Influenza vaccine coverage, effectiveness, and disease burden among pediatric sickle cell patients in Connecticut from 2021-2024: A test-negative case-control study

Abstract Background: Children with sickle cell disease (SCD) are at high risk of influenza-related morbidity and mortality. They are more likely to develop complications like acute chest syndrome (ACS), which is worsened by influenza infection, leading to high mortality and hospitalization. It has been estimated that influenza-related hospitalization rates for pediatric patients with SCD are 56 times higher than for pediatric patients without SCD. Vaccination is the primary strategy to reduce the influenza burden. Limited data exist on the burden of influenza, vaccine coverage, and seasonal influenza vaccine effectiveness (VE) in children and adolescents with SCD. Methods: This was a retrospective, test-negative case-control study to determine the vaccine coverage and to estimate influenza VE against laboratory-confirmed influenza infections among children 6 months to 21 years of age across 2021-2022, 2022-2023, and 2023-2024 influenza seasons (August 1, 2021, to July 31, 2024) in Connecticut, USA. We used electronic health records (EHR) data from the Yale New Haven Health System (YNHH) and the Connecticut Department of Public Health (DPH) to identify SCD patients and match them with their test results and influenza immunization records. We excluded non-SCD patients and those with no influenza test results. Patients with no vaccination at the time of influenza diagnosis were categorized as “unvaccinated,” while patients with a test date less than 14 days since vaccination were classified as “partially vaccinated.” If the test date is greater than or equal to 14 days since vaccination, patients were categorized as “vaccinated.” We used logistic regression models to compare odds ratios (ORs) of vaccination in cases (those with an influenza-positive test result) to controls (those with an influenza-negative test result). We calculated VE as [100% × (1 - adjusted OR)], adjusting for age, gender, race/ethnicity, and season, and computed 95% confidence intervals (CIs) around the estimates. We considered P-values of <0.05 as statistically significant. Results: We identified a population of 502 SCD patients in the YNHH and DPH registry. Of the 502 SCD patients, 161 (32.1 %) had an influenza test result recorded, with a total of 910 test encounters during the 2021-2024 influenza seasons. We identified 45 influenza-positive cases and 865 influenza-negative controls across all three influenza seasons. The median age was 7.9 years (Interquartile range, IQR, 3.9 – 15.6), 506 (55.6%) were females, and 718 (78.9%) were Non-Hispanic Black. Overall, 38.5% of those who had at least one influenza test received the seasonal influenza vaccine. Influenza infection was more frequent among those who were unvaccinated at the time of influenza diagnosis (66.7 % versus 33.3%, (needs p value OR 95% CI). The crude VE against laboratory-confirmed influenza infection was 20.9% (95% CI, -49.2-58.1). Overall adjusted VE estimate across all three influenza seasons was 26.0% (95% CI, –41.1 to 61.2). Influenza VE by season, with adjusted VE being highest in 2021-2022 (81.5%; 95% CI, -47.0 to 97.7). Influenza VE also varied by age and was highest in children 6 months to <5 years of age (27.8%; 95% CI, –99.1 to 73.8). Conclusions: Seasonal influenza vaccine uptake among children and adolescents with SCD was lower than that of the general population. Influenza vaccination decreased the risk of laboratory-confirmed influenza by >26% across three influenza seasons. Influenza VE in patients with SCD varies by season and age. There is a need to continue to monitor uptake and VE among children with SCD, as this will inform evidence-based care recommendations to reduce the burden of influenza-related complications and improve the overall quality of life for children living with SCD.