Differences in referral to a chronic thromboembolic pulmonary hypertension center following acute pulmonary embolism: a locoregional experience.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a treatable complication of acute pulmonary embolism (PE). Identification of factors that impact referral to a comprehensive CTEPH center may improve disease awareness and patient outcomes. We conducted a study of patients with acute PE. Cases were identified through a natural language processing algorithm. ICD coding was used to assess clinical documentation for dyspnea or CTEPH placed at least 90 days after their acute PE diagnosis. We analyzed characteristics of patients who were referred vs. not referred, as well as referral patterns for "at risk" patients. 2454 patients with acute PE were identified, of which 4.9% (120/2454) were referred for CTEPH evaluation. Patients who were not referred were older (61 vs. 54 years, p < 0.001), had higher rates of cancer (28% vs. 10%, p < 0.001), and lived further from the referral center (9.1 miles vs. 6.7 miles, p = 0.03). Of 175 patients identified as "at risk," 12% (21/175) were referred. In the 'at risk' cohort, distance from referral center among referred and not referred was significant (5.7 miles vs. 8.8 miles, p = 0.04). There were low rates of referral to CTEPH center in post-PE patients, and in patients with symptoms who may be at higher risk of CTEPH. Age, co-morbid conditions, distance from comprehensive center, and presence of a primary care provider contribute to differences in referral to a comprehensive CTEPH center. Clinician education about CTEPH is important to ensure optimal care to patients with or at risk for chronic complications of acute PE.

Bacterial Superinfection Pneumonia in Patients Mechanically Ventilated for COVID-19 Pneumonia.

Rationale: Current guidelines recommend patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia receive empirical antibiotics for suspected bacterial superinfection on the basis of weak evidence. Rates of ventilator-associated pneumonia (VAP) in clinical trials of patients with SARS-CoV-2 pneumonia are unexpectedly low. Objectives: We conducted an observational single-center study to determine the prevalence and etiology of bacterial superinfection at the time of initial intubation and the incidence and etiology of subsequent bacterial VAP in patients with severe SARS-CoV-2 pneumonia. Methods: Bronchoscopic BAL fluid samples from all patients with SARS-CoV-2 pneumonia requiring mechanical ventilation were analyzed using quantitative cultures and a multiplex PCR panel. Actual antibiotic use was compared with guideline-recommended therapy. Measurements and Main Results: We analyzed 386 BAL samples from 179 patients with SARS-CoV-2 pneumonia requiring mechanical ventilation. Bacterial superinfection within 48 hours of intubation was detected in 21% of patients. Seventy-two patients (44.4%) developed at least one VAP episode (VAP incidence rate = 45.2/1,000 ventilator days); 15 (20.8%) initial VAPs were caused by difficult-to-treat pathogens. The clinical criteria did not distinguish between patients with or without bacterial superinfection. BAL-based management was associated with significantly reduced antibiotic use compared with guideline recommendations. Conclusions: In patients with SARS-CoV-2 pneumonia requiring mechanical ventilation, bacterial superinfection at the time of intubation occurs in <25% of patients. Guideline-based empirical antibiotic management at the time of intubation results in antibiotic overuse. Bacterial VAP developed in 44% of patients and could not be accurately identified in the absence of microbiologic analysis of BAL fluid.

Arterial Vascular Pruning, Right Ventricular Size, and Clinical Outcomes in Chronic Obstructive Pulmonary Disease. A Longitudinal Observational Study.

Rationale: Cor pulmonale (right ventricular [RV] dilation) and cor pulmonale parvus (RV shrinkage) are both described in chronic obstructive pulmonary disease (COPD). The identification of emphysema as a shared risk factor suggests that additional disease characterization is needed to understand these widely divergent cardiac processes.Objectives: To explore the relationship between computed tomography measures of emphysema and distal pulmonary arterial morphology with RV volume, and their association with exercise capacity and mortality in ever-smokers with COPD enrolled in the COPDGene Study.Methods: Epicardial (myocardium and chamber) RV volume (RVEV), distal pulmonary arterial blood vessel volume (arterial BV5: vessels <5 mm2 in cross-section), and objective measures of emphysema were extracted from 3,506 COPDGene computed tomography scans. Multivariable linear and Cox regression models and the log-rank test were used to explore the association between emphysema, arterial BV5, and RVEV with exercise capacity (6-min-walk distance) and all-cause mortality.Measurements and Main Results: The RVEV was approximately 10% smaller in Global Initiative for Chronic Obstructive Lung Disease stage 4 versus stage 1 COPD (P < 0.0001). In multivariable modeling, a 10-ml decrease in arterial BV5 (pruning) was associated with a 1-ml increase in RVEV. For a given amount of emphysema, relative preservation of the arterial BV5 was associated with a smaller RVEV. An increased RVEV was associated with reduced 6-minute-walk distance and in those with arterial pruning an increased mortality.Conclusions: Pulmonary arterial pruning is associated with clinically significant increases in RV volume in smokers with COPD and is related to exercise capacity and mortality in COPD.Clinical trial registered with www.clinicaltrials.gov (NCT00608764).

Respiratory Symptoms in Young Adults and Future Lung Disease. The CARDIA Lung Study.

RATIONALE: There are limited data on factors in young adulthood that predict future lung disease. OBJECTIVES: To determine the relationship between respiratory symptoms, loss of lung health, and incident respiratory disease in a population-based study of young adults. METHODS: We examined prospective data from 2,749 participants in the CARDIA (Coronary Artery Risk Development in Young Adults) study who completed respiratory symptom questionnaires at baseline and 2 years later and repeated spirometry measurements over 30 years. MEASUREMENTS AND MAIN RESULTS: Cough or phlegm, episodes of bronchitis, wheeze, shortness of breath, and chest illnesses at both baseline and Year 2 were the main predictor variables in models assessing decline in FEV1 and FVC from Year 5 to Year 30, incident obstructive and restrictive lung physiology, and visual emphysema on thoracic computed tomography scan. After adjustment for covariates, including body mass index, asthma, and smoking, report of any symptom was associated with -2.71 ml/yr excess decline in FEV1 (P < 0.001) and -2.18 in FVC (P < 0.001) as well as greater odds of incident (prebronchodilator) obstructive (odds ratio [OR], 1.63; 95% confidence interval [CI], 1.24-2.14) and restrictive (OR, 1.40; 95% CI, 1.09-1.80) physiology. Cough-related symptoms (OR, 1.56; 95% CI, 1.13-2.16) were associated with greater odds of future emphysema. CONCLUSIONS: Persistent respiratory symptoms in young adults are associated with accelerated decline in lung function, incident obstructive and restrictive physiology, and greater odds of future radiographic emphysema.

Association between Cardiorespiratory Fitness and Lung Health from Young Adulthood to Middle Age.

RATIONALE: Beyond the risks of smoking, there are limited data on factors associated with change in lung function over time. OBJECTIVES: To determine whether cardiorespiratory fitness was longitudinally associated with preservation of lung health. METHODS: Prospective data were collected from 3,332 participants in the Coronary Artery Risk Development in Young Adults study aged 18-30 in 1985 who underwent treadmill exercise testing at baseline visit, and 2,735 participants with a second treadmill test 20 years later. The association between cardiorespiratory fitness and covariate adjusted decline in lung function was evaluated. MEASUREMENTS AND MAIN RESULTS: Higher baseline fitness was associated with less decline in lung function. When adjusted for age, height, race-sex group, peak lung function, and years from peak lung function, each additional minute of treadmill duration was associated with 1.00 ml/yr less decline in FEV1 (P < 0.001) and 1.55 ml/yr less decline in FVC (P < 0.001). Greater decline in fitness was associated with greater annual decline in lung function. Each 1-minute decline in treadmill duration between baseline and Year 20 was associated with 2.54 ml/yr greater decline in FEV1 (P < 0.001) and 3.27 ml/yr greater decline in FVC (P < 0.001). Both sustaining higher and achieving relatively increased levels of fitness over 20 years were associated with preservation of lung health. CONCLUSIONS: Greater cardiopulmonary fitness in young adulthood, less decline in fitness from young adulthood to middle age, and achieving increased fitness from young adulthood to middle age are associated with less decline in lung health over time. Clinical trial registered with www.clinicaltrials.gov (NCT 00005130).

The utility of pulmonary function testing in predicting outcomes following liver transplantation.

Although pulmonary function tests (PFTs) are routinely performed in patients during the evaluation period before liver transplantation (LT), their utility in predicting post-LT mortality and morbidity outcomes is not known. The aim of this study was to determine the impact of obstructive and/or restrictive lung disease on post-LT outcomes. We conducted a retrospective analysis of patients who had pre-LT PFTs and underwent a subsequent LT (2007-2013). We used statistical analyses to determine independent associations between PFT parameters and outcomes (graft/patient survival, time on ventilator, and hospital/intensive care unit [ICU] length of stay [LOS]). A total of 415 LT recipients with available PFT data were included: 65% of patients had normal PFTs; 8% had obstructive lung disease; and 27% had restrictive lung disease. There was no difference in patient and graft survival between patients with normal, obstructive, and restrictive lung disease. However, restrictive lung disease was associated with longer post-LT time on ventilator and both ICU and hospital LOS (P < 0.05). More specific PFT parameters (diffusing capacity of the lungs for carbon monoxide, total lung capacity, and residual volume) were all significant predictors of ventilator time and both ICU and hospital LOS (P < 0.05). Although pre-LT PFT parameters may not predict post-LT mortality, restrictive abnormalities correlate with prolonged post-LT ventilation and LOS. Efforts to identify and minimize the impact of restrictive abnormalities on PFTs might improve such outcomes. Liver Transplantation 22 805-811 2016 AASLD.

Pulmonary hypertension associated with lung diseases and hypoxemia.

Pulmonary hypertension that develops in the setting of underlying lung diseases such as COPD or idiopathic pulmonary fibrosis (IPF) is associated with decreased functional status, worsening hypoxemia and quality of life, and increased mortality. This complication of lung disease is complex in its origin and carries a unique set of diagnostic and therapeutic issues. This review attempts to provide an overview of mechanisms associated with the onset of pulmonary hypertension in COPD and IPF, touches on appropriate evaluation, and reviews the state of knowledge on treating pulmonary hypertension related to underlying lung disease.

Loss of Lung Health from Young Adulthood and Cardiac Phenotypes in Middle Age.

RATIONALE: Chronic lung diseases are associated with cardiovascular disease. How these associations evolve from young adulthood forward is unknown. Understanding the preclinical history of these associations could inform prevention strategies for common heart-lung conditions. OBJECTIVES: To use the Coronary Artery Risk Development in Young Adults (CARDIA) study to explore the development of heart-lung interactions. METHODS: We analyzed cardiac structural and functional measurements determined by echocardiography at Year 25 of CARDIA and measures of pulmonary function over 20 years in 3,000 participants. MEASUREMENTS AND MAIN RESULTS: Decline in FVC from peak was associated with larger left ventricular mass (ß = 6.05 g per SD of FVC decline; P < 0.0001) and greater cardiac output (ß = 0.109 L/min per SD of FVC decline; P = 0.001). Decline in FEV1/FVC ratio was associated with smaller left atrial internal dimension (ß = -0.038 cm per SD FEV1/FVC decline; P < 0.0001) and lower cardiac output (ß = -0.070 L/min per SD of FEV1/FVC decline; P = 0.03). Decline in FVC was associated with diastolic dysfunction (odds ratio, 3.39; 95% confidence interval, 1.37-8.36; P = 0.006). CONCLUSIONS: Patterns of loss of lung health are associated with specific cardiovascular phenotypes in middle age. Decline in FEV1/FVC ratio is associated with underfilling of the left heart and low cardiac output. Decline in FVC with preserved FEV1/FVC ratio is associated with left ventricular hypertrophy and diastolic dysfunction. Cardiopulmonary interactions apparent with common complex heart and lung diseases evolve concurrently from early adulthood forward.

Hemodynamic predictors of mortality in adults with sickle cell disease.

BACKGROUND: Pulmonary hypertension (PH) in adults with sickle cell disease (SCD) is associated with early mortality, but no prior studies have evaluated quantitative relationships of mortality to physiological measures of pre- and postcapillary PH. OBJECTIVES: To identify risk factors associated with mortality and to estimate the expected survival in a cohort of patients with SCD with PH documented by right heart catheterization. METHODS: Nine-year follow-up data (median, 4.7 yr) from the National Institutes of Health SCD PH screening study are reported. A total of 529 adults with SCD were screened by echocardiography between 2001 and 2010 with no exclusion criteria. Hemodynamic data were collected from 84 patients. PH was defined as mean pulmonary artery pressure (PAP) ≥ 25 mm Hg. Survival rates were estimated by the Kaplan-Meier method, and mortality risk factors were analyzed by the Cox proportional hazards regression. MEASUREMENTS AND MAIN RESULTS: Specific hemodynamic variables were independently related to mortality: mean PAP (hazard ratio [HR], 1.61; 95% confidence interval [CI], 1.05-2.45 per 10 mm Hg increase; P = 0.027), diastolic PAP (HR, 1.83; 95% CI, 1.09-3.08 per 10 mm Hg increase; P = 0.022), diastolic PAP - pulmonary capillary wedge pressure (HR, 2.19; 95% CI, 1.23-3.89 per 10 mm Hg increase; P = 0.008), transpulmonary gradient (HR, 1.78; 95% CI, 1.14-2.79 per 10 mm Hg increase; P = 0.011), and pulmonary vascular resistance (HR, 1.44; 95% CI, 1.09-1.89 per Wood unit increase; P = 0.009) as risk factors for mortality. CONCLUSIONS: Mortality in adults with SCD and PH is proportional to the physiological severity of precapillary PH, demonstrating its prognostic and clinical relevance despite anemia-induced high cardiac output and less severely elevated pulmonary vascular resistance.

Case report: Multimodality imaging of unusual coronary to pulmonary collaterals in chronic thromboembolic pulmonary hypertension.

We present unusual coronary-pulmonary collaterals in a 65-year-old CTEPH patient. Perfusion mapping of a dual-energy computed tomography (DECT) study revealed areas of right lung that were minimally perfused despite unilateral occlusion of the right pulmonary artery, leading to the discovery of coronary-pulmonary collaterals via invasive coronary angiography. Pulmonary thromboendarterectomy removed the clot en-bloc. Post-surgery DECT and catheterization confirmed restoration of pulmonary arterial circulation and excellent hemodynamic response. Here, suggestion of perfusion to a proximally obstructed lung with DECT helped to document the presence of rarely documented coronary-pulmonary artery collaterals.

Infrared imaging of nitric oxide-mediated blood flow in human sickle cell disease.

Vascular dysfunction is an important pathophysiologic manifestation of sickle cell disease (SCD), a condition that increases risk of pulmonary hypertension and stroke. We hypothesized that infrared (IR) imaging would detect changes in cutaneous bloodflow reflective of vascular function. We performed IR imaging and conventional strain gauge plethysmography in twenty-five adults with SCD at baseline and during intra-arterial infusions of an endothelium-dependent vasodilator acetylcholine (ACh), an endothelium-independent vasodilator sodium nitroprusside (SNP), and a NOS inhibitor L-NMMA. Skin temperature measured by IR imaging increased in a dose-dependent manner to graded infusions of ACh (+1.1°C, p<0.0001) and SNP (+0.9°C, p<0.0001), and correlated with dose-dependent increases in forearm blood flow (ACh: +19.9 mL/min/100 mL, p<0.0001; r(s)=0.57, p=0.003; SNP: +8.6 mL/min/100 mL, p<0.0001; r=0.70, p=0.0002). Although IR measurement of skin temperature accurately reflected agonist-induced increases in blood flow, it was less sensitive to decreases in blood flow caused by NOS inhibition. Baseline forearm skin temperature measured by IR imaging correlated significantly with baseline forearm blood flow (31.8±0.2°C, 6.0±0.4 mL/min/100 mL; r=0.58, p=0.003), and appeared to represent a novel biomarker of vascular function. It predicted a blunted blood flow response to SNP (r=-0.61, p=0.002), and was independently associated with a marker of pulmonary artery pressure, as well as hemoglobin level, diastolic blood pressure, homocysteine, and cholesterol (R(2)=0.84, p<0.0001 for the model). IR imaging of agonist-stimulated cutaneous blood flow represents a less cumbersome alternative to plethysmography methodology. Measurement of baseline skin temperature by IR imaging may be a useful new marker of vascular risk in adults with SCD.

Pulmonary hypertension in advanced chronic obstructive pulmonary disease.

PURPOSE OF REVIEW: Pulmonary hypertension is a common complication seen in patients with advanced chronic obstructive pulmonary disease (COPD). Information related to the true prevalence, implications for functional outcomes, pathogenesis, and therapeutic options available has been lacking. The purpose of this review is to summarize some exciting findings from the last several years that address these holes in our knowledge. RECENT FINDINGS: Several recent studies have explored the prevalence and the functional implications of pulmonary hypertension for patients with COPD. These highlight the importance of clearly defining pulmonary hypertension that can be quite heterogeneous in this patient population. Furthermore, the concept that pulmonary hypertension in COPD is merely driven by hypoxic vasoconstriction has been called into question by several lines of investigation that suggest a much more complex pathogenesis potentially occurring independently of hypoxemia. Finally, there has been much interest in exploring pulmonary hypertension-specific therapies in patients with COPD, but available data to support their use are limited. SUMMARY: The recent findings summarized here have expanded our knowledge regarding this important comorbidity in patients with advanced COPD. We now know that pulmonary hypertension is common, has clear effects on both morbidity and mortality, and has a complex pathophysiology that we are only beginning to understand.

Perivascular T-cell infiltration leads to sustained pulmonary artery remodeling after endothelial cell damage.

Pulmonary hypertension is a vascular proliferative disease characterized by pulmonary artery remodeling because of dysregulated endothelial and smooth muscle cell proliferation. Although the role of inflammation in the development of the disease is not well-defined, plexogenic lesions in human disease are characterized by perivascular inflammation composed, in part, of T cells. We explored the role of T-cell infiltration on pulmonary vascular remodeling after endothelial cell damage. We induced endothelial cell damage using monocrotaline and isolated the role of T cells by using Rag1(tm1Mom) mice and performing adoptive T-cell transfer. We found that monocrotaline causes pulmonary vascular endothelial cell injury followed by a perivascular inflammatory response. The infiltration of inflammatory cells primarily involves CD4(+) T cells and leads to the progressive muscularization of small (<30 µm) arterioles. Pulmonary vascular proliferative changes were accompanied by progressive and persistent elevations in right ventricular pressure and right ventricular hypertrophy. Supporting the central role of CD4(+) T cells in the inflammatory response, Rag1(tm1Mom) (Rag1(-/-)) mice, which are devoid of T and B cells, were protected from the development of vascular injury when exposed to monocrotaline. The introduction of T cells from control mice into Rag1(-/-) mice reproduced the vascular injury phenotype. These data indicate that after endothelial cell damage, CD4(+) T-cell infiltration participates in pulmonary vascular remodeling. This finding suggests that a CD4(+) T-cell immune response may contribute to the pathogenesis of inflammatory vascular lesions seen in some forms of pulmonary hypertension.

Chronic thromboembolic pulmonary hypertension: anticoagulation and beyond.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare complication in pulmonary embolism (PE) survivors, characterized by chronic vascular occlusion and pulmonary hypertension. The identification and diagnosis of CTEPH requires a stepwise approach, starting with symptom evaluation, functional evaluation, screening imaging, and progressing to interventional hemodynamic assessment. On the backbone of anticoagulation, CTEPH management necessitates a multidisciplinary approach. Surgical pulmonary thromboendarterectomy (PTE) is the only potentially curative option. In nonoperable disease or residual disease after PTE, interventional balloon pulmonary angioplasty and/or pulmonary-vasodilator therapies can be offered, in collaboration with interventional and vascular pulmonary colleagues. As it is a disease that can cause high morbidity and mortality, CTEPH requires a high index of suspicion to diagnose and treat in patients following PE.

Timing of Intubation in Coronavirus Disease 2019: A Study of Ventilator Mechanics, Imaging, Findings, and Outcomes.

OBJECTIVES: Determine the variation in outcomes and respiratory mechanics between the subjects who are intubated earlier versus later in their coronavirus disease 2019 course. DESIGN: Retrospective cohort study. SETTING: Northwestern Memorial Hospital ICUs. PATIENTS: All patients intubated for coronavirus disease 2019 between March 2020 and June 2020. INTERVENTIONS: Patients were stratified by time to intubation: 30 subjects were intubated 4-24 hours after presentation and 24 subjects were intubated 5-10 days after presentation. Baseline characteristics, hospitalization, ventilator mechanics, and outcomes were extracted and analyzed. Ten clinically available CT scans were manually reviewed to identify evidence of pulmonary vascular thrombosis and intussusceptive angiogenesis. MEASUREMENTS AND MAIN RESULTS: Median time from symptom onset to intubation was significantly different between the early and late intubation cohorts, with the latter being intubated later in the course of their illness (7.9 vs 11.8 d; p = 0.04). The early intubation cohort had a lower mortality rate than the late intubation cohort (6% vs 30%, p < 0.001) without significantly different respiratory mechanics at the time of intubation. The late intubation cohort was noted to have higher dead space ratio (0.40 vs 0.52; p = 0.03). On review of CT scans, the late intubation cohort also had more dilated peripheral segments on imaging (two segments vs five segments). CONCLUSIONS: The question as to whether delaying intubation is beneficial or harmful for patients with coronavirus disease 2019-induced hypoxemic respiratory failure has yet to be answered. As our approaches to coronavirus disease 2019 continue to evolve, the decision of timing of intubation remains paramount. Although noninvasive ventilation may allow for delaying intubation, it is possible that there are downstream effects of delayed intubation that should be considered, including the potential for pulmonary vascular thrombosis and intussusceptive angiogenesis with delayed intubation.

Adverse effects of immune checkpoint inhibitor therapies on right ventricular function and pulmonary arterial dilatation.

Immunologic risk factors contribute to endothelial dysfunction and development of pulmonary vascular disease. Immune checkpoint inhibitors, used as immunotherapies for malignancies, have a wide range of reported immune-related adverse events. We retrospectively describe the impact of immune checkpoint inhibitors on the development of pulmonary vascular injury and right ventricular dysfunction as compared across both computed tomography and transthoracic echocardiography. Twenty-four of 389 patients treated with immune checkpoint inhibitors at a single academic center between 2015 and 2019 were evaluated. Thirteen (54%) patients were treated with anti-programmed cell death receptor 1 (PD-1), 8 (33%) with anti-programmed death receptor ligand 1 (PD-L1) therapy, and 3 (13%) with combination anti-PD-1 and anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) therapy. At a median of 85 days of immune checkpoint inhibitor therapy, RVfwLS significantly increased from -20.6% to -16.7% (p = 0.002). After a median of 59 days of immune checkpoint inhibitor therapy, median pulmonary artery to aorta ratio worsened from 0.83 to 0.89 (p = 0.03). There was an correlation of duration of immune checkpoint inhibitor therapy (ß = -0.574, p = 0.003) with percent change in RVfwLS. Patients who received anti-PD-1 therapy (ß = -0.796, p = 0.001) showed the greatest correlation of duration of immune checkpoint inhibitor therapy with percent change in RVfwLS. Exposure to immune checkpoint inhibitors are associated with RV dysfunction and vascular changes as measured by strain and computed tomography, respectively.