Several studies conducted during the past decades have demonstrated that influenza is a major cause of respiratory illness in children. 1–8 Recently it was shown that children younger than 1 year of age are hospitalized for influenza-attributable illnesses at rates similar to those for adults at high risk for influenza. 9, 10 The admission rate of children younger than 2 years without any high risk conditions approaches that of children 5 to 17 years of age with high risk conditions. 11 It is obvious, however, that hospitalized children represent only a small fraction of all children infected with influenza viruses. The majority of children are treated as outpatients who may not even be seen by a physician, let alone to be diagnosed as having influenza.
In recent years there has been an increasing discussion on whether children should be routinely vaccinated against influenza. 9, 11, 12 However, the cost effectiveness of general vaccination of children has been difficult to determine because of scarce information on the total burden of pediatric influenza in the society. Many previous studies have estimated the effect of influenza by using epidemiologic surveillance data, rather than by determining the viral etiology on an individual basis. We conducted this prospective cohort study to provide further evidence for the burden of influenza in normal children treated as outpatients.
This study was conducted at the Department of Pediatrics, Turku University Hospital, Turku, Finland, where a separate outpatient clinic was set up for the study. The participating children were recruited before the start of the respiratory season by informing families in our area about the study. All children younger than 13 years were eligible for participation. Before commencement of the study, written informed consent and demographic data were obtained for 1458 children.
The study period consisted of 32 weeks (October 9, 2000 through May 20, 2001). The parents were asked to bring their children to the study clinic whenever the child had fever or signs of respiratory tract infection. The study clinic was open every day, and all visits were free of charge to the families. At each visit the children were thoroughly examined by a study physician, and laboratory and radiologic examinations were performed when deemed clinically necessary. Children without any complications at the initial visit were routinely reexamined after 5 to 7 days, but the parents could bring their child for examination at any time and without any limit for the total number of visits during the study. The parents also filled in a daily symptom card throughout the entire study period.
During each episode of respiratory tract infection, a nasal swab was obtained for determination of the viral etiology of the illness as described earlier. 13 Influenza viruses in the specimens were detected by rapid culture assay. 14
The study protocol was approved by the Ethics Committee of Turku University Hospital.
A total of 1338 children were followed up throughout the study period (51.7% were boys). The age distribution of the children is shown in Figure 1. The total number of visits to the study clinic was 6121 (including control visits), and the number of viral specimens obtained was 3637.
The first case of laboratory-confirmed influenza A infection in the study cohort was detected on November 3, 2000. Despite continuous detection of the virus during the following weeks, influenza activity remained low during the rest of the year. In late January 2001 influenza A activity increased substantially, peaking in February and falling to zero by the end of March 2001. Major influenza B activity was first detected at the end of February, with moderate numbers of cases diagnosed until the end of April. The last case of influenza B infection was detected on May 20, 2001, the last day of the study.
The total number of culture-confirmed influenza infections was 262. Ten children had separate episodes of influenza A and B during the study. The overall attack rate of influenza in the cohort was 18.8% (252 of 1338). Influenza A viruses accounted for 205 (78.2%) and influenza B viruses for 48 (18.3%) of all influenza infections; in 9 (3.4%) cases the isolate remained untyped.
The mean weekly number of nasal swabs obtained from the children was 114. Figure 2 shows the percentage of influenza-positive specimens of all specimens obtained during each week of the study. Influenza viruses accounted for at least 5% of all respiratory infections virtually throughout a period of 24 weeks (from mid-November 2000 to the end of April 2001). During the peak of the epidemic, 15 to 20% of all respiratory infections in the study children were caused by influenza viruses.
This prospective cohort study shows that influenza viruses are an important cause of respiratory tract infections in normal children treated as outpatients. Although the epidemic of 2000 to 2001 was generally considered mild in Europe, almost 20% of the children contracted influenza during the winter. Across the entire winter season, influenza was confirmed as the cause of >7% of all respiratory infections in our cohort. Moreover this figure is likely an underestimate, because for increased compliance and feasibility we chose to obtain nasal swabs instead of nasopharyngeal aspirates for viral detection. In previous studies we have shown that the sensitivity of a nasal swab for detection of influenza viruses by culture or antigen detection is ∼90% when compared with a nasopharyngeal aspirate. 13, 15
Influenza epidemics are usually considered to appear abruptly, peak within 2 to 3 weeks and disappear after 5 to 6 weeks. 16 Our results indicate that this general concept may not hold true, at least not for all influenza outbreaks. In this study influenza viruses could be cultured from children with acute respiratory infections throughout a period of 6.5 months, and for most of this period influenza viruses accounted for at least 5% of all respiratory infections. Perhaps the main reason for this finding is that in the present study the children were sampled during every respiratory infection regardless of the severity of the symptoms, and the study was started well before the expected influenza epidemic. In many instances collection of virologic specimens for detection of influenza is started only after clear epidemiologic and clinical suspicions of an influenza outbreak in the community (e.g. by increased numbers of outpatient visits per week). However, it is not known whether the epidemiologic pattern observed in this study would also apply to influenza epidemics other than the current one, which was caused mainly by A/H1N1 viruses.
In conclusion this study confirms the important role of influenza as a cause of acute respiratory infections in children, even in winters of mild or moderate influenza activity. Considering the 80 to 90% protective efficacy of influenza vaccines in children, 17 more widespread vaccination in this age group could be expected to bring about substantial reductions in the direct and indirect costs caused by influenza-related outpatient visits, medications, hospital admissions and absenteeism. In addition to providing protection for children themselves, vaccination of children might also reduce influenza-related morbidity and mortality in other age groups. 18, 19 However, the potential development of new policies for more extensive vaccination of children against influenza will require careful evaluation of the risks and benefits, inconveniences, logistics and cost effectiveness of the vaccination.
We thank Anne Riihimäki, Jaana Marku, Kirsi-Maija Suomela, Maria Marttila, Satu Heikkinen, Tanja Reunanen, Katja Rannikko, Raija Vainionpää, Tytti Vuorinen and Aimo Salmi for their help in the conduct and analysis of this study. The study was supported by Wyeth, the European Scientific Working Group on Influenza, GlaxoSmithKline, the Academy of Finland, the Foundation for Pediatric Research in Finland and the Jenny and Antti Wihuri Foundation.
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