Diagnosis and treatment of herpangina: Chinese expert consensus.

BACKGROUND: Herpangina is a common infectious disease in childhood caused by an enterovirus. This consensus is aiming to standardize and improve herpangina prevention and clinical diagnosis. METHODS: The Subspecialty Group of Infectious Diseases, the Society of Pediatric, Chinese Medical Association and Nation Medical Quality Control Center for Infectious Diseases gathered 20 experts to develop the consensus, who are specialized in diagnosis and treatment of herpangina. RESULTS: The main pathogenic serotypes of herpangina include Coxsackievirus-A, Enterovirus-A and Echovirus. Its diagnosis can be rendered on the basis of history of epidemiology, typical symptoms, characteristic pharyngeal damage and virological tests. The treatment is mainly symptomatic, and incorporates topical oral spray with antiviral drugs. The course of herpangina generally lasts 4-6 days with a good prognosis. CONCLUSION: The consensus could provide advices and references for the diagnosis, treatment and management of herpangina in children.

Enterovirus 71 seroepidemiology in Taiwan in 2017 and comparison of those rates in 1997, 1999 and 2007.

BACKGROUND: During recent 20 years, enterovirus 71 (EV71) has emerged as a major concern among children, particularly in the Asia-Pacific region. To understand current EV71 serostatus, to find risk factors associated with EV71 infection and to establish future EV71 vaccine policy, we performed a seroepidemiology study in Taiwan in 2017. METHODS: After informed consent was obtained, we enrolled preschool children, 6-15-year-old students, 16-50-year-old people. They received a questionnaire and a blood sample was collected to measure the EV71 neutralization antibody. RESULTS: Altogether, 920 subjects were enrolled with a male-to-female ratio of 1.03. The EV71 seropositive rate was 10% (8/82) in infants, 4% (6/153) in 1-year-old children, 8% (7/83) in 2-year-old children, 8% (13/156) in 3-5-year-old children, 31% (38/122) in 6-11-year-old primary school students, 45% (54/121) in 12-15-year-old high school students and 75% (152/203) in 16-50-year-old people. Risk factors associated with EV71 seropositivity in preschool children were female gender, having siblings, more siblings, and contact with herpangina or hand-foot-and-mouth disease. The risk factor with EV71 seropositivity in 16-50-year-old people was having children in their families in addition to older age (p<0.001). Compared with the rates in 1997, 1999 and 2007, the rates in children were significantly lower in 2017. CONCLUSION: EV71 seropositive rates were very low, at 4% to 10%, in preschool children and not high, at 31%, in primary school students. Preschool children are highly susceptible and need EV71 vaccine most.

Comparison of Nonpolio Enteroviruses in Children With Herpangina and Hand, Foot and Mouth Disease in Taiwan.

BACKGROUND: Nonpolio enterovirus (NPEV) infections are often present with herpangina (HA) and hand, foot and mouth disease (HFMD). Most countries sample NPEVs in HFMD cases, targeting enterovirus A71 (EV-A71) and coxsackievirus A16 (CV-A16) that are associated with outbreaks and severe complications. HA is also monitored in Taiwan and several other countries, but its viral characteristics are underreported. METHODS: Through Taiwan's National Virologic Surveillance, information regarding ~100,000 child respiratory samples (2002-2015) was linked to concurrent (0-6 days before the sampling date) outpatient records from the National Health Insurance databases, including ~15,000 HA-related and ~7000 HFMD-related samples. We assessed sample representation and NPEV positive rates, and estimated total numbers of EV-A71 and CV-A16. RESULTS: There were more HA events (4.0 millions) than HFMD events (1.2 millions) in Taiwan. In every 1000 events with HFMD and HA, 6.0 and 4.1, respectively, respiratory samples were collected. The NPEV positive rate in HFMD-related samples was 48%, consistent across most sampling seasons, and predominantly EV-A71 or CV-A16 (74%). By comparison, the HA-related samples had a lower positive rate overall (43%), occasionally EV-A71 or CV-A16 (13%), and the positive rate depended strongly on HA incidence (P < 10). Compared with sampling HFMD alone, inclusion of HA-related information predicted an earlier onset of EV-A71 outbreak in 2011, and predicted 30% more EV-A71 cases. CONCLUSIONS: This is the first representative report on viral characteristics of HA. Our findings confirm that HFMD monitoring is a reliable strategy, but there is a measurable additional benefit when HA is also monitored.

Diagnostic uncertainty of herpangina and hand-foot-and-mouth disease and its impact on national enterovirus syndromic monitoring.

The community burden of enterovirus is often monitored through syndromic monitoring systems based on reported cases of enterovirus-related infection (EVI) diagnoses. The extent to which this is affected by under- and over-diagnosis has not been reported. In Taiwan, children often make more than one healthcare visit during an episode of infection. We used change of diagnosis within an episode of infection as a guide of diagnostic uncertainty in a nationally representative cohort of Taiwanese children (n = 13 284) followed from birth to the 9th birthday through electronic health records. We conducted a nested case-control analysis and estimated cross-diagnosis ratios (CDRs) as the observed proportion of acute respiratory infection (ARI) diagnoses following an EVI diagnosis in excess of background ARI burdens. With 19 357 EVI diagnoses in this cohort, the CDR within 7 days was 1·51 (95% confidence interval 1·45-1·57), confirming a significant excess of ARI diagnoses within the week following an EVI diagnosis. We used age-specific CDRs to calibrate the weekly EVI burden in children aged 3-5 years in 2008, and the difference between observed and calibrated weekly EVI burdens was small. Therefore, there was evidence suggesting a small uncertainty in EVI diagnosis, but the observed EVI burdens through syndromic monitoring were not substantially affected by the small uncertainty.

Neurological images and the predictors for neurological sequelae of epidemic herpangina/hand-foot-mouth disease with encephalomyelitis.

Since 1998 in Taiwan, enterovirus (EV) 71 epidemics have caused encephalomyelitis and placed a significant burden on parents and physicians. In this study, we present clinical manifestations, magnetic resonance (MR) imaging findings, and neurological sequelae on epidemic EV-infected patients with encephalomyelitis. Of the 46 patients, 14 patients presented with neurological sequelae; of them, 3 patients suffered from complications of mental regression. Predictors of unfavorable neurological sequelae were myoclonic jerks (> 4 times/night) and pleocytosis (167/µL) of the cerebrospinal fluid (CSF). Results from viral culture and MR imaging indicated that positive identification of EV71 infection was associated significantly with lesions on MR imaging. Our results show that hand-foot-mouth disease carries a higher risk of encephalomyelitis and that frequent myoclonic jerks and pleocytosis of the CSF are risk factors for subsequent neurological sequelae. Positive identification of EV71 might be useful as a predictor of lesions in MR imaging.

[Herpangina and erythema multiforme in a three-year boy]. / Opryszczkowe zapalenie gardla i rumien wielopostaciowy u trzyletniego chlopca.

The dentist can be confronted with a vesiculobullous lesion of the oral mucosa are a symptoms of herpes infection (herpangina) of throat. Human enteroviruses (HEVs) are a major cause of herpangina. Herpangina is an acute viral infection caused by certain viruses Coxsackie, is spread by respiratory droplets. The infection is mainly encountered in young children. Oral lesions rarely more than 7 days; treatment is symptomatic. Viral throat infections may accompany various skin rashes, such as erythema multiforme (which can also occur without any connection with a viral infection). At work was presented a case of 3-year-old boy with herpes symptoms of sore throat and mild forms of erythema multiforme.

Molecular diagnosis and clinical presentations of enteroviral infections in Taipei during the 2008 epidemic.

BACKGROUND: In 2008, an epidemic of enterovirus (EV) infection caused hand, foot, and mouth disease (HFMD) and herpangina in children in Taiwan, and some of them died. To establish an early detection and effective management for children with EV71 infection, sensitive molecular diagnostic methods were applied from May to July 2008. METHODS: We used virus isolation, EV71 real-time reverse-transcription polymerase chain reaction (RT-PCR), and viral protein 1 (VP1) RT-PCR followed by direct sequencing to detect EV71 and the other EVs in the infected outpatient or inpatient children. Clinical presentations of children infected with EV71 and other EVs were compared. RESULTS: From May 2008 to July 2008, 255 swabs were tested by both PCR diagnostic methods. Based on the viral isolation results, the sensitivities of EV71 real-time RT-PCR and VP1 RT-PCR followed by direct sequencing were 71% and 86%, respectively. Among the 221 children who were enrolled for clinical analysis, 73% (161 of 221) had herpangina, and 27% (60 of 221) had HFMD. Coxsackievirus A2 (CA2) was the most prevalent among the identifiable viruses (65%, 104 of 160), followed by EV71 (28%, 45 of 160). EV71 was the most commonly detected virus among the HFMD cases (63%, 38 of 60), whereas herpangina was mainly caused by CA2 (61%, 98 of 161). Of the CA2 cases, 94% (98 of 104) had herpangina, and the most common manifestation of EV71 infection was HFMD with or without complications (84%, 38 of 45). Phylogenetic study revealed that the genotype of EV71 cases during this epidemic was of B5 lineage. CONCLUSION: During the 2008 EV epidemic, most of the HFMD was caused by EV71, whereas herpangina was mainly caused by CA2. Real-time RT-PCR for EV71 is a time-saving and sensitive diagnostic tool.

Diseases caused by enterovirus 71 infection.

The purpose of this review was to explore the epidemiology, pathogenesis, virology, and management of enterovirus 71 (EV71) infection. Published literature was surveyed by Medline using the keyword "EV71." The reported incidence of cases of hand-foot-mouth disease/herpangina varied from year to year; seasonal variations in incidence were observed, with a peak in incidence during the summer season. Most cases of hand-foot-mouth disease/herpangina hospitalized for complications occurred in children less than 5 years old. The brainstem was the most likely major target of EV71 infection. Different enteroviruses cocirculate in the community annually. The emergence of the EV71 epidemic in the Asia Pacific region has been associated with the circulation of 5 genetic lineages (genotypes B3, B4, C1, C2, C4) that appear to be undergoing rapid evolutionary changes. The relationship between the gene structure of the EV71 virus and the factors that ensure its survival, ease of transmission, and evasion of immunity is still unclear. EV71 central nervous system involvement causes serious clinical illness, death, and long-term neurologic and psychiatric disorders in young children. EV71 infection has emerged as an important public health problem. Vaccine development is recommended for the prevention of EV71 infection in the future.

[A study on enterovirus infection in Osaka prefecture --comparison with virus isolation and RT-PCR amplifying viral protein 1 region].

Detection of viral genomes with RT-PCR, which amplifies viral protein 1 region, as well as virus isolation was performed on 860 patients (996 specimens) who had been suspected for enterovirus (EV) infection in Osaka Prefecture from April 2003 to Jury 2004. The viral positive rates of the clinical materials, combining above two procedures, were as follows: 48.2% from the feces, 38.3% from the throat swabs, and 18.0% from the cerebrospinal fluids. The positive rate by the clinical diagnosis indicated that herpangina was the highest at 44.7%, while encephalitis was the lowest at 13.4%. Out of the all specimens, the viral positive rate of RT-PCR varied from 22.3 to 24.7%, while that of virus isolation was 15.6%. The total viral positive rate of both procedures combined was 29.8%. Since the detection of EV by RT-PCR amplifing viral protein 1 region was more rapid than virus isolation and superior in detection of coxsackie group A virus, RT-PCR is an effective procedure for diagnosis of herpangina.

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.

Viral exanthems.

Viral exanthems are mostly associated with self-limited diseases. However, in some cases diagnosis of an exanthem may be crucial to patients and their contacts. Certain exanthems have fairly characteristic morphology, but in many cases an accurate diagnosis cannot be made on the basis of morphology alone. Historical factors may be helpful when evaluating these patients, specifically their disease contacts, immunization record, previous exanthematous illnesses, and associated prodromal symptoms. Some illnesses are seasonal and this knowledge may be useful. This manuscript reviews a number of common childhood exanthems. We included the most common viral exanthems encountered by primary-care physicians and dermatologists.

Clinical characteristics of an outbreak of hand, foot and mouth disease in Singapore.

BACKGROUND: We experienced a hand, foot and mouth disease (HFMD) outbreak in late year 2000 in Singapore. Between 14 September 2000 and 14 November 2000, a total of 3526 cases of HFMD were notified. There were 652 patients clinically suspected to have HFMD, who were seen at the Children's Emergency department of KK Women's and Children's Hospital of Singapore. OBJECTIVE OF THE STUDY: To study the clinical profile and virologic isolates of children admitted with HFMD during the outbreak. STUDY DESIGN: A prospective observational study. METHODS: Analysis of clinical features and virologic studies of 129 selected cases of HFMD and herpangina. RESULTS: The median age was 25 months with a range of between 4 months and 11 years. The majority were less than 5 years old (87%). The male-to-female ratio was 1.3:1. The median numbers of day of illness to presentation to the hospital was 3 days. Poor feeding and loss of appetite accounted for 76.7% of the admissions. Symptoms of vomiting were present in 37.2% of the cases. Oral ulcers were found in 96.1%, rashes over hands in 87.6%, over feet in 86.8% and over buttocks in 54.3%. Only 4.7% exhibited no rashes other than oral ulcers and were labelled as herpangina. The median duration of fever was 3 days, ranging from 2 to 7 days. An intravenous drip was required in 68.2% due to poor feeding. Viral cultures were sent in 89.1% of patients of whom 61.7% of patients were positive for viruses. Of the positive cultures, types of viruses isolated were EV71 (enterovirus 71) in 59/71 (83%), Coxsackievirus (A16, A24, A2 B3, B4) in 6/71 (8.4%), EV Untypable in 4/71 (5.6%) and mixed [EV71, echo25, cytomegalovirus (CMV)] in 2/71 (2.8%). EV71 was isolated mostly from stool samples followed by vesicle fluid culture and throat swabs. Two siblings aged 14 months and 2.5 years died during this period at day 5 of illness, their post-mortem examinations showed interstitial pneumonitis of the lungs. EV71 was isolated from the brain, heart, tonsils, intestines, throat and rectal swabs. A raised total white cell count of 14,000/L versus 12,000/L was significantly associated with complicated HFMD (P = 0.04). There was no difference in clinical characteristics of EV71 versus non-EV71 infections. Other viral illnesses, e.g. measles and CMV, may be mistaken for HFMD in the outbreak setting. CONCLUSIONS: HFMD tends to occur in younger children less than 5 years old due to low herd immunity. Poor feeding due to mouth ulcers accounts for admission to hospital requiring intravenous drip. EV71 accounted for the majority (75%) of the positive isolations, followed by coxsackievirus and untypable EV, mixed infection of echovirus or CMV. The yield of virus isolation was highest from stool, followed by vesicles and throat swabs. There is no difference in clinical characteristics of EV71 and non-EV71 virus infections. Enterovirus can cause mild symptoms to fatal death. Two infants died of interstitial pneumonitis and encephalitis.

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.

MRI of Enterovirus 71 myelitis with monoplegia.

We report two boys diagnosed as having herpangina and hand-foot-mouth disease complicated by monoplegia during the outbreak enterovirus infection in Taiwan in 1998. Enterovirus 71 was identified in the stool and throat swab; neither polio nor Coxsackie viruses was identified. MRI showed unilateral lesions in the anterior horns of the spinal cord at T11-12 and C2-5. Although the MRI findings and sites of these lesions were similar to those of poliovirus-associated poliomyelitis, the virological data indicated that these boys were infected with enterovirus type 71.

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.