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Abstract Background Despite their higher risk of developing severe disease, little is known about the burden of influenza in Portugal in children aged

Abstract Background Influenza can have a domino effect, triggering severe conditions and leading to hospitalization or even death. Since influenza testing is not routinely performed, statistical modeling techniques are increasingly being used to estimate annual hospitalizations and deaths associated with influenza, to overcome the known underestimation from registers coded with influenza-specific diagnosis. The aim of this study was to estimate the clinical and economic burden of severe influenza in Portugal. Methods The study comprised ten epidemic seasons (2008/09–2017/18) and used two approaches: (i) a direct method of estimating the seasonal influenza hospitalization incidence, based on the number of National Health Service hospitalizations with influenza-specific International Classification of Diseases (ICD) codes (ICD-9: 487–488; ICD-10: J09-J11), as primary or secondary diagnosis; (ii) an indirect method of estimating excess hospitalizations and deaths using broader groups of ICD codes in time-series models, computed for six age groups and four groups of diagnoses: pneumonia or influenza (ICD-9: 480–488, 517.1; ICD-10: J09–J18), respiratory (ICD-9: 460–519; ICD-10: J00–J99), respiratory or cardiovascular (R&C, ICD-9: 390–459, 460–519; ICD-10: I00–I99, J00–J99), and all-cause. Means are reported excluding the H1N1pdm09 pandemic (2009/10). Results The mean number of hospitalizations coded as due to influenza per season was 1,207, resulting in 11.6 cases per 100,000 people. The mean direct annual cost of these hospitalizations was €3.9 million, of which 78.6% was generated by patients with comorbidities. Mean annual influenza-associated R&C hospitalizations were estimated at 5356 (min: 456; max: 8776), corresponding to 51.5 cases per 100,000 (95% CI: 40.9–62.0) for all age groups and 199.6 (95% CI: 163.9–235.8) for the population aged ≥ 65 years. The mean direct annual cost of the estimated excess R&C hospitalizations was €15.2 million for all age groups and €12.8 million for the population aged ≥ 65 years. Mean annual influenza-associated all-cause deaths per 100,000 people were estimated at 22.7 for all age groups. Conclusions The study findings suggest that there is an under-detection of influenza in the Portuguese population. A high burden of severe influenza remains to be addressed, not only in the elderly population but also in younger people.