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Many respiratory viruses can affect young children, with influenza viruses and respiratory syncytial virus (RSV) being most recognized and important cause of disease of varying severity.[1, 2] Excess morbidity and mortality caused by seasonal influenza have clearly been shown in persons over 65 years or having chronic medical condition. During the past decade, accumulated data on the impact of influenza-related diseases in children have become available. The spectrum of symptoms caused by influenza viruses in children is highly divergent and may lead to the hospitalizations for lower respiratory tract disease or other complications. Respiratory syncytial virus has been recognized as one of the most common causes of serious lower respiratory tract infections worldwide and causes a large disease burden among infants and young children <2 years of age. While the greatest risk of severe disease occurs in infants and children with known high-risk conditions, most infants who are hospitalized with or die of RSV-related causes have no underlying medical conditions.
Effective preventive measures are available for several years against influenza and RSV for high-risk children.[1, 2] In last decade, Slovenian national immunization program recommends vaccination against influenza to children who are diagnosed with chronic medical conditions and are at high risk of developing influenza-related complications. The vaccination program has been expanded in 2009 when influenza vaccine was recommended to healthy children aged from 6 to 23 months. Despite the recommendations, the vaccination coverage remains <1% in children younger than 5 years of age. From 2006 onward, children with serious congenital heart disease, chronic pulmonary disease, or born prematurely (before 29th week of gestation) are given in their first year of life human monoclonal antibodies against RSV (palivizumab) during the RSV season.
Influenza and RSV are important public health problems among children, as hospitalizations related to both pathogens occur frequently with limited number of deaths in developed, industrialized countries.[1, 2] Measuring the pediatric population-based disease burden of influenza is challenging. Using large databases and community influenza surveillance, population-based studies have documented excess hospitalizations, antibiotic use, and outpatient visits among children during the influenza season.[4, 5] Respiratory syncytial virus often circulates concurrently with influenza viruses, and it is difficult to distinguish the impact of those two viruses on morbidity, hospitalizations, and mortality in cold part of the year in the temperate climate. In young children, the estimates of burden of the disease for influenza might be confounded by RSV and vice versa.
We studied the excess hospitalizations for pneumonia, acute bronchitis, and bronchiolitis among children aged 5 years and younger in Slovenia during five influenza and RSV seasons in the period 2006–2011.
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We observed an excess in average weekly hospitalizations for ALRTI (acute bronchiolitis, pneumonia, and acute bronchitis) per 100 000 among children aged 5 years or younger in all five seasons studied when influenza and/or RSV were present in Slovenian population. During three seasons (two predominated by influenza A (H3N2) and one by pandemic influenza A (H1N1) and influenza B virus combined), there was higher excess in the hospitalizations for ALRTI in the period when both pathogens (influenza and RSV) were circulating comparing with the period when only RSV was present. An excess of hospitalizations was highest among youngest children (0-5 months old).
Defining the cut offs for influenza and RSV season, periseasonal and summer period were one of the most challenging parts of our study. We carefully reconsidered certain approaches used in the previously published studies from the United States. In the first study, the beginning of influenza season was defined as the first week (between November 1 and April 30) with at least one positive sample in pediatric population consulting at hospital. Main disadvantage of such definition is that a single patient with imported influenza from Southern Hemisphere could be a “starter” of the season. In two other studies, the influenza season was defined as any period of two or more consecutive weeks (between October and May) with influenza accounting for ≥5% of the season's total number of influenza isolates and less than 5% of RSV isolates.[8, 9] When we tried to apply this methodology to our virological surveillance data, the weeks with intensive influenza circulation in the community (high percentage of samples positive for influenza and high ILI incidence rate) were not classified as influenza virus period as RSV was cocirculating even more intensively.
We believe that both epidemiological and virological data should be a part of influenza season definition. At the start of the season, sentinel doctors are keen to take samples (and are advised to do so) to detect influenza virus as soon as possible—consequently, the number of samples taken is usually high, and the percentage of positives reflects the intensity of the season well. In the middle of the season, not so many samples are taken (percentage of positives usually peaks) and ILI incidence rates are also high. As influenza season is approaching to its end, only few samples are tested, and most of them positive for influenza, with a sharp drop in ILI incidence rates.
Combining virological and epidemiological cut offs enabled us to exclude weeks with high ILI incidence rates due to other respiratory viruses but without confirmed flu (in the reality, high ILI incidence rates were always accompanied by high percentage of flu-positive samples). Inversely, weeks with high percentage of flu positives (as a consequence of very few samples tested) but without elevated ILI incidence rates were excluded too. The epidemiological cutoff value (incidence rate ≥25/100·000) has been chosen on our observation that in the following week after the cutoff was reached ILI incidence rate doubled (three seasons) or even tripled (two seasons). This empirical observation was not far from a modeled value created on our sentinel surveillance data.
For defining the RSV season, we applied the criteria used for regular “Respiratory Syncytial Virus Activity—United States” reports.
Global burden of acute lower respiratory tract infections is high and remains a leading cause of morbidity in young children worldwide. It has been estimated that around 150 million new episodes of ALRTI arise every year globally. Respiratory syncytial virus is most prevalent pathogen in children less than five causing app. 20% of all ALRTI (mostly acute bronchiolitis and acute bronchitis) in this age-group. Majority of children are infected with RSV by 2 years of age, but reinfections can occur throughout of life. There is a considerable annual variation in number of hospitalizations caused by RSV with regular biennial rhythm observed in some studies—a modest RSV season is followed by a more severe one. Moreover, the precise time of RSV activity cannot be foreseen and appears to be an effect of weather and behavior change in cooler part of the year in the temperate climate zones.[14, 15] In our study, the start of RSV seasons differed considerably from year to year as did the duration of RSV circulation.
Studies in the past decade suggested that the burden of ALRTI hospitalization in small children caused by influenza virus is substantial, too.[16, 17] The recent meta-analysis showed that at least 13% of pediatric ALRTI and 7% of severe ALRTI in children are caused by influenza virus. Circulation of influenza viruses starts early in some seasons and late in others without an anticipated pattern. Higher morbidity and mortality was usually generated by influenza A (H3N2) predominance in the elderly, in the patients with chronic conditions, and in small children as well. Less-intensive seasons were observed when influenza B virus or influenza A (H1N1) virus prevailed.[16, 19]
Disentangling the effects of influenza from those of RSV remains a challenge in epidemiological studies like in our study which use an ecological approach to assess the influence of viruses on healthcare utilization. In some previous studies, the effects of influenza or RSV only on the consultation or hospitalization rates were analyzed separately simply by defining a week in a season as an influenza week if influenza virus predominated in virological samples or RSV week when higher percentage of RSVs were found.[5, 8] This approach does not completely eliminate confounding by either RSV or other respiratory pathogens that may occur during the same period as influenza. Thus, there may be an overestimation of actual burden associated with influenza circulation in hospitalization rates reported. As shown in many studies as well as in ours, both pathogens (RSV and influenza) along with other viruses circulate concomitantly. Therefore, we did not attempt to separate the effects of influenza on hospitalizations in children aged ≤5 years from those of RSV, and we analyzed our data also for the period when both pathogens were present.
Only in the pandemic season (2009/2010), we were able to investigate the effect of influenza and RSV on the hospitalizations separately. The results of our study are consistent with the finding that RSV, not influenza, is associated with higher rates of the hospitalizations for lower respiratory tract disease in infants and young children.[5, 17, 20] The burden caused by RSV appeared to be considerably higher also in similar study from the Netherlands, where the total winter excess of hospitalization per 100 000 population (seasons 1997–2003) was estimated to be 142·7 (influenza versus summer baseline period) among children <1 year of age compared with 608·2 (RSV versus summer baseline period), and among children from 2 to 4 years, 19·8 compared with 34·6, respectively.
The rate-difference model for determining the excess hospitalizations during influenza periods compared with base-line periods with lower or no influenza activity used in our study has been applied before.[5, 8, 21, 22] It is less complicated and allows the insight to broader public than more sophisticated statistical models addressing this problem. The use of different definitions of study periods, various definitions of end points, and differences in healthcare systems make the published studies difficult to compare.
Our study implicates that influenza and RSV are associated with substantial increase in burden of the hospitalizations in children aged 5 years or less during the periods when those pathogens are detected compared with periseasonal or summer period. The results of this study are also in agreement with past studies that concluded that RSV and influenza virus account for significant morbidity in young children.[1, 5, 20, 21, 23] The youngest children (0-5 months old) were the most vulnerable for hospitalization compared with older age-group during the presence of RSV and/or influenza, as has been shown in the previous studies. The hospitalizations for acute respiratory infections were less frequent with increasing age.[1, 5, 20, 21, 23]
This study of excess hospitalizations estimates an effect of influenza virus and/or RSV infections on young children in Slovenia. The highest excess of hospitalizations in our study was found among the youngest children aged <6 months. The second most affected group were children aged 6–23 months. These results additionally support recommendations for preventive measures available. Only influenza virus infection is currently vaccine preventable, but vaccination coverage against influenza among children has been low in our country, and increased use of influenza vaccine could reduce the hospitalizations in this population group during winter months. For reducing the hospitalizations among children aged <6 months, the population group without approved vaccine, the “cocoon strategy” of vaccinating pregnant women or new mothers, and family members of newborns with influenza vaccine should be recommended.
Much effort has been focused on prophylaxis of high-risk children for severe RSV disease with the highest burden on healthcare resources, but those control strategies have a limited effect on the total disease burden of RSV infection in the population.[21, 25, 26] The effective and safe vaccine against RSV infection is still under development and has the potential to markedly reduce the pediatric morbidity from acute respiratory infections.[6, 19]
The importance of RSV as a driving force for ALRTI hospitalizations especially in children aged <6 months and the lack of vaccine reveal the need to intensify the education of young parents on how to avoid respiratory infections in newborns—keep them away from crowded places (e.g., shopping malls), not to send elderly siblings to kindergarten while mother is still on maternity leave (of 12 months in Slovenia), and to cease smoking in the proximity of the baby. These simple preventive measures are often ignored but can have an impact on reduction of morbidity.
There are some limitations we should be aware of when we interpret the results from an ecological study like ours. We may have overestimated the excess burden of influenza and/or RSV on the hospitalizations. Our hospital registry (DGR) does not include information on laboratory confirmation, and we were not able to estimate the real number of the hospitalizations from influenza or RSV infections. Part of the hospitalizations that we considered to be associated with influenza or RSV might in fact be a potential confounding factor due to other respiratory viruses like parainfluenza virus, rhinovirus, coronavirus, human metapneumovirus, human bocavirus, enterovirus, and adenovirus. But on the other hand, other respiratory viruses may have contributed to the hospitalizations during base-line periods and could also be the source of confounding.
We were also not able to account for readmissions for the same disease in the same patient and therefore a possible overestimation of the hospitalizations. However, as this limitation is present in all five seasons studied, the results obtained are still comparable between them.
The analysis in this study was limited to the hospitalizations focused on ARLTI. We did not attempt to estimate the total increase in the hospitalizations attributable to influenza and may also underestimate the true burden of this disease. The hospitalizations for other conditions, including sepsis-like illness, acute neurological conditions, exacerbation of asthma, may increase among children during influenza seasons.
The impact of RSV and influenza on ALRTI hospitalizations varied significantly from season to season. RSV was a leading viral pathogen associated with ALRI hospitalizations in children aged ≤5. The cocirculation of influenza virus increased the burden of ALRTI hospital admissions, especially in seasons with influenza A (H3N2) predominance. The RSV and influenza periods overlapped in four of five seasons, which made their impact on excess hospital burden of ALRTI inseparable. To our knowledge, this is also the first comparative study of influence of the pandemic influenza and RSV on excess hospitalization for ALRTI among young children and indicates the greater impact of RSV.