Wendt, Chris H.

Abstract Rationale Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality in the United States. Rural populations experience a disproportionate burden, which likely reflects a combination of factors, including limited access to evidence-based COPD care. Our aim was to identify barriers, facilitators, and recommendations to improve the quality of COPD care received by rural veterans. Methods We performed a qualitative study of veterans with COPD who lived in rural areas. Participants were drawn from the Minneapolis VA Health Care System and the St. Cloud VA Health Care System. We conducted semi-structured interviews to explore rural veterans’ personal experiences navigating the healthcare system to receive COPD care. Interviews were conducted via telephone and were transcribed using NVIVO software. Transcribed interviews were then coded using content analysis. Results - Participants (N = 27) ranged in age from 59 to 85 years of age, 4 (14.8%) were women, and 24 (88.9%) identified as white. - Most veterans, 12 (44.4%) had an 11 to 30 minute drive to their primary care provider and 13 (48.1%) had a greater than 1 hour drive time to the pulmonologist. - Twenty-four (88.9%) participants had at least one exacerbation in the past 12 months, 10 (41.7%) of which ended up hospitalized. - Elucidative quotes are listed in Table 1, which were used to identify general themes. - General Themes: Barriers Primary care provider turnover and shortages, physical limitations related to chronic medical conditions, discomfort with virtual care, long appointment wait times and limited scheduling flexibility, complex referral processes, transportation challenges, and weather-related difficulties. Facilitators Self-motivation, self-advocacy, support from family and friends, timely scheduling and communication, trust and continuity with healthcare providers, and familiarity with or outside assistance in using technology facilitated access to COPD care. Recommendations Participants suggested improving technology-related education, providing necessary technology equipment, enhancing access to clinic appointments, supporting provider continuity, and fostering timely communication between patients and healthcare teams. Conclusion This study identified several barriers, facilitators, and patient-generated recommendations to improve COPD-related care for rural veterans. Participants described physical limitations, lack of provider continuity, and challenges with technology navigation as key barriers. Facilitating factors included strong family support and a sense of self-sufficiency that motivated engagement in care. Recommendations for improvement emphasized enhanced communication, greater patient education, and additional support for using technology in healthcare delivery. This abstract is funded by: NIH

Abstract RATIONALE The best described endotype of COPD is alpha-1 antitrypsin (AAT) deficiency, which is due to a genetic abnormality in the SERPINA1 gene. Homozygotes for the Z allele (PI[asterisk]ZZ individuals) carry the genotype most commonly associated with severe AAT deficiency, but a highly prevalent endotype is the heterozygous state (PI[asterisk]MZ individuals). Here we test the hypothesis that individuals with PI[asterisk]MZ genotype are at higher risk for COPD exacerbation and healthcare utilization compared to those with no pathogenic variants in the SERPINA1 gene (PI[asterisk]MM individuals). METHODS Real-world data on 4,456 individuals with available AAT genotyping were extracted from the Cleveland Clinic Health System (CCHS) electronic health records (EHR) and analyzed to compare the risk of moderate COPD exacerbation (defined as a short-term steroid prescription), all-cause emergent care (defined as an express care visit, urgent care visit, or emergency department visit), and all-cause hospitalization between individuals with PI[asterisk]MZ vs. PI[asterisk]MM genotypes. Cox proportional hazards models were used to adjust for age, sex, race, BMI, smoking status, comorbidity count, liver disease diagnosis, and median income by zip code.To assess the effect of AAT levels on outcomes, we categorized participants into three groups based on AAT level and used 90 mg/dL as a threshold given it is the lower limit of the normal reference range and genotype: MM individuals with an AAT level >90 mg/dL, MZ >90 mg/dL and MZ <90 mg/dL. To assess the effect of PI[asterisk]MZ genotype among individuals with pre-existing lung disease, we performed a subgroup analysis of individuals with at least a six-month inhaler prescription. RESULTS In this cohort, 308 individuals had a PI[asterisk]MZ genotype. PI[asterisk]MZ was associated with increased risk for moderate COPD exacerbations (adjusted HR [95% CI]: 1.66 [1.27, 2.17]) and hospitalizations (adjusted HR [95% CI]: 1.44 [1.19, 1.75]) compared to PI[asterisk]MM. The risk of hospitalization was higher among PI[asterisk]MZ individuals with AAT levels <90 mg/dL (adjusted HR [95% CI]: 1.59 [1.14, 2.23]) but not in those with AAT levels >90 mg/dL, as compared to PI[asterisk]MM. Sensitivity analysis in those treated with inhaler therapy showed overall similar results. CONCLUSIONS Increased hospitalizations and moderate COPD exacerbations among PI[asterisk]MZ individuals compared to PI[asterisk]MM individuals merit future prospective studies to better characterize the longitudinal course and healthcare utilization among those with an PI[asterisk]MZ genotype. Given the high prevalence of these carriers globally, PI[asterisk]MZ represents a COPD phenotype that invites additional investigation to identify biomarkers of worse disease and treatable traits.

HIV is an independent risk factor for lung disease, including chronic obstructive pulmonary disease (COPD) and emphysema. Angiotensin receptor blockers may be beneficial in COPD and emphysema through pathways that have been implicated in HIV-related lung disease. We performed a randomized comparison of the effects of losartan versus placebo on the plasma concentrations of the pneumoproteins, surfactant protein D (SPD) and club cell secretory protein (CCSP), in people living with HIV (PLWH). A total of 108 PLWH were included (52 assigned to losartan and 56 assigned to placebo). We found no difference in the change from baseline in log 2 concentrations of CCSP or SPD over 1 year of follow-up. For SPD, we found a strong interaction by CD4+ counts, where those with CD4+ counts >350 cells/mm 3 treated with losartan had more reduction (improvement) in SPD concentration than those treated with placebo ( p value for interaction <.001). In conclusion, we did not find a beneficial effect of losartan on pneumoprotein concentrations in PLWH, but PLWH with higher CD4+ counts may have improvement in SPD when treated with losartan.

Abstract Rationale Chronic obstructive pulmonary disease is an independent risk factor for lung cancer, but the underlying molecular mechanisms are unknown. We hypothesized that lung stromal cells activate pathological gene expression programs that support oncogenesis. Objectives To identify molecular mechanisms operating in the lung stroma that support the development of lung cancer. Methods The study included subjects with and without lung cancer across a spectrum of lung-function values. We conducted a multiomics analysis of nonmalignant lung tissue to quantify the transcriptome, translatome, and proteome. Measurements and Main Results Cancer-associated gene expression changes predominantly manifested as alterations in the efficiency of mRNA translation modulating protein levels in the absence of corresponding changes in mRNA levels. The molecular mechanisms that drove these cancer-associated translation programs differed based on lung function. In subjects with normal to mildly impaired lung function, the mammalian target of rapamycin (mTOR) pathway served as an upstream driver, whereas in subjects with severe airflow obstruction, pathways downstream of pathological extracellular matrix emerged. Consistent with a role during cancer initiation, both the mTOR and extracellular matrix gene expression programs paralleled the activation of previously identified procancer secretomes. Furthermore, an in situ examination of lung tissue showed that stromal fibroblasts expressed cancer-associated proteins from two procancer secretomes: one that included IL-6 (in cases of mild or no airflow obstruction), and one that included BMP1 (in cases of severe airflow obstruction). Conclusions Two distinct stromal gene expression programs that promote cancer initiation are activated in patients with lung cancer depending on lung function. Our work has implications both for screening strategies and for personalized approaches to cancer treatment.

Abstract Rationale Chronic obstructive pulmonary disease (COPD) is an independent risk factor for lung cancer, but the underlying molecular mechanisms are unknown. We hypothesized that stromal cells comprising the COPD lung contain pathological gene expression programs supporting oncogenesis. Objectives To identify molecular mechanisms operating in the lung stroma that support the development of lung cancer. Methods Study subjects included patients with COPD with (n = 30) or without (n = 30) lung cancer across a spectrum of COPD severity. We conducted multi-omics analysis of nonmalignant lung tissue to quantify the transcriptome, translatome, and proteome. Results Cancer-associated gene expression changes predominantly manifested as alterations in the efficiency of mRNA translation impacting protein levels in the absence of corresponding changes in mRNA levels. The molecular mechanisms driving these procancer translation programs differed on the basis of COPD severity. In mild or no COPD, the mammalian target of rapamycin pathway served as an upstream driver; whereas in advanced COPD, pathways downstream of pathological extracellular matrix emerged. Both the mammalian target of rapamycin and extracellular matrix gene expression programs paralleled activation of previously identified secretomes that can be independently induced and promote cancer initiation in mouse models. These included the senescence secretome in mild to no COPD and the ETS2 (erythroblast transformation-specific 2) secretome in moderate to severe COPD. Furthermore, in situ examination of COPD lung tissue documented stromal fibroblasts expressing key cancer-associated proteins from procancer secretomes including IL-6 (senescence secretome) in mild COPD and bone morphogenetic protein-1 (ETS2 secretome) in advanced COPD. Conclusions Two distinct stromal gene expression programs promoting cancer initiation are activated in patients with lung cancer depending on the severity of COPD as measured by lung function. Our work has implications both for screening strategies and personalized approaches to prevent cancer in COPD.