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BackgroundThe natural history of SARS-CoV-2 infection and transmission dynamics may have changed as SARS-CoV-2 has evolved and population immunity has shifted.MethodsHousehold contacts, enrolled from two multi-site case-ascertained household transmission studies (April 2020–April 2021 and September 2021–September 2022), were followed for 10–14 days after enrollment with daily collection of nasal swabs and/or saliva for SARS-CoV-2 testing and symptom diaries. SARS-CoV-2 virus lineage was determined by whole genome sequencing, with multiple imputation where sequences could not be recovered. Adjusted infection risks were estimated using modified Poisson regression.Findings858 primary cases with 1473 household contacts were examined. Among unvaccinated household contacts, the infection risk adjusted for presence of prior infection and age was 58% (95% confidence interval [CI]: 49–68%) in households currently exposed to pre-Delta lineages and 90% (95% CI: 74–100%) among those exposed to Omicron BA.5 (detected May – September 2022). The fraction of infected household contacts reporting any symptom was similarly high between pre-Delta (86%, 95% CI: 81–91%) and Omicron lineages (77%, 70–85%). Among Omicron BA.5-infected contacts, 48% (41–56%) reported fever, 63% (56–71%) cough, 22% (17–28%) shortness of breath, and 20% (15–27%) loss of/change in taste/smell.InterpretationThe risk of infection among household contacts exposed to SARS-CoV-2 is high and increasing with more recent SARS-CoV-2 lineages. This high infection risk highlights the importance of vaccination to prevent severe disease.FundingFunded by the Centers for Disease Control and Prevention and the Food and Drug Administration.Key points-Monitoring the transmissibility and symptomatology of SARS-CoV-2 lineages is important for informing public health practice and understanding the epidemiology of COVID-19; household transmission studies contribute to our understanding of the natural history of SARS-CoV-2 infections and the transmissibility of SARS-CoV-2 variants.-The Omicron BA.5 sub-lineage is highly transmissible, similar to previous Omicron sub-lineages.-Over 80% of infected household contacts reported at least 1 symptom during their infection and the proportion of household contacts with asymptomatic infection did not differ by SARS-CoV-2 variant. The most common symptom was cough. Change in taste or smell was more common in Omicron BA.5 infections, compared to previous Omicron sub-lineages, but less common compared to pre-Delta lineages.-The high infection risk among household contacts supports the recommendations that individuals maintain up-to-date and lineage-specific vaccinations to mitigate further risks of severe disease.

This retrospective study utilized healthcare claims data to investigate the incidence, patient demographics, and concurrent diagnoses associated with long COVID in the U.S. Medicare population. Nearly 194,000 (0.6%) beneficiaries had post-COVID condition diagnoses, with higher rates among nursing home residents. Of those medically attended for COVID-19, 3-5% were diagnosed with post-COVID conditions. We observed minimal demographic differences between those with and without long COVID. When comparing diagnoses concurrent with long COVID and COVID-19, certain codes (G72 and J84) for myopathies and interstitial pulmonary diseases were disproportionately present with long COVID.

BackgroundWe evaluated prevaccine pandemic period COVID-19 death risk factors among nursing home (NH) residents.MethodsIn a retrospective cohort study covering Medicare fee-for-service beneficiaries aged ≥65 years residing in US NHs, we estimated adjusted hazard ratios (HRs) using multivariate Cox proportional hazards regressions.ResultsAmong 608251 elderly NH residents, 57398 (9.4%) died of COVID-19–related illness 1 April to 22 December 2020; 46.9% (26893) of these deaths occurred without prior COVID-19 hospitalizations. We observed a consistently increasing age trend for COVID-19 deaths. Racial/ethnic minorities shared similarly high risk of NH COVID-19 deaths with whites. NH facility characteristics for-profit ownership and low health inspection ratings were associated with higher death risk. Resident characteristics (male [HR, 1.69], end-stage renal disease [HR, 1.42], cognitive impairment [HR, 1.34], and immunocompromised status [HR, 1.20]) were death risk factors. Other individual-level characteristics were less predictive of death than in community-dwelling population.ConclusionsLow NH health inspection ratings and private ownership contributed to COVID-19 death risks. Nearly half of NH COVID-19 deaths occurred without prior COVID-19 hospitalization and older residents were less likely to get hospitalized with COVID-19. No substantial differences were observed by race/ethnicity and socioeconomic status for NH COVID-19 deaths.

ObjectiveTo estimate the effectiveness of messenger RNA (mRNA) booster doses during the period of Delta and Omicron variant dominance.DesignWe conducted a matched test-negative case–control study to estimate the vaccine effectiveness (VE) of three and two doses of mRNA vaccines against infection (regardless of symptoms) and against COVID-19-related hospitalisation and death.SettingVeterans Health Administration.ParticipantsWe used electronic health record data from 114 640 veterans who had a SARS-CoV-2 test during November 2021–January 2022. Patients were largely 65 years or older (52%), male (88%) and non-Hispanic white (59%).Main outcome measuresFirst positive result for a SARS-CoV-2 PCR or antigen test.ResultsAgainst infection, booster doses had higher estimated VE (64%, 95% CI 63 to 65) than two-dose vaccination (12%, 95% CI 10 to 15) during the Omicron period. For the Delta period, the VE against infection was 90% (95% CI 88 to 92) among boosted vaccinees, higher than the VE among two-dose vaccinees (54%, 95% CI 50 to 57). Against hospitalisation, booster dose VE was 89% (95% CI 88 to 91) during Omicron and 94% (95% CI 90 to 96) during Delta; two-dose VE was 63% (95% CI 58 to 67) during Omicron and 75% (95% CI 69 to 80) during Delta. Against death, the VE with a booster dose was 94% (95% CI 90 to 96) during Omicron and 96% (95% CI 87 to 99) during Delta.ConclusionsAmong an older, mostly male, population with comorbidities, we found that an mRNA vaccine booster was highly effective against infection, hospitalisation and death. Although the effectiveness of booster vaccination against infection was moderately higher against Delta than against the Omicron SARS-CoV-2 variant, effectiveness against severe disease and death was similarly high against both variants.

BackgroundShingrix (recombinant zoster vaccine) was licensed to prevent herpes zoster, dispensed as 2 doses given 2–6 months apart among adults aged ≥50 years. Clinical trials yielded efficacy of >90% for confirmed herpes zoster, but post-market performance has not been evaluated. Efficacy of a single dose and a delayed second dose and efficacy among persons with autoimmune or immunosuppressive conditions have not been studied. We aimed to assess post-market vaccine effectiveness of Shingrix.MethodsWe conducted a cohort study among Medicare Part D community-dwelling beneficiaries aged >65 years. Herpes zoster was identified using a medical office visit diagnosis with treatment, and postherpetic neuralgia was identified using a validated algorithm. We used inverse probability of treatment weighting to improve cohort balance and marginal structural models to estimate hazard ratios.ResultsWe found a vaccine effectiveness of 70.1% (95% confidence interval [CI], 68.6–71.5) and 56.9% (95% CI, 55.0–58.8) for 2 and 1 doses, respectively. The 2-dose vaccine effectiveness was not significantly lower for beneficiaries aged >80 years, for second doses received at ≥180 days, or for individuals with autoimmune conditions. The vaccine was also effective among individuals with immunosuppressive conditions. Two-dose vaccine effectiveness against postherpetic neuralgia was 76.0% (95% CI, 68.4–81.8).ConclusionsThis large real-world observational study of the effectiveness of Shingrix demonstrates the benefit of completing the 2-dose regimen. Second doses administered beyond the recommended 6 months did not impair effectiveness. Our effectiveness estimates were lower than the clinical trials estimates, likely due to differences in outcome specificity.

BackgroundThe current study was performed to evaluate risk factors for severe coronavirus disease 2019 (COVID-19) outcomes among Medicare beneficiaries during the pandemic’s early phase.MethodsIn a retrospective cohort study covering Medicare fee-for-service beneficiaries, we separated out elderly residents in nursing homes (NHs) and those with end-stage renal disease (ESRD) from the primary study population of individuals age ≥65 years. Outcomes included COVID-19 hospital encounters and COVID-19-associated deaths. We estimated adjusted odds ratios (ORs) using logistic regression.ResultsWe analyzed 25 333 329 elderly non-NH beneficiaries without ESRD, 653 966 elderly NH residents, and 292 302 patients with ESRD. COVID-related death rates (per 10 000) were much higher among elderly NH residents (275.7) and patients with ESRD (60.8) than in the primary study population (5.0). Regression-adjusted clinical predictors of death among the primary population included immunocompromised status (OR, 1.43), frailty index conditions such as cognitive impairment (3.16), and other comorbid conditions, including congestive heart failure (1.30). Demographic-related risk factors included male sex (OR, 1.77), older age (3.09 for 80- vs 65-year-olds), Medicaid dual-eligibility status (2.17), and racial/ethnic minority. Compared with whites, ORs were higher for blacks (2.47), Hispanics (3.11), and Native Americans (5.82). Results for COVID-19 hospital encounters were consistent.ConclusionsFrailty, comorbid conditions, and race/ethnicity were strong risk factors for COVID-19 hospitalization and death among the US elderly.

Background Approximately 50 000 influenza-associated deaths occur annually in the United States, overwhelmingly among individuals aged ≥65 years. Although vaccination is the primary prevention tool, investigations have shown low vaccine effectiveness (VE) in recent years, particularly among the elderly. We analyzed the relative VE (RVE) of all influenza vaccines among Medicare beneficiaries aged ≥65 years to prevent influenza hospital encounters during the 2019–2020 season. Methods Retrospective cohort study using Poisson regression and inverse probability of treatment weighting (IPTW). Exposures included egg-based high-dose trivalent (HD-IIV3), egg-based adjuvanted trivalent (aIIV3), egg-based standard dose (SD) quadrivalent (IIV4), cell-based SD quadrivalent (cIIV4), and recombinant quadrivalent (RIV4) influenza vaccines. Results We studied 12.7 million vaccinated beneficiaries. Following IPTW, cohorts were well balanced for all covariates and health-seeking behavior indicators. In the adjusted analysis, RIV4 (RVE, 13.3%; 95% CI, 7.4–18.9%), aIIV3 (RVE, 8.2%; 95% CI, 4.2–12.0%), and HD-IIV3 (RVE, 6.8%; 95% CI, 3.3–10.1%) were significantly more effective in preventing hospital encounters than the reference egg-based SD IIV4, while cIIV4 was not significantly more effective than IIV4 (RVE, 2.8%; 95% CI, −2.8%, 8.2%). Our results were consistent across all analyses. Conclusions In this influenza B-Victoria and A(H1N1)–dominated season, RIV4 was moderately more effective than other vaccines, while HD-IIV3 and aIIV3 were more effective than the IIV4 vaccines, highlighting the contributions of antigen amount and adjuvant use to VE. Egg adaptation likely did not substantially affect our RVE evaluation. Our findings, specific to the 2019–2020 season, should be evaluated in other studies using virological case confirmation.

ImportancePrevious studies have analyzed effectiveness of booster mRNA Covid-19 vaccination and compared it with 2-dose primary series for both Delta and Omicron variants. Observational studies that estimate effectiveness by comparing outcomes among vaccinated and unvaccinated individuals may suffer from residual confounding and exposure misclassification.ObjectiveTo estimate relative effectiveness of booster vaccination versus the 2-dose primary series with self-controlled study designDesign, Setting and ParticipantsWe used the Veterans Health Administration (VHA) Corporate Data Warehouse to identify U.S. Veterans enrolled in care ≥2 years who received the 2-dose primary mRNA Covid-19 vaccine series and a mRNA Covid-19 booster following expanded recommendation for booster vaccination, and who had a positive SARS-CoV-2 test during the Delta (9/23/2021-11/30/2021) or Omicron (1/1/22-3/1/22) predominant period. Among them, we conducted a self-controlled risk interval (SCRI) analysis to compare odds of SARS-CoV-2 infection during a booster exposure interval versus a control interval.Exposurescontrol interval (days 4-6 post-booster vaccination, presumably prior to gain of booster immunity), and booster exposure interval (days 14-16 post-booster vaccination, presumably following gain of booster immunity)Outcomes and MeasuresPositive PCR or antigen SARS-CoV-2 test. Separately for Delta and Omicron periods, we used conditional logistic regression to calculate odds ratios (OR) of a positive test for the booster versus control interval and calculated relative effectiveness of booster versus 2-dose primary series as (1-OR)*100. The SCRI approach implicitly controlled for time-fixed confounders.ResultsWe found 42 individuals with a positive SARS-CoV-2 test in the control interval and 14 in the booster exposure interval during Delta period, and 137 and 66, respectively, in Omicron period. For the booster versus 2-dose primary series, the odds of infection were 70% (95%CI: 42%, 84%) lower during the Delta period and 56% (95%CI: 38%, 67%) lower during Omicron. Results were similar for ages ConclusionsBooster vaccination was more effective relative to a 2-dose primary series, the relative effectiveness was consistent across age groups and was higher during the Delta predominant period than during the Omicron period.

Key Points Question What was the COVID-19 vaccination coverage and estimated mRNA COVID-19 vaccine effectiveness (VE) among US veterans in the first 3 months following vaccine rollout? Findings In this case-control study including 6 647 733 veterans, 23% of veterans received at least 1 COVID-19 vaccination during the first 3 months of vaccine rollout. VE against infection was estimated to be 95% for full vaccination; estimated VE against COVID-19-related hospitalization was 91%, and there were no COVID-19–related deaths among fully vaccinated veterans. Meaning These findings suggest that early vaccination rollout for veterans was efficient, and estimated VE was high for this diverse US population., This case-control study describes the scope of the mRNA COVID-19 vaccination rollout and estimates the association between vaccination and reductions in SARS-CoV-2 infections among veterans during the first 3 months of vaccine rollout., Importance Effectiveness of mRNA vaccinations in a diverse older population with high comorbidity is unknown. Objectives To describe the scope of the COVID-19 vaccination rollout among US veterans, and to estimate mRNA COVID-19 vaccine effectiveness (VE) as measured by rates of SARS-CoV-2 infection. Design, Setting, and Participants This matched test–negative case-control study was conducted using SARS-CoV-2 test results at Veterans Health Administration sites from December 14, 2020, to March 14, 2021. Vaccine coverage was estimated for all veterans. VE against SARS-CoV-2 infection and COVID-19–related hospitalization and death were estimated using electronic health records from veterans who routinely sought care at a VHA facility and had a test result positive for SARS-CoV-2 (cases) or negative for SARS-CoV-2 (controls). Cases and controls were matched on time of test and geographic region. Data were analyzed from May to July 2021. Exposures Vaccination status, defined as unvaccinated, partially vaccinated (≥14 days after first dose until second dose), or fully vaccinated (≥14 days after second dose), at time of test. Main Outcomes and Measures The main outcome of interest was a positive result for SARS-CoV-2 on a polymerase chain reaction or antigen test. Secondary outcomes included COVID-19–related hospitalization and death, defined by discharge data and proximity of event to positive test result. VE was estimated from odds ratios for SARS-CoV-2 infection with 95% CIs. Results Among 6 647 733 veterans included (3 350 373 veterans [50%] aged ≥65 years; 6 014 798 [90%] men and 632 935 [10%] women; 461 645 Hispanic veterans of any race [7%], 1 102 471 non-Hispanic Black veterans [17%], and 4 361 621 non-Hispanic White veterans [66%]), 1 363 180 (21%) received at least 1 COVID-19 vaccination by March 7, 2021. In this period, during which the share of SARS-CoV-2 variants Alpha, Epsilon, and Iota had started to increase in the US, estimates of COVID-19 VE against infection, regardless of symptoms, was 95% (95% CI, 93%-96%) for full vaccination and 64% (95% CI, 59%-68%) for partial vaccination. Estimated VE against COVID-19–related hospitalization for full vaccination was 91% (95% CI 83%-95%); there were no deaths among veterans who were fully vaccinated. VE against infection was similar across subpopulations (non-Hispanic Black, 94% [95% CI, 88%-97%]; Hispanic [any race], 83% [95% CI, 45%-95%]; non-Hispanic White, 92% [95% CI 88%-94%]; rural, 94% [95% CI, 89%-96%]; urban, 93% 95% CI, 89%-95%]). Conclusions and Relevance For veterans of all racial and ethnic subgroups living in urban or rural areas, mRNA vaccination was associated with substantially decreased risk of COVID-19 infection and hospitalization, with no deaths among fully vaccinated veterans.

Background Guillain-Barre syndrome (GBS) is a serious acute demyelinating disease, an increased risk of which was found after the 1976 swine flu vaccinations. The U.S. Food and Drug Administration, in collaboration with the Centers for Medicare & Medicaid Services, has been conducting active surveillance for GBS after influenza vaccinations of Medicare Fee-For-Service beneficiaries since 2009. Methods We conducted active surveillance for GBS claims in the 2015–2016 and 2016–2017 influenza seasons using the Updating Sequential Probability Ratio Test (USPRT) to monitor for signals of GBS risk. We performed self-controlled risk interval (SCRI) analyses at the end of both seasons, including chart confirmation in the 2015–2016 season, to estimate the odds ratio of GBS risk. We used 1–42 and 8–21 days post-vaccination as primary and secondary risk windows, respectively, and 43–84 days post-vaccination as the control window. Results Over 13 million beneficiaries were vaccinated in each season. USPRT found a low magnitude signal for GBS in both seasons. SCRI analyses did not find excess GBS risk following any influenza vaccine for days 1–42 post-vaccination in either season. In the 2015–2016 season, for the 8–21 day window, our chart-confirmation showed an attributable GBS risk of 0.87 (95% CI: 0.16, 1.49) and 1.68 (95% CI: 0.69, 2.41) cases per million vaccinees after all seasonal and high dose (HD) vaccines, respectively, an elevated GBS risk for beneficiaries aged ≥75 years following all seasonal vaccines (OR: 2.25; 95% CI: 1.15, 4.39) and HD vaccine (OR: 3.67, 95% CI: 1.52, 8.85), and an elevated GBS risk for males who received seasonal vaccines (OR: 2.18; 95% CI: 1.15, 4.15) and HD vaccine (OR: 3.33; 95% CI: 1.35, 8.20). The finding of elevated GBS risk with advancing age and in males is consistent with literature; however, a distinction between HD and SD was a new finding. In the 2016–17 season, for the 8–21 day window, attributed cases showed an attributable GBS risk of 0.87 (95% CI: 0.03, 1.61) and 1.11 (95% CI: 0.00, 2.01) cases per million vaccinees after all seasonal and HD vaccines, respectively. We found no excess GBS risk for standard dose vaccines in the 8–21 day window in either season. Conclusions Our primary analysis finding of no excess GBS risk during both seasons was reassuring. The slightly elevated GBS risk, although in the expected range, in the 8–21 day window after all seasonal and high dose vaccines, but not after standard dose vaccines is hypothesis-generating because the difference may be due to vaccine factors such as antigen amount or strains in various seasons or due to host factors.

BackgroundStudies have found that the high-dose influenza vaccine has a higher relative vaccine effectiveness (RVE) versus standard-dose vaccines in some seasons. We evaluated the effect of age on the RVE of high-dose versus standard-dose influenza vaccines among Medicare beneficiaries.MethodsA 6-season retrospective cohort study from 2012 to 2018 among Medicare beneficiaries aged ≥65 years was performed. Poisson regression was used to evaluate the effect of age on the RVE of high-dose versus standard-dose influenza vaccines in preventing influenza-related hospitalizations.ResultsThe study included >19 million vaccinated beneficiaries in a community pharmacy setting. The Poisson models indicated a slightly increasing trend in RVE with age in all seasons. The high-dose vaccine was more effective than standard-dose vaccines in preventing influenza-related hospital encounters (ie, influenza-related inpatient stays and emergency department visits) in the 2012–2013 (RVE, 23.1%; 95% confidence interval [CI], 17.6%–28.3%), 2013–2014 (RVE, 15.3%; 95% CI, 7.8%–22.3%), 2014–2015 (RVE, 8.9%; 95% CI, 5.6%–12.1%), and 2016–2017 (RVE, 12.6%; 95% CI, 6.3%–18.4%) seasons and was at least as effective in all other seasons. We also found that the high-dose vaccine was consistently more effective than standard-dose vaccines across all seasons for people aged ≥85 years. Similar trends were observed for influenza-related inpatient stays.ConclusionsThe RVE of high-dose versus standard-dose influenza vaccines increases with age.

Purpose Medicare claims can provide real-world evidence (RWE) to support the Food and Drug Administration's ability to conduct postapproval studies to validate products' safety and effectiveness. However, Medicare claims do not contain comprehensive information on some important sources of bias. Thus, we piloted an approach using the Medicare Current Beneficiary Survey (MCBS), a nationally representative survey of the Medicare population, to (a) assess cohort balance with respect to unmeasured confounders in a herpes zoster vaccine (HZV) effectiveness claims-based study and (b) augment Medicare claims with MCBS data to include unmeasured covariates. Methods We reanalyzed data from our published HZV effectiveness Medicare analysis, using linkages to MCBS to obtain information on impaired mobility, education, and health-seeking behavior. We assessed survey variable balance between the matched cohorts and selected imbalanced variables for model adjustment, applying multiple imputation by chained equations (MICE) to impute these potential unmeasured confounders. Results The original HZV effectiveness study cohorts appeared well balanced with respect to variables we selected from the MCBS. Our imputed results showed slight shifts in HZV effectiveness point estimates with wider confidence intervals, but indicated no statistically significant differences from the original study estimates. Conclusions Our innovative use of linked survey data to assess cohort balance and our imputation approach to augment Medicare claims with MCBS data to include unmeasured covariates provide potential solutions for addressing bias related to unmeasured confounding in large database studies, thus adding new tools for RWE studies.

Using Medicare claims data on prescriptions of oseltamivir dispensed to people 65 years old and older, we present a descriptive analysis of patterns of influenza activity in the United States for 579 core-based statistical areas (CBSAs) from the 2010–2011 through the 2015–2016 influenza seasons. During this time, 1,010,819 beneficiaries received a prescription of oseltamivir, ranging from 45,888 in 2011–2012 to 380,745 in 2014–2015. For each season, the peak weekly number of prescriptions correlated with the total number of prescriptions (Pearson’s r ≥ 0.88). The variance in peak timing decreased with increasing severity (p

Importance The scope of vaccination rollout and effectiveness of mRNA SARS-CoV-2 vaccines in the United States (US), and US Veterans specifically, has not been fully assessed. Objective To estimate receipt of SARS-CoV-2 vaccines, and vaccine effectiveness (VE) against SARS-CoV-2 infection, subsequent disease-related severity and mortality. Design, Setting, and Participants First, receipt of any SARS-CoV-2 vaccine by March 7, 2021 was described for all enrolled and alive Veterans within the Veterans Health Administration (VHA). Second, to evaluate mRNA SARS-CoV-2 VE, a matched test negative case-control evaluation was conducted across all VHA facilities utilizing SARS-CoV-2 positive (cases [n=16,690]) and negative (controls [n=61,610]) tests from Veterans aged ≥18 years old who routinely sought care at a VHA facility and were tested for SARS-CoV-2 from December 14, 2020, through March 14, 2021. Exposures Vaccination histories were obtained from pharmacy and medical records to determine if patients were unvaccinated, partially vaccinated (from 7 days after first dose until day of second dose of mRNA SARS-CoV-2 vaccine), or fully vaccinated (from 7 days after second dose of mRNA SARS-CoV-2 vaccine) at time of SARS-CoV-2 test. Main Outcome Measures Primary outcomes were (1) vaccine receipt among Veterans and specific subpopulations, (2) VE calculated from odds ratios (ORs) with 95% confidence intervals (95% CI) for the association between SARS-CoV-2 infection and full vs. no vaccination, and (3) VE against infection for partial vs. no vaccination. VE against COVID-19-related hospitalization and death were also estimated. Results By March 7, 2020, among 6,170,750 Veterans, 1,547,045 (23.1%) received at least one SARS-CoV-2 vaccine. Based on the analysis of mRNA SARS-CoV-2 vaccines, VE against infection was 93.7% (95% CI 92.0-95.0) and 57.7% (95% CI 53.5-61.5) for full and partial vaccination (vs. no vaccination), respectively. VE was similar for subpopulations. VE against COVID-19-related hospitalization and death for full vs. no vaccination was 90.7% (95% CI 90.0-91.3) and 94.7% (95% CI 91.3-98.1), respectively. Conclusion and Relevance Vaccines are effective in reducing SARS-CoV-2 infections and disease-related severity and mortality in the Veteran population. Effective vaccine, as well as their efficient and equitable distribution, are important for reducing COVID-19 disease burden among Veterans. Key Points Question What is the scope of VHA vaccination rollout and the impact of mRNA SARS-CoV-2 vaccination among Veterans? Findings Vaccination rollout reached all Veteran subpopulations in the first three months. Effectiveness of full vaccination with mRNA SARS-CoV-2 vaccines was 93.7% for preventing infection, comparable to that demonstrated in clinical trials. Effectiveness was similarly high for the elderly, ethnic and racial minorities, individuals with low income, homeless persons, and immunocompromised Veterans. Meaning Effective vaccines and their efficient and equitable distribution helped the VHA to reduce COVID-19 disease burden and disparities among Veterans within the first three months of vaccine distribution.

Background There are theoretical concerns that angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) could increase the risk of severe Covid-19. Objective To determine if ACEIs and ARBs are associated with an increased risk of Covid-19 hospitalization overall, or hospitalization involving intensive care unit (ICU) admission, invasive mechanical ventilation, or death. Design Observational case-control study. Participants Medicare beneficiaries aged ≥ 66 years with hypertension, treated with ACEIs, ARBs, calcium channel blockers (CCBs), or thiazide diuretics. Main Measures Adjusted odds ratios (OR) and 95% confidence intervals (CI) for the outcomes of Covid-19 hospitalization, or hospitalization involving ICU admission, invasive mechanical ventilation, or death. Results A total of 35,300 cases of hospitalized Covid-19 were matched to 228,228 controls on calendar date and neighborhood of residence. The median age of cases was 79 years, 57.4% were female, and the median duration of hospitalization was 8 days (interquartile range 5–12). ACEIs and ARBs were associated with a slight reduction in Covid-19 hospitalization risk compared with treatment with other first-line antihypertensives (OR for ACEIs 0.95, 95% CI 0.92–0.98; OR for ARBs 0.94, 95% CI 0.90–0.97). Similar results were obtained for hospitalizations involving ICU admission, invasive mechanical ventilation, or death. There were no meaningful differences in risk for ACEIs compared with ARBs. In an analysis restricted to monotherapy with a first-line agent, CCBs were associated with a small increased risk of Covid-19 hospitalization compared with ACEIs (OR 1.09, 95% CI 1.04–1.14), ARBs (OR 1.10, 95% CI 1.05–1.15), or thiazide diuretics (OR 1.11, 95% CI 1.03–1.19). Conclusions ACEIs and ARBs were not associated with an increased risk of Covid-19 hospitalization or with hospitalization involving ICU admission, invasive mechanical ventilation, or death. The finding of a small increased risk of Covid-19 hospitalization with CCBs was unexpected and could be due to residual confounding. Supplementary Information The online version contains supplementary material available at 10.1007/s11606-021-07155-z.

Meta-analysis can be especially useful for evaluation of vaccine safety, since individual studies often have limited power to detect an increase in safety risk. In order to gain a perspective on the current state of utilization of the technique of meta-analysis for evaluation of vaccine safety and to assess the methodological characteristics of these meta-analyses, we conducted a systematic review of published meta-analyses. We identified 61 meta-analyses of vaccine safety. Safety outcomes for influenza and human papillomavirus (HPV) vaccines were most frequently meta-analysed. The most studied safety outcomes were local and systemic reactions, as well as Serious Adverse Events. Most meta-analyses were literature based. Differences in the definitions of safety outcomes across the different studies and the poor reporting of safety in the published literature were described as challenges when conducting a meta-analysis of vaccine safety. A way to overcome these challenges is through the implementation of standardized safety outcomes definitions and reporting. A prospectively conducted meta-analysis, i.e. a meta-analysis planned prior to the conduct of the trials, as well as implementation of subject-level meta-analysis techniques can also reduce or eliminate the impact of these difficulties.

Background The low influenza vaccine effectiveness (VE) observed during the A(H3N2)-dominated 2017–2018 season may be due to vaccine virus adaptation to growth in eggs. We compared the effectiveness of cell-cultured and egg-based vaccines among Medicare beneficiaries. Methods Retrospective cohort study on Medicare beneficiaries aged ≥65 years who received an influenza vaccine (cell-cultured, egg-based quadrivalent; egg-based high-dose, adjuvanted, or standard-dose trivalent) during the 2017–2018 season. We used Poisson regression to evaluate relative VE (RVE) in preventing influenza-related hospital encounters. Results Of >13 million beneficiaries, RVE for cell-cultured vaccines relative to egg-based quadrivalent vaccines was 10% (95% confidence interval [CI], 7%–13%). In a midseason interim analysis, this estimate was 16.5% (95% CI, 10.3%–22.2%). In a 5-way comparison, cell-cultured (RVE, 11%; 95% CI, 8%–14%) and egg-based high-dose (RVE, 9%; 95% CI, 7%–11%) vaccines were more effective than egg-based quadrivalent vaccines. Conclusions The modest VE difference between cell-cultured and egg-based vaccines only partially explains the low overall VE reported by the Centers for Disease Control and Prevention, suggesting that egg adaptation was not the main contributor to the low VE found among individuals aged ≥65 years. The midseason interim analysis we performed demonstrates that our methods can be used to evaluate VE actively during the influenza season.

BACKGROUND Over 34 million residents of the United States aged 65 years and older are also Medicare prescription drug beneficiaries. Medical claims records for this age group potentially provide a wealth of data for better understanding influenza epidemiology. OBJECTIVE The purpose of this study was to evaluate data on oseltamivir dispensing extracted from medical claims records as an indicator of influenza activity in the United States for the 2010-11 through 2014-15 influenza seasons. METHODS We used Centers for Medicare and Medicaid Services (CMS) medical claims data to evaluate the weekly number of therapeutic oseltamivir prescriptions dispensed following a rapid influenza diagnostic test among beneficiaries 65 years old and older as an indicator of influenza timing and intensity. We compared the temporal changes in this indicator to changes in the proportion of influenza-like illnesses among outpatient visits in the US Outpatient Influenza-like Illness Surveillance Network (ILINet) by administrative regions defined by the US Department of Health and Human Services. Using the moving epidemic method, we determined intensity thresholds and categorized the severity of seasons for both CMS and ILINet data. RESULTS Centers for Medicare and Medicaid Services oseltamivir data and ILINet data were strongly correlated by administrative region (median Spearman's ρ = 0.78; interquartile range = 0.73-0.80). CMS oseltamivir data and ILINet data substantially agreed (Cohen's weighted κ = 0.62) as to the seasonal severity across administrative regions. CONCLUSIONS Our results support the use of oseltamivir dispensing in medical claims data as an indicator of US influenza activity.

BACKGROUND Hemolytic reactions (HRs) are rare serious adverse events after immune globulin (IG) use. Our large claims-based study evaluated occurrence of same-day hemolysis after administration of different IG products and potential risk factors, during the 2008 to 2014 study period. STUDY DESIGN AND METHODS We conducted a retrospective cohort study using a large commercial administrative database. The study included individuals exposed to IG products as identified by procedure codes. HRs were ascertained using ICD-9-CM diagnosis codes. Unadjusted same-day hemolysis rates (per 1000 persons) were estimated overall, by age, sex, and IG products. Multivariable regression analyses were used to evaluate potential risk factors. RESULTS Of 20,440 persons exposed, 211 (10.3 per 1000) had same-day HRs. The median numbers of doses for IG users with versus without same-day hemolysis were one and six, respectively. The unadjusted product-specific HR rates ranged from 1.92 for subcutaneous product Hizentra to 17.99 for intravenous Octagam. The multivariable regression analyses showed significantly increased same-day HR risk in males and in IG users with histories of hemolysis, pneumonia, and hereditary hemolytic anemias. Compared to Gammagard Liquid, significantly elevated overall hemolysis risk was identified with Octagam (odds ratio, 2.36; 95% confidence interval, 1.04-5.35), using Firth's method to account for small sample size bias. CONCLUSION The study showed variation in the same-day IG-related hemolysis by age, sex, and IG products administered. The results suggest importance of underlying health conditions, especially prior hemolysis, and first IG product dose. Differences in HR occurrence may also be explained by product manufacturing processes, indications, routes, and rates of administration, which warrant further investigation.

BACKGROUND Acute renal failure (ARF) is a rare serious adverse event after immune globulin (IG) use. Our large claims-based study evaluated occurrence of same-day ARF after administration of different IGs and ascertained potential risk factors, during the 2008 to 2014 study period. STUDY DESIGN AND METHODS A retrospective cohort study was conducted using a large commercial administrative database. The cohort included individuals exposed to IG products as identified by procedure codes. ARF was ascertained using ICD-9-CM diagnoses. Unadjusted same-day ARF rates (per 1000 persons exposed) were estimated overall and by age, sex, and IG products. Regression analyses were conducted to control for confounding and assess potential risk factors. RESULTS Of 20,440 persons exposed, 163 (7.97 per 1000) had a recorded same-day ARF. The unadjusted nonzero same-day ARF rates (per 1000) ranged from 1.92 (95% confidence interval [CI], 0.05-10.69) for Hizentra to 16.97 (95% CI, 11.36-24.37) for Privigen and differed by sex. In multivariate analyses, compared to Gammagard Liquid, no significantly elevated ARF risks were identified with any IGs. A significantly lower odds ratio was identified with Gamunex, 0.53 (95% CI, 0.30-0.93). Age 45 and over, prior renal impairment, hypertension, and other factors were associated with increased risk of same-day ARF. CONCLUSION The study showed variation in the risk of IG-related ARF by age, sex, and IG products. The study results suggest the importance of recipient factors, such as older age and underlying health conditions. Variations in ARF occurrence may also be explained by product dosage, administration route and rate, and manufacturing processes, which warrant further evaluation.

Background Tens of millions of seniors are at risk of herpes zoster (HZ) and its complications. Live attenuated herpes zoster vaccine (HZV) reduces that risk, although questions regarding effectiveness and durability of protection in routine clinical practice remain. We used Medicare data to investigate HZV effectiveness (VE) and its durability. Methods This retrospective cohort study included beneficiaries ages ≥65 years during January 2007 through July 2014. Multiple adjustments to account for potential bias were made. HZV-vaccinated beneficiaries were matched to unvaccinated beneficiaries (primary analysis) and to HZV-unvaccinated beneficiaries who had received pneumococcal vaccination (secondary analysis). HZ outcomes in community and hospital settings were analyzed, including ophthalmic zoster (OZ) and postherpetic neuralgia (PHN). Results Among eligible beneficiaries (average age 77 years), the primary analysis found VE for community HZ of 33% (95% CI: 32%-35%) and 19% (95% CI: 17%-22%), for the first 3, and subsequent 4+ years postvaccination, respectively. In the secondary analysis, VE was, respectively, 37% (95% CI: 36%-39%) and 22% (95% CI: 20%-25%). In the primary analysis, VE for PHN was 57% (95% CI: 52%-61%) and 45% (95% CI: 36%-53%) in the first 3 and subsequent 4+ years, respectively; VE for hospitalized HZ was, respectively, 74% (95% CI: 67%-79%) and 55% (95% CI: 39%-67%). Differences in VE by age group were not significant. Conclusions In both the primary and secondary analyses, HZV provided protection against HZ across all ages, but effectiveness declined over time. VE was higher and better preserved over time for PHN and HZ-associated hospitalizations than for community HZ.

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BackgroundStudies among individuals ages ≥65 years have found a moderately higher relative vaccine effectiveness (RVE) for the high-dose (HD) influenza vaccine compared with standard-dose (SD) products for most seasons. Studies during the A(H3N2)-dominated 2017–2018 season showed slightly higher RVE for the cell-cultured vaccine compared with SD egg-based vaccines. We investigated the RVE of influenza vaccines among Medicare beneficiaries ages ≥65 years during the 2018–2019 season.MethodsThis is a retrospective cohort study using inverse probability of treatment weighting and Poisson regression to evaluate RVE in preventing influenza hospital encounters.ResultsAmong 12 777 214 beneficiaries, the egg-based adjuvanted (RVE, 7.7%; 95% confidence interval [CI], 3.9%–11.4%) and HD (RVE, 4.9%; 95% CI, 1.7%–8.1%) vaccines were marginally more effective than the egg-based quadrivalent vaccines. The cell-cultured quadrivalent vaccine was not significantly more effective than the egg-based quadrivalent vaccine (RVE, 2.5%; 95% CI, −2.4% to 7.3%).ConclusionsWe did not find major effectiveness differences between licensed vaccines used among the elderly during the 2018–2019 season. Consistent with prior research, we found that the egg-based adjuvanted and HD vaccines were slightly more effective than the egg-based quadrivalent vaccines.

BACKGROUND Studies have found that the high-dose influenza vaccine has a higher relative vaccine effectiveness (RVE) versus standard-dose vaccines in some seasons. We evaluated the effect of age on the RVE of high-dose versus standard-dose influenza vaccines among Medicare beneficiaries. METHODS A 6-season retrospective cohort study from 2012 to 2018 among Medicare beneficiaries aged ≥65 years was performed. Poisson regression was used to evaluate the effect of age on the RVE of high-dose versus standard-dose influenza vaccines in preventing influenza-related hospitalizations. RESULTS The study included >19 million vaccinated beneficiaries in a community pharmacy setting. The Poisson models indicated a slightly increasing trend in RVE with age in all seasons. The high-dose vaccine was more effective than standard-dose vaccines in preventing influenza-related hospital encounters (ie, influenza-related inpatient stays and emergency department visits) in the 2012-2013 (RVE, 23.1%; 95% confidence interval [CI], 17.6%-28.3%), 2013-2014 (RVE, 15.3%; 95% CI, 7.8%-22.3%), 2014-2015 (RVE, 8.9%; 95% CI, 5.6%-12.1%), and 2016-2017 (RVE, 12.6%; 95% CI, 6.3%-18.4%) seasons and was at least as effective in all other seasons. We also found that the high-dose vaccine was consistently more effective than standard-dose vaccines across all seasons for people aged ≥85 years. Similar trends were observed for influenza-related inpatient stays. CONCLUSIONS The RVE of high-dose versus standard-dose influenza vaccines increases with age.

Background Statins are used to reduce cardiovascular disease risk. Recent studies suggest that statin use may be associated with an increased influenza risk among influenza vaccinees. We used Medicare data to evaluate associations between statins and risks of influenza-related encounters among vaccinees. Methods In this retrospective cohort study, we identified Medicare beneficiaries aged > 65 years who received high-dose (HD) or standard-dose (SD) influenza vaccines at pharmacies from 2010-2011 through 2014-2015. Statin users were matched to nonusers by vaccine type, demographics, prior medical encounters, and comorbidities. We used multivariable Poisson models to estimate associations between statin use around the time of vaccination and risk of influenza-related encounters. Study outcomes included influenza-related office visits with a rapid test followed by dispensing of oseltamivir and influenza-related hospitalizations (including emergency room visits) during high influenza circulation periods. Results The study included 1403651 statin users matched to nonusers. Cohorts were well balanced, with standardized mean differences ≤0.03 for all measured covariates. For statin users compared to nonusers, the adjusted relative risk was 1.086 (95% confidence interval [CI], 1.025-1.150) for influenza-related visits and 1.096 (95% CI, 1.013-1.185) for influenza-related hospitalizations. The risk difference ranged from ‒0.02 to 0.23 for influenza-related visits and from ‒0.04 to 0.13 for hospitalizations, depending on season severity. Results were similar for HD and SD vaccinees and for nonsynthetic and synthetic statin users. Conclusions Among 2.8 million Medicare beneficiaries, these results suggest that statin use around the time of vaccination does not substantially affect the risk of influenza-related medical encounters among older adults.

Hemolytic reactions (HRs) are rare serious adverse events after immune globulin (IG) use. Our large claims-based study evaluated occurrence of same-day hemolysis after administration of different IG products and potential risk factors, during the 2008 to 2014 study period.We conducted a retrospective cohort study using a large commercial administrative database. The study included individuals exposed to IG products as identified by procedure codes. HRs were ascertained using ICD-9-CM diagnosis codes. Unadjusted same-day hemolysis rates (per 1000 persons) were estimated overall, by age, sex, and IG products. Multivariable regression analyses were used to evaluate potential risk factors.Of 20,440 persons exposed, 211 (10.3 per 1000) had same-day HRs. The median numbers of doses for IG users with versus without same-day hemolysis were one and six, respectively. The unadjusted product-specific HR rates ranged from 1.92 for subcutaneous product Hizentra to 17.99 for intravenous Octagam. The multivariable regression analyses showed significantly increased same-day HR risk in males and in IG users with histories of hemolysis, pneumonia, and hereditary hemolytic anemias. Compared to Gammagard Liquid, significantly elevated overall hemolysis risk was identified with Octagam (odds ratio, 2.36; 95% confidence interval, 1.04-5.35), using Firth's method to account for small sample size bias.The study showed variation in the same-day IG-related hemolysis by age, sex, and IG products administered. The results suggest importance of underlying health conditions, especially prior hemolysis, and first IG product dose. Differences in HR occurrence may also be explained by product manufacturing processes, indications, routes, and rates of administration, which warrant further investigation.

Acute renal failure (ARF) is a rare serious adverse event after immune globulin (IG) use. Our large claims-based study evaluated occurrence of same-day ARF after administration of different IGs and ascertained potential risk factors, during the 2008 to 2014 study period.A retrospective cohort study was conducted using a large commercial administrative database. The cohort included individuals exposed to IG products as identified by procedure codes. ARF was ascertained using ICD-9-CM diagnoses. Unadjusted same-day ARF rates (per 1000 persons exposed) were estimated overall and by age, sex, and IG products. Regression analyses were conducted to control for confounding and assess potential risk factors.Of 20,440 persons exposed, 163 (7.97 per 1000) had a recorded same-day ARF. The unadjusted nonzero same-day ARF rates (per 1000) ranged from 1.92 (95% confidence interval [CI], 0.05-10.69) for Hizentra to 16.97 (95% CI, 11.36-24.37) for Privigen and differed by sex. In multivariate analyses, compared to Gammagard Liquid, no significantly elevated ARF risks were identified with any IGs. A significantly lower odds ratio was identified with Gamunex, 0.53 (95% CI, 0.30-0.93). Age 45 and over, prior renal impairment, hypertension, and other factors were associated with increased risk of same-day ARF.The study showed variation in the risk of IG-related ARF by age, sex, and IG products. The study results suggest the importance of recipient factors, such as older age and underlying health conditions. Variations in ARF occurrence may also be explained by product dosage, administration route and rate, and manufacturing processes, which warrant further evaluation.

Background Recipients of high-dose vs standard-dose influenza vaccines have fewer influenza illnesses. We evaluated the comparative effectiveness of high-dose vaccine in preventing postinfluenza deaths during 2012-2013 and 2013-2014, when influenza viruses and vaccines were similar. Methods We identified Medicare beneficiaries aged ≥65 years who received high-dose or standard-dose vaccines in community-located pharmacies offering both vaccines. The primary outcome was death in the 30 days following an inpatient or emergency department encounter listing an influenza International of Classification of Diseases, Ninth Revision, Clinical Modification code. Effectiveness was estimated by using multivariate Poisson regression models; effectiveness was allowed to vary by season. Results We studied 1039645 recipients of high-dose and 1683264 recipients of standard-dose vaccines during 2012-2013, and 1508176 high-dose and 1877327 standard-dose recipients during 2013-2014. Vaccinees were well-balanced for medical conditions and indicators of frail health. Rates of postinfluenza death were 0.028 and 0.038/10000 person-weeks in high-dose and standard-dose recipients, respectively. Comparative effectiveness was 24.0% (95% confidence interval [CI], .6%-42%); there was evidence of variation by season (P = .12). In 2012-2013, high-dose was 36.4% (95% CI, 9.0%-56%) more effective in reducing mortality; in 2013-2014, it was 2.5% (95% CI, -47% to 35%). Conclusions High-dose vaccine was significantly more effective in preventing postinfluenza deaths in 2012-2013, when A(H3N2) circulation was common, but not in 2013-2014.

BackgroundHuman babesiosis, caused by intraerythrocytic protozoan parasites, can be an asymptomatic or mild-to-severe disease that may be fatal. The study objective was to assess babesiosis occurrence among the U.S. elderly Medicare beneficiaries, ages 65 and older, during 2006-2013.MethodsOur retrospective claims-based study utilized large Medicare administrative databases. Babesiosis occurrence was ascertained by recorded ICD-9-CM diagnosis code. The study assessed babesiosis occurrence rates (per 100,000 elderly Medicare beneficiaries) overall and by year, age, gender, race, state of residence, and diagnosis months.ResultsA total of 10,305 elderly Medicare beneficiaries had a recorded babesiosis diagnosis during the eight-year study period, for an overall rate of about 5 per 100,000 persons. Study results showed a significant increase in babesiosis occurrence over time (pConclusionOur study reveals increasing babesiosis occurrence among the U.S. elderly during 2006-2013, with highest rates in the babesiosis-endemic states. The study also shows variation in babesiosis occurrence by age, gender, race, state of residence, and diagnosis months. Overall, our study highlights the importance of large administrative databases in assessing the occurrence of emerging infections in the United States.

BACKGROUND Thrombotic events (TEs) are serious adverse events that can occur following administration of clotting factors (CFs). OBJECTIVES To evaluate occurrence of same-day TEs for different CF products and potential risk factors. METHODS A retrospective cohort study of individuals exposed to CF products during 2008-2013 was conducted using a large commercial insurance database. CF products were identified by procedure codes, and TEs were ascertained via diagnosis codes. Crude same-day TE rates (per 1000 persons exposed) were estimated overall and by congenital factor deficiency (CFD) status, CF products, age and gender. Multivariable logistic regression analyses were used to control for confounding. Laboratory analysis was used to compare the procoagulant activities of FIX products. RESULTS Of 3801 individuals exposed to CFs, 117 (30.8 per 1000) had same-day TEs recorded. The crude same-day TE rate was higher for CF users without CFD, 70.2 (102 of 1452), as compared with those with CFD, 6.4 (15 of 2349) (RR, 11.0; 95% CI, 6.4-18.9). For individuals without CFD, a significantly increased same-day TE risk was identified for factor IX complex (OR, 6.92; 95% CI, 3.11-15.40), factor VIIa (OR, 9.42; 95% CI, 4.99-17.78) and other products when compared with fibrin sealant. An increased risk of a TE was found with older age (≥ 45 years), history of TEs and underlying health conditions. The laboratory identified elevated procoagulant activity in Profilnine(®) and Benefix(®) . CONCLUSIONS The study shows an increased same-day TE risk for CF users without CFD and suggests substantial off-label CF use. The study findings also show elevated same-day TE rates for different CF products and suggest the importance of product properties and patient factors.

Summary Background A high-dose trivalent inactivated influenza vaccine was licensed in 2009 by the US Food and Drug Administration (FDA) on the basis of serological criteria. We sought to establish whether high-dose inactivated influenza vaccine was more effective for prevention of influenza-related visits and hospital admissions in US Medicare beneficiaries than was standard-dose inactivated influenza vaccine. Methods In this retrospective cohort study, we identified Medicare beneficiaries aged 65 years and older who received high-dose or standard-dose inactivated influenza vaccines from community pharmacies that offered both vaccines during the 2012–13 influenza season. Outcomes were defined with billing codes on Medicare claims. The primary outcome was probable influenza infection, defined by receipt of a rapid influenza test followed by dispensing of the neuraminidase inhibitor oseltamivir. The secondary outcome was a hospital or emergency department visit, listing a Medicare billing code for influenza. We estimated relative vaccine effectiveness by comparing outcome rates in Medicare beneficiaries during periods of high influenza circulation. Univariate and multivariate Poisson regression models were used for analyses. Findings Between Aug 1, 2012 and Jan 31, 2013, we studied 929 730 recipients of high-dose vaccine and 1 615 545 recipients of standard-dose vaccine. Participants enrolled in each cohort were well balanced with respect to age and presence of underlying medical disorders. The high-dose vaccine (1·30 outcomes per 10 000 person-weeks) was 22% (95% CI 15–29) more effective than the standard-dose vaccine (1·01 outcomes per 10 000 person-weeks) for prevention of probable influenza infections (rapid influenza test followed by oseltamivir treatment) and 22% (95% CI 16–27%) more effective for prevention of influenza hospital admissions (0·86 outcomes per 10 000 person-weeks in the high-dose cohort vs 1·10 outcomes per 10 000 person-weeks in the standard-dose cohort). Interpretation Our retrospective cohort study in US Medicare beneficiaries shows that, in people 65 years of age and older, high-dose inactivated influenza vaccine was significantly more effective than standard-dose vaccine in prevention of influenza-related medical encounters. Additionally, the large population in our study enabled us to show, for the first time, a significant reduction in influenza-related hospital admissions in high-dose compared to standard-dose vaccine recipients, an outcome not shown in randomised studies. These results provide important new information to be considered by policy makers recommending influenza vaccinations for elderly people. Funding FDA and the office of the Assistant Secretary of Planning and Evaluation.

Background Although some studies have suggested that transfusion recipients may have better medical outcomes if transfused with red blood cell units stored for a short time, the overall body of evidence shows mixed results. It is important to understand how using fresher stored red blood cell units for certain patient groups may affect blood availability. Methods Based on the Stock-and-Flow simulation model of the US blood supply developed by Simonetti et al. 2014, we evaluated a newly implemented allocation method of preferentially transfusing fresher stored red blood cell units to a subset of high-risk group of critically ill patients and its potential impact on supply. Results Simulation results showed that, depending on the scenario, the US blood total supply might be reduced between 2-42%, when compared to the standard of care in transfusion medicine practice. Among our simulated scenarios, we observed that the number of expired red blood cell units modulated the supply levels. The age threshold of the required red blood cell units was inversely correlated with both the supply levels and the number of transfused units that failed to meet that age threshold. Conclusion To our knowledge, this study represents the first attempt to develop a comprehensive framework to evaluate the impact of preferentially transfusing fresher stored red blood cells to the higher-risk critically ill patients on supply. Model results show the difficulties to identify an optimal scenario.