Childhood Influenza In The Outpatient Setting In Shanghai, China

[Background]:Influenza is a highly contagious airborne disease caused by influenza virus. Influenza is one of the most common infectious diseases.Influenza spreads around the world in seasonal epidemics, resulting in5%-10%morbidity and the deaths of between250,000and500,000people every year worldwide based on the WHO estimation. The attack rates of influenza are highest among children and the risks for complications, hospitalizations and deaths from seasonal influenza are higher among young children aged <5years in the United States. Two long-term observational studies showed that the average annual seasonal incidence of influenza was4.6%in children aged0-19years and9.5%in children <5years. During the influenza seasons, the incidence of influenza among Finnish children<13years was12%-19%between2000and2002,10%-19%of medical office visits and6%-29%of emergency department visits were due to influenza among children aged <5years in the United States between2002and2004, and the attack rate of influenza was as high as30.7%among Italian children<14years during2008-2009influenza season. The pandemic A/H1N1originating from Mexico and the Unites States in April2009spread globally and caused the first influenza pandemic in the21st century. In terms of the early surveillance data from the Unites States,60%of confirmed cases were children and adolescent<18years of age during the initial stage of pandemic A/H1N1. These facts suggest that the outbreaks of seasonal and pandemic influenza have a significant impact on children. In addition to the high attack rates of influenza in children, the central role of children in the transmission of influenza in the community was well demonstrated during local outbreaks. The disease burden of seasonal influenza is substantial during the outbreaks, which results in the significant socioeconomic impact on the medical services, children and their families, including excess pediatric outpatient visits, physician visits, medications, school absence for sick children and their siblings, missed work days for parents. Childhood influenza has long received attention in the developed nations. The routine childhood vaccination against influenza would be expected to reduce influenza-related morbidity and mortality. Series of accumulating evidence for the substantial burden of influenza on children encourage the extensive vaccination against influenza among all children>6months in the North America and Europe.China CDC reported that70%-90%influenza-like illness (ILI) occurred in children<15years and the ILI-associated outpatient visits increased markedly in the peak season of influenza during2001to2003. This preliminary data suggested that children are the main population susceptible to influenza in China. However, the state of childhood influenza is far less understood in mainland China. Periodical excess pediatric outpatient visits for fever and acute respiratory infection were observed every year in Shanghai. The linkage between this phenomenon and influenza epidemics needs the medical attention, especially after the introduction of2009pandemic H1N1influenza virus into the local population in Shanghai, which is the biggest metropolitan city in China and has a high-dense and dynamic population. Attention to childhood influenza has a public health implication in Shanghai with a population of～2.5million children and adolescents younger than18years of age. Currently, public attitude towards influenza vaccination is reluctant since influenza vaccine hasn’t included in the free reimbursed category in China, and on the other hand, public knowledge about influenza and the benefit of influenza vaccination is limited. Hence, in-depth understanding of childhood influenza helps public health authority and medical personnel to formulate a reasonable influenza vaccination strategy and educate the public, which is quite important for guiding prevention and control efforts in childhood influenza in China.In this prospective surveillance study we investigated the epidemiological characteristics of influenza in outpatient children in Shanghai from June2009through May2011, aiming to understand the rates of influenza-related outpatient visits and the epidemic pattern of influenza among children with ILI at Children’s Hospital, Fudan University in Shanghai, which is the largest tertiary teaching hospital and services one third of local pediatric population.Part1Epidemic trend of influenza in children in ShanghaiObjective:To survey the seasonal pattern of influenza in children in Shanghai after the emergence of2009pandemic A/H1N1in China.Material and methods:We prospectively collected nasopharyngeal swab or throat swab samples from each enrolled children with influenza-like illness (ILI) attending the outpatient department at their first visits.One-step real-time fluorescence quantitative RT-PCR was performed to detect seasonal influenza A/H1N1and A/H3N2viruses、influenza B virus and2009pandemic A/H1N1influenza virus.Result:Among a total of3304respiratory samples, influenza A and B viruses were detected in948(28.69%) of samples. Five hundred and fifty-one (58.12%) were influenza A virus and,414(43.67%) were influenza B virus with17(1.79%) being co-infection. Of551influenza A isolates,318(57.71%) were seasonal A/H3N2,222(40.29%) were pandemic A/H1N1,4(0.73%) were seasonal A/H1N1(detected in June, August and September2009) and10(1.81%)were untyped, of which,3(0.54%) were co-infected with A/H3N2(3detected in2009) and2009pandemic A/H1N1. The annual epidemic of influenza was observed among children in Shanghai and seasonal A/H3N2,2009pandemic A/H1N1and influenza B viruses were epidemic alternatively in the autumn, winter and spring, however, seasonal A/H1N1virus was detected sporadically in July and August2009.2009pandemic A/H1N1emerged among local children in the second week of August2009, and peaked from September through December with the detection rates of21.85%-24.32%, then ended in the first week of February2010. During2010-2011influenza season, pandemic A/H1N1appeared in early December2010and followed by another striking outbreak in January2011with the detection rate of47.83%, then ended in mid-February. Since then,2009pandemic A/H1N1virus was not detected. For seasonal A/H3N2, a large outbreak occurred in August and September2009with the detection rates of39.50%～59.32%during2009-2010influenza season, a smaller outbreak occurred in September and October2010with the detection rates of25.88%-27.17%during2010-2011season, and a second smaller outbreak occurred in February and March2012with the detection rates of17.70%～34.62%during2011-2012season. Influenza B was detected throughout a year and the high activity of influenza B followed the end of epidemic wave of influenza A and usually peaked in late winter and spring during2009-2010(peaking between January and March2010with the detection rates of15.28%-34.00%)and2010-2011seasons (peaking between February and May with the detection rates of12.86%-17.58%), however, a large outbreak of influenza B occurred between December2011and February2012with the detection rates of52.20%-73.50%, and the activity weakened in March2012with the detection rates of15.39%.Conclusion:The periodic outbreaks of influenza occur every year among children in Shanghai from June2009to March2012. The epidemics of influenza in Children usually appeared in autumn, winter and spring with seasonal A/H3N2and influenza B,2009pandemic A/H1N1viruses circulating alternatively among Children in Shanghai. Influenza vaccination should initiate prior to the beginning of autumn semester to prevent influenza outbreak among children in school and kindergarten, so as to prevent influenza outbreaks in children. Part2Clinical epidemiological features of outpatient children with influenzaObjective:To understand the demographic and clinical features and exposure history of outpatient children with influenza.Methods:The demographic information, clinical symptoms, exposure history, influenza immunization history and laboratory tests were recorded and analyzed for the enrolled children.Results:Of948children confirmed with influenza,579(61.08%) were boys and369(38.92%) were girls;419(44.20%) were <3years of age and529(55.80%) were＜3years of age. All laboratory-confirmed children with influenza were previously healthy children. In2009-2010pandemic season,72.11%of children with pandemic A/H1N1infection were preschool and school-age childre≥>3years; however, in2010-2011season when pandemic A/H1N1became seasonal strain, young children <3years were affected more often than in previous season (58.67%verse27.89%, P=0.001). The median age of children with2009pandemic A/H1N1infection in2009-2010pandemic season were statistically older than those in2010-2011epidemic season (53.5months verse32months, Z=-4.601, P=0.000). Seasonal A/H3N2affected more young children <3years of age between2009-2010and2010-2011seasons, who accounted for66.47%and56.52%, respectively, and no statistical difference was found in the median ages of influenza A/H3N2in the two seasons (26.5months verse32months, P=0.261);however, in2011-2012season65.82%of children with A/H3N2infection were^3years of age with the median age of44months, significantly older than those in the previous two seasons. Influenza B affected children aged≥3years old more frequently, who constituted with67.37%,55.31%, and60.95%respectively during the three seasons with the median ages of48months,36months and44months, respectively (P=0.261)Out of948children with influenza,466(49.15%) had close contacts with primary cases suffering from fever or acute respiratory infection. It was observed that more children with pandemic A/H1N1influenza had the definite exposure history in2010-2011season than in the2009-2010season (70.67%verse44.90%, χ2=13.260, P=0.000). For seasonal influenza A and B, family members were the major primary exposure subjects, accounting for56.41%-81.08%. During the pandemic A/H1N1outbreak in2009-2010season, both family members and school students were the major primary exposure subjects, accounting for45.45%and42.42%, respectively. Overall,280(60.09%) out of466primary index cases were family members. Cough (84.24%) and runny nose (61.37%) are the most common concomitant symptoms in febrile children with influenza and high fever≥39℃is the main manifestation which was reported in70.25%of cases. Only19cases had been vaccinated against influenza vaccine before based on parental report.Conclusion:Influenza outbreaks occurred in young children and preschool and school children in Shanghai. More institutionalized children aged≥3years were affected during the first pandemic season of2009A/H1N1influenza and the outbreak of influenza B. Household transmission was the main model for children to contract influenza in Shanghai. However, family members and school children were the major spreaders of influenza during the influenza pandemic. It is reasonable and necessary to encourage influenza vaccination among preschool and school children, home-cared young children and household members caring for children to prevent childhood influenza.Part3Investigation of the disease burden of influenza in outpatient childrenObjective:To Understand of the socioeconomic burden of influenza on children and their families in outpatient children.Material and methods:During2011-2012influenza season, children confirmed with influenza were prospectively followed up until the fully recovery through telephone interviewing parents. The detailed information inquired were as follows: duration of fever, frequency of visits, direct medical costs, medications, outcome, school absence, missed work days for parents..Result:A total of199children with influenza during the2011-2012season was followed up during the entire illness episodes.50cases were infected with influenza A and149cases were infected with influenza B. We compared children with influenza A with those with influenza B, we found that the overall socioeconomic impact was similar between the two groups although the number of hospital visits among children with influenza B was more than among those with influenza A (3.56verse3.36, p=0.006). The mean medical cost were874.71Yuan in influenza A group and598.85Yuan in influenza B group (p=0.092), respectively. Antibiotics was used more often in children with influenza A than in those with influenza B (74%verse63.09%, p=0.159). Influenza-related pneumonia was diagnosed in6%of influenza A cases and5.33%of influenza B cases (p=0.866). Influenza-related hospitalizations occurred in2%of influenza A cases and5.37%of influenza B cases (p=0.866). Missed school days were6.93and6.88(p=0.895), respectively, in children with influenza A and influenza B and lost working days among parents were3.33and4.75(p=0.111),Conclusion:Influenza imposes a significant socioeconomic burden on children and their families.Part4Genetic analysis of hemagglutinin gene in2009pandemic influenza A/H1N1virus circulating in ShanghaiObjective:To understand genetic evolution of HA1domain of hemagglutinin gene in2009pandemic influenza A/HIN1virus circulating in ShanghaiMaterial and methods:Phylogenetic analysis based on the HA1subunit of the haemagglutinin gene was carried out on162009pandemic influenza A/H1N1viruses circulating during the2009-2010and2010-2011seasons. The nucleotide sequences were compared between vaccine strain A/California/07/2009and local strains.Result:Seven different genetic clusters were identified among circulating2009pandemic A/H1N1viruses. The nucleotide sequences were highly homologous among vaccine strain A/California/07/2009and local strains with99%of identities. Q293R substitution was detected in in antigenic epitopes of HA and D222G mutations associated with severe disease outcome were not found.Conclution:The current circulating2009pandemic A/H1N1viruses in Shanghai have not undergone significant genetic changes in HA1.