Clinical and socioeconomic impact of pediatric seasonal and pandemic influenza

Abstract

Influenza is frequent among otherwise healthy day-care and school-aged children. Recent studies have demonstrated its significant effect on various outcome factors, including significantly more school and parental work absenteeism, and secondary illnesses among family members. Other studies have shown that the potential benefit of vaccinating children against influenza extends to other members of their families, thus supporting earlier economic modeling analyses of immunization programs. Although there are some differences in the clinical and socio-economic impact of seasonal and pandemic influenza, the benefits of vaccination are similar in both cases. The vaccination of otherwise healthy children may significantly reduce direct and indirect influenza-related costs, which supports the recommendation to make wider use of influenza vaccine in healthy children of any age in order to reduce the burden of infection on the community.

Keywords: :

• children
• epidemiology
• influenza
• pandemic
• seasonal

Introduction

Influenza can have a particularly negative clinical and socio-economic impact on children, particularly those aged less than five years. A number of studies have shown that 7–12 additional medical examinations and 5–7 additional antibiotic prescriptions are needed for every 100 children during the influenza period, and that pediatric hospitalization rates are now quite similar to those usually observed among other subjects normally considered to be at higher risk of influenza-related complications, such as those aged more than 65 y.^1-6

The socio-economic impact of pediatric influenza may be considerable because younger patients shed larger amounts of viruses over longer periods than adults, and are thus mainly responsible for spreading household infections. A survey of 3,771 pediatric patients with respiratory disease (including 352 with laboratory-confirmed influenza) found that the number of medical examinations, the number of missed working or school days, and the need for help at home to care for sick children were all significantly greater among the household contacts of influenza-positive children than those of children infected by other agents.⁷

Furthermore, contrary to previous belief, recent studies have clearly shown that influenza can evolve negatively not only in children with severe chronic underlying diseases, but also in otherwise healthy children. Of the 149 laboratory-confirmed influenza-related pediatric deaths reported during the 2003–2004 influenza season in the US, 100 (67%) involved children without any underlying medical condition.⁸ Similarly, 51% of the children aged <18 y with laboratory-confirmed influenza who died in California during the 2003–2004 and 2004–2005 influenza seasons, and 40% of those requiring admission to an intensive care unit, were not affected by any risk condition.⁹

It therefore seems to be highly desirable to adopt adequate influenza prevention measures, which could theoretically take the form of administering antiviral drugs or vaccines. However, the use of the former is widely questioned because they are expensive, difficult to administer, not very active, and may lead to resistance.¹⁰ Furthermore, the very few data concerning the efficacy of drug-induced influenza prevention in the first five years of life (the age group that could benefit most) make it clear that antiviral drug prophylaxis can only be recommended in very few pediatric cases: i.e., unvaccinated children with a chronic underlying disease who are at high risk of complications, or vaccinated children affected by a condition that may weaken their response, such as congenital or acquired immunodeficiency.

Vaccination therefore still seems to be the best means of reducing the incidence and risks of influenza infection in children, which is why the US Advisory Committee for Immunization Practices and the American Academies of Pediatrics and Family Practice recommend universal pediatric vaccination.^11,12 It also explains why, even in Europe (where influenza vaccination has long been considered only for children with severe chronic underlying diseases), countries such as Finland, Austria, Estonia, Slovakia and Latvia have recently included healthy children in the list of subjects for whom influenza vaccine is strongly recommended.^13,14

Impact of Pandemic and Seasonal Influenza

An A/H1N1 quadruple reassortant influenza virus (A/H1N1/2009) of swine origin recently arose from a subtype A/H1N1 influenza virus that was already endemic in humans, and caused a pandemic with a very high disease burden among children and young adults.¹⁵

Since the declaration of the pandemic by the World Health Organization, a number of descriptions of the presentation and outcomes of pediatric pandemic A/H1N1/2009 influenza have been published.^16-18 However, as most of these studies involved a very small number of children and/or children admitted to hospitals or intensive care units, they only described the most severe cases that frequently occur in children with underlying chronic disease at risk of influenza-related complications. Moreover, there are very few pediatric data allowing a systematic comparison of the characteristics of pandemic and seasonal influenza infection,^19-22 and none at all concerning the socio-economic impact of pediatric pandemic influenza on family members or the possible differences between pandemic and seasonal influenza.

Every winter season for a number of years, we have systematically evaluated the total burden of influenza in children referred to the emergency room (ER) and hospitalized in the in-patient units of our large, university-based pediatric hospital, using the same methods to collect clinical and socio-economic data regarding the children with influenza-like illness and their families. As the diagnosis of influenza was always confirmed by means of real-time polymerase chain reaction (PCR), we have now been able to make a direct comparison between the total burden of pandemic influenza and that of other seasonal influenza A viral subtypes in a large number of children.

Our recent data has extended our knowledge of the impact of the new pandemic A/H1N1/2009 influenza virus on the general pediatric population.²² This study involved a large number of healthy children and precisely compared some aspects of the clinical and socio-economic impact of the different influenza A subtypes in different years using the same methods and the same researchers. It is usually thought that, in comparison with a seasonal epidemic, an influenza pandemic is not only associated with more cases of influenza, but also with more severe disease, mainly because of the lack of any pre-existing immunity against the new virus in the majority of pediatric subjects. However, we found that the clinical impact of the influenza associated with the pandemic A/H1N1/2009 virus was not substantially different from that associated with the seasonal A/H3N2 and A/H1N1 subtypes.²² The prevalent clinical manifestations of influenza in all three groups were upper respiratory tract infections, and no child was admitted to the pediatric intensive care unit or died. In this regard, our data are similar to those previously found in children^23,24 and adults.^25,26

However, there are some differences from those of previously published pediatric studies that allow a more detailed analysis of the characteristics of pandemic and seasonal influenza. As we could identify both of the recently circulating seasonal influenza A subtypes, we were able to demonstrate that the pandemic A/H1N1/2009 and seasonal A/H3N2 viruses were the most virulent subtypes, and that they can lead to a slightly higher incidence of lower respiratory tract infections and hospitalizations regardless of the patients’ age or gender.

In their studies, Hawkes et al.²³ and Gordon et al.¹⁹ evaluated all seasonal A subtypes together, and so they could not analyze the real impact of each one individually. Their different conclusions (i.e., the similar impact of pandemic and seasonal influenza A viruses in the case of Hawkes et al.,²³ and the greater impact of the pandemic subtype in the case of Gordon et al.¹⁹) may be explained by the different proportions of the two seasonal A subtypes in each study population. Moreover, it has to be pointed out that our data differ from those collected by Belongia et al.,²⁴ who did not find any significant clinical difference between the pandemic and seasonal strains. However, they enrolled older children and adults, and their population with pandemic A/H1N1/2009 influenza was significantly younger than that of their population with seasonal A/H3N2 influenza.

Our study also indicated that only a small number of children experienced gastrointestinal manifestations as presenting symptoms of pandemic influenza. This conflicts with the Nicaraguan findings of Gordon et al.,¹⁹ who observed a larger number of cases of diarrhea, probably due to the higher proportion of children with malnutrition. Moreover, Gordon et al. enrolled all of the children with fever who attended their ER,¹⁹ whereas we only included with influenza-like illness as defined by the Italian Ministry of Health (i.e., mainly subjects with respiratory symptoms).²²

All of our findings could theoretically have been influenced by differences in the use of antiviral agents and vaccinations in the three influenza seasons. However, this is very unlikely because antivirals were not used in Italy in 2007–2008 or 2008–2009, and only a minority of the children with pandemic A/H1N1/2009 influenza were treated with oseltamivir. Furthermore, vaccination coverage against both seasonal and pandemic influenza was marginal because seasonal influenza vaccines are not recommended by the Italian health authorities for healthy pediatric children, and the pandemic influenza vaccine was poorly accepted by the general population.²⁷ The observed differences between the viral subtypes support the hypothesis that some may be more pathogenic than others per se, and not because immune responses are conditioned by previous childhood exposure to influenza viruses.²⁸

Nevertheless, although it was not more clinically severe than seasonal A/H3N2 influenza, pandemic A/H1N1/2009 infection led to longer hospital stays and more school absences. As the clinical findings were similar, it is reasonable to think that these differences may have been related to the physicians’ need to observe the evolution of a disease due to a previously unknown infectious agent, and the health authorities’ recommendation that children developing pandemic A/H1N1/2009 influenza should be kept at home in order to avoid viral transmission.

Our family data confirm what has been repeatedly demonstrated: pediatric influenza is not only a problem for patients, but can also lead to substantial socio-economic costs for households.^29-31 The spread of a similar infection among parents and siblings is associated with additional medical examinations and antibiotic prescriptions, and the loss of school and working days. Although we did not calculate the socio-economic consequences of the household spread of a child’s influenza in detail, our findings suggest that they are roughly proportional to the virulence of the infecting strain and changes in the A subtypes, and not related to the age of the infected child. In our study population, pandemic A/H1N1/2009 influenza virus caused the same socio-economic problems as seasonal A/H3N2 influenza, and more problems than the seasonal A/H1N1 subtype.

In conclusion, perceived symptom severity and the risk of serious outcomes (admission to a pediatric intensive care unit or death) seem to be similar in children with influenza due to pandemic A/H1N1/2009 or seasonal A/H3N2 influenza, but both of these viruses appear to have a greater clinical and socio-economic impact than seasonal A/H1N1 virus, regardless of the patients’ age or gender. Our data were collected from otherwise healthy children, and we do not know whether these conclusions would have been the same if we had studied patients at higher risk of influenza-related complications. However, the total number of healthy children who suffer from influenza viruses during an influenza season is always significantly higher than that of patients at risk, and so it is particularly important to have detailed information of the impact of the different influenza viruses in this population.

Conclusions

Influenza is frequent among otherwise healthy day-care and school-aged children. Recent studies have demonstrated the significant effect of influenza on multiple outcome factors, including significantly more school and parental work absenteeism, and secondary illnesses among family members.^1-6 Other studies have shown that the potential benefit of vaccinating children against influenza also extends to other members of their families,^32-34 thus supporting earlier economic modeling analyses of influenza immunization programs. Although there are some differences in the clinical and socio-economic impact of seasonal and pandemic viruses, the benefits of influenza vaccination are similar in both cases. The vaccination of otherwise healthy day-care and school-aged children can significantly reduce the direct and indirect influenza-related costs associated with the children themselves and their unvaccinated household contacts, thus supporting the recommendation to make wider use of influenza vaccine in healthy children of any age in order to reduce the burden of the infection on the community.

Acknowledgments

This review was supported by grants from the Italian Ministry of Health (Bando Giovani Ricercatori 2007) and Amici del Bambino Malato (ABM) Onlus.