Wenzel, Sally E.

ImportanceIdentifying factors associated with resilience during the COVID-19 pandemic can inform targeted interventions and resource allocation for groups disproportionately affected by systemic inequities.ObjectiveTo examine factors associated with self-reported resilience during the COVID-19 pandemic in racially and ethnically diverse, community-dwelling US adults.Design, Setting, and ParticipantsThis cross-sectional study was conducted as part of the Collaborative Cohort of Cohorts for COVID-19 Research (C4R) study, which assessed the associations of the pandemic with self-reported resilience of participants from 14 established US prospective cohorts since January 2021. This report includes participants who responded to the self-reported resilience question on C4R questionnaires. Data was initially analyzed from October 2023 to May 2024, with updated analyses performed from August 2024 to April 2025.ExposureRace and ethnicity, behavior factors, health conditions, and social determinants of health measurements accessed before and during the COVID-19 pandemic through cohort visits and C4R questionnaires.Main Outcomes and MeasuresSelf-reported resilience was collected via 1 question (from the Brief Resilience Scale) in C4R questionnaires, “I tend to bounce back quickly after hard times.” Participants who answered agree or strongly agree were classified as resilient, and those who reported neutral, disagree, or strongly disagree were classified as not resilient. Modified Poisson regression was performed to estimate prevalence ratios (PRs) and access multivariable-adjusted associations with resilience.ResultsOf 31 045 participants (18 672 [60%] women; 10 746 [34.6%] aged <65 years), 1185 (3.8%) identified as American Indian, 6728 (21.7%) as Black, 293 (0.9%) as East Asian, 6311 (20.3%) as Hispanic, 565 (1.8%) as South Asian, and 15 961 (51.3%) as White; a total of 23 103 participants (74.4%) self-identified as resilient. Compared with White participants, Black and Hispanic participants had higher prevalence of self-reported resilience (adjusted PR [aPR], 1.04; 95% CI, 1.02-1.06; aPR, 1.08; 95% CI, 1.06-1.11; respectively) and American Indian and East Asian participants had lower prevalence (aPR, 0.90; 95% CI, 0.86-0.94; aPR, 0.76; 95% CI, 0.68-0.84; respectively). Higher education, being married or living as married, higher income, and overweight were also associated with higher prevalence of resilience. Being female, having diabetes, and being unemployed were associated with lower prevalence of self-reported resilience. Compared with participants with public insurance only, participants with private insurance had higher prevalence of resilience (aPR, 1.07; 95% CI, 1.03-1.10). COVID-19 vaccination and infection statuses were not significantly associated with resilience. Modification analyses showed important racial and ethnic differences in how factors such as hypertension, marital status, and insurance status were associated with resilience.Conclusions and RelevanceIn this cross-sectional study of 31 045 adults, self-reported resilience varied by race, ethnicity, and sociodemographic factors. These findings highlight the complex interplay of individual and social factors in shaping the perception of resilience.

Abstract RATIONALE: Susceptibility to severe COVID-19 and long COVID may be influenced by pre-existing lung structure. ECG-gated, non-contrast cardiac CT scans, originally acquired for assessing coronary artery calcium, are available in multiple longitudinal cohort studies and have been previously validated against lung CT scans for densitometry; however, protocol variation across cohorts may hinder direct comparison. To address this, we developed a quality control (QC) rubric to grade cardiac CT scans for standardized quantitative lung measures across cohorts. METHODS: C4R assessed SARS-CoV-2 infection and outcomes in 14 NHLBI cohorts, of which 10 (six community-based and four longitudinal case-control studies) included CT scans (12,459 participants with lung and 13,752 with cardiac CTs). Logic rules were applied to categorize scans (Table): Grade “A-B” scans had 2-3.5mm slice thickness, at least 20 axial slices, no lung cropping in axial view and lung and airway volumes greater than the cohort-specific 1st percentile. “C-D” scans had one lung obscured by cropping around the heart, so quantitative measures were restricted to the lung in complete view. “F-H” scans were deemed unusable, suffering from low slice count (<20), severe image cropping, low lung or airway volumes (< 1st%ile). Visual inspection was performed on a sample from each category to ensure accuracy. Percent of lung voxels in low attenuation areas < -950 HU (LAA950), high attenuation areas (-600 to -250 HU, HAA) and 15th percentile HU value (perc15) were measured. Within-participant variability was quantified using the intraclass correlation coefficient (ICC). RESULTS: We performed QC on cardiac CT scans from an initial sample of 6,275 participants from three C4R cohorts (ARIC, CARDIA, MASALA), imaged with GE or Siemens scanners. Of these, 5,125 (81.7%) were graded “A-B”, 496 (7.9%) were “C-D” and 654 (10.4%) were “F-H”. The percentage of “F-H” scans varied widely across cohorts [<1% to 26%] due to image cropping. Among the 5,621 cardiac CT scans graded A-D, the mean±SD for LAA950, HAA and perc15 respectively were 1.1±2.1%, 7.2±4.7% and -887±33 HU. Repeated imaging was available for 107 participants (time interval 5.1±0.7y). For paired scans in grades A-B (n=101/107), the within-participant correlation for LAA950, HAA and perc15 were 0.91, 0.38 and 0.74 respectively. CONCLUSION: Initial application of QC to cardiac CT scans identified scans with high reproducibility, with the aim to provide valid quantitative lung metrics on over 20,000 highly characterized participants in C4R.

Abstract RATIONALE. Significant sex-differences exist in asthma across the lifespan. Asthma prevalence and severity are greater in pre-pubescent boys compared to girls but greater in women after puberty. In women, asthma may improve after menopause when sex hormones wane. To address potential mechanisms underlying these changes, we compared the airway transcriptomics signatures of post-menopausal vs. premenopausal women. METHODS. We used bulk RNA seq data from bronchial epithelial cells from three different cohorts (SARP III, GEO-GSE85567, GEO-GSE201955) to perform a comprehensive analysis of differential gene expression and regulation. Data were combined into a meta-analysis, to compare pre-menopausal (n=114 cases with asthma, 48 controls) to post-menopausal women (n=52 cases with asthma, 13 controls). Differential gene expression between pre- and postmenopausal women was analyzed separately for asthma (Figure 1A) and control groups (not shown). Significant differentially expressed genes (DEGs) were identified by contrasting effect sizes (log fold-changes) between asthma and control groups using a Z-score interaction test. Accordingly, a scatter plot (Figure 1B) was created to represent whether differential gene expression between pre- and post-menopausal conditions is modified by disease status (asthma vs. control). The scatter plot also highlights that these findings are related to asthma per. se. and not to normal aging and menopausal transition. Pathway enrichment analysis was conducted using the differential expression data, followed by differential regulation analysis of the identified pathways. Statistical significance was assessed using a false discovery rate (FDR) threshold of 5%. RESULTS. Out of 15,468 genes that passed quality control, 19 genes were differentially expressed in bronchial epithelial cells from pre- and post-menopausal women with asthma (as compared to controls) (Figure 1A). Of these, 5 genes were down-regulated (ITLN1, POSTN, FCRL3, CCL22, PCSK6), and 14 genes were up-regulated (SPP1, S100A9, A2ML1, TNFRSF10C, CSF3R, OLFM1, C1QL2, NLRP3, HAL, PI3, RNASE1, TMEM178B, TNNI3, RNF175) when comparing pre- and post-menopausal women with asthma (Figure 1A). Of these 19 DEGs, 14 were differentially expressed in pre- as compared to post-menopausal women with asthma, but not in controls (Figure 1B). Comparing pre- to post-menopausal women with asthma, biologic pathways related to the innate and adaptive immune system activation and mitochondrial function (Electron transport Chain oxidative phosphorylation and ATP production) were both differentially regulated and expressed. CONCLUSIONS. This analysis highlights several DEGs and pathways that characterize asthma pathogenesis when comparing pre- and post-menopausal women, and emphasize the role of female sex hormones on the immune system response and mitochondrial function in asthma pathogenesis.

Abstract Introduction: The airway inflammation of asthma is characterized by immune phenotypes, often classified as Type 2 inflammation high or low. Social determinants of health (SDoH) can influence asthma risk and severity, but whether or not SDoH influence immune phenotypes is unclear. The social deprivation index (SDI) is a composite measure of seven neighborhood level characteristics: poverty level, less than 12 years of education, single parent household, living in rented housing unit, living in overcrowded housing unit, households without a car, and non-employed adults under 65 years of age. The scale of SDI ranges from 1 to 100, correlating with increasing deprivation. We hypothesized that social deprivation influences immune phenotype of asthma, and that deprivation effects vary by sex and race. Methods: Using the American Community Survey summary file spanning 2015 to 2019, we linked SDI to participant zip codes for 680 Black and White participants in the Severe Asthma Research Program (SARP), a NHLBI-multicenter network phenotyping asthma across the US from 2001-2024 (table 1). We compared SDI among the cohort by sex, race and asthma severity, and correlated SDI to superoxide dismutase (SOD) and T2-high biomarkers, such as eosinophils, IgE and Fraction of Exhaled Nitric Oxide (FENO). Results: SDI is similar across healthy and asthmatic participants (SDI: median [interquartile range]: healthy: 40 [56]; asthmatics: 51 [53], P = 0.53). When evaluated by race, SDI is significantly higher in Black asthmatics, independent of sex (SDI: Black male: 76 [4], White male: 35 [45]; P<0.0001; Black females: 77 [35], White females: 40 [45]; P<0.00010). Within SARP asthmatics, SDI shows a positive association with the T2 inflammatory markers, log IgE (R=0.13 [90%CI: 0.1, 0.2)] and log FENO (R=0.15 [90%CI: 0.1, 0.2]), while it correlates negatively with log of absolute neutrophil count (R= -0.12 [90%CI: -0.19,-0.1]). The antioxidant enzyme SOD increases with SDI (R=0.11, [90% CI: 0.04, 0.17]). Notably, within Black asthmatic males only, SDI is associated with Type 2 biomarkers, showing a positive correlation with log FENO (R=0.24 [90%CI: 0.1,0.4]) and negative correlation with log IgE levels (R= -0.25, [90% CI: -0.4, -0.1]). No association was found between SDI and eosinophils or with SOD in Black males. Conclusions: Neighborhood level social deprivation is associated with a unique asthma phenotype in Black males. Black males living at high social deprivation have a lower IgE and higher FENO, with no change in SOD activity.

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.

Abstract Despite the availability of effective vaccines and a recent decrease in annual deaths, COVID-19 remains a leading cause of death. Serological studies provide insights into host immunobiology of adaptive immune response to infection, which holds promise for identifying high-risk individuals for adverse COVID-19 outcomes. We investigated correlates of anti-nucleocapsid antibody responses following SARS-CoV-2 infection in a US population-based meta-cohort of adults participating in longstanding National Institutes of Health–funded cohort studies. Anti-nucleocapsid antibodies were measured from dried blood spots collected between February 2021 and February 2023. Among 1419 Collaborative Cohort of Cohorts for COVID-19 Research participants with prior SARS-CoV-2 infection, the mean age (standard deviation) was 65.8 (12.1), 61% were women, and 42.8% self-reported membership in a race/ethnicity minority group. The proportion of participants reactive to nucleocapsid peaked at 69% by 4 months after infection and waned to only 44% ≥12 months after infection. Higher anti-nucleocapsid antibody response was associated with older age, Hispanic or American Indian Alaskan Native (vs White) race/ethnicity, lower income, lower education, former smoking, and higher anti-spike antibody levels. Asian race (vs White) and vaccination (even after infection) were associated with lower nucleocapsid reactivity. Neither vaccine manufacturer nor common cardiometabolic comorbidities were not associated with anti-nucleocapsid response. These findings inform the underlying immunobiology of adaptive immune response to infection, as well as the potential utility of anti-nucleocapsid antibody response for clinical practice and COVID-19 serosurveillance.

Abstract Asthma is a heterogeneous disease with variable presentation and characteristics. There is a critical need to identify underlying molecular endotypes of asthma. We performed the largest transcriptomic analysis of 808 bronchial epithelial cell samples across 11 independent cohorts, including 3 cohorts from the Severe Asthma Research Program. Using seven datasets (218 patients with asthma, 148 healthy control subjects) as discovery cohorts, we identified 505 differentially expressed genes, which we validated in the remaining four datasets. Unsupervised clustering using the 505 differentially expressed genes identified four reproducible clusters of patients with asthma across all datasets, corresponding to healthy control subjects, patients with mild/moderate asthma, and patients with severe asthma with significant differences in several clinical markers of severity, including pulmonary function, Type 2 inflammation, fractional exhaled nitric oxide, and maximum bronchodilator reversibility. Importantly, we found the same clusters in pediatric patients using nasal lavage fluid cells, demonstrating the gene signature and clusters are not confounded by age and are conserved in both lower and upper airways. The four asthma clusters may represent a unifying framework for understanding the molecular heterogeneity of asthma. Further study could potentially enable a precision medicine approach of matching therapies with patients with asthma most likely to benefit.

ImportancePersistent symptoms and disability following SARS-CoV-2 infection, known as post–COVID-19 condition or “long COVID,” are frequently reported and pose a substantial personal and societal burden.ObjectiveTo determine time to recovery following SARS-CoV-2 infection and identify factors associated with recovery by 90 days.Design, Setting, and ParticipantsFor this prospective cohort study, standardized ascertainment of SARS-CoV-2 infection was conducted starting in April 1, 2020, across 14 ongoing National Institutes of Health–funded cohorts that have enrolled and followed participants since 1971. This report includes data collected through February 28, 2023, on adults aged 18 years or older with self-reported SARS-CoV-2 infection.ExposurePreinfection health conditions and lifestyle factors assessed before and during the pandemic via prepandemic examinations and pandemic-era questionnaires.Main Outcomes and MeasuresProbability of nonrecovery by 90 days and restricted mean recovery times were estimated using Kaplan-Meier curves, and Cox proportional hazards regression was performed to assess multivariable-adjusted associations with recovery by 90 days.ResultsOf 4708 participants with self-reported SARS-CoV-2 infection (mean [SD] age, 61.3 [13.8] years; 2952 women [62.7%]), an estimated 22.5% (95% CI, 21.2%-23.7%) did not recover by 90 days post infection. Median (IQR) time to recovery was 20 (8-75) days. By 90 days post infection, there were significant differences in restricted mean recovery time according to sociodemographic, clinical, and lifestyle characteristics, particularly by acute infection severity (outpatient vs critical hospitalization, 32.9 days [95% CI, 31.9-33.9 days] vs 57.6 days [95% CI, 51.9-63.3 days]; log-rank P < .001). Recovery by 90 days post infection was associated with vaccination prior to infection (hazard ratio [HR], 1.30; 95% CI, 1.11-1.51) and infection during the sixth (Omicron variant) vs first wave (HR, 1.25; 95% CI, 1.06-1.49). These associations were mediated by reduced severity of acute infection (33.4% and 17.6%, respectively). Recovery was unfavorably associated with female sex (HR, 0.85; 95% CI, 0.79-0.92) and prepandemic clinical cardiovascular disease (HR, 0.84; 95% CI, 0.71-0.99). No significant multivariable-adjusted associations were observed for age, educational attainment, smoking history, obesity, diabetes, chronic kidney disease, asthma, chronic obstructive pulmonary disease, or elevated depressive symptoms. Results were similar for reinfections.Conclusions and RelevanceIn this cohort study, more than 1 in 5 adults did not recover within 3 months of SARS-CoV-2 infection. Recovery within 3 months was less likely in women and those with preexisting cardiovascular disease and more likely in those with COVID-19 vaccination or infection during the Omicron variant wave.