Enterovirus Infections In Children Research Articles

Features of the etiological structure of non-polio enterovirus infection in children in the pre-pandemic and post-pandemic periods

BACKGROUND: Regional features of the etiological structure of nonpolio enterovirus infection (NPEVI) in children in the pre- and post-pandemic periods must be registered.
 AIM: To determine the features of the etiological structure of NPEVI in children in the pre- and post-pandemic periods in the KhantyMansiysk Autonomous Okrug.
 MATERIALS AND METHODS: Statistical observation data for 20132022 and results of molecular genetic studies of the structure of NPEVI in children in the pre- and post-pandemic periods were analyzed.
 RESULTS: The tendency of the incidence of NPEVI in the KhantyMansiysk Autonomous Okrug to increase in the pre-COVID-19 pandemic and a predominance of children aged 6 years has been established. In the study period up to 2019 (pre-pandemic), enteroviruses Coxsackie A6 in combination with E A71 were dominant, for which the calculated trends of the short-term forecast were confirmed in 2022. In the same year, these enteroviruses were the most common causes of focal diseases with exanthemic forms of NPEVI. In 2022, the circulation of eight more enteroviruses genovariants was recorded, among which Coxsackie A10 EV prevailed (20.5% of cases), which caused the majority of enterovirus vesicular pharyngitis cases. Enterovirus meningitis was registered in 5 (11.4%) children with the release of ECHO 6, ECHO 9, and Coxsackie A9, which were not noted in other clinical forms and circulated irregularly and in smaller numbers during the pre-pandemic period than in post-pandemic period (2022).
 CONCLUSIONS: The analysis of the monitoring data of the NPEVI in KhantyMansiysk Autonomous Okrug revealed a trend of a gradual increase in incidence in children, which must be considered when organizing epidemiological surveillance of NPEVI. The completeness of the registration of NPEVI cases with mandatory genotyping of the detected enterovirus strains will allow to more accurately determine the spectrum of strains endemic to this territory, assess the probability of their spread, forecast about the true level of morbidity, and conduct appropriate scientifically based antiepidemic and preventive measures among children with NPEVI in KhantyMansiysk Autonomous Okrug.

Effectiveness of case isolation and class suspension in mitigation of enterovirus transmission in children

BackgroundAppropriate mitigation strategy to minimize enterovirus (EV) transmission among children is essential to control severe EV epidemics. Scientific evidence for the effectiveness of case isolation and class suspension is lacking. MethodsEV-infected children ≤ eight years are asked to stay at home for seven days. Classes were suspended for seven days if there are more than two classmates having an onset of herpangina or hand, foot, and mouth disease in one classroom within one week. Study subjects are divided into two groups, group A with class suspension for one week and group B without class suspension. ResultsAmong 4153 reported EV-infected children from 1085 classes in May and June, 2015 were enrolled. Median incidence of EV infection in a class was 7% (range 3% −60%). The incidence was higher in group A (median 14%, range 3–60%) than that in group B (median 6%, range 3–80%) (P < 0.01). The median incidence is highest in day care center (20%), followed by kindergarten (8%), and primary school (4%) (P < 0.01). Most secondary cases in group A appeared within seven days after the disease onset of index case in the same class. The incidence of EV infection remained low and was similar between the two groups eight days and beyond after the disease onset of index cases. ConclusionsTargeted class suspension for seven days with case isolation for seven days is an effective measure to mitigate transmission of EV infection in children.

Non-polio enterovirus infections in children with central nervous system disorders in Shanghai, 2016-2018: Serotypes and clinical characteristics.

Non-polio enrerovirus causes a wide spectrum of neurologic syndromes. The epidemiological and clinical profiles of non-polio enrerovirus-associated central nervous system infections vary by regions and over year. This study aimed to understand the prevalence, serotypes and clinical characteristics of enterovirus-associated aseptic meningitis, encephalitis and meningo-encephalitis in children in Shanghai during 2016-2018. We collected the clinical data and the cerebrospinal fluid specimens from the pediatric patients with aseptic meningitis, encephalitis and meningo-encephalitis during 2016-2018. The nested RT-PCR and sequencing were performed to identify enterovirus and serotypes. A total of 424 patients were included in this study and their non-duplicated cerebrospinal fluid specimens were collected during the acute stage of illness. Based on PCR assay, enterovirus was detected in 272 (64.15 %) patients, of whom, the ratio of male to female subjects was 1.99, and the mean age was 5.71 ± 3.55 years (range: 0.03-16 years). There were 17 serotypes identified. Echovirus 30 (24.63 %), Coxsackievirus A10 (20.96 %), Coxsackievirus A6 (18.01 %) accounted for 63.6 %, followed by Coxsackievirus B5 (7.72 %), Echovirus 6 (5.88 %), and other serotypes (22.8 %). Of the 10 (3.68 %) critically severe patients, all had refractory seizure, 8 required mechanical ventilation, 7 survivors had recurrent attacks of epilepsy and 3 abandoned treatment; Coxsackievirus A10, Echovirus 9, Coxsackievirus A2, Coxsackievirus A6 and Echovirus 6 were identified. Non-polio enterovirus is the major pathogen causing aseptic meningitis, encephalitis and meningo-encephalitis in Chinese children and can cause life-threatening encephalitis and severe sequelae.

Prospective research of human parechovirus and cytokines in cerebrospinal fluid of young children less than one year with sepsis-like illness: Comparison with enterovirus

BackgroundHuman parechovirus (PeV) and enterovirus are important pathogens that cause viral infection and aseptic meningitis in young children. We aimed to investigate the rate of HPeV and enterovirus detection, and to characterize cytokine profiles in the cerebrospinal fluid (CSF) of young infants with sepsis-like illness or meningitis/encephalitis. Study designThis was a prospective cohort study. CSF samples were collected from 90 infants less than 1 year of age. PeV and enterovirus detection was performed using reverse transcription polymerase chain reaction. Fifteen cytokines in the CSF were measured simultaneously by using multiplex immunoassays. ResultsPeV (PeV-group) and enterovirus (EV-group) were detected in 10 (11.1%) and 12 (13.3%) CSF samples, respectively. Other aseptic meningitis (AM-group) was diagnosed in 22 (24.4%) patients. Forty-six (51.1%) patients exhibited non-central nervous system infection (Ngroup). The PeV-group had the lowest CSF leukocyte (2.1 ± 3.5/mm3, p=0.022) and blood leukocyte (7,953 ± 4,583/mm3, p=0.046) count and Creactive protein levels (0.2 ± 0.1 mg/dL, p=0.036), than did those in the EV- and AM-groups. CSF leukocyte count and protein levels were not significantly different between the PeV- and N-groups. The levels of interleukin (IL)-1β, IL-5, IL-6, IL-12, and IL-17 were higher in the EVgroup; conversely, IL-2, IL-4, IL-7, and IL-13 were higher in the PeVgroup. ConclusionsExaminations to detect PeV in the CSF may help identify the etiological basis of undiagnosed febrile illness in young children. Significant differences in CSF and blood laboratory findings were observed between PeV- and enterovirus-infected children.

Characterization of lymphocyte subsets in peripheral blood cells of children with EV71 infection.

Enterovirus 71 (EV71) is one of the major causative pathogens of hand, foot, and mouth disease (HFMD). Immune cells play a critical role in determining the outcomes of virus infection. We aimed to characterize the lymphocyte subsets and transcriptional levels of T lymphocytes-associated transcription factors in peripheral blood cells of children with EV71 infection. Peripheral blood samples from 32 children with EV71 infection and 32 control subjects were included in this study. The frequencies of T-, B-lymphocytes, and their subsets were determined by flow cytometry. The expression of transcription factors, including T-bet, Gata3, ROR γ t, Foxp3, TCF-1, and BCL-6 in the whole blood cells were evaluated by real-time reverse-transcription quantitative polymerase chain reaction (RT-qPCR). The frequencies of T cells, helper T cells (Th), cytotoxic T cells (Tc), IFN-γ+ Th1, IFN-γ+ Tc1, and regulatory T (Treg) cells were significantly decreased (P<0.01) in children with EV71 infection. As for IL-4+ Th2, IL-4+ Tc2, IL-17+ Th17, IL-17+ Tc17, follicular helper T cells (Tfh), CD3+CD8+IL-21+ T cells, CD19+ B cells, and CD19+IL-10+ B10cells, their frequencies were significantly increased in the EV71 group (P<0.01). The EV71 group had lower mRNA expressions of T-bet, Gata3, and Foxp3 than the control group (P<0.05), whereas the expressions of ROR γ t, TCF-1, and BCL-6 showed no significant difference between two groups. EV71 infection in children caused a decreased frequency of total Th, Tc and Treg cells, and increased percentages of B cell, Th2 and Th17cells in blood.

Клинико-эпидемиологические особенности энтеровирусной инфекции у детей в Саратовской области

Клинико-эпидемиологические особенности энтеровирусной инфекции у детей в Саратовской области

Enterovirus Infection and Subsequent Risk of Kawasaki Disease: A Population-based Cohort Study.

The relationship of enterovirus (EV) infection and Kawasaki disease (KD) is still unclear. The purpose of this study was to conduct a population-based cohort study to determine the relationship between KD and EV infection in Taiwan. A population-based cohort study was conducted to analyze the children file (age < 18 years) of the Taiwan National Health Insurance program between 2000 and 2008. In total, 285,636 children with EV infection and 285,636 children without EV infection were included and followed up. The subsequent KD was the major outcome event. The cumulative incidence of KD was significantly higher in the EV-infected cohort than in the non-EV-infected cohort (log-rank test, P < 0.001). The overall incidence of KD was 56% higher in the EV-infected cohort than in the non-EV-infected cohort, with an adjusted hazard ratio of 1.56 (95% confidence interval: 1.44-1.69). Stratified analysis showed higher KD risk associated with previous EV infection in children 3-5 years old, in girls, in children living in less urbanization levels, in children with parental low-income occupation, and in children with allergic diseases. There is a higher association between KD and previous EV infection in Taiwanese children, especially in those 3-5 years old, with female sex, with less urbanization level, with low-income parental occupation, and with allergy.

Клинико-эпидемиологические особенности энтеровирусной инфекции у детей в весенне‑летнем сезоне 2017 года в Кабардино-Балкарской Республике

Клинико-эпидемиологические особенности энтеровирусной инфекции у детей в весенне‑летнем сезоне 2017 года в Кабардино-Балкарской Республике

Increased Risk of Tics in Children Infected with Enterovirus: A Nationwide Population-Based Study.

Both tics and enterovirus (EV) infections are common in children. The association between EV infections and tics has been seldom evaluated. The aim of this study was to evaluate the risk of diagnosed tics after EV infections in children. A nationwide retrospective cohort study was conducted to determine the risk of tics after EV infections by analyzing data from the National Health Insurance Research Database in Taiwan. Children aged < 18 years with EV infection during 2000 to 2007 were enrolled. For comparison, non-EV-infected children were randomly selected and matched with EV-infected children at a 1:1 ratio according to sex, age, urbanization level, parental occupation, and the year of EV infection. All patients were followed up until the diagnosis of tics, death, loss to follow-up, withdrawal from the insurance system, or December 31, 2008. A total of 282,321 EV-infected and 282,317 non-EV-infected children were included in this study. The mean age was 2.39 years in both cohorts. The overall incidences of tics were 9.12 and 6.21 per 10,000 person-years in the EV-infected and non-EV-infected cohorts, respectively. Children with EV infection were significantly associated with an increased risk of tics compared with those without EV infection (adjusted hazard ratio, 1.38; 95% confidence interval, 1.27-1.5). Multivariable analyses showed that boys, children living in urbanized areas, children whose parents had white-collar jobs, and children with allergic rhinitis or bronchial asthma exhibited a significantly increased risk of tics. This study revealed an increased risk of tics after EV infection in children.

Human enteroviruses in cerebrospinal fluid of children with suspected aseptic meningitis: A study in northern Iran.

Background:Enterovirus (EV) infections are one of the most common causes of aseptic meningitis in pediatrics. To diagnose EV meningitis, virus isolation in cell cultures is often time consuming and lacks sensitivity to be of clinical relevance. This makes the virus culture results difficult to interpret. The rapid detection of EVs in cerebrospinal fluid (CSF) by molecular diagnostic techniques may improve the management of patients with aseptic meningitis. The purpose of the present study was to develop a more convenient and sensitive alternative technique to viral culture. The current investigation aimed to explore the prevalence of EVs in CSF of children with suspected aseptic meningitis in northern Iran, between June 2014 and March 2015 via the one-step real-time RT-PCR technique.Methods:A single center cross-sectional study was carried out on 50 children suspected with aseptic meningitis, aged 6 months to 13 years. The presence of EV RNA in CSF samples was screened by the use of qualitative one-step real-time RT-PCR.Results:Enteroviral RNA was detected in 9 (18%) subjects using the one-step real-time RT-PCR assay. There was significant difference between EV positive and negative subjects regarding mean age (P=0.023), mean lymphocyte percentage (P=0.001) and mean glucose levels in CSF (P=0.037). The disease onset data indicate that the majority of EV meningitis occurred in the summer.Conclusion:This study provides the first data on the prevalence and epidemiology of EV infections in children with suspected aseptic meningitis in northern Iran.

Эффективность противовирусной терапии при комбинированных формах энтеровирусной инфекции у детей

Эффективность противовирусной терапии при комбинированных формах энтеровирусной инфекции у детей

Galectin-3 and Its Genetic Variation rs4644 Modulate Enterovirus 71 Infection.

Galectin-3, a chimeric type β-galactoside-binding protein, is known to modulate viral infection; however, its role in enterovirus 71 (EV71) infection has not been investigated. We generated galectin-3 null rhabdomyosarcoma (RD) cells and evaluated whether EV71 infection would be affected. In galectin-3 null cells, the released and intracellular EV71 viral loads were suppressed after 24 h of infection, and cell death rates were significantly lower, while cell proliferation remained unaltered. In addition, RD cells expressing a nonsynonymous genetic variant of galectin-3, rs4644 (LGALS3 +191C/A, P64H), produced lower virus titers than those with wild-type galectin-3 (C allele). To clarify whether the in vitro viral load reduction correlates with clinical severity, we enrolled children with laboratory-confirmed EV71 infection. Since hyperglycemia is an indicator of severe EV71 infection in children, 152 of 401 enrolled children had glucose examinations at admission, and 59 subjects had serum glucose levels ≥ 150 mg/dL. In comparison to the rs4644 AA genotype (2.2 ± 0.06 log10 mg/dL), serum glucose levels during EV71 infection were higher in patients with CC (2.4 ± 0.17 log10 mg/dL, p = 0.03) and CA (2.4 ± 0.15 log10 mg/dL, p = 0.02) genotypes, respectively. These findings suggest that the rs4644 AA genotype of galectin-3 might exert a protective effect. In summary, galectin-3 affects EV71 replication in our cellular model and its variant, rs4644, is associated with hyperglycemia in the clinical setting. The underlying mechanism and its potential therapeutic application warrant further investigation.

Ambulatory Pediatric Surveillance of Hand, Foot and Mouth Disease as Signal of an Outbreak of Coxsackievirus A6 Infections, France, 2014-2015.

The clinical impact of enteroviruses associated with hand, foot and mouth disease (HFMD) is unknown outside Asia, and the prevalence of enterovirus A71 (EV-A71) in particular might be underestimated. To investigate the prevalence of enterovirus serotypes and the clinical presentations associated with HFMD in France, we conducted prospective ambulatory clinic-based surveillance of children during April 2014-March 2015. Throat or buccal swabs were collected from children with HFMD and tested for the enterovirus genome. Physical examinations were recorded on a standardized form. An enterovirus infection was detected in 523 (79.3%) of 659 children tested. Two epidemic waves occurred, dominated by coxsackievirus (CV) A6, which was detected in 53.9% of enterovirus-infected children. CV-A6 was more frequently related to atypical HFMD manifestations (eruptions extended to limbs and face). Early awareness and documentation of HFMD outbreaks can be achieved by syndromic surveillance of HFMD by ambulatory pediatricians and rapid enterovirus testing and genotyping.

Risk of Nephrotic Syndrome following Enteroviral Infection in Children: A Nationwide Retrospective Cohort Study.

PurposeNephrotic syndrome is a common chronic illness encountered during childhood. Infections have been identified as a cause of nephrotic syndrome. The aim of this study was to evaluate the association between enteroviral infection and nephrotic syndrome.MethodsA nationwide retrospective cohort study was conducted by analyzing data from the National Health Insurance Research Database in Taiwan. Children aged <18 years with enteroviral infection were enrolled. Non-enterovirus-infected children were randomly selected as the comparison cohort. The primary endpoint was the occurrence of nephrotic syndrome.MethodsThis study included 280,087 enterovirus-infected children and 280,085 non-enterovirus-infected children. The mean age of the enterovirus-infected children was 2.38 years, and 53.7% of these children were boys. The overall incidence densities of nephrotic syndrome for enterovirus- and non-enterovirus-infected children were 2.65 and 2.21 per 10,000 person-years, respectively. The enterovirus-infected cohort had a higher cumulative incidence of nephrotic syndrome than did the non-enterovirus-infected cohort (log-rank test, p = 0.01). Multivariable analyses revealed that children with enteroviral infection were significantly associated with an increased risk of nephrotic syndrome compared with those without enteroviral infection (adjusted hazard ratio, 1.20; 95% confidence interval, 1.04–1.39; p = 0.01), particularly in children infected with coxsackievirus. Subgroup analyses revealed that enterovirus-infected girls, children of blue-collar workers, and children without allergies had a higher risk of nephrotic syndrome than did children in the non-enterovirus-infected cohort.ConclusionThis study revealed a significant association between enteroviral infection and nephrotic syndrome. Additional studies elucidating the role and pathogenesis of enterovirus in nephrotic syndrome are warranted.

Severe Enterovirus Infections in Hospitalized Children in the South of England: Clinical Phenotypes and Causative Genotypes.

Background:Most enterovirus surveillance studies lack detailed clinical data, which limits their clinical usefulness. This study aimed to describe the clinical spectrum and outcome of severe enterovirus infections in children, and to determine whether there are associations between causative enterovirus genotypes and clinical phenotypes.Methods:Retrospective analysis of microbiological and clinical data from a tertiary children’s hospital in the South of England over a 17-month period (2012–2013).Results:In total, 30 patients were identified, comprising sepsis (n = 9), myocarditis (n = 8), meningitis (n = 8) and encephalitis (n = 5). Cases with sepsis or myocarditis were significantly younger than those with central nervous system disease (median age 21 and 15 days vs. 79 days; P = 0.0244 and P = 0.0310, respectively). There was considerable diversity in the causative genotypes in each of the clinical phenotypes, with some predominance of echoviruses in the meningitis group, and coxsackie B viruses in the myocarditis group. Thirteen cases required mechanical ventilation, 11 cases inotropic support, 3 cases dialysis and 3 cases extracorporal membrane oxygenation. The overall mortality was 10% (sepsis group, n = 1; myocarditis group, n = 2). Of the survivors, 5 (19%) had long-term sequelae (myocardial dysfunction, n = 2; neurological sequelae, n = 3). Patients with encephalitis had the longest hospital stay (median: 16 days), compared with 9, 6 and 3 days in patients with myocarditis, sepsis and meningitis, respectively (P = 0.005).Conclusions:Enterovirus infections, particularly enteroviral myocarditis and encephalitis, can cause significant morbidity and mortality. The results show that there are currently no strong associations between clinical phenotypes and particular causative enterovirus genotypes in the South of England.

Peculiarities of enterovirus infection in children in Lviv region in 2015 year

Introduction. Enterovirus diseases occupy the one of the main places among the viral infections in Ukraine and beyond it. More than half of all diseases with tremens in children are caused by enteroviruses.Grounding of research. The significant prevalence of enteroviruses, their high durability in the external environment, absence of the specific prophylaxis and also the cases of virus spread after the end of disease are the cause of both sporadic and mass diseases, result in the growth of their number caused by the wide spectrum of enteroviruses (Kockaki ЕСНО viruses) and development of the different clinical forms – from asymptomatic and catarrhal ones to the forms with the heavy injuries of the nervous system and internal organs. The most patients are children.Aim. To analyze the epidemiological and clinical features of enterovirus infection in children of the different age groups according to the results of retrospective studies.Materials and methods. There were analyzed 305 medical records of stationary sick children 1 month – 18 years old (mean age– 64,31 month (95% EI:51,78 – 60,75), who were treated in MI LRC “LRICH”from 01.01.2015to 31.12.2015 for enterovirus infection (EI), reports of sanitary-epidemiological institution of the Lviv region for this period.Results of research. During the year on the stationary treatment were patients with the different clinic forms of EI. There was observed the distinct summer-autumn seasonality of EI with the reliably higher morbidity index in August– 26 persons (38,23±5,8%), September – 16 (38,09±12,1%), October – 43 (78,18±5,5%). Patients without the injury of brain cortex dominated - 195 persons (63,93±2,7%), serous meningitis developed in 110 children (36,07±2,7%). It was detected that in 19,09% of cases the serous meningitis was caused by ЕСНО-30 and Kokcaki- V. I. viruses. ЕІ was registered more frequently in children of 1-4 years old (112 patients 36,72±2,7%), among which prevailed patients with herpangina - 96 patients (85,71±3,3%). There was established the negative correlation between the cases of herpangina and the age of patients (r= - 0,57 (р&lt;0,05). Between the frequency of the serous meningitis and age of child – the reliable positive correlation (r=0,602, p=0,0001). Conclusions:1. Among the patients hospitalized at LRICH during 2015 the most frequent cases of EI were diagnosed in children of 1-4 years old, most patients had herpangina 96 (85,71±3,3%), among them in 10 (8,933,1%) herpangina was combined with exanthema, meningitis was detected in 9 patients (8,0±2,5%).2. The number of cases of serous meningitis grows with the age of child that is proved with the reliable positive correlation (r=0,602, p=0,0001).3. There was established the distinct summer-autumn seasonality of both EI (the most patients were detected in August - 68 (22,29±2,3%), October - 55 (18,03±2,2%), September - 42 (13,77±2,0%) and serous meningitis (in August - 26 (23,63±4,0%), in September - 16 (14,54±3,4%), in October - 43 (39 03±4,6%).4. The spinal puncture, general and virological studies of CSF in the season of higher EI morbidity level is the necessary component of diagnostics of the serous meningitis even at the absence of meningeal symptoms

Prospective assessment of clinical symptoms associated with enterovirus and parechovirus genotypes in a multicenter study in Dutch children

BackgroundHuman non-polio enterovirus (EV) and human parechovirus (HPeV) are important pathogens of viral infection and aseptic meningitis in children. The aim of this study is to prospectively compare the incidence, clinical signs, blood and cerebrospinal fluid in EV and HPeV infected children. ObjectivesTo compare the clinical symptoms and laboratory data of children with different EV and HPeV genotypes. Study designThis study is part of a multicenter prospective cohort study. Children were included in 3 different hospitals in The Netherlands from 2008 to 2011. ResultsOf 285 included patients, 140 (49%) had EV and 44 (15%) HPeV infection. Of children with EV infection 9 (6%) had EV-A, 109 (78%) EV-B, 12 (9%) had a non-type able EV and in 10 (7%) no genotyping was performed. Of children with HPeV infection, 24 (55%) had HPeV-3, 6 (14%) HPeV-1, 2 (5%) HPeV-4 and 1 (2%) HPeV-6. Meningitis was more frequent in EV than in HPeV infected children (54% vs. 36%, p=0.046), and in EV-B than EV-A infected children (60 vs. 33%). In contrast gastroenteritis was more frequent in HPeV than EV infected children (30% vs. 15%, p=0.030), and significantly more in HPeV-1 than HPeV-3 infected children (p<0.001). ConclusionsEV infection is more often associated with meningitis and HPeV infection more often with a gastro-enteritis. EV genotype B infection is more often associated with meningitis than EV genotype A infection. HPeV-1 infection was more often associated with gastroenteritis than HPeV-3 infection.

ENTEROVIRUS INFECTION IN CHILDREN: CLINICAL AND EPIDEMIOLOGICAL FEATURES AT THE CURRENT STAGE

The article presents the current clinical and epidemiological features of enterovirus infection in children of Krasnoyarsk Territory. A retrospective analysis of the incidence of enterovirus infection and enterovirus meningitis in the period 2014—2015 according to the forms of state statistical reporting №2 «Information on infectious and parasitic diseases». Clinical and epidemiological analysis of enterovirus infection in 454 children who were treated at MBUZ «City Children's Infectious Hospital №1» in the period of seasonal rise of morbidity in 2014 revealed a prevalence of etiological structure of enteroviruses Coxsackie B, Coxsackie B5, Coxsackie B3, Coxsackie B4. The region recorded the different clinical forms of enterovirus infection (rash, myalgia, diarrhea, gerpangina), the structure of which is still, aseptic meningitis prevails.

Risk of leukaemia in children infected with enterovirus: a nationwide, retrospective, population-based, Taiwanese-registry, cohort study

The association between enterovirus infections in children and risk of leukaemia is unclear. We aimed to assess the risk of leukaemia after enterovirus infection in children. We did a nationwide retrospective cohort study by analysing data from the National Health Insurance Research Database (NHIRD) in Taiwan. Children with enterovirus infections aged younger than 18 years were identified. With use of computer-generated random numbers, children not infected with enterovirus were randomly selected and frequency matched (1:1) with children infected with enterovirus by sex, age, urbanisation level, parental occupation, and index year of enterovirus infection. We only included children with complete baseline data for age and sex and who had at least three clinic visits with the diagnosis of enterovirus infection. The diagnosis date of the first clinic visit for the enterovirus infection was defined as the index date for initiation of follow-up person-year measurement and participants. All study patients were followed up until they developed leukaemia, were lost to follow-up, withdrew from the NHI programme, or until the end of the study without leukaemia (censored). Our primary endpoint was a diagnosis of leukaemia during follow-up. Insurance claims data for 3 054 336 children younger than 18 years were randomly selected from all insured children in the NHIRD. We identified 282 360 children infected with enterovirus and 282 355 children not infected with enterovirus between Jan 1, 2000, and Dec 31, 2007. The incidence density rates of leukaemia were 3·26 per 100 000 person-years for the enterovirus-infected and 5·84 per 100 000 person-years for the non-enterovirus-infected cohorts. The risk of leukaemia was significantly lower in the enterovirus-infected cohort than in the non-enterovirus-infected cohort (adjusted subhazard ratio [SHR] 0·44, 95% CI 0·31-0·60; p<0·0001). Children infected with enterovirus have a reduced risk of both lymphocytic leukaemia (adjusted SHR 0·44, 0·30-0·65; p<0·0001) and acute myeloid leukaemia (adjusted SHR 0·40, 0·17-0·97; p=0·04). Herpangina and hand-foot-and-mouth disease were the main diseases associated with the reduced risk of leukaemia. The association between enterovirus infection and the reduced risk of developing leukaemia supports Greaves' delayed infection hypothesis for the cause of childhood leukaemia.

Proteome demonstration of alpha-1-acid glycoprotein and alpha-1-antichymotrypsin candidate biomarkers for diagnosis of enterovirus 71 infection.

Human enterovirus 71 (EV71) is the major causative agents of hand-foot-and-mouth disease and frequently associated with severe complications such as encephalitis and death. Understanding the host response following enteroviral infection may facilitate the development of biomarkers for EV71 infections. We implemented two-dimensional gel electrophoresis technology on proteins prepared from serum obtained from 4 mild and 4 severe cases of EV71 infections and 4 healthy control children, to investigate the differentially expressed proteins. The differential expressed proteins were further identified with liquid chromatography-mass spectrometry/mass spectrometry analysis and western blotting validation. A total of 27 differentially expressed proteins were picked and identified with liquid chromatography-mass spectrometry/mass spectrometry. Of the 27 identified proteins, 6 proteins were up-regulated in the mild-infected and severe EV71-infected patients in comparison to the healthy control group. Two proteins, alpha-1-acid-glycoprotein (AGP1) and alpha-antichymotrypsin (AACT), were not detected in the EV71-infected patients, but appeared in the control patient. Western blotting analysis demonstrated that AGP1 and AACT proteins were negatively associated with the clinical severity of EV71 infection. Similarly, both of the proteins were not detected in the secretion medium from the EV71-infected neuroblastoma cells, but detected in the mock-infected cells, suggesting that differentially expressed AGP1/AACT protein levels are in response to EV71 infections. Two candidate proteins AGP1 and AACT, whose expression levels were reduced under the EV71 infection pathological condition, provide useful source of information for potential diagnostic biomarkers of EV71 infection in children.