Reflecting on the 1998 enterovirus outbreak: A 25-year retrospective and learned lessons.

Enterovirus A71 (EV-A71) infections pose a significant public health concern in the Asia-Pacific region. EV-A71 is primarily responsible for causing hand, foot, and mouth disease (HFMD) in children. However, this virus can also lead to severe and potentially fatal neurological consequences in affected individuals. This review aims to provide a comprehensive understanding of the molecular virology, epidemiology, and recombination events associated with EV-A71. The literature extensively covers the clinical manifestations and neurological symptoms that accompany EV-A71 infections. One of the complications explored in this review is brainstem encephalitis, which can arise as a result of EV-A71 infections. Brainstem encephalitis refers to inflammation of the brainstem, a critical region responsible for various bodily functions. The review examines the underlying mechanisms, diagnostic criteria, treatment options, and prognosis for central nervous system infections involving EV-A71. Neurological complications associated with EV-A71 infections are diverse and can have severe consequences. These complications may include aseptic meningitis, acute flaccid paralysis, and acute transverse myelitis. The review delves into the pathophysiology of these complications, shedding light on the molecular mechanisms through which EV-A71 affects the central nervous system. Accurate diagnosis of EV-A71 infections is crucial for appropriate management and treatment. Treatment options for EV-A71 infections primarily focus on supportive care, as there are currently no specific antiviral drugs available for this virus. The review highlights the importance of managing symptoms, such as fever, dehydration, and pain relief, to alleviate the burden on affected individuals. Prognosis for individuals with central nervous system (CNS) infections involving EV-A71 can vary depending on the severity of the complications. The review provides insights into the long-term outcomes and potential neurological sequelae associated with EV-A71 infections. In conclusion, EV-A71 infections have emerged as a major public health concern in the Asia-Pacific region. This review aims to enhance our understanding of the molecular virology, epidemiology, and neurological complications associated with EV-A71. By examining the underlying mechanisms, diagnostic criteria, treatment options, and prognosis, this review contributes to the development of effective strategies for the prevention, diagnosis, and management of EV-A71 infections. The paper presents a comprehensive analysis of worldwide data pertaining to outbreaks of EV-A71 and HFMD. The subsequent discourse delves into the advancement and strategic formulation pertaining to the creation of vaccines targeting EV-A71. In summary, this study provides a comprehensive examination of the potential obstacles and considerations involved in the management and treatment of EV-A71 infections. Additionally, it proposes suggestions for future research and development endeavors with the objective of formulating efficacious treatment approaches for this viral infection.

Clinical characteristics of echovirus 11 and coxsackievirus B5 infections in Taiwanese children requiring hospitalization.

BACKGROUND: Severe illness can occur in young children infected with certain types of enteroviruses including echovirus 11 (Echo11) and coxsackievirus B5 (CoxB5). The manifestations and outcomes of Echo11 and CoxB5 diseases across all ages of children remained not comprehensively characterized in Taiwan. METHODS: Culture-confirmed Echo11 (60 patients) or CoxB5 (65 patients) infections were identified in a hospital from 2010 to 2018. The demographics, clinical presentations, laboratory data and outcomes were abstracted and compared between the two viruses infections. RESULTS: Echo11 and CoxB5 was respectively identified in 7 (77.8%) and 2 (22.2%) of 9 calendar years. The median age of all patients was 15 months (range, 1 day-14.5 years). For infants ≤3 months old, Echo11 (23 cases) was associated with higher incidence of aseptic meningitis (35% versus 0%, P = 0.003), and a lower rate of upper respiratory tract infections (URI) (22% versus 65%, P = 0.004) compared to CoxB5 (20 cases) infections. For patients >3 months old, URI was the cardinal diagnosis (60%) for both viruses. Aseptic meningitis was also more commonly identified in elder children with Echo11 infections (27% versus 11%), though with marginal significance (P = 0.07). Acute liver failure was identified in four young infants with Echo11 infections including one neonate dying of severe sepsis and myocarditis. All patients with CoxB5 infections recovered uneventfully. CONCLUSION: Aseptic meningitis, sepsis-like illness and acute liver failure were more commonly identified in children with Echo11 than those with CoxB5 infections, suggesting greater neurological tropism and virulence toward Echo11.

Time-dependent associations between presentation-based infections and subsequent risk of childhood immune cell malignancies.

BACKGROUND: Infection is hypothesised as a contributory cause of childhood immune cell malignancies. Although some have reported associations between individual infections and immune cell malignancies, some could be spurious due to infections caused by malignancies that were already active prior to diagnosis. METHODS: Identified from Taiwan Cancer Registry, ∼3000 children with four commonest immune cell malignancies diagnosed during 2001-2015 at age 1-20 years were identified and matched with 1:10 controls. Using logistic regression, we estimated the time-specific case-versus-control odds ratios of seven common infection presentations in their health records. We also compared recorded unexplained lymph nodes between cases and controls to explore for how long malignancy may be active prior to diagnosis. RESULTS: Unexplained lymph nodes were increasingly recorded months before the diagnosis of childhood leukaemias and years before the diagnosis of childhood lymphomas. When using p < 0.01 as a guide, large case-control differences in infection records were found mostly within 0-2 months prior to the diagnosis (15 out of 28 comparisons). Changes in odds ratios within 3-35 months (2 out of 28 comparisons) and case-control differences beyond 36+ months prior to diagnosis (7 out of 28 comparisons) was relatively small (∼10 % difference in leukaemias). Statistical power varied according to incidence of malignancy, incidence of infection records, and the age distribution. CONCLUSION: Immune cell malignancies were likely to be active some time before the diagnosis. Previous studies using conventional population-based methods may not be able to distinguish any small causal link between infection and immune cell malignancies from spurious associations.

Sex differences in common childhood infections in Taiwan.

Sex differences in childhood infections are commonly reported in case-only studies. In this population-based study of 278000 Taiwanese children followed from 3 months to 18 years of age during the period 2000-2012, age-trajectories of monthly numbers of all-cause healthcare visits and monthly rates of infection-specific healthcare visits were compared between boys and girls. For all-cause healthcare visits and for healthcare visits related to conjunctivitis, respiratory tract infections, enteritis, hand, foot, and mouth disease, and herpangina, there was good resemblance of age trajectories between boys and girls. Despite this resemblance, there was evidence of a slightly higher rate in boys than in girls under age 6 years (i.e., a male tendency, or male-to-female ratio >1.0) across all diagnoses except herpangina. For urinary tract infection, where an age-specific sex difference is well reported in case-only studies, this population-based study confirmed that there was a much higher rate of kidney infection among boys than among girls during infancy, and a higher rate of kidney and bladder infection among girls than among boys after this period. The age-specific sex difference in urinary tract infections was so strong that the age trajectories in boys and girls were qualitatively different. This report confirms previously reported sex differences in other countries, whilst placing this in the context of age dynamics in childhood infection.

Childhood cancer, type 1 diabetes and other immune diseases: healthcare visits in the year before diagnosis in Taiwan.

BACKGROUND: Children with cancer, type 1 diabetes and other immune diseases often present initially with non-specific problems. It is unknown how long children with these conditions seek medical help before a diagnosis is reached. METHODS: During the period 2002 to 2013, 7238 children aged 2-15 years diagnosed with cancer at seven sites, type 1 diabetes, and three other immune diseases were registered in the Taiwan National Health Insurance Catastrophic Illness Database. Their healthcare visit records in the year before diagnosis were extracted and compared to the records of matched controls during comparable periods using mixed-effect models. RESULTS: Except for diabetes, there were substantial increases in healthcare visit rates in the last few months before a diagnosis of cancer or immune conditions, suggesting that some children had been seeking medical help and it had taken months to achieve a diagnosis. Many recorded presentations during this time were consistent with typical manifestations of the underlying condition, such as increasing apparent injuries before the diagnosis of bone cancer (6.6-fold increase in the most recent 4 months, 95% CI 4.9 to 9.0). Comparatively, healthcare visits in the year before the diagnosis of diabetes were less common, but at the time of diagnosis 64% (1504/2335) of children presented with diabetes ketoacidosis. CONCLUSIONS: Many children with cancer or immune diseases, even with typical presentations, required a period of time for the diagnosis to be confirmed. By contrast, children with type 1 diabetes typically did not visit a doctor until ketoacidosis had occurred.

Seroprevalence of Herpes Simplex Virus Type 1 and 2 in Taiwan and Risk Factor Analysis, 2007.

BACKGROUND: Herpes simplex virus type 1 (HSV-1) and 2 (HSV-2) are common human pathogens and might cause severe illness. Following primary infection, the viruses establish lifelong latent infection and are transmitted by close contact, both sexual and nonsexual. However, the information about the seroprevalence of HSV-1 and HSV-2 across all age groups is limited. METHODS: Residual sera collected during the nationwide serosurvey in 2007 in Taiwan were selected for the study. The enzyme-linked immunosorbent assay was used to detect anti-HSV-1 and anti-HSV-2 type-specific glycoprotein IgG. Demographics and personal health data were used for risk analysis. RESULTS: A total of 1411 and 1072 serum samples were included for anti-HSV-1 and anti-HSV-2 seroprevalence analysis, respectively. The weighted overall seroprevalence was 63.2% for HSV-1, and 7.7% for HSV-2, respectively. The HSV-1 seropositive rate was 19.2% for those less than 5 years old, increased to 46.4% for those aged 5-13 years, 60.9% for those aged 14-29 years, and reached as much as 95.0% for those aged over 30 years. In contrast, the HSV-2 seropositve rate was 1.6% for those less than 30 years old, rose to 10.1% for those age 30-39 years, and was up to 31.2% for those aged over 60 years. A significantly higher HSV-2 seropositive rate was noted in females than males aged over 40 years (26.3% v.s. 16.8%), and the overall HSV-2 seropositive rate was almost twice higher in females than males. Smoking history, drinking habit, and educational level were associated with the HSV-1 seropositivity. Female gender and rural residence were independent factors for the HSV-2 seropositivity. CONCLUSIONS: An obvious increase of primary HSV-1 infection occurred in late adolescents and young adults, joined by the rise of HSV-2 infection in middle-aged adults, especially females. The acquistion and transmission of HSV warrant further studies in the susceptible population.

A Potent Virus-Specific Antibody-Secreting Cell Response to Acute Enterovirus 71 Infection in Children.

BACKGROUND: Enterovirus 71 (EV71) remains a leading pathogen for acute infectious diseases in children, especially in Asia. The cellular basis for establishing a virus-specific antibody response to acute EV71 infections is unclear in children. METHODS: We studied the magnitude of virus-specific antibody-secreting B cells (ASCs) and its relationship with serological response, clinical parameters, and virological parameters among children with laboratory-confirmed EV71 infection. RESULTS: A potent EV71 genogroup B- and virus-specific ASC response was detected in the first week of illness among genotype B5 EV71-infected children. The cross-reactive EV71-specific ASC response to genogroup C viral antigens composed about 10% of the response. The EV71-specific ASC response in children aged ≥3 years produced immunoglobulin G predominantly, but immunoglobulin M was predominant in younger children. Proliferation marker was expressed by the majority of circulating ASCs in the acute phase of EV71 infection. Virus-specific ASC responses significantly correlated with throat viral load, fever duration, and serological genogroup-specific neutralization titer. CONCLUSIONS: The presence of a virus-specific ASC response serves an early cellular marker of an EV71-specific antibody response. Further detailed study of EV71-specific ASCs at the monoclonal level is crucial to delineate the specificity and function of antibody immunity in children.

Virus-specific antibody secreting cell, memory B-cell, and sero-antibody responses in the human influenza challenge model.

BACKGROUND: Antibodies play a major role in the protection against influenza virus in human. However, the antibody level is usually short-lived and the cellular mechanisms underlying influenza virus-specific antibody response to acute infection remain unclear. METHODS: We studied the kinetics and magnitude of influenza virus-specific B-cell and serum antibody responses in relation to virus replication during the course of influenza infection in healthy adult volunteers who were previously seronegative and experimentally infected with seasonal influenza H1N1 A/Brisbane/59/07 virus. RESULTS: Our data demonstrated a robust expansion of the virus-specific antibody-secreting cells (ASCs) and memory B cells in the peripheral blood, which correlated with both the throat viral load and the duration of viral shedding. The ASC response was obviously detected on day 7 post-infection when the virus was completely cleared from nasal samples, and serum hemagglutination-inhibition antibodies were still undetectable. On day 28 postinfection, influenza virus-specific B cells were further identified from the circulating compartment of isotype-switched B cells. CONCLUSIONS: Virus-specific ASCs could be the earliest marker of B-cell response to a new flu virus infection, such as H7N9 in humans.

Bedside immunochromatographic test for enterovirus 71 infection in children.

BACKGROUND: Enterovirus 71 (EV71) causes frequent outbreaks worldwide, particularly in the Asia-Pacific area. Its quick spread is a critical challenge for public health and timely preventive measures and clinical management therefore rely on early detection. There is a need for a rapid, easy-to-use, and reliable method for detecting EV71 infections. OBJECTIVE: The study aimed to evaluate a bedside immunochromatography (ICT) kit for diagnosing acute EV71 infection in children. STUDY DESIGN: Pediatric patients with herpangina or hand-foot-mouth disease were randomly and prospectively enrolled from hospitals across Taiwan. Throat or rectal swabs were collected for viral culture and reverse-transcriptase polymerase chain reaction (RTPCR). For the ICT kit, whole blood was obtained by ear piercing, finger-sticking, or venipuncture. The results of ICT, virus isolation and RTPCR in clinical samples were compared. RESULTS: Of the 156 patients enrolled, 91 (58%), 64 (41%) and 72 (46%) had positive results of the ICT kit, viral culture and RTPCR, respectively. Laboratory-confirmed infection with either positive EV71 culture or RTPCR was used as the diagnostic standard. The sensitivity and specificity of the ICT kit was 84% and 77%, respectively. The viral culture and RTPCR had relatively lower sensitivity but higher specificity. The patient's age did not affect the performance of the ICT, viral culture and RTPCR. However, a low sensitivity of ICT kit was noted before the second day of disease onset. CONCLUSIONS: The ICT kit may serve as a simple, quick and reliable method for the bedside diagnosis of acute EV71 infection in children.