Elkind, Mitchell S

Abstract RATIONALE: Chronic lower respiratory diseases (CLRD) confer higher risks from respiratory viral infections, hence CLRD patients are prioritized for influenza, pneumococcal, and COVID-19 vaccination. Nonetheless, vaccine deferral and declination remain common. Given that COVID-19 vaccination is particularly polarizing, and attitudes toward it may differ from other vaccines, we assessed COVID-19 vaccination behaviors and attitudes in adults with versus without CLRD and/or smoking history, which is strongly associated with CLRD risk. METHODS: We pooled data from 10 cohorts participating in the Collaborative Cohort of Cohorts for COVID-19 Research (C4R) that collected pre-pandemic data on self-reported physician diagnosis of asthma or COPD. C4R assessed COVID-19 vaccination status through three waves of standardized questionnaires (2020-2022, 2021-2023, 2023-2024). Prompt COVID-19 vaccination was defined as self-report of receiving at least one COVID-19 vaccine by May 1, 2021. Cumulative COVID-19 vaccine count was self-reported on the Wave 3 Questionnaire. Vaccine attitudes and receipt of influenza and/or pneumococcal vaccines were self-reported on the Wave 1 or 2 Questionnaire. Age-adjusted Poisson regression was used to test associations of vaccination behaviors with CLRD and smoking status at the most recent pre-pandemic exam. RESULTS: Of 20,034 participants (pre-pandemic COPD, 9.3%; asthma, 11.7%; current smoking, 13.4%; former smoking, 36.3%), 64.2% reported prompt COVID-19 vaccination. Among the subset of 10,626 participants completing the Wave 3 Questionnaire in 2023-24, the median COVID-19 vaccine count was 3 (Q1:2, Q3:4). Compared to participants without CLRD, prompt vaccination was more likely in those with asthma (RR=1.04, 95%CI:1.01-1.07, p=0.008) and less likely with COPD (RR=0.94, 95%CI:0.91-0.98, p=0.001), but there were no differences in doses for asthma and COPD. Compared to never smokers, former smoking participants were more likely to receive prompt vaccination (RR=1.11, 95%CI:1.08-1.13, p<0.0001) and more vaccine doses (RR=1.03, 95%CI:1.01-1.05, p=0.015); conversely, current smoking was inversely associated with prompt vaccination (RR=0.94, 95%CI:0.91-0.97, p=0.001) and was associated with fewer doses (RR=0.93, 95%CI:0.89-0.96, p<0.0001). Participants with CLRD versus without CLRD were more likely to report receiving influenza and pneumococcal vaccines, but they were more likely to believe that vaccines are unsafe or ineffective (figure). CONCLUSIONS: COPD was associated with lower likelihood of prompt COVID-19 vaccination. Current smoking was associated with both lower likelihood of prompt COVID-19 vaccination and a lower number of COVID-19 vaccine doses by 2023-24. These associations may be partly attributed to negative vaccine attitudes and beliefs. How the COVID-19 pandemic may have influenced vaccine behaviors and attitudes merits additional study.

Abstract RATIONALE: Deferral and declination of the COVID-19 vaccine is correlated with many factors, including different health guidelines and difficulties accessing the vaccine. In the US, COVID-19 vaccines were made available in tranches of clinical risk starting in December 2020 and were available to all adults on April 19, 2021. In the post-pandemic period, repeating COVID-19 vaccination with updated formulations is broadly recommended. Given that the public health impact of vaccine allocation strategies depends on public acceptance of vaccination, we aimed to evaluate demographic, clinical and social correlates of (1) receiving at least one COVID-19 vaccine by May 1, 2021 (prompt vaccination) and (2) the total number of vaccine doses received (vaccine count) through 2023-2024. METHODS: The Collaborative Cohort of Cohorts for COVID-19 Research (C4R) is a prospective observational meta-cohort study comprising 14 extant NIH-funded population-based cohorts. C4R assessed COVID-19 vaccination using three waves of standardized questionnaires (2020-2021, 2021-2023, 2023-2024). Prompt vaccination was defined by participant self-report of vaccination before May 1, 2021; participants vaccinated after May1, 2021 were classified as non-prompt; participants with missing vaccination information were excluded. Vaccine count was defined by self-report on the 2023-2024 wave Questionnaire. Demographic, clinical and social factors were classified by self-report and/or objective measures from the most recent pre-pandemic cohort exam. Poisson models regressed either prompt vaccination or vaccine count on pre-pandemic factors. RESULTS: Of 17,866 participants (mean age, 6713 years; 60.1% female; 42.1% non-Hispanic White, 22.0% Black, 28.9% Hispanic/Latino, 3.4% American Indian, 2.3% South Asian, 1.4% East Asian), 11,481 (64.3%) reported prompt vaccination. Of the subset of 14,529 participants completing the Wave 3 questionnaire, the median vaccine count in 2023-24 was 3 (Q1, 2; Q3 4). Likelihood of prompt vaccination was higher with greater age, income, and education and with history of diabetes and hypertension; prompt vaccination was less likely with male sex, current smoking, and non-White race and ethnicity (table). Similar associations were observed with respect to vaccine count (table). CONCLUSIONS: In a diverse C4R cohort community-based sample, earlier and greater COVID-19 vaccination was associated with older age and several clinical comorbidities; in contrast, later and lesser vaccine uptake was observed among historically marginalized groups. Whether disparities in COVID-19 vaccination could contribute to disparities in post-COVID-19 conditions merits further investigation.

Abstract Rationale: SARS-CoV-2 infection may be associated with new or worsening respiratory symptoms that, if persistent, may contribute to “Long COVID.” Research is needed on the prevalence and risk determinants of Long COVID and related respiratory symptoms in adults with and without pre-existing obstructive lung disease or smoking history. Methods: C4R is a prospective, observational study that collected information on SARS-CoV-2 infection using standardized methods across 14 NIH-funded cohorts. The third wave of C4R questionnaires, administered June 2023 to January 2025, assessed self-reported Long COVID via the question, “Do you think that you are experiencing, or have ever experienced, what has been called “long COVID,” or symptoms related to COVID at least a month after your infection?” Questionnaires also assessed the presence (vs absence) of 22 symptoms that have been linked to Long COVID, including cough, shortness of breath, and post-exertional malaise. Pre-pandemic obstructive lung disease (COPD or asthma) and smoking status (ever/never) were harmonized from self-reported data collected at the most recent pre-pandemic cohort exam. Poisson regression was used to assess prevalence ratios (PRs) adjusting for age, sex, BMI, education, and pre-pandemic hypertension, diabetes, cardiovascular disease, and depressive symptoms. PRs for respiratory symptoms were tested according to self-reported Long COVID and history of non-hospitalized or hospitalized infection; effect modification by pre-pandemic lung disease and smoking was assessed by multiplicative interaction terms and in fully stratified models. Results: Among 23,434 questionnaire respondents, 1,484 (6.3%) self-reported Long COVID, including 246/1,262 (19.5%) with pre-pandemic lung disease and 664/4,018 (16.5%) with smoking history. The adjusted PR for Long COVID was 1.17 (95%CI:0.99-1.39;P=0.06) comparing participants with/without lung disease and 1.17 (95%CI:1.04-1.32;P=0.01) comparing participants with/without smoking history. Respiratory symptoms were more prevalent in those with self-reported Long COVID, as well as in those with a history of hospitalized or non-hospitalized infection (Table). Associations were generally stronger in participants without pre-pandemic lung disease (p-interaction<0.05 for all comparisons). Respiratory symptoms were also more prevalent with a history of repeated, and pre-Omicron infections, and were less prevalent among participants vaccinated prior to their first infection; findings were similar even after excluding participants with self-reported Long COVID. Conclusions: Long COVID is common, particularly in adults with pre-existing COPD or asthma or smoking history. Long COVID and history of SARS-CoV-2 infection, including non-hospitalized infections, was associated with greater respiratory symptom burden. Whether SARS-CoV-2 infection or Long COVID are associated with development or progression of obstructive lung diseases warrants future studies.

Abstract Rationale Increased risk of coronavirus disease (COVID-19) hospitalization and death has been reported among patients with clinical lung disease. Objectives To test the association of objective measures of prepandemic lung function and structure with COVID-19 outcomes in U.S. adults. Methods Prepandemic obstruction (FEV1/FVC < 0.70) and restriction (FEV1/FVC ⩾ 0.7, FVC < 80%) were defined based on the most recent spirometry exam conducted in 11 prospective U.S. general population–based cohorts. Severe obstruction was classified by FEV1 < 50%. Percentage emphysema, percentage high-attenuation areas, and interstitial lung abnormalities were defined on computed tomography in a subset. Incident COVID-19 was ascertained via questionnaires, serosurvey, and medical records from 2020 to 2023 and classified as severe (hospitalized or fatal) or nonsevere. Cause-specific hazard models were adjusted for sociodemographics, anthropometry, smoking, comorbidities, and COVID-19 vaccination status. Measurements and Main Results Among 29,323 participants (mean age, 67 yr), there were 748 severe incident COVID-19 cases over median follow-up of 17.3 months from March 1, 2020. Greater hazards of severe COVID-19 were associated with severe obstruction (vs. normal; adjusted hazard ratio [aHR], 2.11; 95% confidence interval [CI], 1.02–1.27), restriction (vs. normal; aHR, 1.40; 95% CI, 1.12–1.76), and percentage emphysema (highest vs. lowest quartile; aHR, 1.64; 95% CI, 1.03–2.61), but not greater high-attenuation areas or interstitial lung abnormalities. COVID-19 vaccination provided greater absolute risk reduction in these groups. Results were similar in participants without smoking, obesity, or clinical cardiopulmonary disease. Conclusions Prepandemic severe spirometric obstruction, spirometric restriction, and greater percentage emphysema lung on computed tomography were associated with risk of severe COVID-19. These findings support enhanced COVID-19 risk mitigation for individuals with impaired lung health and warrant further mechanistic studies on interactions of lung function, structure, and vulnerability to acute respiratory illnesses.

Background: Adults with cardiovascular co-morbidities and risk factors are at greater risk of severe COVID-19. These same risk factors may also be associated with an attenuated antibody response to COVID-19 vaccines, although studies in diverse, U.S. population-based cohorts have been limited. Methods: The Collaborative Cohort of Cohorts for COVID-19 Research (C4R) conducted a serosurvey for SARS-CoV-2 antibodies via dried blood spot (DBS) in 14 U.S. cohorts. IgG antibodies to SARS-CoV-2 spike subunit 1 (S1) and nucleocapsid (N) were measured from DBS using a semi-quantitative microsphere immunoassay and reported as median fluorescence intensity (MFI). Multivariable adjusted linear models regressed log-transformed anti-S1 MFI on age, sex, race/ethnicity, education attainment, self-reported diabetes, hypertension, cardiovascular disease (CVD), chronic kidney disease, smoking history, body mass index (BMI), asthma, obstructive lung diseases, DBS batch, anti-N MFI, vaccine type, time between vaccine and DBS, and vaccine dose at time of DBS collection. Results are presented as the percent difference in anti-S1 MFI compared with a reference group. Results: There were 6614 vaccinated participants prior to booster regimens and DBS collection (April 2021-July 2022) with 50%, 48%, and 2% of the cohort who received BNT162b2, mRNA-1273, or other vaccines, respectively. The mean (SD) time between vaccination and DBS was 3.8 (1.8) months. Over 10% of the cohort had self-reported a history of diabetes, 55% had hypertension, and 74% had a BMI>25 kg/m 2 . Anti-S1 MFI decreased as the time between vaccine dose and DBS collection increased. Diabetes was associated with a 16.1% lower anti-S1 MFI (95%CI:-22.4,-9.5) whereas neither hypertension (-3.8%;95%CI:-9.3,2.1), nor cardiovascular disease history (-5.3%;95%CI:-16.3,7.4) were associated with anti-S1 MFI. Former and current smoking history were each associated with a lower anti-S1 MFI: (-6.6%;95%CI:-12.1,-0.8) and (-16.1%;95%CI:-24.7,-6.6), respectively. Participants with a BMI 25-29.9 kg/m 2 had a 7.6% higher anti-S1 MFI (95%CI:0.3,15.4) whereas those with a BMI of 30-35 kg/m 2 and >35 kg/m 2 had 6.2% (95%CI:-2.4,15.5) higher and 8.9% lower (95%CI:-17.6,0.7) MFI levels, respectively. Older age and male sex were each associated with a lower anti-S1 MFI and mRNA-1273 vaccine, Asian subgroup, higher anti-N titer, and prior COVID-19 infection were each associated with higher anti-S1 MFI. Chronic kidney disease, education attainment, and lung disease were not associated with anti-S1 MFI. Conclusions: Several traditional cardiovascular disease risk factors were associated with diminished humoral responses to the initial COVID-19 vaccine regimens in a diverse U.S. population-based cohort and may have implications on strategies to improve vaccine responses.

Background: Collateral blood flow, modulated by inflammation and arteriogenesis, alters ischemic injury in intracranial atherosclerosis. We investigated the potential link between several inflammatory and arteriogenic biomarkers with angiographic findings at enrollment in BIOSIS/SAMMPRIS. Methods: Baseline angiography and blood biomarkers of BIOSIS/SAMMPRIS, which included subjects with stroke or TIA due to 70-99% intracranial stenosis were analyzed. Collateral blood flow status at angiography was categorized by the combination of antegrade flow (TICI) and corresponding extent of collaterals (ASITN/SIR). Collateral status was analyzed with respect to blood progenitor cell markers (CD34) at baseline and inflammatory biomarkers (Plasminogen Activator Inhibitor-1 (PAI-1), E-selectin, high sensitivity C-reactive protein (hsCRP) and Lipoprotein-associated phospholipase A2 (Lp-PLA 2 ) activity and concentrations) at baseline, 30 days and 4 months. Results: 376 subjects (mean age 60.44 years SD 11; 149/376 (39.6%) women) enrolled in BIOSIS/SAMMPRIS had angiography of collaterals and biomarker data. Collateral perfusion was impaired in 71 (19%) and intermediate in 188 (50%), with robust collaterals in 117 (30%) subjects. Better collateral status was associated with younger age (p=0.001), male sex (p=0.029) and greater baseline physical activity (p=0.007). Baseline blood progenitor cell (CD34+) counts were unrelated to angiographic features at enrollment, whereas inflammatory Lp-PLA 2 activity was linked (p=0.059) with blood flow categories, and lower hsCRP (p=0.025) with better collaterals. Lp-PLA 2 activity was lowest in those with robust collaterals at 30 days (p=0.070) and 4 months (p=0.120). Those with robust collaterals had the greatest decrease in Lp-PLA 2 activity (p=0.021) and concentration (p=0.027) by 30 days, with a continued decline of Lp-PLA 2 activity (p=0.037) to 4 months. Disparate trends in inflammatory markers were seen in the medical and stenting arms. Conclusions: Inflammatory biomarkers are linked with collateral blood flow status in intracranial atherosclerosis. The impact of physical activity, medications and other therapeutic investigations may disclose important mechanisms to avert ischemia.

Introduction: Recent reports have linked visit-to-visit blood pressure (BP) variability to risk of mortality and stroke, independent of the effect of mean BP level. We sought to confirm these findings in the Cardiovascular Health Study (CHS), a cohort study of cardiovascular risk factors. Hypothesis: Variability in visit-to-visit SBP, defined as intraindividual SBP SD, is directly associated with risk of mortality, myocardial infarction (MI), and stroke, independent of intraindividual SBP mean and trend over time. Methods: Participants from CHS were eligible if they attended their first five annual clinic visits and did not have stroke, MI, or death by the 5th visit (N=3513). Follow-up started at the 5th visit and extended through June 2008. Analyses were further restricted to subjects who used no antihypertensive medications during the entire 5-year baseline period (non-users, n=1570) and subjects who used the same antihypertensive regimen during that time (users, n=978). Intraindividual SBP variables were defined using each subject’s 5-visit BPs. Cox proportional hazards models estimated adjusted hazard ratios (HR) per standard deviation (SD) increase in intraindividual SD (iSD) SBP or intraindividual mean (iMean) SBP. Results were stratified on medication use or non-use. Results: Participants’ mean age was 71 years, 42% were men, and 95% were white. Mean(SD) of iSD SBP was 9.8(4.6) mmHg for anti-hypertensive medications non-users and 12.0(6.0) mmHg for users. iMean SBP was significantly associated with all 3 outcomes among non-users and with stroke among users (table). iSD SBP was significantly associated with mortality in all participants and with MI among non-users; associations for stroke were not significant. Conclusion: Long-term visit-to-visit SBP variability may be an important determinant of MI and mortality risk in the elderly. Results for stroke are not consistent with other, previous reports. More research is needed to determine the clinical implications.

Introduction: Recent trials using insertable cardiac monitors (ICMs) show high rates of atrial fibrillation (AF) in those at risk of developing AF based on demographics. Further identifying subsets who could benefit most from ICMs is desirable. We evaluated if the recently-developed HAVOC risk score which has predicted AF in cryptogenic stroke patients also predicts AF detection by ICMs in those without a recent stroke. Methods: Participants from the prospective REVEAL AF study, which reported frequent clinically unrecognized AF in patients at risk for AF (CHADS 2 scores ≥3 or =2 with ≥1 additional risk factor), with ICM data and not on anti-arrhythmic drugs were included. Ischemic stroke <1 year ago excluded participation. HAVOC scores were calculated using points for hypertension (2), age ≥75 (2), valvular disease (2), vascular disease (1), obesity (1), congestive heart failure (4), and coronary artery disease (2). Prior stroke, an AF outcome, generally not a cause, is not included. Score classification is: low (0-4), intermediate (5-9), or high (10-14). Corresponding AF detection rates were compared via the log-rank test. Results: Among 391 participants, 95 (24%), 241 (62%), and 55 (14%) had low, intermediate, and high HAVOC scores, respectively. At 18 months, AF incidence was significantly less for those with low (19.5%) vs intermediate (32.1%) or high (34.2%) scores (p=0.045, Figure). At 18 months, AF incidence was similar among those with (n=79) vs. without (n=312) a history of remote stroke (27.1% vs. 29.9%; p>0.05, median time from stroke to ICM insertion=4 years). Conclusions: The HAVOC risk score identified a subset of high risk individuals at greatest risk of developing AF. AF incidence rates were similar among those with and without prior remote stroke. Remote strokes may not be a strong predictor of AF in this population. HAVOC scores could be a useful approach to identify those at high likelihood of manifesting AF, as best documented by long-term monitoring.