Heterogeneity of Lung Function Phenotypes in Sarcoidosis: Role of Race and Sex Differences.

Rationale: Historically, sarcoidosis was described as a restrictive lung disease, but several alternative phenotypes of pulmonary function have been observed. Pulmonary function phenotypes in sarcoidosis may represent different clinical and/or molecular phenotypes. Objectives: To characterize the prevalence of different pulmonary function phenotypes in a large and diverse sarcoidosis cohort from a tertiary care referral center. Methods: We identified individuals seen between 2005-2015 with a confirmed diagnosis of sarcoidosis. Data were collected from the first pulmonary function test (PFT) performed at our institution which included spirometry and diffusing capacity of the lung for carbon monoxide (DlCO). Demographics and clinical data were collected. Chi-squared analyses and multiple linear regressions were done to assess statistical differences and associations. Global Lung Function Initiative equations were used to calculate percent predicted measurements for spirometry and DlCO. Results: Of 602 individuals with sarcoidosis, 93% (562) had pulmonary involvement, 64% (385) were female, and 57% (341) were Black. Of those with pulmonary involvement, 56% had abnormal pulmonary function. Lung function impairment phenotypes included: 47% restriction, 22% obstruction, 15% isolated reduction in DlCO, and 16% combined obstructive restrictive phenotype. Restriction was the most common PFT phenotype among Black individuals (41%), while no lung impairment was most common among White individuals (66%) (P < 0.001). Males more frequently had obstruction (19%) compared with females (9%) P = 0.001, and females had more restriction (30%) compared with males (21%) P = 0.031. Conclusions: Among individuals with sarcoidosis and pulmonary function impairment, less than half demonstrated a restrictive phenotype. There were significant differences in pulmonary function phenotypes by race and sex.

A shift in lung macrophage composition is associated with COVID-19 severity and recovery.

Although it has been more than 2 years since the start of the coronavirus disease 2019 (COVID-19) pandemic, COVID-19 continues to be a worldwide health crisis. Despite the development of preventive vaccines, therapies to treat COVID-19 and other inflammatory diseases remain a major unmet need in medicine. Our study sought to identify drivers of disease severity and mortality to develop tailored immunotherapy strategies to halt disease progression. We assembled the Mount Sinai COVID-19 Biobank, which was composed of almost 600 hospitalized patients followed longitudinally through the peak of the pandemic in 2020. Moderate disease and survival were associated with a stronger antigen presentation and effector T cell signature. In contrast, severe disease and death were associated with an altered antigen presentation signature, increased numbers of inflammatory immature myeloid cells, and extrafollicular activated B cells that have been previously associated with autoantibody formation. In severely ill patients with COVID-19, lung tissue-resident alveolar macrophages not only were drastically depleted but also had an altered antigen presentation signature, which coincided with an influx of inflammatory monocytes and monocyte-derived macrophages. In addition, we found that the size of the alveolar macrophage pool correlated with patient outcome and that alveolar macrophage numbers and functionality were restored to homeostasis in patients who recovered from COVID-19. These data suggest that local and systemic myeloid cell dysregulation are drivers of COVID-19 severity and modulation of alveolar macrophage numbers and activity in the lung may be a viable therapeutic strategy for the treatment of critical inflammatory lung diseases.

Bronchodilators in Tobacco-Exposed Persons with Symptoms and Preserved Lung Function.

BACKGROUND: Many persons with a history of smoking tobacco have clinically significant respiratory symptoms despite an absence of airflow obstruction as assessed by spirometry. They are often treated with medications for chronic obstructive pulmonary disease (COPD), but supporting evidence for this treatment is lacking. METHODS: We randomly assigned persons who had a tobacco-smoking history of at least 10 pack-years, respiratory symptoms as defined by a COPD Assessment Test score of at least 10 (scores range from 0 to 40, with higher scores indicating worse symptoms), and preserved lung function on spirometry (ratio of forced expiratory volume in 1 second [FEV1] to forced vital capacity [FVC] ≥0.70 and FVC ≥70% of the predicted value after bronchodilator use) to receive either indacaterol (27.5 µg) plus glycopyrrolate (15.6 µg) or placebo twice daily for 12 weeks. The primary outcome was at least a 4-point decrease (i.e., improvement) in the St. George's Respiratory Questionnaire (SGRQ) score (scores range from 0 to 100, with higher scores indicating worse health status) after 12 weeks without treatment failure (defined as an increase in lower respiratory symptoms treated with a long-acting inhaled bronchodilator, glucocorticoid, or antibiotic agent). RESULTS: A total of 535 participants underwent randomization. In the modified intention-to-treat population (471 participants), 128 of 227 participants (56.4%) in the treatment group and 144 of 244 (59.0%) in the placebo group had at least a 4-point decrease in the SGRQ score (difference, -2.6 percentage points; 95% confidence interval [CI], -11.6 to 6.3; adjusted odds ratio, 0.91; 95% CI, 0.60 to 1.37; P = 0.65). The mean change in the percent of predicted FEV1 was 2.48 percentage points (95% CI, 1.49 to 3.47) in the treatment group and -0.09 percentage points (95% CI, -1.06 to 0.89) in the placebo group, and the mean change in the inspiratory capacity was 0.12 liters (95% CI, 0.07 to 0.18) in the treatment group and 0.02 liters (95% CI, -0.03 to 0.08) in the placebo group. Four serious adverse events occurred in the treatment group, and 11 occurred in the placebo group; none were deemed potentially related to the treatment or placebo. CONCLUSIONS: Inhaled dual bronchodilator therapy did not decrease respiratory symptoms in symptomatic, tobacco-exposed persons with preserved lung function as assessed by spirometry. (Funded by the National Heart, Lung, and Blood Institute and others; RETHINC ClinicalTrials.gov number, NCT02867761.).

Mesenchymal stromal cell therapy for acute respiratory distress syndrome due to coronavirus disease 2019.

BACKGROUND AIMS: The acute respiratory distress syndrome (ARDS) resulting from coronavirus disease 2019 (COVID-19) is associated with a massive release of inflammatory cytokines and high mortality. Mesenchymal stromal cells (MSCs) have anti-inflammatory properties and have shown activity in treating acute lung injury. Here the authors report a case series of 11 patients with COVID-19-associated ARDS (CARDS) requiring mechanical ventilation who were treated with remestemcel-L, an allogeneic MSC product, under individual patient emergency investigational new drug applications. METHODS: Patients were eligible if they were mechanically ventilated for less than 72 h prior to the first infusion. Patients with pre-existing lung disease requiring supplemental oxygen or severe liver or kidney injury were excluded. Each patient received two infusions of remestemcel-L at a dose of 2 million cells/kg per infusion given 48-120 h apart. RESULTS: Remestemcel-L infusions were well tolerated in all 11 patients. At the end of the 28-day follow-up period, 10 (91%, 95% confidence interval [CI], 59-100%) patients were extubated, nine (82%, 95% CI, 48-97%) patients remained liberated from mechanical ventilation and were discharged from the intensive care unit and two (18%, 95 CI%, 2-52%) patients died. The median time to extubation was 10 days. Eight (73%, 95% CI, 34-100%) patients were discharged from the hospital. C-reactive protein levels significantly declined within 5 days of MSC infusion. CONCLUSIONS: The authors demonstrate in this case series that remestemcel-L infusions to treat moderate to severe CARDS were safe and well tolerated and resulted in improved clinical outcomes.

Shift of lung macrophage composition is associated with COVID-19 disease severity and recovery.

Though it has been 2 years since the start of the Coronavirus Disease 19 (COVID-19) pandemic, COVID-19 continues to be a worldwide health crisis. Despite the development of preventive vaccines, very little progress has been made to identify curative therapies to treat COVID-19 and other inflammatory diseases which remain a major unmet need in medicine. Our study sought to identify drivers of disease severity and death to develop tailored immunotherapy strategies to halt disease progression. Here we assembled the Mount Sinai COVID-19 Biobank which was comprised of ~600 hospitalized patients followed longitudinally during the peak of the pandemic. Moderate disease and survival were associated with a stronger antigen (Ag) presentation and effector T cell signature, while severe disease and death were associated with an altered Ag presentation signature, increased numbers of circulating inflammatory, immature myeloid cells, and extrafollicular activated B cells associated with autoantibody formation. Strikingly, we found that in severe COVID-19 patients, lung tissue resident alveolar macrophages (AM) were not only severely depleted, but also had an altered Ag presentation signature, and were replaced by inflammatory monocytes and monocyte-derived macrophages (MoMΦ). Notably, the size of the AM pool correlated with recovery or death, while AM loss and functionality were restored in patients that recovered. These data therefore suggest that local and systemic myeloid cell dysregulation is a driver of COVID-19 severity and that modulation of AM numbers and functionality in the lung may be a viable therapeutic strategy for the treatment of critical lung inflammatory illnesses.

Recent Advances in the Management of Acute Exacerbations of Chronic Obstructive Pulmonary Disease.

Chronic obstructive pulmonary disease is a chronic, irreversible obstructive lung disease that results from exposure to noxious stimuli. Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) usually result from viral or bacterial respiratory infections, but may also result from exposure to environmental pollution. AECOPD are associated with functional decline, increased risk of subsequent exacerbations, and death. Despite the poor prognosis of AECOPD, patients are empowered through self-management programs in their battle against this lethal disease. Morbidity and mortality of chronic obstructive pulmonary disease hospitalizations are reduced by implementing standardized treatment modalities outlined in this article throughout the hospitalization and beyond.

Comparative Effectiveness of Robotic-Assisted Surgery for Resectable Lung Cancer in Older Patients.

BACKGROUND: Robotic-assisted surgery (RAS) is a novel surgical approach increasingly used for patients with non-small cell lung cancer (NSCLC). However, data comparing the effectiveness and costs of RAS vs open thoracotomy and video-assisted thoracoscopic surgery (VATS) for NSCLC are limited. METHODS: Patients > 65 years old with stage I to IIIA NSCLC treated with RAS, VATS, or open thoracotomy were identified from the Surveillance, Epidemiology, and End Results-Medicare database and matched according to age, sex, stage, and extent of resection. Propensity score methods were used to compare adjusted rates of postoperative complications, adequate lymph node staging, survival, and treatment-related costs. RESULTS: In this matched study cohort of 2,766 patients with resected NSCLC, RAS was associated with lower complication rates (OR, 0.57; 95% CI, 0.42-0.79) compared with open thoracotomy, and similar complication rates (OR, 1.02; 95% CI, 0.76-1.37) compared with VATS. Patients undergoing RAS were as likely to have adequate lymph node sampling as those undergoing open thoracotomy (OR, 1.28; 95% CI, 0.94-1.74) or VATS (OR, 0.88; 95% CI, 0.66-1.18). There was no significant difference in overall survival after RAS vs open thoracotomy (hazard ratio, 0.81; 95% CI, 0.63-1.04) or VATS (hazard ratio, 0.91; 95% CI, 0.70-1.18). Costs were similar for RAS ($54,702) vs open thoracotomy ($57,104; P = .08), and higher compared with VATS ($48,729; P = .02). CONCLUSIONS: RAS led to improved operative outcomes compared with open thoracotomy but may not offer an advantage over VATS. The comparative effectiveness of RAS should be further evaluated prior to widespread adoption.

Interstitial Lung Abnormalities and Lung Cancer Risk in the National Lung Screening Trial.

BACKGROUND: Some interstitial lung diseases are associated with lung cancer. However, it is unclear whether asymptomatic interstitial lung abnormalities convey an independent risk. OBJECTIVES: The goal of this study was to assess whether interstitial lung abnormalities are associated with an increased risk of lung cancer. METHODS: Data from all participants in the National Lung Cancer Trial were analyzed, except for subjects with preexisting interstitial lung disease or prevalent lung cancers. The primary analysis included those who underwent low-dose CT imaging; those undergoing chest radiography were included in a confirmatory analysis. Participants with evidence of reticular/reticulonodular opacities, honeycombing, fibrosis, or scarring were classified as having interstitial lung abnormalities. Lung cancer incidence and mortality in participants with and without interstitial lung abnormalities were compared by using Poisson and Cox regression, respectively. RESULTS: Of the 25,041 participants undergoing low-dose CT imaging included in the primary analysis, 20.2% had interstitial lung abnormalities. Participants with interstitial lung abnormalities had a higher incidence of lung cancer (incidence rate ratio, 1.61; 95% CI, 1.30-1.99). Interstitial lung abnormalities were associated with higher lung cancer incidence on adjusted analyses (incidence rate ratio, 1.33; 95% CI, 1.07-1.65). Lung cancer-specific mortality was also greater in participants with interstitial lung abnormalities. Similar findings were obtained in the analysis of participants undergoing chest radiography. CONCLUSIONS: Asymptomatic interstitial lung abnormalities are an independent risk factor for lung cancer that can be incorporated into risk score models.

Outcomes of Older Patients with Pulmonary Fibrosis and Non-Small Cell Lung Cancer.

Rationale: Characteristics and outcomes of lung cancer in patients with idiopathic pulmonary fibrosis (IPF) in the United States remain understudied.Objectives: To determine the tumor characteristics and survival of patients with IPF with non-small cell lung cancer (NSCLC) using U.S. population-based data.Methods: We selected Medicare beneficiaries from the Surveillance, Epidemiology, and End Results registry with histologically confirmed NSCLC diagnosed between 2007 and 2011. IPF was identified using two validated claims-based algorithms. We compared tumor characteristics and used logistic and Cox regression to compare rates of stage-appropriate therapy and of overall and lung cancer-specific survival in those with IPF and without IPF.Results: A total of 54,453 patients with NSCLC were included. Those with IPF were more likely to be diagnosed at an earlier stage (P < 0.01) and to have squamous histology (46% vs. 35%; P < 0.01) and lower-lobe tumors (38% vs. 28%; P < 0.01) than those without IPF. Patients with IPF and stages I-II disease had odds of receiving stage-appropriate therapy similar to patients without IPF who had stages I-II disease (odds ratio [OR], 1.13; 95% confidence interval [CI], 0.89-1.43); however, those with advanced disease were less likely to be treated (OR, 0.82; 95% CI, 0.68-0.99). Overall and lung cancer-specific survival were worse in patients with IPF (respectively, hazard ratio [HR], 1.35; 95% CI, 1.26-1.45; and HR, 1.21; 95% CI, 1.10-1.32).Conclusions: NSCLC has a unique presentation in patients with IPF and is associated with poorer prognosis. Further research is needed to identify optimal treatment strategies in this population.

Idiopathic Pulmonary Fibrosis and Lung Cancer. A Systematic Review and Meta-analysis.

Rationale: The association between idiopathic pulmonary fibrosis (IPF) and lung cancer has been previously reported. However, there is the potential for significant confounding by age and smoking, and an accurate summary risk estimate has not been previously ascertained.Objectives: To determine the risk and burden of lung cancer in patients with IPF, accounting for known confounders.Methods: We conducted a comprehensive literature search of MEDLINE, EMBASE, and SCOPUS databases and used the Newcastle Ottawa criteria to assess study quality. We then assessed the quality of ascertainment of IPF cases based on modern consensus criteria. Data that relied on administrative claims or autopsies were excluded. We calculated summary risk estimates using a random effects model.Results: Twenty-five cohort studies were included in the final analysis. The estimated adjusted incidence rate ratio from two studies was 6.42 (95% confidence interval [CI], 3.21-9.62) and accounted for age, sex, and smoking. The summary incidence rate from 11 studies was 2.07 per 100 person-years (95% CI, 1.46-2.67), and the summary mortality rate was 1.06 per 100 person-years (95% CI, 0.62-1.51) obtained from three studies. The summary prevalence from 11 studies was 13.74% (95% CI, 10.17-17.30), and the proportion of deaths attributable to lung cancer was 10.20 (95% CI, 8.52-11.87) and was obtained from nine studies.Conclusions: IPF is an increased independent risk factor for lung cancer, even after accounting for smoking. Further well-designed studies using modern consensus criteria are needed to explore mechanisms of this association.

Obesity Trends among Asthma Patients in the United States: A Population-based Study.

BACKGROUND: Obesity is strongly associated with worse asthma control and poorer quality of life. The current obesity epidemic has reached historically high levels, with an estimated prevalence rate of 37% in the general United States (US) population. However, less is known about trends in the prevalence of obesity among individuals with asthma or which sociodemographic groups are at higher risk for increased weight. METHODS: The study was conducted with data from the Behavioral Risk Factor Surveillance System (BRFSS) study, a nationally representative probability-based sample of the US population. We included participants ≥18 years of age who were interviewed between 1999 and 2016. Using stratified weighting, we estimated the annual prevalence of participants with, and without a diagnosis of asthma, classified according to their body mass index (BMI), into: normal weight (18.5-25 kg/m2), overweight (25-30 kg/m2), or obese (>30 kg/m2). We calculated the annual odds of obesity among participants with vs. without asthma to assess if trends among individuals with asthma followed those of the general US population. Nominal regression analysis assessed the association between age, sex, race/ethnicity, and income with prevalence of obesity among participants with asthma. RESULTS: Among the 543,574 BRSFF participants with asthma, the prevalence of overweight and obesity changed from 34.3% and 24.7% in 1999 to 28.8% and 41.1% in 2016, respectively. The odds ratio (OR) of obesity in patients with asthma compared to the general population without asthma, increased during the same period from 1.39 (95% confidence interval [CI]: 1.36-1.36) in 1999 to 1.75 (95% CI: 1.75-1.76) in 2016. Adjusted analysis showed that older (OR: 2.32, 95% CI: 2.32-2.33), Black (OR: 1.61, 95% CI: 1.61-1.61) and Hispanic (OR: 1.29, 95%. CI: 1.28-1.29) participants with asthma had higher rates of obesity. CONCLUSIONS: There has been a substantial increase in the prevalence of obesity among individuals with asthma in the last two decades, beyond what could be explained by general population trends. These results suggest that obesity is an increasing determinant of asthma morbidity and should be particularly targeted in minorities with asthma.

The effect of radiographic emphysema in assessing lung cancer risk.

PURPOSE: Lung cancer risk models optimise screening by identifying subjects at highest risk, but none of them consider emphysema, a risk factor identifiable on baseline screen. Subjects with a negative baseline low-dose CT (LDCT) screen are at lower risk for subsequent diagnosis and may benefit from risk stratification prior to additional screening, thus we investigated the role of radiographic emphysema as an additional predictor of lung cancer diagnosis in participants with negative baseline LDCT screens of the National Lung Screening Trial. METHODS: Our cohorts consist of participants with a negative baseline (T0) LDCT screen (n=16 624) and participants who subsequently had a negative 1-year follow-up (T1) screen (n=14 530). Lung cancer risk scores were calculated using the Bach, PLCOm2012 and Liverpool Lung Project models. Risk of incident lung cancer diagnosis at the end of the study and number screened per incident lung cancer were compared between participants with and without radiographic emphysema. RESULTS: Radiographic emphysema was independently associated with nearly double the hazard of lung cancer diagnosis at both the second (T1) and third (T2) annual LDCT in all three risk models (HR range 1.9-2.0, p<0.001 for all comparisons). The number screened per incident lung cancer was considerably lower in participants with radiographic emphysema (62 vs 28 at T1 and 91 vs 40 at T2). CONCLUSION: Radiographic emphysema is an independent predictor of lung cancer diagnosis and may help guide decisions surrounding further screening for eligible patients.

The Relationship Between Tobacco Smoke Exposure and Airflow Obstruction in US Children: Analysis of the National Health and Nutrition Examination Survey (2007-2012).

BACKGROUND: It has been difficult to determine the individual impact of prenatal and postnatal tobacco smoke exposure (TSE) on childhood lung function, as children are often exposed to both. OBJECTIVE: The goal of this study was to determine the association between current TSE and airflow obstruction while adjusting for self-reported prenatal TSE. METHODS: Children aged 6 to 11 years who participated in the National Health and Nutrition Examination Survey (2007-2012) who had serum cotinine levels measured and spirometry performed were included. Logistic regression was used to determine the association between log-transformed serum cotinine level and airflow obstruction while adjusting for confounders; the analysis was then stratified according to asthma status. The final model included both log-transformed serum cotinine level and prenatal exposure as covariates. RESULTS: The sample consisted of 2,070 children; 9.6% had airflow obstruction. The association between cotinine levels and airflow obstruction was significant in an unadjusted analysis (OR, 1.12 [95% CI, 1.02-1.23]). In the multivariate analysis with both exposures included as covariates, serum cotinine level was not significantly associated with airflow obstruction (ORadj, 1.07 [95% CI, 0.94-1.21]), and no association was seen in children with asthma and nonasthmatic children. Prenatal smoking was associated with airflow obstruction in children with asthma (ORadj, 2.51 [95% CI, 1.08-5.79]) but not in nonasthmatic children (ORadj, 1.08 [95% CI, 0.53-2.18]). CONCLUSIONS: Current TSE was not independently associated with airflow obstruction in school-aged children. Prenatal TSE was associated with airflow obstruction in children with asthma. Repeated studies into potential mediators and confounders of this relationship are needed.