Clinical and socioeconomic impact of different types and subtypes of seasonal influenza viruses in children during influenza seasons 2007/2008 and 2008/2009

A number of recent surveys of the total burden of pediatric seasonal influenza [1–4] have demonstrated that, although generally more dangerous in children at risk of influenza-related complications because of chronic underlying disease, it is also very common in otherwise healthy children, a considerable number of whom experience severe disease leading to excess hospitalisation rates, increased outpatient visits and antibiotic prescriptions, and (although rarely) even death [5]. Moreover, as children are particularly responsible for the spread of influenza, their disease has substantial socio-economic consequences because of the high rate of transmission among family members [3, 6].

Among the influenza viruses causing disease in humans, types A and B are the most frequently isolated [7]. Despite all of them can infect subjects of all ages, community-based surveillance systems have found that A/H3N2 influenza virus is more frequently isolated in adults (including elderlies), influenza A/H1N1in young children and influenza B in school-age children [8]. However, there are few and debated data regarding possible differences in the clinical presentations of influenza A and B viruses in children. Some studies found a similar constellation of clinical signs and symptoms [9, 10], whereas others indicate that influenza B infection may be more frequently associated with encephalitis, fatal pneumonia and myositis [11–13]. On the other hand, an ill appearance and more severe signs and symptoms of disease leading to higher hospitalisation rates are considered to be more common in children infected with influenza A [14–16].

Among the influenza A viruses, the H1N1 and H3N2 subtypes are the most common causes of disease [7, 9], but little is known about their relative importance in determining the clinical features of the disease in pediatrics. Because the use of extensive vaccination against influenza among healthy children is not recommended in most industrialised countries [17, 18], more data are needed to define whether the different subtypes may be risk factors for severe disease and hospitalisation. Furthermore, an awareness of the different clinical manifestations relating to viral subtype is particularly necessary when antiviral agents are used because the resistance of viral strains seems to be different [19, 20].

This paper describes the clinical presentation and socio-economic impact of laboratory-confirmed influenza A (H1N1 and H3N2) or B infection in 901 otherwise healthy children attending an Emergency Room (ER) because of influenza-like illness during the influenza seasons 2007-2008 and 2008-2009.

The study involved a total of 4,726 children (2,599 males; mean age ± SD, 3.34 ± 3.06 years): 1,170 (24.8%) during winter 2007-2008 and 3,556 (75.2%) during winter 2008-2009. Influenza A viruses were detected in 729 (15.4%): 164/1,170 (14.0%) in the first year and 565/3,556 (15.9%) in the second; influenza B viruses were detected in 239 (5.1%), 179/1,170 (15.3%) in 2007-2008 and 60/3,556 (1.7%; p < 0.0001) in 2008-2009. Despite the differences in prevalence during the two seasons, all the viral types co-circulated during 2007-2008 and 2008-2009, and no co-infection between different influenza types was observed. The influenza A viruses were subtyped in 150 of the 164 samples collected in the first year (91.5%) and 512 of the 565 samples collected in the second year (90.6%): subtype A/H1N1 was identified in respectively 126/150 (84%) and 17/512 cases (3.3%; p < 0.0001), and subtype A/H3N2 in 24/150 (16%) and 495/512 (96.7%; p < 0.0001). There was no between-centre difference in the prevalence of the different viral types or subtypes. As a preliminary evaluation showed that the demographic characteristics, clinical presentations, clinical outcomes and socio-economic impact were similar in the two seasons, the patients were considered together on the basis of the detected viral type and subtype. Consequently, the analysis was based on 662 children with influenza A (143 A/H1N1 and 519 A/H3N2) and 239 with influenza B.

Most of the data collected during this study confirm that influenza can cause substantial clinical and socio-economic problems not only in children at risk of complications but also in otherwise healthy children [1–5]. Our study population consisted only of otherwise healthy children, the great majority of whom attended the ERs with fever and respiratory tract infection, and a considerable number were hospitalised and received drug therapy, thus confirming that influenza leads to high rates of hospitalisation and antipyretic and antibiotic prescriptions also among healthy pediatric subjects [1, 2].

Data showing that more than 70% of patients with influenza received antibiotics are impressive in the light of campaigns to reduce antibiotic usage in Europe, especially related to viral infections like influenza. The use of rapid tests to confirm influenza diagnosis during epidemic periods in settings like ERs may be helpful for reducing this inappropriate antibiotic abuse [26].

The findings also confirm that influenza can present with fever without other accompanying symptoms, and that its initial presentation may be gastroenteritis or febrile seizures. Moreover, as previously reported [13], we found that influenza B infection can present with unusual manifestation, including myositis. However, the prevalence of acute otitis media (AOM) was significantly lower than that reported in other studies of the complications of influenza [15, 27] but similar to that previously found by our group [6, 26]. These differences can be explained by the fact that we analysed signs and symptoms upon enrolment, whereas AOM can arise some days after the beginning of the disease. Moreover, the antibiotic prescription rate was very high in our population, thus reducing the probability of AOM due to bacterial superinfection. Finally, our findings confirm that influenza has a significant impact on households and considerable socio-economic consequences among parents and siblings [3, 6].

The new study findings are those related to the impact of the different viral types and subtypes, which show that disease due to influenza A/H3N2 virus is significantly more severe than that due to influenza A/H1N1 viral subtype and influenza B virus upon adjustment for age and gender. In studies showing the greater clinical importance of influenza A virus [18–20], this finding has been mainly attributed to the fact that younger children are at higher risk of severe influenza disease and that influenza A infection is usually more common among patients in the first five years of life. Our data suggest that the viral subtypes themselves may play different roles in conditioning the clinical and socio-economic impact of influenza infection in children. Although our patients infected by the A/H1N1 subtype were significantly younger than those infected by the A/H3N2 subtype, the severity of the disease was less and quite similar to that due to influenza B virus. Moreover, a specific multivariate analysis upon adjustment for age group and gender has been done showing that the greater severity of A/H3N2 in this and other studies [28–31] may be due to specific characteristics leading to greater virulence.

This study was mainly focused on different types and subtypes of seasonal influenza viruses, and no other respiratory virus was evaluated. Further studies that include possible differences and co-infections with other respiratory viruses should be useful also for a better understanding of influenza viruses' pathogenesis. Moreover, only the ER setting was evaluated and findings in primary care could be partially different. Finally, our data refer to the influenza seasons 2007-2008 and 2008-2009, before the circulation of the pandemic A/H1N1 influenza virus. It is therefore possible that these conclusions may not apply to the present situation in which the new A/H1N1 subtype has completely replaced its predecessor. However, to the best of our knowledge this is the largest study that evaluates clinical as well as socioeconomic characteristics of different types and subtypes of seasonal influenza viruses in pediatrics.

Disease due to influenza A/H3N2 virus is significantly more severe than that due to influenza A/H1N1 viral subtype and influenza B virus, which indicates that the characteristics of the different viral types and subtypes should be adequately considered by health authorities when planning preventive and therapeutic measures.