1.4; 95% CI: 1.2-1.6). Twenty-nine percent of preschool children who were infected with EV71 developed HFMD/herpangina. Younger age and contact with HFMD/herpangina were significant factors for the development of EV71-related HFMD/herpangina in these children. CONCLUSIONS: An increased incidence of EV71 infection in young children occurred more often in geographic areas with increased mortality rates. Intrafamilial and kindergarten transmissions among preschool children were major modes of disease transmission during the widespread EV71 epidemic in Taiwan in 1998.

Incidence and case-fatality rates resulting from the 1998 enterovirus 71 outbreak in Taiwan.

In 1998, an epidemic of hand-foot-and-mouth disease and herpangina caused by enterovirus 71 occurred in Taiwan, leaving many fatalities and severely handicapped survivors in its wake. The reasons this rather common pathogen would cause such a large-scale epidemic remain unknown. A seroepidemiological survey to elucidate the epidemiological characteristics of this outbreak, including its incidence and case-fatality rates was undertaken. Microneutralization tests for antibodies against enterovirus 71 were used to screen four collections of serum samples: 1) 202 specimens taken from individuals > or = 4 years old in 1994; 2) 245 specimens collected from individuals of all ages in 1997; 3) 1,258 specimens collected from individuals of all ages in 1999; and 4) sera samples from a birth cohort of 81 children who had yearly blood samples taken from 1988-98. After the maternal antibody had declined, the seropositive rates began to increase with age. Approximately half of all children aged 6 years or older were enterovirus 71 seropositive. Significantly higher seropositive rates were noted in 1999 than in 1997, in children aged 0.5-3 years. The incidence of enterovirus 71 infection during the epidemic was estimated to be 13-22%, with the higher rates in younger children. The case-fatality rate was highest (96.96 per 100,000) in infants aged 6-11 months, and declined in older children. The results showed that enterovirus 71 is endemic in Taiwan. The apparent lack of large-scale enterovirus 71 activity in the 3 years before 1998 might have been the prelude to the epidemic's appearance in 1998, and might suggest that enterovirus 71 infection will reappear every few years. The lack of a protective antibody in younger children may account for the high incidence and case-fatality rate in this age group.

Clinical features and risk factors of pulmonary oedema after enterovirus-71-related hand, foot, and mouth disease.

BACKGROUND: In Taiwan, from April to July, 1998, an epidemic of hand, foot, and mouth disease associated with enterovirus 71 (EV71) occurred with fatal complications. We did a clinical study of EV71-related diseases in Taiwan. METHODS: We studied 154 children with virus-culture confirmed EV71 infection. Children were divided into three groups: 11 patients with pulmonary oedema; 38 patients with central nervous system (CNS) involvement and no pulmonary oedema; and 105 children without complications. We compared the clinical features, laboratory findings, risk factors, and outcome among these three groups. FINDINGS: Nine children with pulmonary oedema had hand, foot, and mouth disease, one had herpangina, and one had febrile illness with eight children with limb weakness and one with limb hypesthesia. All children had had sudden onset of tachycardia, tachypnoea, and cyanosis 1-3 days after onset of the disease. Nine of 11 children died within 12 h of intubation; one child was braindead within 15 h and died 17 days after intubation; one child was in deep coma and died 3 months later. In children with CNS complication and no pulmonary oedema, one child died of pneumonia after 4 months of ventilator support and four children had sequelae. All 105 children without complications recovered. There was a significant association between CNS involvement and pulmonary oedema (odds ratio 12.4 [95% CI 2.6-60.1], p=0.001). Risk factors for pulmonary oedema after CNS involvement were hyperglycaemia, leucocytosis, and limb weakness. Hyperglycaemia was the most significant prognostic factor for pulmonary oedema (odds ratio 21.5 [3-159], p=0.003). INTERPRETATION: EV71 can cause hand, foot, and mouth disease, CNS involvement with severe sequelae, and fatal pulmonary oedema. Hyperglycaemia is the most important prognostic factor.

An epidemic of enterovirus 71 infection in Taiwan. Taiwan Enterovirus Epidemic Working Group.

BACKGROUND: Enteroviruses can cause outbreaks of hand-foot-and-mouth disease (characterized by vesicular lesions on the hands, feet, and oral mucosa) or herpangina, usually without life-threatening manifestations. In 1998 an epidemic of enterovirus 71 infection caused hand-foot-and-mouth disease and herpangina in thousands of people in Taiwan, some of whom died. METHODS: We assessed the epidemiologic aspects of this outbreak. Cases of hand-foot-and-mouth disease or herpangina in ambulatory patients were reported to the Taiwan Department of Health by a mean of 818 sentinel physicians. Severe cases in hospitalized patients were reported by 40 medical centers and regional hospitals. Viruses were isolated by 10 hospital laboratories and the department of health. RESULTS: The sentinel physicians reported 129,106 cases of hand-foot-and-mouth disease or herpangina in two waves of the epidemic, which probably represents less than 10 percent of the estimated total number of cases. There were 405 patients with severe disease, most of whom were five years old or younger; severe disease was seen in all regions of the island. Complications included encephalitis, aseptic meningitis, pulmonary edema or hemorrhage, acute flaccid paralysis, and myocarditis. Seventy-eight patients died, 71 of whom (91 percent) were five years of age or younger. Of the patients who died, 65 (83 percent) had pulmonary edema or pulmonary hemorrhage. Among patients from whom a virus was isolated, enterovirus 71 was present in 48.7 percent of outpatients with uncomplicated hand-foot-and-mouth disease or herpangina, 75 percent of hospitalized patients who survived, and 92 percent of patients who died. CONCLUSIONS: Although several enteroviruses were circulating in Taiwan during the 1998 epidemic, enterovirus 71 infection was associated with most of the serious clinical manifestations and with nearly all the deaths. Most of those who died were young, and the majority died of pulmonary edema and pulmonary hemorrhage.