Altered ontogeny and transcriptomic signatures of tissue-resident pulmonary interstitial macrophages ameliorate allergic airway hyperresponsiveness.

Introduction: Environmental exposures and experimental manipulations can alter the ontogenetic composition of tissue-resident macrophages. However, the impact of these alterations on subsequent immune responses, particularly in allergic airway diseases, remains poorly understood. This study aims to elucidate the significance of modified macrophage ontogeny resulting from environmental exposures on allergic airway responses to house dust mite (HDM) allergen. Methods: We utilized embryonic lineage labeling to delineate the ontogenetic profile of tissue-resident macrophages at baseline and following the resolution of repeated lipopolysaccharide (LPS)-induced lung injury. We investigated differences in house dust mite (HDM)-induced allergy to assess the influence of macrophage ontogeny on allergic airway responses. Additionally, we employed single-cell RNA sequencing (scRNAseq) and immunofluorescent staining to characterize the pulmonary macrophage composition, associated pathways, and tissue localization. Results: Our findings demonstrate that the ontogeny of homeostatic alveolar and interstitial macrophages is altered after the resolution from repeated LPS-induced lung injury, leading to the replacement of embryonic-derived by bone marrow-derived macrophages. This shift in macrophage ontogeny is associated with reduced HDM-induced allergic airway responses. Through scRNAseq and immunofluorescent staining, we identified a distinct subset of resident-derived interstitial macrophages expressing genes associated with allergic airway diseases, localized adjacent to terminal bronchi, and diminished by prior LPS exposure. Discussion: These results suggest a pivotal role for pulmonary macrophage ontogeny in modulating allergic airway responses. Moreover, our findings highlight the implications of prior environmental exposures in shaping future immune responses and influencing the development of allergies. By elucidating the mechanisms underlying these phenomena, this study provides valuable insights into potential therapeutic targets for allergic airway diseases and avenues for further research into immune modulation and allergic disease prevention.

Risk of Atherosclerotic Cardiovascular Disease Hospitalizations after COPD Hospitalization among Older Adults.

BACKGROUND: Meta-analyses have suggested the risk of cardiovascular disease (CVD) events is significantly higher after a chronic obstructive pulmonary disease (COPD) exacerbation. However, many of these studies have included a broad array of CVD events or have been limited to highly selected patient populations potentially not generalizable to the broader population of COPD. METHODS: We assessed the risk of atherosclerotic cardiovascular disease (ASCVD)hospitalizations after COPD hospitalization compared to before COPD hospitalization and identified patient factors associated with ASCVD hospitalizations after COPD hospitalization. This retrospective cohort study used claims data from 920,550 Medicare beneficiaries hospitalized for COPD from 2016-2019 in the US. The primary outcome was risk of a ASCVD hospitalization composite outcome (myocardial infarction, percutaneous coronary intervention, coronary artery by-pass graft surgery, stroke, or transient ischemic attack) in the 30-days and 1 year after-COPD hospitalization relative to the same time period before-COPD hospitalization. Time in the before- and after-COPD hospitalization time periods to a composite ASCVD hospitalization outcome were modeled using an extension of the Cox Proportional-Hazards model, the Anderson-Gill model with adjustment for patient characteristics. Additional analyses evaluated for interactions in subgroups associated with the composite ASCVD hospitalization outcome. RESULTS: Among 920,550 patients in the 30-day and 1-year cohorts, (mean age, 73-74 years) the hazard ratio estimate (HR; 95% CI) for the composite ASCVD hospitalization outcome after-COPD hospitalization vs before-COPD hospitalization for the 30-day cohort was 0.99 (0.93, 1.05; p = 0.67) and for the 1-year cohort was 0.99 (0.97, 1.02; p = 0.53) following adjustment. We observed 3 subgroups that were significantly associated with higher risk for ASCVD hospitalizations 1 year after COPD hospitalization: 76+ years old, women, COPD hospitalization severity. CONCLUSION: Among Medicare beneficiaries hospitalized for COPD, the risk of ASCVD hospitalizations was not significantly increased 30-day or 1-year after COPD-hospitalization relative to before-COPD hospitalization. In sub-group analyses, we identified age 76+ years old, female sex, and COPD hospitalization severity as high risk subgroups with increased risk of ASCVD events 1-year after-COPD hospitalization. Further research is needed to characterize the COPD exacerbation populations at highest ASCVD hospitalization risk.

SARS-CoV-2 viremia but not respiratory viral load is associated with respiratory complications in patients with severe COVID-19.

BACKGROUND: Severe COVID-19 carries a high morbidity and mortality. Previous studies have shown an association between COVID-19 severity and SARS-CoV-2 viral load (VL). We sought to measure VL in multiple compartments (urine, plasma, lower respiratory tract) in patients admitted to the intensive care unit (ICU) with severe COVID-19 pneumonia and correlate with clinical outcomes. METHODS: Plasma, urine, and endotracheal aspirate (ETA) samples were obtained on days 1, 3, 7, 14, and 21 from subjects admitted to the ICU with severe COVID-19. VL was measured via reverse transcriptase polymerase chain reaction. Clinical data was collected from the electronic health record. Grouped comparisons were performed using Student's t-test or 1-way ANOVA. Linear regression was used to correlate VL from different compartments collected at the same time. Logistic regression was performed to model ventilator-freedom at 28 days as a function of peak plasma VL. RESULTS: We enrolled 57 subjects with severe COVID-19 and measured VL in plasma (n = 57), urine (n = 25), and ETA (n = 34). Ventilator-associated pneumonia developed in 63% of subjects. 49% of subjects were viremic on study day 1. VL in plasma and ETA both significantly decreased by day 14 (P < 0.05), and the two were weakly correlated on study day 1 (P = 0.0037, r2 = 0.2343) and on all study days (P < 0.001, r2 = 0.2211). VL were not detected in urine. While no associations were observed with peak ETA VL, subjects with higher peak plasma VL experienced a greater number of respiratory complications, including ventilator-associated pneumonia and fewer ventilator-free and hospital-free days. There was no association between VL in either plasma or ETA and mortality. In viremic patients, plasma VL was significantly lower in subjects that were ICU-free and ventilator-free (P < 0.05), with trends noted for hospital-freedom, ventilator-associated pneumonia, and survival to discharge (P < 0.1). By logistic regression, plasma VL was inversely associated with ventilator-freedom at 28 days (odds ratio 0.14, 95% confidence interval 0.02-0.50). CONCLUSIONS: Elevated SARS-CoV-2 VL in the plasma but not in the lower respiratory tract is a novel biomarker in severe COVID-19 for respiratory complications.

Tuberculosis Is Associated with Chronic Hypoxemia among Kenyan Adults (CHAKA): A Case-Control Study.

Rationale: Data on risk factors for chronic hypoxemia in low- and middle-income countries are lacking. Objectives: We aimed to quantify the association between potential risk factors and chronic hypoxemia among adults hospitalized in Kenya. Methods: A hospital-based, case-control study was conducted at Moi Teaching and Referral Hospital in Eldoret, Kenya. Adult inpatients were screened on admission and enrolled in a 1:2 case-to-control ratio. Cases were patients with chronic hypoxemia, defined as resting oxygen saturation as measured by pulse oximetry (SpO2) ⩽ 88% on admission and either 1-month postdischarge SpO2 ⩽ 88% or, if they died before follow-up, documented SpO2 ⩽ 88% in the 6 months before enrollment. Control subjects were randomly selected, stratified by sex, among nonhypoxemic inpatients. Data were collected using questionnaires and structured chart review. Regression was used to assess the associations between chronic hypoxemia and age, sex, smoking status, biomass fuel use, elevation, and self-reported history of tuberculosis and human immunodeficiency virus diagnosis. Odds ratios (ORs) and 95% confidence intervals (CIs) are reported. Results: We enrolled 108 chronically hypoxemic cases and 240 nonhypoxemic control subjects into our Chronic Hypoxemia among Kenyan Adults (CHAKA) cohort. In multivariable analysis, compared with control subjects, chronically hypoxemic cases had significantly higher odds of older age (OR, 1.2 per 5-year increase [95% CI, 1.1-1.3]), female sex (OR, 3.6 [95% CI, 1.8-7.2]), current or former tobacco use (OR, 4.7 [95% CI, 2.3-9.6]), and prior tuberculosis (OR, 11.8 [95% CI, 4.7-29.6]) but no increase in the odds of human immunodeficiency virus diagnosis and biomass fuel use. Conclusions: These findings highlight the potential impact of prior tuberculosis on chronic lung disease in Kenya and the need for further studies on posttuberculosis lung disease.

Tissue-Resident Alveolar Macrophages Reduce Ozone-induced Inflammation via MerTK-mediated Efferocytosis.

Lung inflammation, caused by acute exposure to ozone (O3), one of the six criteria air pollutants, is a significant source of morbidity in susceptible individuals. Alveolar macrophages (AMØs) are the most abundant immune cells in the normal lung, and their number increases after O3 exposure. However, the role of AMØs in promoting or limiting O3-induced lung inflammation has not been clearly defined. In this study, we used a mouse model of acute O3 exposure, lineage tracing, genetic knockouts, and data from O3-exposed human volunteers to define the role and ontogeny of AMØs during acute O3 exposure. Lineage-tracing experiments showed that 12, 24, and 72 hours after exposure to O3 (2 ppm) for 3 hours, all AMØs were of tissue-resident origin. Similarly, in humans exposed to filtered air and O3 (200 ppb) for 135 minutes, we did not observe at ∼21 hours postexposure an increase in monocyte-derived AMØs by flow cytometry. Highlighting a role for tissue-resident AMØs, we demonstrate that depletion of tissue-resident AMØs with clodronate-loaded liposomes led to persistence of neutrophils in the alveolar space after O3 exposure, suggesting that impaired neutrophil clearance (i.e., efferocytosis) leads to prolonged lung inflammation. Moreover, depletion of tissue-resident AMØs demonstrated reduced clearance of intratracheally instilled apoptotic Jurkat cells, consistent with reduced efferocytosis. Genetic ablation of MerTK (MER proto-oncogene, tyrosine kinase), a key receptor involved in efferocytosis, also resulted in impaired clearance of apoptotic neutrophils after O3 exposure. Overall, these findings underscore the pivotal role of tissue-resident AMØs in resolving O3-induced inflammation via MerTK-mediated efferocytosis.

Cluster Analysis to Identify Long COVID Phenotypes Using 129Xe Magnetic Resonance Imaging: A Multi-centre Evaluation.

BACKGROUND: Long COVID impacts ∼10% of people diagnosed with COVID-19, yet the pathophysiology driving ongoing symptoms is poorly understood. We hypothesised that 129Xe magnetic resonance imaging (MRI) could identify unique pulmonary phenotypic subgroups of long COVID, therefore we evaluated ventilation and gas exchange measurements with cluster analysis to generate imaging-based phenotypes. METHODS: COVID-negative controls and participants who previously tested positive for COVID-19 underwent 129XeMRI ∼14-months post-acute infection across three centres. Long COVID was defined as persistent dyspnea, chest tightness, cough, fatigue, nausea and/or loss of taste/smell at MRI; participants reporting no symptoms were considered fully-recovered. 129XeMRI ventilation defect percent (VDP) and membrane (Mem)/Gas, red blood cell (RBC)/Mem and RBC/Gas ratios were used in k-means clustering for long COVID, and measurements were compared using ANOVA with post-hoc Bonferroni correction. RESULTS: We evaluated 135 participants across three centres: 28 COVID-negative (40±16yrs), 34 fully-recovered (42±14yrs) and 73 long COVID (49±13yrs). RBC/Mem (p=0.03) and FEV1 (p=0.04) were different between long- and COVID-negative; FEV1 and all other pulmonary function tests (PFTs) were within normal ranges. Four unique long COVID clusters were identified compared with recovered and COVID-negative. Cluster1 was the youngest with normal MRI and mild gas-trapping; Cluster2 was the oldest, characterised by reduced RBC/Mem but normal PFTs; Cluster3 had mildly increased Mem/Gas with normal PFTs; and Cluster4 had markedly increased Mem/Gas with concomitant reduction in RBC/Mem and restrictive PFT pattern. CONCLUSION: We identified four 129XeMRI long COVID phenotypes with distinct characteristics. 129XeMRI can dissect pathophysiologic heterogeneity of long COVID to enable personalised patient care.

Short-term cardiovascular events after bariatric surgery in patients with metabolic syndrome.

BACKGROUND: Patients with metabolic syndrome (MetS) are at increased risk of developing cardiovascular disease along with other adverse events after bariatric surgery. OBJECTIVES: The incidence of short-term major adverse cardiovascular events (MACE) in patients with MetS undergoing bariatric surgery is not well characterized. SETTING: Accredited bariatric surgery centers in the United States and Canada. METHODS: A total of 760,076 patients aged ≥18 years with body mass index ≥35 kg/m2 who underwent primary bariatric surgery between 2015 and 2018 were included. Patients with both diabetes and hypertension were described as the MetS cohort. Patient characteristics, operative technique, and 30-day outcomes were compared. The primary outcome was incidence of MACE, a composite of myocardial infarction, stroke, and all-cause mortality. Unadjusted and multivariable logistic regression analyses were performed and included an interaction between MetS and hyperlipidemia (HLD). RESULTS: Of the 577,882 patients included, 111,128 (19.2%) exhibited MetS. Patients with MetS more frequently experienced MACE compared with patients without MetS (.3% versus .1%; P < .001). The odds of MACE were greater for patients with MetS versus Non-MetS (odds ratio [OR] 2.87; 95% CI, 2.49-3.32) in the unadjusted analysis. MetS without HLD, MetS with HLD, and Non-MetS with HLD are significantly associated with MACE when compared with those with non-MetS without HLD. CONCLUSIONS: Patients with MetS have an increased frequency of cardiac events following bariatric surgery. Future studies should determine if optimization of 1 or more components of MetS or other related co-morbidities reduces the cardiovascular risk for patients.

Association of alpha globin gene copy number with exhaled nitric oxide in a cross-sectional study of healthy Black adults.

INTRODUCTION: The genetic determinants of fractional exhalation of nitric oxide (FeNO), a marker of lung inflammation, are understudied in Black individuals. Alpha globin (HBA) restricts nitric oxide signalling in arterial endothelial cells via interactions with nitric oxide synthase; however, its role in regulating the release of NO from respiratory epithelium is less well understood. We hypothesised that an HBA gene deletion, common among Black individuals, would be associated with higher FeNO. METHODS: Healthy Black adults were enrolled at four study sites in North Carolina from 2005 to 2008. FeNO was measured in triplicate using a nitric oxide analyzer. The -3.7 kb HBA gene deletion was genotyped using droplet digital PCR on genomic DNA. The association of FeNO with HBA copy number was evaluated using multivariable linear regression employing a linear effect of HBA copy number and adjusting for age, sex and serum immunoglobulin-E levels. Post-hoc analysis employing a recessive mode of inheritance was performed. RESULTS: 895 individuals were in enrolled in the study and 720 consented for future genetic research; 643 had complete data and were included in this analysis. Median (25th, 75th) FeNO was 20 (13, 31) ppb. HBA genotypes were: 30 (4.7%) -a/-a, 197 (30.6%) -a/aa, 405 (63%) aa/aa and 8 (1.2%) aa/aaa. Subjects were 35% male with median age 20 (19, 22) years. Multivariable linear regression analysis revealed no association between FeNO and HBA copy number (ß=-0.005 (95% CI -0.042 to 0.033), p=0.81). In the post-hoc sensitivity analysis, homozygosity for the HBA gene deletion was associated with higher FeNO (ß=0.107 (95% CI 0.003 to 0.212); p=0.045). CONCLUSION: We found no association between HBA copy number and FeNO using a prespecified additive genetic model. However, a post hoc recessive genetic model found FeNO to be higher among subjects homozygous for the HBA deletion.

Prevalence and phenotypic trajectories of hypoxaemia among hospitalised adults in Kenya: a single-centre, prospective cohort study.

OBJECTIVE: Global medical oxygen security is limited by knowledge gaps in hypoxaemia burden and oxygen access in low-income and middle-income countries. We examined the prevalence and phenotypic trajectories of hypoxaemia among hospitalised adults in Kenya, with a focus on chronic hypoxaemia. DESIGN: Single-centre, prospective cohort study. SETTING: National tertiary referral hospital in Eldoret, Kenya between September 2019 and April 2022. PARTICIPANTS: Adults (age ≥18 years) admitted to general medicine wards. PRIMARY AND SECONDARY OUTCOME MEASURES: Our primary outcome was proportion of patients who were hypoxaemic (oxygen saturation, SpO2 ≤88%) on admission. Secondary outcomes were proportion of patients with hypoxaemia on admission who had hypoxaemia resolution, hospital discharge, transfer, or death among those with unresolved hypoxaemia or chronic hypoxaemia. Patients remaining hypoxaemic for ≤3 days after admission were enrolled into an additional cohort to determine chronic hypoxaemia. Chronic hypoxaemia was defined as an SpO2 ≤ 88% at either 1-month post-discharge follow-up or, for patients who died prior to follow-up, a documented SpO2 ≤88% during a previous hospital discharge or outpatient visit within the last 6 months. RESULTS: We screened 4104 patients (48.5% female, mean age 49.4±19.4 years), of whom 23.8% were hypoxaemic on admission. Hypoxaemic patients were significantly older and more predominantly female than normoxaemic patients. Among those hypoxaemic on admission, 33.9% had resolution of their hypoxaemia as inpatients, 55.6% had unresolved hypoxaemia (31.0% died before hospital discharge, 13.3% were alive on discharge and 11.4% were transferred) and 10.4% were lost to follow-up. The prevalence of chronic hypoxaemia was 2.1% in the total screened population, representing 8.8% of patients who were hypoxaemic on admission. Chronic hypoxaemia was determined at 1-month post-discharge among 59/86 patients and based on prior documentation among 27/86 patients. CONCLUSION: Hypoxaemia is highly prevalent among adults admitted to a general medicine ward at a national referral hospital in Kenya. Nearly 1 in 11 patients who are hypoxaemic on admission are chronically hypoxaemic.

Asthma, Airflow Obstruction, and Eosinophilic Airway Inflammation Prevalence in Western Kenya: A Population-Based Cross-Sectional Study.

Objectives: Determine the prevalence of airway disease (e.g., asthma, airflow obstruction, and eosinophilic airway inflammation) in Kenya, as well as related correlates of airway disease and health-related quality of life. Methods: A three-stage, cluster-randomized cross-sectional study in Uasin Gishu County, Kenya was conducted. Individuals 12 years and older completed questionnaires (including St. George's Respiratory Questionnaire for COPD, SGRQ-C), spirometry, and fractional exhaled nitric oxide (FeNO) testing. Prevalence ratios with 95% confidence intervals (CIs) were calculated. Multivariable models were used to assess correlates of airflow obstruction and high FeNO. Results: Three hundred ninety-two participants completed questionnaires, 369 completed FeNO testing, and 305 completed spirometry. Mean age was 37.5 years; 64% were women. The prevalence of asthma, airflow obstruction on spirometry, and eosinophilic airway inflammation was 21.7%, 12.3% and 15.7% respectively in the population. Women had significantly higher SGRQ-C scores compared to men (15.0 vs. 7.7). Wheezing or whistling in the last year and SGRQ-C scores were strongly associated with FeNO levels >50 ppb after adjusting for age, gender, BMI, and tobacco use. Conclusion: Airway disease is a significant health problem in Kenya affecting a young population who lack a significant tobacco use history.

Effects of Oxidative Stress on Airway Epithelium Permeability in Asthma and Potential Implications for Patients with Comorbid Obesity.

20 million adults and 4.2 million children in the United States have asthma, a disease resulting in inflammation and airway obstruction in response to various factors, including allergens and pollutants and nonallergic triggers. Obesity, another highly prevalent disease in the US, is a major risk factor for asthma and a significant cause of oxidative stress throughout the body. People with asthma and comorbid obesity are susceptible to developing severe asthma that cannot be sufficiently controlled with current treatments. More research is needed to understand how asthma pathobiology is affected when the patient has comorbid obesity. Because the airway epithelium directly interacts with the outside environment and interacts closely with the immune system, understanding how the airway epithelium of patients with asthma and comorbid obesity is altered compared to that of lean asthma patients will be crucial for developing more effective treatments. In this review, we discuss how oxidative stress plays a role in two chronic inflammatory diseases, obesity and asthma, and propose a mechanism for how these conditions may compromise the airway epithelium.

Efficacy and tolerability of zinc acetate for treatment of chronic refractory cough: pilot randomised futility trial.

Background: Cough is the most reported symptom in the United States, with chronic refractory cough representing significant morbidity to patients. Zinc acetate may have beneficial effects in the cough reflex pathway. We sought to assess the safety and efficacy of zinc acetate in the management of chronic refractory cough. Study design and methods: This was a randomised, placebo-controlled, parallel-design pilot trial of individuals with chronic refractory cough. The effects of 6 weeks of zinc acetate versus placebo on quality of life and symptoms as measured by the Cough Quality-of-Life Questionnaire (CQLQ), Leicester Cough Questionnaire (LCQ), cough visual analogue score (C-VAS) and Global Assessment of Change in Cough (GACC) scores were evaluated. A futility analysis plan with a one-sided 80% confidence interval was used to compare treatment effect to published minimum clinically important differences (MCID) for each outcome. Results: 34 participants, 17 in each group, were enrolled and randomised. Participants were primarily white females with moderate-severe cough. Participants assigned to zinc acetate had a significant increase in serum zinc levels after 6 weeks, while those assigned to placebo did not. Both groups showed improvement in CQLQ, LCQ, C-VAS and GACC scores, but the treatment effects of zinc acetate versus placebo were small with confidence intervals that did not include the MCIDs. Interpretation: We observed no benefit of zinc therapy over placebo on cough symptoms or quality of life and conclude that larger trials of zinc for chronic cough are not warranted.

Vertical sleeve gastrectomy associates with airway hyperresponsiveness in a murine model of allergic airway disease and obesity.

Introduction: Asthma is a chronic airway inflammatory disease marked by airway inflammation, remodeling and hyperresponsiveness to allergens. Allergic asthma is normally well controlled through the use of beta-2-adrenergic agonists and inhaled corticosteroids; however, a subset of patients with comorbid obesity experience resistance to currently available therapeutics. Patients with asthma and comorbid obesity are also at a greater risk for severe disease, contributing to increased risk of hospitalization. Bariatric surgery improves asthma control and airway hyperresponsiveness in patients with asthma and comorbid obesity, however, the underlying mechanisms for these improvements remain to be elucidated. We hypothesized that vertical sleeve gastrectomy (VSG), a model of metabolic surgery in mice, would improve glucose tolerance and airway inflammation, resistance, and fibrosis induced by chronic allergen challenge and obesity. Methods: Male C57BL/6J mice were fed a high fat diet (HFD) for 13 weeks with intermittent house dust mite (HDM) allergen administration to induce allergic asthma, or saline as control. At week 11, a subset of mice underwent VSG or Sham surgery with one week recovery. A separate group of mice did not undergo surgery. Mice were then challenged with HDM or saline along with concurrent HFD feeding for 1-1.5 weeks before measurement of lung mechanics and harvesting of tissues, both of which occurred 24 hours after the final HDM challenge. Systemic and pulmonary cytokine profiles, lung histology and gene expression were analyzed. Results: High fat diet contributed to increased body weight, serum leptin levels and development of glucose intolerance for both HDM and saline treatment groups. When compared to saline-treated mice, HDM-challenged mice exhibited greater weight gain. VSG improved glucose tolerance in both saline and HDM-challenged mice. HDM-challenged VSG mice exhibited an increase in airway hyperresponsiveness to methacholine when compared to the non-surgery group. Discussion: The data presented here indicate increased airway hyperresponsiveness in allergic mice undergoing bariatric surgery.

Allergic Asthma Responses Are Dependent on Macrophage Ontogeny.

The ontogenetic composition of tissue-resident macrophages following injury, environmental exposure, or experimental depletion can be altered upon re-establishment of homeostasis. However, the impact of altered resident macrophage ontogenetic milieu on subsequent immune responses is poorly understood. Hence, we assessed the effect of macrophage ontogeny alteration following return to homeostasis on subsequent allergic airway responses to house dust mites (HDM). Using lineage tracing, we confirmed alveolar and interstitial macrophage ontogeny and their replacement by bone marrow-derived macrophages following LPS exposure. This alteration in macrophage ontogenetic milieu reduced allergic airway responses to HDM challenge. In addition, we defined a distinct population of resident-derived interstitial macrophages expressing allergic airway disease genes, located adjacent to terminal bronchi, and reduced by prior LPS exposure. These findings support that the ontogenetic milieu of pulmonary macrophages is a central factor in allergic airway responses and has implications for how prior environmental exposures impact subsequent immune responses and the development of allergy.

Roflumilast May Increase Risk of Exacerbations When Used to Treat Poorly Controlled Asthma in People with Obesity.

Rationale: People with obesity often have severe, difficult-to-control asthma. There is a need to develop better treatments for this population. One potential treatment is roflumilast, a phosphodiesterase 4 inhibitor, as it is reported to have efficacy for the treatment of asthma and can promote weight loss. Objectives: To investigate the potential efficacy of roflumilast for the treatment of poorly controlled asthma in people with obesity. Methods: A randomized, double-masked, placebo-controlled trial of 24 weeks of roflumilast versus placebo for the treatment of poorly controlled asthma in people with obesity (body mass index of 30 kg/m2 or higher). The primary outcome was a change in ACT (Asthma Control Test) score. Results: Twenty-two people were randomized to roflumilast and 16 to placebo. Roflumilast had no effect on change in the ACT (increased by 2.6 [interquartile range (IQR), 0.5-4.4] in those on roflumilast vs. 2.0 [IQR, 0.7-3.3] in those on placebo). Participants assigned to roflumilast had a 3.5-fold (relative risk [RR] 95% confidence interval [CI], 1.3-9.4) increased risk of an episode of poor asthma control and an 8.1-fold (RR 95% CI, 1.01-65.0) increased risk of an urgent care visit for asthma. Ten participants (56%) assigned to roflumilast required a course of oral corticosteroids for asthma exacerbations, and none in the placebo group. Participants losing 5% or more of their body weight experienced a clinically and statistically significant improvement in asthma control (ACT increased by 4.4 [IQR, 2.5-6.3] vs. 1.5 [IQR, 0.0-3.0] in those who lost less than 5%). Conclusions: Roflumilast had no effect on asthma control. Of concern, roflumilast was associated with an increased risk of exacerbation in obese individuals with poorly controlled asthma. These results highlight the importance of studying interventions in different subpopulations of people with asthma, particularly people with obesity and asthma who may respond differently to medications than lean people with asthma. Weight loss of at least 5% was associated with improved asthma control, indicating that interventions other than roflumilast promoting weight loss may have efficacy for the treatment of poorly controlled asthma in people with obesity. Clinical trial registered with www.clinicaltrials.gov (NCT03532490).

Risk of Atherosclerotic Cardiovascular Disease Hospitalizations after COPD Hospitalization among Older Adults.

BACKGROUND: Meta-analyses have suggested the risk of atherosclerotic cardiovascular disease (ASCVD) events is significantly higher after a chronic obstructive pulmonary disease (COPD) exacerbation. However, these studies have been limited to highly selected patient populations potentially not generalizable to the broader population of COPD. METHODS: We assessed the risk of ASCVD hospitalizations after COPD hospitalization compared to before COPD hospitalization and identified patient factors associated with ASCVD hospitalizations after COPD hospitalization. This retrospective cohort study used claims data from 920,550 Medicare beneficiaries hospitalized for COPD from 2016-2019 in the US. The primary outcome was risk of a ASCVD hospitalization composite outcome (myocardial infarction, percutaneous coronary intervention, coronary artery by-pass graft surgery, stroke, or transient ischemic attack) in the 1 year after-COPD hospitalization relative to the 1 year before-COPD hospitalization. Time from discharge to a composite ASCVD hospitalization outcome was modeled using an extension of the Cox Proportional-Hazards model, the Anderson-Gill model with adjustment for patient characteristics. Additional analyses evaluated for interactions in subgroups and risk factors associated with the composite ASCVD hospitalization outcome. RESULTS: Among 920,550 patients (mean age, 73 years) the hazard ratio estimate (HR; 95% CI) for the composite ASCVD hospitalization outcome after-COPD hospitalization vs before-COPD hospitalization was 0.99 (0.97, 1.02; p = 0.53) following adjustment. We observed 3 subgroups that were significantly associated with higher risk for ASCVD hospitalizations after COPD hospitalization: 76+ years old, women, COPD hospitalization severity. Among the 19 characteristics evaluated, 10 were significantly associated with higher risk of CVD events 1 year after COPD hospitalization with hyperlipidemia (2.78; 2.67, 2.90) and history of cardiovascular disease (1.77; 1.72 1.83) associated with the greatest risk. CONCLUSION: Among Medicare beneficiaries hospitalized for COPD, the risk of ASCVD hospitalizations was not significantly increased after COPD-hospitalization relative to before-COPD hospitalization. Although, we identified age 76+ years old, female sex, and COPD hospitalization severity as high risk subgroups and 10 risk factors associated with increased risk of ASCVD events after-COPD hospitalization. Further research is needed to characterize the COPD exacerbation populations at highest ASCVD hospitalization risk.

Effects of biological therapies on patients with Type-2 high asthma and comorbid obesity.

Over 20 million adults and 6 million children in the United States (US) have asthma, a chronic respiratory disease characterized by airway inflammation, bronchoconstriction, and mucus hypersecretion. Obesity, another highly prevalent disease in the US, is a major risk factor for asthma and a significant cause of diminished asthma control, increased submucosal eosinophilia, and reduced quality of life. A large subgroup of these patients experiences severe symptoms and recurrent exacerbations despite maximal dosage of standard asthma therapies. In the past two decades, the development of biological therapies has revolutionized the field and advanced our understanding of type 2 inflammatory biomarkers. However, patients with obesity and comorbid asthma are not principally considered in clinical trials of biologics. Large landmark cluster analyses of patients with asthma have consistently identified specific asthma phenotypes that associate with obesity but may be differentiated by age of asthma onset and inflammatory cell profiles in sputum. These patterns suggest that biologic processes driving asthma pathology are heterogenous among patients with obesity. The biological mechanisms driving pathology in patients with asthma and comorbid obesity are not well understood and likely multifactorial. Future research needs to be done to elicit the cellular and metabolic functions in the relationship of obesity and asthma to yield the best treatment options for this multiplex condition. In this review, we explore the key features of type 2 inflammation in asthma and discuss the effectiveness, safety profile, and research gaps regarding the currently approved biological therapies in asthma patients with obesity.

Subgroup Analysis of a Randomized Trial of the Effects of Positive Messaging on Patient-Reported Outcomes with Asthma - Effect of Obesity.

Objective: Asthma in obese patients represents a specific phenotype that is associated with increased symptoms, more frequent and severe exacerbations, reduced responsiveness to treatment, and decreased quality of life. Marketing and placebos have been shown to alter subjective responses to interventions in both asthma and obesity. We evaluated obesity as a potential treatment effect modifier of the effects enhanced drug messaging or placebos on subjective asthma outcomes. Methods: We conducted a secondary analysis of a multicenter, randomized clinical trial that studied the effect of messaging and placebos on asthma outcomes. A total of 601 participants were randomized (1:1:1:1:1) to one of 5 groups: enhanced messaging with montelukast or placebo, neutral messaging with montelukast or placebo, or usual care and followed for 4 weeks after randomization. We compared baseline characteristics by obesity status for 600 participants with data on body weight. Obesity was evaluated as an effect modifier for enhanced messaging (versus neutral messaging) and on placebo effects (versus usual care) in 362 participants assigned to a placebo group or usual care for three asthma questionnaires: Asthma Control Questionnaire, Asthma Quality of Life Questionnaire and Asthma Symptoms Utility Index. Results: Overall, 227 (37%) of participants were obese. Obese participants were older (mean age 41 vs 34), more likely female (82% vs 67%) and self-identified as Black (44% vs 25%) than non-obese participants. As previously published, enhanced messaging was associated with improvements in patient-reported asthma scores, but there was no evidence for a placebo effect. Obesity status did not influence the message effects nor did it modify responses to placebo. Conclusion: Obesity has been shown to be an important factor associated with asthma outcomes and an effect modifier of drug treatment effects. We conducted a post hoc, subgroup analysis of data from a multicenter randomized trial of enhanced messaging and placebo associated with drug treatment on asthma outcomes. Our findings suggest that observed differences in treatment effects between obese and non-obese patients sometimes seen in trials of asthma treatments are unlikely to be due to different "placebo" effects of treatment and may reflect differential physiologic effects of active agents.

Age and Comorbidities Predict COVID-19 Outcome, Regardless of Innate Immune Response Severity: A Single Institutional Cohort Study.

The COVID-19 pandemic has claimed over eight hundred thousand lives in the United States alone, with older individuals and those with comorbidities being at higher risk of severe disease and death. Although severe acute respiratory syndrome coronavirus 2-induced hyperinflammation is one of the mechanisms underlying the high mortality, the association between age and innate immune responses in COVID-19 mortality remains unclear. DESIGN: Flow cytometry of fresh blood and multiplexed inflammatory chemokine measurements of sera were performed on samples collected longitudinally from our cohort. Aggregate impact of comorbid conditions was calculated with the Charlson Comorbidity Index, and association between patient factors and outcomes was calculated via Cox proportional hazard analysis and repeated measures analysis of variance. SETTING: A cohort of severely ill COVID-19 patients requiring ICU admission was followed prospectively. PATIENTS: In total, 67 patients (46 male, age 59 ± 14 yr) were included in the study. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Mortality in our cohort was 41.8%. We identified older age (hazard ratio [HR] 1.09 [95% CI 1.07-1.11]; p = 0.001), higher comorbidity index (HR 1.24 [95% CI 1.14-1.35]; p = 0.039), and hyponatremia (HR 0.90 [95% CI 0.82-0.99]; p = 0.026) to each independently increase risk for death in COVID-19. We also found that neutrophilia (R = 0.2; p = 0.017), chemokine C-C motif ligand (CCL) 2 (R = 0.3; p = 0.043), and C-X-C motif chemokine ligand 9 (CXCL9) (R = 0.3; p = 0.050) were weakly but significantly correlated with mortality. Older age was associated with lower monocyte (R = -0.2; p = 0.006) and cluster of differentiation (CD) 16+ cell counts (R = -0.2; p = 0.002) and increased CCL11 concentration (R = 0.3; p = 0.050). Similarly, younger patients (< 65 yr) demonstrated a rise in CD4 (b-coefficient = 0.02; p = 0.036) and CD8 (0.01; p = 0.001) counts, as well as CCL20 (b-coefficient = 6.8; p = 0.036) during their ICU stay. This CD8 count rise was also associated with survival (b-coefficient = 0.01; p = 0.023). CONCLUSIONS: Age, comorbidities, and hyponatremia independently predict mortality in severe COVID-19. Neutrophilia and higher CCL2 and CXCL9 levels are also associated with higher mortality, while independent of age.