The current study showed that during the 2017–2018 influenza season, approximately 10% of all hospitalized cases of influenza virus infection were complicated, as defined by admission to an ICU, need for mechanical ventilation, or death. Factors associated with complicated hospitalization in patients with influenza virus infection included COPD, diabetes, and hospitalization during the previous 12 months, although male sex, cardiovascular disease, and some lifestyle factors (smoking and obesity), were also identified in certain subgroups. Age was also an important factor associated with complicated hospitalization and a longer hospital stay in patients with influenza virus infection. Most of these factors are known risk factors for severe influenza illness [4]. In addition to these factors, prescription of antiviral medication during the current episode was associated with an increased frequency of complications, probably because antivirals were mostly prescribed for influenza cases with a high likelihood of developing complications.
Influenza A infections are often thought to result in more severe illness than influenza B infections [15]. The current study, however, did not find a difference between influenza A and B or between A/H1N1pdm09 and A/H3N2 in the risk for complicated hospitalization, its individual components, or a longer hospital stay. These findings support a systematic literature review that concluded that clinical presentation and severity of influenza illness do not appear to differ between influenza strains [16].
During the 2017–2018 influenza season, influenza accounted for approximately one-third of hospital admissions with influenza-like symptoms, which agrees with previous influenza seasons in the GISHN, where proportions were between 21% and 31% [8–10, 17]. As in previous studies, all strains of influenza were detected, with widely varying strain circulation between sites and even neighboring regions. Influenza B/Yamagata was the most frequently detected influenza strain, although A/H3N2 and A/H1N1pdm09 were nearly as common. There were some minor differences in timing, although these three strains essentially co-circulated globally. Furthermore, although a B/Victoria-lineage strain had been included in 2017–2018 Northern Hemisphere and 2018 Southern Hemisphere trivalent influenza vaccine, the Yamagata was the dominant lineage of influenza B [18, 19]. Finally, as in previous studies, more than half of the patients hospitalized with influenza virus infection did not have known chronic conditions, highlighting that influenza can cause severe illness even in individuals without high-risk conditions.
By using a shared protocol combined with active, prospective surveillance across many countries and continents, the GIHSN provides a combination of extensive global virological and clinical data on severe seasonal influenza illness. Data from the GIHSN can be used to identify associations between influenza virology/epidemiology, patient characteristics, and severe cases of influenza illness. In the current study, we pooled data from more than 4,000 influenza-positive patients at 14 coordinating sites in 13 countries on four continents. Although this provided a large enough dataset to assess many factors potentially associated with complications, the influence of some factors known to be associated with severe influenza, such as human immunodeficiency virus infection and neurological conditions [4], could not be assessed because related information was not collected.
Analyzing pooled surveillance data can be complicated by differences in clinical practice, case definitions, and procedures between sites, as well as patients’ health-seeking behaviors and access to care and vaccination. The GIHSN improves comparability between sites by using a common core protocol for identifying hospitalized cases of influenza illness, active surveillance, and validated RT-PCR. In addition, to reduce bias caused by false-negative tests due to decreasing viral shedding over time [8], only patients who had been hospitalized within 7 days of symptom onset were eligible. To further reduce the effects of bias from differences between sites, factors associated with complicated influenza-related hospitalization were identified using a mixed effects model with a random effect per site [20, 21]. These steps represent improvements over many surveillance efforts, where interpretability may be limited by non-systematic sampling, incomplete case ascertainment, lack of adjustment for confounders, sparse numbers, lack of consensus about case definitions and risk factors, and a lack of comparison groups. Despite the efforts to reduce heterogeneity, CIs were wide, which limited the ability to detect certain factors and interpret the size of the effects.
We did not examine the effect of influenza vaccination on complications or length of hospital stay because of low vaccination rates; the overall influenza vaccination rate across all sites and all included patients was below 15%, and, for more than half of the sites, the rate of influenza vaccination was below 10%, although a few sites had rates above 30%. This highlights differences in clinical practice, access to care, and included populations across the different sites.
Our results should be interpreted in the context of the definition for complicated hospitalization, as well as the case definition for influenza. There is currently no consensus of how to define complicated hospitalization, although some studies have reported on ICU admission, mechanical ventilation, and in-hospital death [4, 16, 22, 23]. In the current study, complicated hospitalization was a composite of three outcomes, one of which is a treatment or support modality (mechanical ventilation), one mostly a metric for health care utilization (ICU admission), and one an indicator of severity (death during hospitalization). These, as well as length of hospitalization, capture different underlying aspects of severity, and each is influenced by a variety of patient, cultural, and healthcare practice factors, which may complicate interpreting results for individual factors. Nonetheless, this study was able to identify some common factors associated with complicated hospitalization and a longer hospital stay in influenza-positive patients. Given the limitations of influenza-like-illness case definitions for predicting influenza in individuals, particularly in older adults, to identify the maximum number of hospitalized influenza cases, potential cases were identified based on the presence of any acute respiratory symptoms possibly associated with influenza rather than based on a specific influenza-like illness case definition. Although this would reduce specificity of the inclusion criteria, specificity was ensured by confirming influenza virus infection by RT-PCR.
Care should be taken when generalizing the findings of the study. Although substantial efforts were made to improve comparability of data, the current results represent a single season and depend on the strains, sites, and populations included.