Cytomegalovirus (CMV) is a common herpesvirus that establishes lifelong latency and becomes increasingly prevalent with age. We systematically characterized CMV-associated immune remodeling by analyzing six human cohorts (two newly built) using single-cell RNA sequencing, T cell receptor (TCR) sequencing, and flow cytometry. Beyond the well-known expansion of CD4+/CD8+ TEMRA, adaptive NK, and γδ T cells, CMV(+) adults exhibited increased frequencies of GZMK+ CD8+ T cells and atypical B cells, alongside a reduction of CD56dim NK cells. Longitudinal profiling of an individual who seroconverted revealed rapid CMV-driven shifts in circulating immune cell frequencies. Single-cell TCR data analyzed using a large database of CMV-associated clones combined with predictive modelling (CMVerify), identified novel CMV-specific clonal expansions reproduced across two independent cohorts. In the CD8+ lineage, CMV-specific clones were enriched in GZMK+ CD8+ and CD8+ TEMRA cells, while in the CD4+ lineage, Th1 cells showed clonal expansion alongside CD4+ TEMRA cells. This integrative study revealed how latent CMV alters the cellular and clonal landscape, defining GZMK+ CD8+ and Th1 cells as newly recognized elements of response to CMV in humans.

Improving the quality of medication use and medication safety are important priorities for healthcare providers who care for older adults. The objective of this article was to identify four exemplary articles with this focus in 2023. We selected high-quality studies that advanced this field of research. The chosen articles cover domains related to deprescribing/discontinuation, optimizing medication use, medication safety/adverse drug events, and other. The first study was a randomized clinical trial evaluating the efficacy of the patient-centered Shed-MEDS deprescribing intervention among older adults transitioning from the hospital to postacute care facilities (domain: deprescribing/discontinuation). The second study, a retrospective cohort study among Medicare beneficiaries, described the phenomenon of a prescribing cascade relic and evaluated continued potassium use after discontinuation of a loop diuretic (domain: optimizing medication use). The third study was a systematic review and meta-analysis describing the prevalence of drug-drug interactions among community-dwelling older adults (domain: other). Lastly, the fourth study was a retrospective cohort study among Medicare beneficiaries that evaluated concurrent gabapentin and opioid use and risk of mortality (domain: medication safety). Collectively, this review succinctly highlights pertinent topics related to promoting safe use of medications and promotes awareness of optimizing older adults' medication regimens.

Abstract Background Despite a recent increase in the burden of complicated urinary tract infections (cUTI), contemporary data on healthcare utilization, outcomes and antimicrobial use related to cUTIs are lacking. We describe healthcare utilization, inpatient antibiotic use, and mortality associated with cUTI across a nationwide US hospital network. Methods This cohort study included inpatients aged ≥18 years with cUTI (using ICD-10 diagnostic codes) from 240 hospitals in the Premier Healthcare Claims Database between January 2016 – June 2020. Demographics, clinical characteristics, antibiotic use, and healthcare utilization measures were evaluated. In addition to antibiotic days of therapy, we calculated daily average Antibiotic Spectrum Index (ASI) which measures the spectrum of antimicrobial action based on number of organisms susceptible to that drug (total = 14 organism categories, e.g. ASI of penicillin is 2 while meropenem is 10, validated by Gerber et. al, PMID: 28560946). Primary outcome of inpatient mortality was assessed in a multivariable logistic regression model. Results In this cohort of 16,011 inpatients with cUTI, median age was 67 years (IQR 54- 77], 52.6% (N=8419) were female and 76.1% (N=12181) were white (Table 1). Over two thirds of patients with cUTI required intensive care unit care, while over 25% were bacteremic and required vasopressors. Median duration of antimicrobial therapy was 11 days [IQR: 7, 18] and median daily ASI was 10.40 [IQR: 7.80, 13.87]. Inpatient mortality was 6.4% and 30 day readmission rates were 17.7%. On multivariable analysis, significant risk factors for inpatient mortality in patients with cUTI included increasing age, with highest risk over 80 years of age (adjusted odds ratio (aOR) 3.25 (2.50 - 4.23); higher Charleston’s comorbidity index (aOR 1.05 (1.04 - 1.06)); admission from skilled nursing facility (aOR 1.39 (1.11 - 1.76) and higher ASI (aOR 1.05 (1.04 - 1.05, Table 2)). Conclusion In our cohort of 240 US hospitals, older adults and men experienced more than half of inpatient cUTIs. A large proportion of cUTIs were associated with high severity of illness requiring higher acuity of care. Older age, more comorbidities, and higher ASI were associated with increased mortality in patients with cUTI. Disclosures Sonali Advani, MBBS, MPH, FIDSA, Biomerieux: Advisor/Consultant|GSK: Advisor/Consultant|Locus Biosciences: Advisor/Consultant|Sysmex America: Advisor/Consultant Charles Scales, MD MSHS, BMS: Grant/Research Support|Exelixis: Grant/Research Support|Flume Catheter: Grant/Research Support|Lilac Therapeutics: Advisor/Consultant|Merck: Grant/Research Support|Pfizer: Grant/Research Support

Our interviews of inpatient clinicians (physicians, physician assistants) modeled after the Capability, Opportunity, and Motivation Model of Behavior model revealed opportunity and motivation as important drivers for overdiagnosis and overprescribing for asymptomatic bacteriuria in older adults. Understanding these barriers is an important step toward implementing age-friendly stewardship interventions.

This article comments on the article by Rochon et al . in this issue.

IntroductionAs the older adult population increases, hospitals treat more older adults with injuries. After leaving, these patients suffer from decreased mobility and independence, relying on care from others. Family members often assume this responsibility, mostly informally and unpaid. Caregivers of other older adult populations have increased stress and decreased caregiver-related quality of life (CRQoL). Validated CRQoL measures are essential to capture their unique experiences. Our objective was to review existing CRQoL measures and their validity in caregivers of older adult trauma patients.MethodsA professional librarian searched published literature from the inception of databases through August 12, 2022 in MEDLINE (via PubMed), Embase (via Elsevier), and CINAHL Complete (via EBSCO). We identified 1063 unique studies of CRQoL in caregivers for adults with injury and performed a systematic review following COnsensus-based Standards for the selection of health Measurement Instruments guidelines for CRQoL measures.ResultsFrom the 66 studies included, we identified 54 health-related quality-of-life measures and 60 domains capturing caregiver-centered concerns. The majority (83%) of measures included six or fewer CRQoL content domains. Six measures were used in caregivers of older adults with single-system injuries. There were no validated CRQoL measures among caregivers of older adult trauma patients with multisystem injuries.ConclusionsWhile many measures exist to assess healthcare-related quality of life, few, if any, adequately assess concerns among caregivers of older adult trauma patients. We found that CRQoL domains, including mental health, emotional health, social functioning, and relationships, are most commonly assessed among caregivers. Future measures should focus on reliability and validity in this specific population to guide interventions.

We conducted an opportunistic pharmacokinetic study to evaluate the population pharmacokinetics of meropenem, an antimicrobial commonly used to treat Gram-negative infections in adults of different ages, including older adults, and determined optimal dosing regimens. A total of 99 patients were included. The population pharmacokinetic models used had two compartments: zero-order input and linear elimination. Covariates evaluated included renal function, body size, age, sex, vasopressor use, and frailty, using the Canadian Study of Health and Aging Clinical Frailty score (in patients aged ≥ 65 years). We simulated optimal dosing regimens by renal function and by age group to achieve therapeutic target attainment. Participants’ ages ranged from 20 to 95 years, with an average age of 57.4 years, and 22

BACKGROUND:Central nervous system (CNS) medications are linked to higher morbidity and mortality in older adults. Hospitalization allows for deprescribing opportunities. This qualitative study investigates clinician and patient perspectives on CNS medication deprescribing during hospitalization using a behavioral change framework, aiming to inform interventions and identify recommendations to enhance hospital deprescribing processes. METHODS:This qualitative study focused on hospitalists, primary care providers, pharmacists, and patients aged ≥60 years hospitalized on a general medicine service and prescribed ≥1 CNS medications. Using semi-structured interviews and focus groups, we aimed to evaluate patient medication knowledge, prior deprescribing experiences, and decision-making preferences, as well as provider processes and tools for medication evaluation and deprescribing. Rapid qualitative analysis applying the Capability, Opportunity, Motivation, and Behavior (COM-B) framework revealed themes influencing deprescribing behavior in patients and providers. RESULTS:A total of 52 participants (20 patients and 32 providers) identified facilitators and barriers across deprescribing steps and generated recommended strategies to address them. Clinicians and patients highlighted the opportunity for CNS medication deprescribing during hospitalizations, facilitated by multidisciplinary teams enhancing clinicians' capability to make medication changes. Both groups also stressed the importance of intensive patient engagement, education, and monitoring during hospitalizations, acknowledging challenges in timing and extent of deprescribing, with some patients preferring decisions deferred to outpatient clinicians. Hospitalist and pharmacist recommendations centered on early pharmacist involvement for medication reconciliation, expanding pharmacy consultation and clinician education on deprescribing, whereas patients recommended enhancing shared decision-making through patient education on medication adverse effects, tapering plans, and alternatives. Hospitalists and PCPs also emphasized standardized discharge instructions and transitional care calls to improve medication review and feedback during care transitions. CONCLUSIONS:Clinicians and patients highlighted the potential advantages of hospital interventions for CNS medication deprescribing, emphasizing the necessity of addressing communication, education, and coordination challenges between inpatient and outpatient settings.

BACKGROUND:Central nervous system (CNS) medication use is common among older adults, yet the impact of hospitalizations on use remains unclear. This study details CNS medication use, discontinuations, and user profiles during hospitalization periods. METHODS:Retrospective cohort study using electronic health records on patients ≥65 years, from three hospitals (2018-2020), and prescribed a CNS medication around hospitalization (90 days prior to 90 days after). Latent class transitions analysis (LCTA) examined profiles of CNS medication class users across four time points (90 days prior, admission, discharge, 90 days after hospitalization). RESULTS:Among 4666 patients (mean age 74.3 ± 9.3 years; 63% female; 70% White; mean length of stay 4.6 ± 5.6 days (median 3.0 [2.0, 6.0]), the most commonly prescribed CNS medications were antidepressants (56%) and opioids (49%). Overall, 74% (n = 3446) of patients were persistent users of a CNS medication across all four time points; 7% (n = 388) had discontinuations during hospitalization, but of these, 64% (216/388) had new starts or restarts within 90 days after hospitalization. LCTA identified three profile groups: (1) low CNS medication users, 54%-60% of patients; (2) mental health medication users, 30%-36%; and (3) acute/chronic pain medication users, 9%-10%. Probability of staying in same group across the four time points was high (0.88-1.00). Transitioning to the low CNS medication use group was highest from admission to discharge (probability of 9% for pain medication users, 5% for mental health medication users). Female gender increased (OR 2.4, 95% CI 1.3-4.3), while chronic kidney disease lowered (OR 0.5, 0.2-0.9) the odds of transitioning to the low CNS medication use profile between admission and discharge. CONCLUSIONS:CNS medication use stays consistent around hospitalization, with discontinuation more likely between admission and discharge, especially among pain medication users. Further research on patient outcomes is needed to understand the benefits and harms of hospital deprescribing, particularly for medications requiring gradual tapering.

Alzheimer's disease (AD) involves a complex pathological process that evolves over years, and its etiology is understood as a classic example of gene-environment interaction. The notion that exposure to microbial organisms may play some role in AD pathology has been proposed and debated for decades. New evidence from model organisms and -omic studies, as well as epidemiological data from the recent COVID-19 pandemic and widespread use of vaccines, offers new insights into the "germ hypothesis" of AD. To review new evidence and identify key research questions, the Duke/University of North Carolina (Duke/UNC) Alzheimer's Disease Research Center hosted a virtual symposium and workshop: "New Approaches for Understanding the Potential Role of Microbes in Alzheimer's disease." Discussion centered around the antimicrobial protection hypothesis of amyloid accumulation, and other mechanisms by which microbes could influence AD pathology including immune cell activation, changes in blood-brain barrier, or direct neurotoxicity. This summary of proceedings reviews the content presented in the symposium and provides a summary of major topics and key questions discussed in the workshop.

Purpose:Patients with suspected UTIs are categorized into 3 clinical phenotypes based on current guidelines: no UTI, asymptomatic bacteriuria (ASB), or UTI. However, all patients may not fit neatly into these groups. Our objective was to characterize clinical presentations of patients who receive urine tests using the "continuum of UTI" approach.Materials and Methods:This was a retrospective cohort study of a random sample of adult noncatheterized inpatient and emergency department encounters with paired urinalysis and urine cultures from 5 hospitals in 3 states between January 01, 2017, and December 31, 2019. Trained abstractors collected clinical (eg, symptom) and demographic data. A focus group discussion with multidisciplinary experts was conducted to define the continuum of UTI, a 5-level classification scheme that includes 2 new categories: lower urinary tract symptoms/other urologic symptoms and bacteriuria of unclear significance. The newly defined continuum of UTI categories were compared to the current UTI classification scheme.Results:Of 220,531 encounters, 3392 randomly selected encounters were reviewed. Based on the current classification scheme, 32.1% (n = 704) had ASB and 53% (n = 1614) did not have a UTI. When applying the continuum of UTI categories, 68% of patients (n = 478) with ASB were reclassified as bacteriuria of unclear significance and 29% of patients (n = 467) with "no UTI" were reclassified to lower urinary tract symptoms/other urologic symptoms.Conclusions:Our data suggest the need to reframe our conceptual model of UTI vs ASB to reflect the full spectrum of clinical presentations, acknowledge the diagnostic uncertainty faced by frontline clinicians, and promote a nuanced approach to diagnosis and management of UTIs.

Importance Quadrivalent adjuvanted inactivated influenza vaccine (aIIV4) and adjuvanted recombinant zoster vaccine (RZV) contain novel adjuvants. Data are limited on the comparative safety, reactogenicity, and health-related quality of life (HRQOL) effects of the simultaneous administration of these vaccines. Objective To compare the safety and reactogenicity after simultaneous doses of RZV and aIIV4 administration (opposite arms) with simultaneous doses of RZV with quadrivalent high-dose inactivated influenza vaccine [HD-IIV4]). Design, Setting, and Participants This randomized blinded clinical trial was conducted during the 2021-2022 and 2022-2023 influenza seasons at 2 centers in the US among community-dwelling adults aged 65 years or older. Analysis was performed on an intention-to-treat basis. Intervention Simultaneous intramuscular administration of RZV dose 1 and aIIV4 or HD-IIV4 in opposite arms after age stratification (65-69 and >= 70 years) and randomization. Main Outcomes and Measures The primary outcome was the proportions of participants with 1 or more severe solicited reactions during days 1 to 8, using a noninferiority test (10% noninferiority margin). Additional measures included serious adverse events and adverse events of clinical interest during days 1 to 43 of the study period. Results A total of 267 adults (median age, 71 years [range, 65-92 years]; 137 men [51.3%]) were randomized; 130 received simultaneous RZV and aIIV4, and 137 received simultaneous RZV and HD-IIV4. The proportion of patients reporting 1 or more severe reactions after simultaneous administration of RZV and aIIV4 (15 of 115 [11.5%]) was noninferior compared with simultaneous RZV and HD-IIV4 (17 of 119 [12.5%]) (absolute difference, -1.0% [95% CI, -8.9% to 7.1%]). There were no significant differences in the number of serious adverse events or adverse events of clinical interest between the groups. Conclusions and Relevance In this clinical trial of simultaneous doses of RZV and aIIV4 compared with simultaneous doses of RZV and HD-IIV4, overall safety findings were similar between groups. From a safety standpoint, this study supports the simultaneous administration of RZV and aIIV4 among older adults. Trial Registration ClinicalTrials.gov Identifier: NCT05007041

This article is a summary of the first AGS Symposium entitled "Update on Vaccination Strategies for Older Adults: Matching the Approach to the Individual and the Care Setting." Given declines in host defenses and immune function with aging, vaccinations play a pivotal role in fortifying older adults against preventable infections, resulting diseases, disability, and death. Current guidelines generally list recommendations applicable for an average older adult of a given chronological age. However, growing evidence indicates that heterogeneity in terms of factors as varied as biological sex, frailty, functional status, and multimorbidity may impact vaccine responses and clinical outcomes. As a result, clinicians will increasingly need to take these additional factors into consideration as they seek to improve outcomes through improved targeting of such aging-related heterogeneity. Moreover, efforts at protecting older citizens through vaccination must also include strategies to overcome barriers to the adoption of vaccine recommendations in varied settings including long-term care. This 2023 AGS Plenary Symposium sought to commence a broader dialogue across AGS and beyond on optimizing vaccinations for older adults, ensuring not only extended lifespans but also healthier and more active lives. This report is not a systematic review, and thus should not be considered comprehensive.

Abstract Pragmatic, randomized, controlled trials hold the potential to directly inform clinical decision making and health policy regarding the treatment of people experiencing pain. Pragmatic trials are designed to replicate or are embedded within routine clinical care and are increasingly valued to bridge the gap between trial research and clinical practice, especially in multidimensional conditions, such as pain and in nonpharmacological intervention research. To maximize the potential of pragmatic trials in pain research, the careful consideration of each methodological decision is required. Trials aligned with routine practice pose several challenges, such as determining and enrolling appropriate study participants, deciding on the appropriate level of flexibility in treatment delivery, integrating information on concomitant treatments and adherence, and choosing comparator conditions and outcome measures. Ensuring data quality in real-world clinical settings is another challenging goal. Furthermore, current trials in the field would benefit from analysis methods that allow for a differentiated understanding of effects across patient subgroups and improved reporting of methods and context, which is required to assess the generalizability of findings. At the same time, a range of novel methodological approaches provide opportunities for enhanced efficiency and relevance of pragmatic trials to stakeholders and clinical decision making. In this study, best-practice considerations for these and other concerns in pragmatic trials of pain treatments are offered and a number of promising solutions discussed. The basis of these recommendations was an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) meeting organized by the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks.

Background: Human infections with the avian influenza A(H7N9) virus were first reported in China in 2013 and continued to occur in annual waves. In the 2016/2017 fifth wave, Yangtze River Delta (YRD) lineage viruses, which differed antigenically from those of earlier waves, predominated. Methods: In this phase 2 double-blinded trial we randomized 720 adults >= 19 years of age to receive two injections of a YRD lineage inactivated A/Hong Kong/125/2017 fifth-wave H7N9 vaccine, given 21 days apart, at doses of 3.75, 7.5, and 15 mu g of hemagglutinin (HA) with AS03A adjuvant and at doses of 15 and 45 mu g of HA without adjuvant. Results: Two doses of adjuvanted vaccine were required to induce HA inhibition (HI) antibody titers > 40 in most participants. After two doses of the 15 mu g H7N9 formulation, given with or without AS03 adjuvant, the proportion achieving a HI titer >= 40 against the vaccine strain at 21 days after the second vaccination was 65 % (95 % CI, 57 %-73 %) and 0 % (95 % CI, 0 %-4%), respectively. Among those who received two doses of the 15 mu g adjuvanted formulation the proportion with HI titer >= 40 at 21 days after the second vaccination was 76 % (95 % CI, 66 %-84 %) in those 19-64 years of age and 49 % (95 % CI, 37 %-62 %) in those >= 65 years of age. Responses to the adjuvanted vaccine formulations did not vary by HA content. Antibody responses declined over time and responses against drifted H7N9 strains were diminished. Overall, the vaccines were well tolerated but, as expected, adjuvanted vaccines were associated with more frequent solicited systemic and local adverse events. Conclusions: AS03 adjuvant improved the immune responses to an inactivated fifth-wave H7N9 influenza vaccine, particularly in younger adults, but invoked lower responses to drifted H7N9 strains. These findings may inform future influenza pandemic preparedness strategies.

ImportanceGuidelines recommend withholding antibiotics in asymptomatic bacteriuria (ASB), including among patients with altered mental status (AMS) and no systemic signs of infection. However, ASB treatment remains common.ObjectivesTo determine prevalence and factors associated with bacteremia from a presumed urinary source in inpatients with ASB with or without AMS and estimate antibiotics avoided if a 2% risk of bacteremia were used as a threshold to prompt empiric antibiotic treatment of ASB.Design, Setting, and ParticipantsThis cohort study assessed patients hospitalized to nonintensive care with ASB (no immune compromise or concomitant infections) in 68 Michigan hospitals from July 1, 2017, to June 30, 2022. Data were analyzed from August 2022 to January 2023.Main Outcomes and MeasuresThe primary outcome was prevalence of bacteremia from a presumed urinary source (ie, positive blood culture with matching organisms within 3 days of urine culture). To determine factors associated with bacteremia, we used multivariable logistic regression models. We estimated each patient’s risk of bacteremia and determined what percentage of patients empirically treated with antibiotics had less than 2% estimated risk of bacteremia.ResultsOf 11 590 hospitalized patients with ASB (median [IQR] age, 78.2 [67.7-86.6] years; 8595 female patients [74.2%]; 2235 African American or Black patients [19.3%], 184 Hispanic patients [1.6%], and 8897 White patients [76.8%]), 8364 (72.2%) received antimicrobial treatment for UTI, and 161 (1.4%) had bacteremia from a presumed urinary source. Only 17 of 2126 patients with AMS but no systemic signs of infection (0.7%) developed bacteremia. On multivariable analysis, male sex (adjusted odds ratio [aOR], 1.45; 95% CI, 1.02-2.05), hypotension (aOR, 1.86; 95% CI, 1.18-2.93), 2 or more systemic inflammatory response criteria (aOR, 1.72; 95% CI, 1.21-2.46), urinary retention (aOR, 1.87; 95% CI, 1.18-2.96), fatigue (aOR, 1.53; 95% CI, 1.08-2.17), log of serum leukocytosis (aOR, 3.38; 95% CI, 2.48-4.61), and pyuria (aOR, 3.31; 95% CI, 2.10-5.21) were associated with bacteremia. No single factor was associated with more than 2% risk of bacteremia. If 2% or higher risk of bacteremia were used as a cutoff for empiric antibiotics, antibiotic exposure would have been avoided in 78.4% (6323 of 8064) of empirically treated patients with low risk of bacteremia.Conclusions and RelevanceIn patients with ASB, bacteremia from a presumed urinary source was rare, occurring in less than 1% of patients with AMS. A personalized, risk-based approach to empiric therapy could decrease unnecessary ASB treatment.

Introduction A surge of human influenza A(H7N9) cases began in 2016 in China from an antigenically distinct lineage. Data are needed about the safety and immunogenicity of 2013 and 2017 A(H7N9) inactivated influenza vaccines (IIVs) and the effects of AS03 adjuvant, prime-boost interval, and priming effects of 2013 and 2017 A(H7N9) IIVs.Methods Healthy adults (n = 180), ages 19-50 years, were enrolled into this partially blinded, randomized, multicenter phase 2 clinical trial. Participants were randomly assigned to 1 of 6 vaccination groups evaluating homologous versus heterologous prime-boost strategies with 2 different boost intervals (21 vs 120 days) and 2 dosages (3.75 or 15 mu g of hemagglutinin) administered with or without AS03 adjuvant. Reactogenicity, safety, and immunogenicity measured by hemagglutination inhibition and neutralizing antibody titers were assessed.Results Two doses of A(H7N9) IIV were well tolerated, and no safety issues were identified. Although most participants had injection site and systemic reactogenicity, these symptoms were mostly mild to moderate in severity; injection site reactogenicity was greater in vaccination groups receiving adjuvant. Immune responses were greater after an adjuvanted second dose, and with a longer interval between prime and boost. The highest hemagglutination inhibition geometric mean titer (95% confidence interval) observed against the 2017 A(H7N9) strain was 133.4 (83.6-212.6) among participants who received homologous, adjuvanted 3.75 mu g + AS03/2017 doses with delayed boost interval.Conclusions Administering AS03 adjuvant with the second H7N9 IIV dose and extending the boost interval to 4 months resulted in higher peak antibody responses. These observations can broadly inform strategic approaches for pandemic preparedness. Clinical Trials Registration. NCT03589807. The 2013 and 2017 A(H7N9) inactivated influenza vaccines were well tolerated and no new safety concerns were identified. Administering AS03 adjuvant with the second H7N9 inactivated influenza vaccine dose and extending the boost interval to 4 months resulted in higher peak antibody responses.

In a multihospital cohort study of 3392 patients, positive urinalysis parameters had poor positive predictive value for diagnosing urinary tract infection (UTI). Combined urinalysis parameters (pyuria or nitrite) performed better than pyuria alone for ruling out UTI. However, performance of all urinalysis parameters was poor in older women.

Walsh, Julie1; Wischmeyer, Paul2; Tiko-Okoye, Chidinma1; Molinger, Jeroen3; Howell, Shauna4; Agarwal, Suresh4; Cox, Christopher4; Schmader, Kenneth4; Haines, Krista4 Author Information

Importance Limited randomized clinical trial data exist on the safety of simultaneous administration of COVID-19 and influenza vaccines. Objective To compare the reactogenicity, safety, and changes in health-related quality of life (HRQOL) after simultaneous vs sequential receipt of messenger RNA (mRNA) COVID-19 vaccine and quadrivalent inactivated influenza vaccine (IIV4). Design, Setting, and Participants This randomized, placebo-controlled clinical trial was conducted between October 8, 2021, and June 14, 2023, at 3 US sites. Participants were nonpregnant persons aged 5 years or older with the intention of receiving both influenza and mRNA COVID-19 vaccines. Interventions Intramuscular administration in opposite arms of either IIV4 or saline placebo simultaneously with mRNA COVID-19 vaccine at visit 1. Those who received placebo at visit 1 received IIV4 and those who received IIV4 at visit 1 received placebo 1 to 2 weeks later at visit 2. Main Outcomes and Measures The primary composite reactogenicity outcome was the proportion of participants with fever, chills, myalgia, and/or arthralgia of moderate or greater severity within 7 days after vaccination visits 1 and/or 2, using a 10% noninferiority margin. Secondary outcomes were solicited reactogenicity events and unsolicited adverse events (AEs) for 7 days after each visit separately and HRQOL after visit 1, assessed by the EuroQol 5-Dimension 5-Level (EQ-5D-5L) Index. Serious AEs (SAEs) and AEs of special interest (AESIs) were assessed for 121 days. Outcomes were compared between groups. Results A total of 335 persons (mean [SD] age, 33.4 [15.1] years) were randomized (169 to the simultaneous group and 166 to the sequential group); 211 (63.0%) were female, and 255 (76.1%) received bivalent BNT162b2 mRNA COVID-19 vaccine. The proportion with the primary composite reactogenicity outcome in the simultaneous group (25.6% [n = 43]) was noninferior to the proportion in the sequential group (31.3% [n = 52]) (site-adjusted difference, -5.6 percentage points [pp]; 95% CI, -15.2 to 4.0 pp). Respective proportions in each group were similar after each visit separately (visit 1, 40 [23.8%] vs 47 [28.3%]; visit 2, 5 [3.0%] vs 9 [5.4%]). No significant group differences in participants with AEs (21 [12.4%] vs 16 [9.6%]), SAEs (1 [0.6%] vs 1 [0.6%]), and AESIs (19 [11.2%] vs 9 [5.4%]) were observed in the simultaneous vs sequential groups, respectively. Among participants with severe reactogenicity, the mean (SD) EQ-5D-5L Index score decreased from 0.92 (0.08) to 0.92 (0.09) prevaccination to 0.81 (0.09) to 0.82 (0.12) postvaccination. Conclusions and Relevance In this randomized clinical trial assessing simultaneous vs sequential administration of mRNA COVID-19 and IIV4 vaccines, reactogenicity was comparable in both groups. These findings support the option of simultaneous administration of these vaccines. Trial RegistrationClinicalTrials.gov Identifier: NCT05028361