Preserved Ratio Impaired Spirometry and Risks of Macrovascular, Microvascular Complications and Mortality Among Individuals With Type 2 Diabetes.

BACKGROUND: The prospective associations of preserved ratio impaired spirometry (PRISm) with new-onset macrovascular and microvascular complications and mortality among individuals with type 2 diabetes (T2D) and whether PRISm enhances the prediction ability of an established office-based risk score remain to be elucidated. RESEARCH QUESTION: Can PRISm be used as a predictor of poor prognosis in individuals with T2D? STUDY DESIGN AND METHODS: We included 20,047 study participants with T2D and complete data on spirometry at recruitment from the UK Biobank cohort. Multivariable Cox proportional hazards models were used to assess the associations of baseline PRISm (FEV1 to FVC ratio, ≥ 0.70; FEV1, < 80% predicted) with subsequent risks of incident stroke (any type), ischemic stroke, myocardial infarction, unstable angina, coronary heart disease, diabetic retinopathy, diabetic kidney disease, all-cause mortality, cardiovascular mortality, and respiratory mortality. RESULTS: For this cohort analysis, 4,521 patients (22.55% of participants with T2D) showed comorbid PRISm at baseline. Over a median follow-up of 11.52 to 11.87 years, patients with T2D with PRISm at baseline showed higher risks than those with normal spirometry findings of various T2D complications developing and mortality; the adjusted hazard ratios for PRISm were 1.413 (95% CI, 1.187-1.681) for stroke (any type), 1.382 (95% CI, 1.129-1.690) for ischemic stroke, 1.253 (95% CI, 1.045-1.503) for myocardial infarction, 1.206 (95% CI, 1.086-1.339) for coronary heart disease, 1.311 (95% CI, 1.141-1.506) for diabetic retinopathy, 1.384 (95% CI, 1.190-1.610) for diabetic kidney disease, 1.337 (95% CI, 1.213-1.474) for all-cause mortality, 1.597 (95% CI, 1.296-1.967) for cardiovascular mortality, and 1.559 (95% CI, 1.189-2.044) for respiratory mortality, respectively. The addition of PRISm significantly improved the reclassification ability, based on the net reclassification index, of an office-based risk score by 15.53% (95% CI, 10.14%-19.63%) to 33.60% (95% CI, 20.90%-45.79%). INTERPRETATION: Individuals with T2D with comorbid PRISm, accounting for a considerable proportion of the population with T2D, showed significantly increased risks of adverse macrovascular and microvascular complications and mortality.

Preserved Ratio Impaired Spirometry, Metabolomics, and the Risk of Type 2 Diabetes.

CONTEXT: Whether baseline preserved ratio impaired spirometry (PRISm) is associated with the risk of developing type 2 diabetes (T2D) and if this association could be mediated by circulating metabolites remains to be elucidated. OBJECTIVE: To measure the prospective association of PRISm with T2D and potential metabolic mediators thereof. METHODS: This study used data from the UK Biobank and included 72 683 individuals without diabetes at baseline. PRISm was defined as the predicted forced expiratory volume in 1 second (FEV1) <80% and the FEV1/forced vital capacity ratio ≥0.70. Cox proportional hazards modeling was performed to assess the longitudinal relation between baseline PRISm and incident T2D. Mediation analysis was used to explore the mediation effects of circulating metabolites in the path from PRISm to T2D. RESULTS: During a median follow-up of 12.06 years, 2513 participants developed T2D. Individuals who had PRISm (N = 8394) were 47% (95% CI, 33%-63%) more likely to develop T2D compared with those who had normal spirometry (N = 64 289). A total of 121 metabolites showed statistically significant mediation effects in the path from PRISm to T2D (false discovery rate <0.05). Glycoprotein acetyls, cholesteryl esters in large high-density lipoprotein (HDL), degree of unsaturation, cholesterol in large HDL, and cholesteryl esters in very large HDL were the top 5 metabolic markers, with mediation proportions (95% CI) being 11.91% (8.76%-16.58%), 11.04% (7.34%-15.55%), 10.36% (7.34%-14.71%), 9.87% (6.78%-14.09%), and 9.51% (6.33%-14.05%), respectively. A total of 11 principal components that explained 95% variance of the metabolic signatures accounted for 25.47% (20.83%-32.19%) of the relation between PRISm and T2D. CONCLUSIONS: Our study revealed the association of PRISm with T2D risk and the potential roles of circulating metabolites in mediating this association.

Subcutaneous sarilumab for the treatment of hospitalized patients with moderate to severe COVID19 disease: A pragmatic, embedded randomized clinical trial.

IMPORTANCE AND OBJECTIVE: The aim of this pragmatic, embedded, adaptive trial was to measure the effectiveness of the subcutaneous anti-IL-6R antibody sarilumab, when added to an evolving standard of care (SOC), for clinical management of inpatients with moderate to severe COVID-19 disease. DESIGN: Two-arm, randomized, open-label controlled trial comparing SOC alone to SOC plus sarilumab. The trial used a randomized play-the-winner design and was fully embedded within the electronic health record (EHR) system. SETTING: 5 VA Medical Centers. PARTICIPANTS: Hospitalized patients with clinical criteria for moderate to severe COVID-19 but not requiring mechanical ventilation, and a diagnostic test positive for SARS-CoV-2. INTERVENTIONS: Sarilumab, 200 or 400 mg subcutaneous injection. SOC was not pre-specified and could vary over time, e.g., to include antiviral or other anti-inflammatory drugs. MAIN OUTCOMES AND MEASURES: The primary outcome was intubation or death within 14 days of randomization. All data were extracted remotely from the EHR. RESULTS: Among 162 eligible patients, 53 consented, and 50 were evaluated for the primary endpoint of intubation or death. This occurred in 5/20 and 1/30 of participants in the sarilumab and SOC arms respectively, with the majority occurring in the initial 9 participants (3/4 in the sarilumab and 1/5 in the SOC) before the sarilumab dose was increased to 400 mg and before remdesivir and dexamethasone were widely adopted. After interim review, the unblinded Data Monitoring Committee recommended that the study be stopped due to concern for safety: a high probability that rates of intubation or death were higher with addition of sarilumab to SOC (92.6%), and a very low probability (3.4%) that sarilumab would be found to be superior. CONCLUSIONS AND RELEVANCE: This randomized trial of patients hospitalized due to respiratory compromise from COVID-19 but not mechanical ventilation found no benefit from subcutaneous sarilumab when added to an evolving SOC. The numbers of patients and events were too low to allow definitive conclusions to be drawn, but this study contributes valuable information about the role of subcutaneous IL-6R inhibition in the treatment of hospitalized COVID-19 patients. Methods developed and piloted during this trial will be useful in conducting future studies more efficiently. TRIAL REGISTRATION: Clinicaltrials.gov-NCT04359901; https://clinicaltrials.gov/ct2/show/NCT04359901?cond=NCT04359901&draw=2&rank=1.

Diagnostic Performance of the Herder Model in Veterans Undergoing PET Scans for Pulmonary Nodule Evaluation.

British Thoracic Society (BTS) guidelines recommend using the Herder model to risk-stratify lung nodules after positron emission tomography (PET). However, this approach has not been adequately evaluated, particularly among Veterans. A single-center retrospective cohort study was carried out in U.S. Veterans with pulmonary nodules assessed by PET to validate the Herder model; decision analysis using risk thresholds from the BTS guidelines was performed. One hundred subjects met inclusion criteria. Area under the curve of the Herder model for predicting malignancy was 0.87 for all lung nodules and 0.90 for newly discovered nodules. For low- and high-risk lung nodules, BTS guidelines would have recommended appropriate care in this patient cohort.

Mild Pulmonary Hypertension Is Associated With Increased Mortality: A Systematic Review and Meta-Analysis.

Background Recent studies have demonstrated a continuum in clinical risk related to mean pulmonary artery pressure that begins at >19 mm Hg, which is below the traditional threshold used to define pulmonary hypertension ( PH ) of 25 mm Hg. Because of the implications on patient diagnosis and prognosis, the generalizability and validity of these data need further confirmation. Methods and Results Databases were searched from inception through January 31, 2018, to identify studies comparing all-cause mortality between patients with mildly elevated mean pulmonary artery pressure near but <25 mm Hg versus the referent group. The meta-analysis included 15 nonrandomized studies and 16 482 patients (7451 [45.2%] with measured or calculated mean pulmonary artery pressure of 19-24 mm Hg by right heart catheterization [n=6037] and echocardiography [n=1414] [mild PH ]). The mean duration of follow-up was 5.2 years. Compared with the referent group, mild PH was associated with an increased risk of mortality (risk ratio, 1.52; 95% confidence interval, 1.32-1.74; P<0.001; I2=47%). Secondary analysis using risk-adjusted time-to-event estimates showed a similar result (hazard ratio, 1.19; 95% confidence interval, 1.09-1.31; P<0.001; I2=42%). The findings were consistent between subgroups of right heart catheterization and echocardiography studies ( Pinteraction>0.05). There was evidence of publication bias; however, this did not influence the risk estimate (Duval and Tweedie's trim and fill adjusted risk ratio, 1.34; 95% confidence interval, 1.15-1.56). Conclusions The risk of mortality is increased in patients with mild PH , defined as measured or calculated mean pulmonary artery pressure >19 mm Hg. These data emphasize a need for diagnosing patients with mild PH with consideration to enrollment in PH clinical studies investigating pharmacological and nonpharmacological interventions to attenuate clinical risk and improve outcomes.

Daptomycin-induced eosinophilic pneumonia - a systematic review.

PURPOSE: Eosinophilic pneumonia comprises a group of lung diseases in which eosinophils appear in increased numbers in the lungs and sometimes in the bloodstream. Several case reports link daptomycin use to this phenomenon. SUMMARY: We performed a systematic literature review to identify cases of eosinophilic pneumonia associated with daptomycin use. Relevant studies were identified by searching Pubmed/Medline, EMBASE, Google Scholar, Cochrane Database of Systematic Reviews, and Clin-Alert from inception to May 2016, and manual searches of reference lists. All case reports that include information regarding patient age, indication, clinical and objective findings, treatment and outcome were evaluated. Abstracts from conference proceedings as well as case reports not in English were excluded. Descriptive statistics were used to analyze the data. Thirty-five patient-cases were included in the final analysis. Patients most likely to be identified with daptomycin-induced eosinophilic pneumonia were male (83%) and elderly (mean age 65.4 ± 15 years). The dose for daptomycin ranged from 4 to 10 mg/kg/day, but included a large number of patients with renal dysfunction. The average duration of daptomycin therapy upon onset of EP symptoms was 2.8 ± 1.6 weeks. Majority of patients presented with dyspnea (94%), fever (57%) and were also found to have peripheral eosinophilia (77%) and infiltrates/opacities of CT/CXR (86%). Symptom improvement was seen after daptomycin discontinuation (24 h to 1 week). The majority of patients were also prescribed treatment with corticosteroids (66%). CONCLUSION: Clinicians should be aware of daptomycin-induced eosinophilic pneumonia and its symptoms along with its presentation and treatment.

Effects of Implementation of Lung Cancer Screening at One Veterans Affairs Medical Center.

BACKGROUND: Lung cancer screening recommendations have been developed, but none are focused on veterans. We report the results of the lung cancer screening program at our Veterans Affairs medical center and compare them with historic results. METHODS: All veterans between 55 and 74 years who were current smokers or quit within the past 15 years and had at least a 30-pack-year smoking history were invited to receive an annual low-dose chest CT scan beginning in December 2013. Demographics, CT scan results, and pathologic data of screened patients were recorded retrospectively. Overall results during the screening period were compared with results in veterans who received diagnoses from January 2011 to December 2013 (prescreening period). RESULTS: From December 2013 through December 2014 (screening period), 1,832 patients obtained a screening CT scan. Their mean age was 65 years. A lung nodule was present in 439 of 1,832 patients (24%). Lung cancer was diagnosed in 55 of 1,832 screened patients (3.0%). During the prescreening period, 37% of every lung cancer detected at our center (30 of 82) was stage I or stage II. After implementation of the screening program that percentage rose to 60% (52 of 87; P < .01). During the screening period, 55 of the 87 diagnosed lung cancers (63%) were detected through the screening program. The number of lung cancers detected per month rose from 2.4 to 6.7 after implementation of the screening program (P < .01). CONCLUSIONS: Implementation of lung cancer screening in the veteran population leads to detection of an increased number and proportion of early-stage lung cancers. Lung cancer screening in veterans may also increase the rate of lung cancer diagnoses in the immediate postimplementation period.

Association of Elevated Plasma Endothelin-1 Levels With Pulmonary Hypertension, Mortality, and Heart Failure in African American Individuals: The Jackson Heart Study.

IMPORTANCE: Despite pathophysiological links between endothelin-1 and pulmonary vascular remodeling, to our knowledge, the association between plasma endothelin-1 levels and pulmonary hypertension has not been studied in the general population. Also, whether endothelin-1 can predict future heart failure and mortality, outcomes that are associated with pulmonary hypertension, in a population cohort is unclear. OBJECTIVE: To determine whether elevated plasma endothelin-1 levels are associated with pulmonary hypertension, mortality, and heart failure. DESIGN, SETTING, AND PARTICIPANTS: Data from the Jackson Heart Study, a longitudinal, prospective observational cohort study of heart disease in African American individuals from Jackson, Mississippi, were analyzed. The community population sample was limited to participants with detectable tricuspid regurgitation on echocardiography. The study participants included self-identified African American individuals with plasma endothelin-1 levels and tricuspid regurgitation on echocardiogram (n = 3223) at the time of first examination (2000-2004). The analysis of the data began on April 14, 2014, and was completed on February 23, 2016. EXPOSURE: Log-transformed plasma endothelin-1 level. MAIN OUTCOMES AND MEASURES: Cross-sectional analysis: presence of pulmonary hypertension (defined as an elevated pulmonary artery systolic pressure >40 mm Hg on echocardiogram). Longitudinal outcomes were all-cause mortality (median follow-up, 7.75 years) and heart failure admissions (median follow-up, 5.32 years). RESULTS: Of the 3223 participants enrolled in the study, 1051 were men (32.6%). Mean (SD) endothelin-1 levels were 1.36 (0.64) pg/mL; 217 of 3223 cohort members (6.7%) had pulmonary hypertension. After adjusting for potential confounders, log-transformed endothelin-1 levels were associated with increased odds of pulmonary hypertension (adjusted odds ratio per log increment in endothelin-1, 1.66; 95% CI, 1.16-2.37). Log-transformed endothelin-1 levels were associated with mortality (adjusted hazard ratio per log increment in endothelin-1, 1.69; 95% CI, 1.27-2.25; median follow-up, 7.75 years) and heart failure (adjusted hazard ratio per log increment in endothelin-1, 1.57, 95% CI, 1.05-2.37; median follow-up, 5.32 years) in the study cohort. Phenotyping by pulmonary hypertension and endothelin-1 level showed mortality decreasing in order from subgroup with pulmonary hypertension and high endothelin-1 (high endothelin-1: ≥1.7 pg/mL; upper quartile); pulmonary hypertension and low endothelin-1 <1.7 pg/mL; lower 3 quartiles); no pulmonary hypertension and high endothelin-1; and no pulmonary hypertension and low endothelin-1 (log-rank χ2 = 77.16; P < .01 ). CONCLUSIONS AND RELEVANCE: Elevated plasma endothelin-1 levels, especially associated with an elevated pulmonary artery systolic pressure on echocardiogram, may identify an at-risk population that could be evaluated for targeted prevention and management strategies in future studies.

The Vital Capacity Is Vital: Epidemiology and Clinical Significance of the Restrictive Spirometry Pattern.

Epidemiologic research has revealed a substantial portion of the general population with abnormal spirometry results that are characterized by decreased FEV1 and FVC but a preserved FEV1/FVC ratio. This restrictive spirometry pattern (RSP) is inconsistently defined in the literature and not well addressed by current guidelines; there is an accumulating body of evidence, however, that RSP is prevalent to a similar degree as airflow obstruction. Genetic and other risk factors for RSP, such as inhalational injuries and early life exposures, continue to be actively described. Although it seems that RSP is closely associated with the metabolic syndrome, diabetes, and systemic inflammation, it is not a simple marker of obesity. RSP is associated with adverse cardiovascular outcomes, as well as mortality, and it may be an underappreciated cause of functional impairments and respiratory symptoms. Improvement in outcomes in this population will require that clinicians have an appreciation for the significance of this spirometry pattern; additional research into the clinical and radiologic phenotype of these subjects is also needed. This article provides an overview of the recent developments in our understanding of this prevalent and highly morbid spirometry pattern.

Clinical profile and underdiagnosis of pulmonary hypertension in US veteran patients.

BACKGROUND: Pulmonary hypertension (PH) is a key contributor to cardiovascular morbidity and early mortality; however, reports are lacking on the epidemiology of PH in at-risk patient populations. METHODS AND RESULTS: The echocardiography registries from 2 major Veterans Affairs hospitals were accessed to identify patients with at least moderate PH, defined here as a pulmonary artery systolic pressure ≥60 mm Hg detected echocardiographically. From a total of 10 471 individual patient transthoracic echocardiograms, we identified moderate or severe PH in 340 patients (332 men; mean, 77 years; mean pulmonary artery systolic pressure, 69.4±10.5 mm Hg), of which PH was listed as a diagnosis in the medical record for only 59 (17.3%). At a mean of 832 days (0-4817 days) following echocardiography diagnosing PH, 150 (44.1%) patients were deceased. PH was present without substantial left heart remodeling: the mean left ventricular ejection fraction was 0.50±0.16, left ventricular end-diastolic dimension was 5.0±0.9 cm, and left atrial dimension was 4.4±0.7 cm. Cardiac catheterization (n=122, 36%) demonstrated a mean pulmonary artery pressure of 40.5±11.4 mm Hg, pulmonary capillary wedge pressure of 22.6±8.9 mm Hg, and pulmonary vascular resistance of 4.6±2.9 Wood units. Diagnostic strategies for PH were variable and often incomplete; for example, only 16% of appropriate patients were assessed with a nuclear ventilation/perfusion scan for thromboembolic causes of PH. CONCLUSIONS: in an at-risk patient population, PH is underdiagnosed and associated with substantial mortality. Enhanced awareness is necessary among practitioners regarding contemporary PH diagnostic strategies.

Combined pulmonary fibrosis and emphysema syndrome: a review.

There is increasing clinical, radiologic, and pathologic recognition of the coexistence of emphysema and pulmonary fibrosis in the same patient, resulting in a clinical syndrome known as combined pulmonary fibrosis and emphysema (CPFE) that is characterized by dyspnea, upper-lobe emphysema, lower-lobe fibrosis, and abnormalities of gas exchange. This syndrome frequently is complicated by pulmonary hypertension, acute lung injury, and lung cancer. The CPFE syndrome typically occurs in male smokers, and the mortality associated with this condition, especially if pulmonary hypertension is present, is significant. In this review, we explore the current state of the literature and discuss etiologic factors and clinical characteristics of the CPFE syndrome.

Combined pulmonary fibrosis and emphysema alters physiology but has similar mortality to pulmonary fibrosis without emphysema.

Studies have described individuals with combined pulmonary fibrosis and emphysema (CPFE), with preserved lung volumes, significant reductions in gas exchange, and high prevalence of pulmonary hypertension. While physiologic changes in CPFE are well documented, there is little mortality data in the CPFE population compared to appropriate controls. A study was performed to determine the features and outcomes of a group of individuals with imaging and/or pathologic evidence of CPFE to determine if individuals with combined pulmonary fibrosis and emphysema have different features and survival than individuals with pulmonary fibrosis alone. We conducted a retrospective study at a Veterans Affairs Medical Center. Included in the study were individuals hospitalized over a 5-year period who were given a clinical diagnosis of pulmonary fibrosis. Individuals with confirmed imaging or pathologic evidence of pulmonary fibrosis were divided into a study group with concomitant emphysema (CPFE group, n = 20) and a control group without emphysema (isolated pulmonary fibrosis (PF) group, n = 24). The CPFE group, all current or former cigarette smokers, had significantly larger lung volumes, more expiratory airflow obstruction, and worse gas exchange than the isolated pulmonary fibrosis group. Mortality did not differ between the groups. Combined pulmonary fibrosis and emphysema results in unique physiologic features but no difference in survival compared with a group with pulmonary fibrosis alone.

Decreased lung function is associated with increased arterial stiffness as measured by peripheral pulse pressure: data from NHANES III.

BACKGROUND: Individuals with impaired lung function have an elevated risk of cardiovascular events. Improved understanding of the factors associated with increased cardiovascular risk in the setting of lung function impairment is needed. We set out to determine in a nationwide population-based cohort whether impaired lung function as measured by forced expiratory volume in 1 s (FEV1) is associated with evidence of increased arterial stiffness measured by peripheral pulse pressure, a risk factor for cardiovascular events. METHODS: Cross-sectional study of adults > or = 20 years of age in the Third National Health and Nutrition Examination Survey (NHANES III) who had valid and reproducible FEV1 data and serial blood pressure measurements allowing for the calculation of a mean pulse pressure, a measure of central arterial stiffness (n = 13,090). RESULTS: There was a significant negative correlation between FEV1 and mean pulse pressure (r = -0.37). After controlling for demographic variables and confounders including cardiovascular risk factors, smoking history, and lung disease, the negative relationship between pulse pressure and FEV1 varies with age and becomes apparent only after age 40. In individuals aged 40-59 and > or = 60 years, there was respectively a 2 and 3 mm Hg increment in pulse pressure for every one standard deviation decrement in FEV1. CONCLUSIONS: FEV1 is significantly related to pulse pressure, a clinically important measure of arterial stiffness, among those aged > or = 40 years. This relationship may help to explain the increased risk of cardiovascular events found in individuals with impaired lung function.

Heterogeneity in combined pulmonary fibrosis and emphysema.

BACKGROUND: Combined pulmonary fibrosis and emphysema (CPFE) is a unique disorder described in several case series of upper lobe emphysema associated with lower lobe fibrosis. Patients with this entity have relatively preserved lung volumes and spirometry but marked reductions in diffusing capacity on pulmonary function testing. Smoking appears to be the predominant risk factor for this disorder. Usual interstitial pneumonia has been the most common histological pattern of interstitial lung disease described on biopsy in the literature. OBJECTIVES: To characterize the clinical, imaging and pathological features of a cohort of patients with CPFE. METHODS: Retrospective review of electronic medical record data, radiological imaging, and available lung biopsy specimens for a series of 10 patients with CPFE at the Providence VA Medical Center, Providence, R.I., USA. RESULTS: We describe a series of 10 patients with CPFE. All had severe reductions in diffusing capacity out of proportion to their lung volumes and spirometry. All had predominantly upper lobe emphysema on computed tomography; 8/10 had lower lobe subpleural reticular abnormalities and honeycombing, while 2 had lower lobe ground glass changes on imaging. These 2 patients demonstrated a pattern of interstitial lung disease on biopsy characterized by intra-alveolar macrophage accumulation in association with marked alveolar septal fibrosis, consistent with a variant form of desquamative interstitial pneumonia with extensive fibrosis. CONCLUSIONS: The imaging findings and pathology in patients with CPFE are heterogeneous.