Number of Influenza Risk Factors Informs an Adult's Increased Potential of Severe Influenza Outcomes: A Multiseason Cohort Study From 2015 to 2020.

Background: While studies have evaluated factors influencing the risk of severe influenza outcomes, there is limited evidence on the additive impact of having multiple influenza risk factors and how this varies by age. Methods: Patients ≥18 years of age in the United States were evaluated retrospectively in 5 seasonal cohorts during the 2015-2020 influenza seasons. Patient-level electronic medical records linked to pharmacy and medical claims were used to ascertain covariates and outcomes. Multivariable logistic regression models were fitted for the overall population and by age subgroups to evaluate the association of demographic and clinical characteristics with odds of influenza-related medical encounters (ICD-10 codes J09*-J11*). The logistic regression models included sex, race/ethnicity, geographic region, baseline health care resource use, vaccination status, specific high-risk comorbidities, number of influenza risk factors, body mass index, and smoking status. Odds ratios from each of the 5 seasons were summarized via fixed effect meta-analysis. Results: Season cohort sizes ranged from 887 260 to 3 628 168 adults. Of all patient characteristics evaluated, an individual's cumulative number of high-risk influenza conditions, as defined per the Centers for Disease Control and Prevention, was the most predictive of an increased probability of having an influenza-related medical encounter overall and across age groups. For adults of any age, odds ratios for influenza hospitalization ranged from 1.8 (95% CI, 1.7-2.0) for 1 risk factor to 6.4 (95% CI, 5.8-7.0) for ≥4 risk factors. Conclusions: These results show that a simple measure such as the number of influenza risk factors can be highly informative of an adult's potential for severe influenza outcomes.

Relative Vaccine Effectiveness of Cell- vs Egg-Based Quadrivalent Influenza Vaccine Against Test-Confirmed Influenza Over 3 Seasons Between 2017 and 2020 in the United States.

Background: Influenza vaccine viruses grown in eggs may acquire egg-adaptive mutations that may reduce antigenic similarity between vaccine and circulating influenza viruses and decrease vaccine effectiveness. We compared cell- and egg-based quadrivalent influenza vaccines (QIVc and QIVe, respectively) for preventing test-confirmed influenza over 3 US influenza seasons (2017-2020). Methods: Using a retrospective test-negative design, we estimated the relative vaccine effectiveness (rVE) of QIVc vs QIVe among individuals aged 4 to 64 years who had an acute respiratory or febrile illness and were tested for influenza in routine outpatient care. Exposure, outcome, and covariate data were obtained from electronic health records linked to pharmacy and medical claims. Season-specific rVE was estimated by comparing the odds of testing positive for influenza among QIVc vs QIVe recipients. Models were adjusted for age, sex, geographic region, influenza test date, and additional unbalanced covariates. A doubly robust approach was used combining inverse probability of treatment weights with multivariable regression. Results: The study included 31 824, 33 388, and 34 398 patients in the 2017-2018, 2018-2019, and 2019-2020 seasons, respectively; ∼10% received QIVc and ∼90% received QIVe. QIVc demonstrated superior effectiveness vs QIVe in prevention of test-confirmed influenza: rVEs were 14.8% (95% CI, 7.0%-22.0%) in 2017-2018, 12.5% (95% CI, 4.7%-19.6%) in 2018-2019, and 10.0% (95% CI, 2.7%-16.7%) in 2019-2020. Conclusions: This study demonstrated consistently superior effectiveness of QIVc vs QIVe in preventing test-confirmed influenza over 3 seasons characterized by different circulating viruses and degrees of egg adaptation.

Incidence of Influenza-Related Medical Encounters and the Associated Healthcare Resource Use and Complications Across Adult Age Groups in The United States During the 2015-2020 Influenza Seasons.

BACKGROUND: Research on influenza burden in adults has focused on crude subgroups with cut-points at 65-years, limiting insight into how burden varies with increasing age. This study describes the incidence of influenza-related outpatient visits, emergency room (ER) visits, and hospitalizations, along with healthcare resource use and complications in the aging adult population. METHODS: Individuals ≥18 years of age in the United States were evaluated retrospectively in five seasonal cohorts (2015-2020 seasons) in strata of age with 5-year increments. Person-level electronic medical records linked to pharmacy and medical claims were used to ascertain patient characteristics and outcomes. Influenza-related medical encounters were identified based on diagnostic codes (ICD-10 codes J09*-J11*). RESULTS: Incidence of influenza-related outpatient visits was highest among people aged 18-34 years and declined with increasing age. For ER visits, incidence tended to be elevated for people aged 18-34 years, relatively stable from 35 through 60, and increased rapidly after 60. Hospitalization incidence remained relatively stable until about 50 years of age and then increased with age. One in three patients was diagnosed with pneumonia after hospitalization, regardless of age. Across seasons, age groups, and clinical settings, on average, 40.8% of individuals were prescribed antivirals and 17.2% antibiotics. CONCLUSIONS: Incidence of influenza-related hospitalizations begins to increase around age 50 rather than the more common cut-point of 65, whereas incidence of outpatient visits was highest among younger adults. Influenza infections frequently led to antiviral and antibiotic prescriptions, underscoring the role influenza vaccination can play in combating antimicrobial resistance.

Relative Effectiveness of the MF59®-Adjuvanted Influenza Vaccine Versus High-Dose and Non-Adjuvanted Influenza Vaccines in Preventing Cardiorespiratory Hospitalizations During the 2019-2020 US Influenza Season.

BACKGROUND: Adults ≥ 65 years of age have suboptimal influenza vaccination responses compared to younger adults due to age-related immunosenescence. Two vaccines were specifically developed to enhance protection: MF59-adjuvanted trivalent influenza vaccine (aIIV3) and high-dose egg-based trivalent influenza vaccine (HD-IIV3e). METHODS: In a retrospective cohort study conducted using US electronic medical records linked to claims data during the 2019-2020 influenza season, we compared the relative vaccine effectiveness (rVE) of aIIV3 with HD-IIV3e and a standard-dose non-adjuvanted egg-based quadrivalent inactivated influenza vaccine (IIV4e) for the prevention of cardiorespiratory hospitalizations, including influenza hospitalizations. We evaluated outcomes in the "any" diagnosis position and the "admitting" position on the claim. A doubly robust methodology using inverse probability of treatment weighting and logistic regression was used to adjust for covariate imbalance. rVE was calculated as 100 * (1 - ORadjusted). RESULTS: The study included 4,299,594 adults ≥ 65 years of age who received aIIV3, HD-IIV3e, or IIV4e. Overall, aIIV3 was associated with lower proportions of cardiorespiratory hospitalizations with diagnoses in any position compared to HD-IIV3e (rVE = 3.9% [95% CI, 2.7-5.0]) or IIV4e (9.0% [95% CI, 7.7-10.4]). Specifically, aIIV3 was more effective compared with HD-IIV3e and IIV4e in preventing influenza hospitalizations (HD-IIV3e: 9.7% [95% CI, 1.9-17.0]; IIV4e: 25.3% [95% CI, 17.7-32.2]). Consistent trends were observed for admitting diagnoses. CONCLUSION: Relative to both HD-IIV3e and IIV4e, aIIV3 provided improved protection from cardiorespiratory or influenza hospitalizations.

Effectiveness of the MF59-adjuvanted trivalent or quadrivalent seasonal influenza vaccine among adults 65 years of age or older, a systematic review and meta-analysis.

BACKGROUND: Standard-dose seasonal influenza vaccines often produce modest immunogenic responses in adults ≥65 years old. MF59 is intended to elicit a greater magnitude and increased breadth of immune response. OBJECTIVE: To determine the effectiveness of seasonal MF59-adjuvanted trivalent/quadrivalent influenza vaccine (aTIV/aQIV) relative to no vaccination or vaccination with standard or high-dose egg-based influenza vaccines among people ≥65 years old. METHODS: Cochrane methodological standards and PRISMA-P guidelines were followed. Real-world evidence from non-interventional studies published in peer-reviewed journals and gray literature from 1997 through to July 15, 2020, including cluster-randomized trials, were eligible. Two reviewers independently extracted data; risk of bias was assessed using the ROBINS-I tool. RESULTS: Twenty-one studies conducted during the 2006/07-2019/20 influenza seasons were included in the qualitative review; 16 in the meta-analyses. Meta-analysis of test-negative studies found that aTIV reduced medical encounters due to lab-confirmed influenza with pooled estimates of 40.7% (95% CI: 21.9, 54.9; I2  = 0%) for non-emergency outpatient visits and 58.5% (40.7, 70.9; I2  = 52.9%) for hospitalized patients. The pooled estimate of VE from case-control studies was 51.3% (39.1, 61.1; I2  = 0%) against influenza- or pneumonia-related hospitalization. The pooled estimates for the relative VE of aTIV for the prevention of influenza-related medical encounters were 13.9% (4.2, 23.5; I2  = 95.9%) compared with TIV, 13.7% (3.1, 24.2; I2  = 98.8%) compared with QIV, and 2.8% (-2.9, 8.5; I2  = 94.5%) compared with HD-TIV. CONCLUSIONS: Among adults ≥65 years, aTIV demonstrated significant absolute VE, improved relative VE compared to non-adjuvanted standard-dose TIV/QIV, and comparable relative VE to high-dose TIV.

Observational safety study of specific outcomes after trivalent cell culture seasonal influenza vaccination (Optaflu® ) among adults in THIN database of electronic UK primary healthcare records.

PURPOSE: To investigate the safety of trivalent seasonal influenza vaccine (TIVc) (Optaflu® ), the first cell culture seasonal trivalent influenza vaccine available in Europe. METHODS: Codes and unstructured text in adult electronic healthcare records (The Health Improvement Network) were searched for a TIVc brand name or batch number and possible outcomes within a 3 month pre- to 6 month post-TIVc exposure study period (2012-2015). The outcomes were severe allergic reactions, Bell's palsy, convulsions, demyelination, paresthesia, noninfectious encephalitis, neuritis (optic and brachial), vasculitis, inflammatory bowel disease, and thrombocytopenia. Risk periods were defined based on biologically plausible time frame postvaccination when an outcome caused by the vaccine might be expected to occur. Possible outcomes were adjudicated against outcome specific case definitions and a date of onset assigned by using electronic and other medical records. Observed (risk period) to expected (outside risk and preexposure periods) rate ratios, postexposure incidence, and plots of time from exposure to outcome were reported. RESULTS: Sixteen of 1011 events from 4578 exposures fulfilled a primary case definition and had a date of onset during the study period. Three were in observed time. The observed-to-expected rate ratios were (3.3, 95% CI 0.3, 31.7) for convulsions and (1.5, 95% CI 0.2, 14.9) for thrombocytopenia with 1 outcome each in observed time. There was 1 incident inflammatory bowel disease in observed, but none in expected, time. CONCLUSION: The small sample size restricts interpretation; however, no hypothesis of an increased risk of a study outcome was generated. Adjudication of events against case definitions to reduce misclassification of onset and outcomes allowed use of precise risk periods. KEY POINTS This observational study did not generate a hypothesis of an association between the first cell-culture seasonal influenza vaccination available in the European Union and any of the study outcomes (severe allergic reactions, Bell's palsy, convulsions, demyelination, paresthesia, noninfectious encephalitis, neuritis [optic and brachial], vasculitis, inflammatory bowel disease [IBD], and thrombocytopenia). The small sample size limits interpretation of the results. The review of each possible outcome identified from electronic healthcare records against case definitions was included to minimize misclassification of time and outcomes and allow the use of precise risk-periods in an observed-to-expected within cohort analysis. Plots of time from exposure to outcome were included to assess the risk windows.

Use of antithrombotic drugs and the presence of cerebral microbleeds: the Rotterdam Scan Study.

BACKGROUND: Cerebral microbleeds are hemosiderin deposits in the brain that are indicative of microangiopathy. Microbleeds in strictly lobar brain locations have been related to cerebral amyloid angiopathy, a bleeding-prone disease state. OBJECTIVE: To investigate the relation between antithrombotic drug use and the presence of cerebral microbleeds, especially those in strictly lobar locations. DESIGN: A population-based, cross-sectional analysis that used magnetic resonance imaging (MRI) to assess the presence and location of microbleeds. Complete information on outpatient use of platelet aggregation inhibitors and anticoagulant drugs before MRI was obtained from automated pharmacy records. SETTING: The Rotterdam Scan Study, a population-based imaging study in a general elderly community in the Netherlands. PARTICIPANTS: A population-based sample of 1062 persons from a longitudinal cohort, 60 years and older, free of dementia, who underwent MRI examinations between August 15, 2005, and November 22, 2006. MAIN OUTCOME MEASURES: Presence of cerebral microbleeds on MRI. RESULTS: Compared with nonusers of antithrombotic drugs, cerebral microbleeds were more prevalent among users of platelet aggregation inhibitors (adjusted odds ratio [OR], 1.71; 95% confidence interval [CI], 1.21-2.41). We did not find a significant association for anticoagulant drugs and microbleed presence (OR, 1.49; 95% CI, 0.82-2.71). Strictly lobar microbleeds were more prevalent among aspirin users (adjusted OR compared with nonusers, 2.70; 95% CI, 1.45-5.04) than among persons using carbasalate calcium (adjusted OR, 1.16; 95% CI, 0.66-2.02). This difference was even more pronounced when comparing persons who had used similar dosages of both drugs. CONCLUSIONS: This cross-sectional study shows that use of platelet aggregation inhibitors is related to the presence of cerebral microbleeds. Furthermore, aspirin and carbasalate calcium use may differently relate to the presence of strictly lobar microbleeds.

Cyclooxygenase selectivity of nonsteroidal anti-inflammatory drugs and risk of stroke.

BACKGROUND: In clinical trials, cyclooxygenase (COX)-2-selective nonsteroidal anti-inflammatory drugs (NSAIDs) were associated with an increased risk of thromboembolic events. We studied the association between NSAID use and risk of stroke in the prospective, population-based Rotterdam Study. METHODS: We followed 7636 persons free of stroke at baseline (1991-1993) for incident stroke until September 2004. Data on all filled prescriptions came from pharmacy records. With Cox regression models, we calculated crude and adjusted hazard ratios (HRs) of stroke for time-dependent current use, compared with never use, of NSAIDs grouped according to COX selectivity (COX-1 selective, nonselective, and COX-2 selective) and individual NSAIDs. RESULTS: At baseline, the mean age of the study sample was 70.2 years, and 61.3% were female. During 70 063 person-years of follow-up (mean, 9.2 years), 807 persons developed a stroke (460 ischemic, 74 hemorrhagic, and 273 unspecified). Current users of nonselective (HR, 1.72; 95% confidence interval [CI], 1.22-2.44) and COX-2-selective (HR, 2.75; 95% CI, 1.28-5.95) NSAIDs had a greater risk of stroke, but not users of COX-1-selective NSAIDs (HR, 1.10; 95% CI, 0.41-2.97). Hazard ratios (95% CIs) for ischemic stroke were 1.68 (1.05-2.69) for nonselective and 4.54 (2.06-9.98) for COX-2-selective NSAIDs. For individual NSAIDs, current use of the nonselective naproxen (HR, 2.63; 95% CI, 1.47-4.72) and the COX-2-selective rofecoxib (HR, 3.38; 95% CI, 1.48-7.74) was associated with a greater risk of stroke. Hazard ratios (95% CIs) for diclofenac (1.60 [1.00-2.57]), ibuprofen (1.47 [0.73-3.00]), and celecoxib (3.79 [0.52-27.6]) were greater than 1.00 but were not statistically significant. CONCLUSIONS: In the general population, we found a greater risk of stroke with current use of nonselective and COX-2-selective NSAIDs. The risk of stroke was not limited to the use of COX-2-selective NSAIDs.

Nonsteroidal anti-inflammatory drugs and the risk of Parkinson disease.

BACKGROUND: Several lines of evidence suggest a role of inflammatory processes in Parkinson disease, although it is still unclear whether inflammation is a cause or rather a consequence of neurodegeneration. METHODS: In a prospective population-based cohort study among 6,512 participants aged >or=55 years, with repeated in-person examination, we evaluated the association between cumulative use of nonsteroidal anti-inflammatory drugs (NSAIDs) and the risk of Parkinson disease. Complete information on filled prescriptions was available from automated pharmacy records. Data were analyzed by means of Cox proportional hazards regression analysis, adjusted for age, sex, smoking habits and coffee consumption. RESULTS: After an average 9.4 years of follow-up, 88 new cases of Parkinson disease were detected. No association was found between use of NSAIDs and the risk of Parkinson disease (adjusted hazard ratio for any NSAID use, 1.50; 95% confidence interval, 0.95-2.37). CONCLUSION: Our findings do not support the hypothesis that NSAIDs might decrease the risk of Parkinson disease.