Risk of Immune Thrombocytopenia Induced By Influenza Vaccine. a Nationwide Population-Based Study in France

Introduction: Epidemiological studies suggest a risk of immune thrombocytopenia (ITP) following viral infections, particularly influenza. Conversely, an increased risk of ITP following vaccination has been proven for some vaccines like Measles-Mumps-Rubella vaccine. However, the risk of ITP induced by influenza vaccine is debated. Two case-controls studies has been conducted, with contradictory results: in the Berlin Case-Control Surveillance Study, an increased risk has been found (odds ratio - OR: 3.8 [95% confidence interval - CI: 1.5- 9.1]. Conversely, the French PGRx study suggested the absence of risk of ITP after influenza vaccination [OR: 0.9; 95% CI: 0.4-2.1]. These studies were limited by the number of ITP patients included (169 and 198, respectively) and other limitations. Therefore, we aimed to assess the risk of ITP induced by influenza vaccine in a nationwide cohort in France.

Methods: We conducted a population-based study in France within the FAITH cohort (NCT03429660). This cohort is built within the National Health Database that links sociodemographic, hospital and out-hospital data. The FAITH cohort includes all adult patients with incident ITP in France since 2009. Patients are identified using a validated algorithm combining diagnosis codes and drug exposures (with very high positive predictive values). We included in the present study all patients with incident primary ITP aged ≥65 years at ITP diagnosis (indication of influenza vaccination in the general population in France) between July 2009 and June 2015. We assessed the link between influenza vaccine and ITP onset using two designs: a case-control and a self-controlled case series designs. In the case-control design, ITP cases were matched with four controls from the general population for age, sex and place of residency. Index dates for controls were similar to index dates of their matched cases. Cases and controls were compared for exposure to influenza vaccine in the 6 weeks before the index date using conditional logistic regression models adjusted for exposure to other drugs known as inducers of ITP. In the self-controlled case series study, only vaccinated ITP cases were included. The analysis compared the incidence of ITP within periods of risk (6 weeks following vaccination) to the incidence of ITP within other periods of time. We further excluded the 2 weeks prior to vaccine dispensing from the analysis to address selective survival bias (healthy vaccinee effect). Incidence rate ratios (IRRs) adjusted for seasonality were calculated.

Results: We included 3,142 incident primary ITP patients aged ≥65 years matched with 12,528 controls in the case-control study. Overall, 147 cases (4.7%) and 579 controls (4.6%) were vaccinated with influenza vaccine during the 6 weeks prior to the index date (adjusted OR: 0.99; 95% CI: 0.80-1.23]). In the self-controlled case series study, 1,875 vaccinated ITP cases were included. Among them, 146 (7.8%) patients were diagnosed for ITP during one of the risk periods following vaccination. The adjusted IRR was 0.96 [95 CI%: 0.80-1.17].

Conclusion: This nationwide population-based study using two different designs showed no increased risk of ITP after influenza vaccination.