Prophylactic epinephrine attenuates severe bleeding in lung transplantation patients undergoing transbronchial lung biopsy: Results of the PROPHET randomized trial.

BACKGROUND: Severe hemorrhage is an uncommon yet potentially life-threatening complication of transbronchial lung biopsy. Lung transplantation recipients undergo multiple bronchoscopies with biopsy and are considered to be at an increased risk for bleeding from transbronchial biopsy, independent of traditional risk factors. We aimed to evaluate the efficacy and safety of endobronchial administration of prophylactic topical epinephrine in attenuating transbronchial biopsy-related hemorrhage in lung transplant recipients. METHODS: The Prophylactic Epinephrine for the Prevention of Transbronchial Lung Biopsy-related Bleeding in Lung Transplant Recipients study was a 2-center, randomized, double blind, placebo-controlled clinical trial. Participants undergoing transbronchial lung biopsy were randomized to receive 1:10,000-diluted topical epinephrine vs saline placebo administered prophylactically into the target segmental airway. Bleeding was graded based on a clinical severity scale. The primary efficacy outcome was incidence of severe or very severe hemorrhage. The primary safety outcome was a composite of 3-hours all-cause mortality and an acute cardiovascular event. RESULTS: A total of 66 lung transplantation recipients underwent 100 bronchoscopies during the study period. The primary outcome of severe or very severe hemorrhage occurred in 4 cases (8%) in the prophylactic epinephrine group and in 13 cases (24%) in the control group (p = 0.04). The composite primary safety outcome did not occur in any of the study groups. CONCLUSIONS: In lung transplantation recipients undergoing transbronchial lung biopsy, prophylactic administration of 1:10,000-diluted topical epinephrine into the target segmental airway before biopsy attenuates the incidence of significant endobronchial hemorrhage without conveying a significant cardiovascular risk. (ClinicalTrials.gov identifier: NCT03126968).

Epigenetic marker of telomeric age is associated with exacerbations and hospitalizations in chronic obstructive pulmonary disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is an age-related condition that has been associated with early telomere attrition; the clinical implications of telomere shortening in COPD are not well known. In this study we aimed to determine the relationship of the epigenetic regulation of telomeric length in peripheral blood with the risk of exacerbations and hospitalization in patients with COPD. METHODS: Blood DNA methylation profiles were obtained from 292 patients with COPD enrolled in the placebo arm of the Macrolide Azithromycin to Prevent Rapid Worsening of Symptoms Associated with Chronic Obstructive Pulmonary Disease (MACRO) Study and who were followed for 1-year. We calculated telomere length based on DNA methylation markers (DNAmTL) and related this biomarker to the risk of exacerbation and hospitalization and health status (St. George Respiratory Questionnaire [SGRQ]) score over time using a Cox proportional hazards model. We also used linear models to investigate the associations of DNAmTL with the rates of exacerbation and hospitalization (adjusted for chronological age, lung function, race, sex, smoking, body mass index and cell composition). RESULTS: Participants with short DNAmTL demonstrated increased risk of exacerbation (P = 0.02) and hospitalization (P = 0.03) compared to those with longer DNAmTL. DNAmTL age acceleration was associated with higher rates of exacerbation (P = 1.35 × 10-04) and hospitalization (P = 5.21 × 10-03) and poor health status (lower SGRQ scores) independent of chronological age (P = 0.03). CONCLUSION: Telomeric age based on blood DNA methylation is associated with COPD exacerbation and hospitalization and thus a promising biomarker for poor outcomes in COPD.

Projecting Long-term Health and Economic Burden of COPD in the United States.

BACKGROUND: In the United States, COPD is a leading cause of mortality, with a substantial societal health and economic burden. With anticipated population growth, it is important for various stakeholders to have an estimate for the projected burden of disease. RESEARCH QUESTION: The goal of this study was to model the 20-year health and economic burden of COPD, from 2019 to 2038, in the United States. STUDY DESIGN AND METHODS: Using country-specific data from published literature and publicly available datasets, a dynamic open cohort Markov model was developed in a probabilistic Monte Carlo simulation. Population growth was modeled across different subgroups of age, sex, and smoking. The COPD prevalence rates were calibrated for different subgroups, and distributions of severity grades were modeled based on smoking status. Direct costs, indirect absenteeism costs, losses of quality-adjusted life years (QALYs), and number of exacerbations and deaths associated with COPD were projected. RESULTS: The 20-year discounted direct medical costs attributable to COPD were estimated to be $800.90 billion (95% credible interval [CrI], 565.29 billion-1,081.29 billion), with an expected $337.13 billion in male subjects and $463.77 billion in female subjects. The 20-year discounted indirect absenteeism costs were projected to be $101.30 billion (70.82 billion-137.41 billion). The 20-year losses of QALYs, number of exacerbations, and number of deaths associated with COPD were 45.38 million (8.63 million-112.07 million), 315.08 million (228.59 million-425.33 million), and 9.42 million (8.93 million-9.93 million), respectively. The proportion of disease burden attributable to continued smoking was 34% in direct medical costs, 35% in indirect absenteeism costs, and 37% in losses of QALYs over 20 years. INTERPRETATION: This study projects the substantial burden of COPD that the American society is expected to incur with current patterns for treatments and smoking rates. Mitigating such burden requires targeted budget appropriations and cost-effective interventions.

Lymphoproliferative disorder in a lung transplant recipient.

Post-transplantation lymphoproliferative disorder (PTLD) is uncommon following solid organ transplantation. We present a case of PTLD presenting as hematochezia and abdominal pain in a 66-year-old man, who had undergone bilateral lung transplantation with alemtuzumab induction 7 months prior to presentation. The transplant serologic status was "high-risk" for the presence of both Epstein-Barr virus (EBV) serologies in the donor and negative serologies in the recipient. Biopsies taken during colonoscopy stained strongly positive for EBV-encoded RNA. Mediastinal lymph node biopsies also showed atypical, EBV-positive lymphohistiocytic infiltration with focal necrosis. The patient's hospital course was complicated by treatment side effects, most notably bowel perforation following rituximab. In this case report the topic of PTLD is reviewed and consideration is given to whether alemtuzumab induction may have contributed to the patient's development of PTLD.

Rapidly progressive interstitial lung disease due to anti-melanoma differentiation associated protein-5 requiring a bilateral lung transplant, and complicated by kennel cough.

The association between inflammatory myopathies anti-synthetase syndrome and interstitial lung disease has been recognized since the 1950s. Patients generally present with gradual onset of symptoms and slow progression of fibrosis over months to years. Herein, we describe a previously well 51-year-old man who presented with three months of progressive small joint arthritis, cough, dyspnea, and eventually hypoxemic respiratory failure following a viral prodrome. He continued to decompensate despite high dose corticosteroids and mycophenolate mofetil, ultimately requiring extracorporeal membranous oxygenation as a bridge to bilateral lung transplantation. Clinically amyopathic dermatomyositis (CADM) was confirmed through serum positivity for anti-Melanoma Differentiation Associated Protein-5 (MDA-5) antibody. Interestingly, his post-operative course was complicated by a zoonotic infection with Bordetella bronchiseptica. This case highlights the importance of identifying rare autoimmune diseases, and the utility of transfer to a lung transplant center.

Modified Heterotopic Hindlimb Osteomyocutaneous Flap Model in the Rat for Translational Vascularized Composite Allotransplantation Research.

Vascularized composite allotransplantation (VCA) is a relatively new field in the reconstructive surgery. Clinical achievements in human VCA include hand and face transplants and, more recently, abdominal wall, uterus, and urogenital transplants. Functional outcomes have exceeded initial expectations, and most recipients enjoy an improved quality of life. However, as clinical experience accumulates, chronic rejection and complications from the immunosuppression must be addressed. In many cases where grafts have failed, the causative pathology has been ischemic vasculopathy. The biological mechanisms of the acute and chronic rejection associated with VCA, especially ischemic vasculopathy, are important areas of research. However, due to the very small number of VCA patients, the evaluation of proposed mechanisms is better addressed in an experimental model. Multiple groups have used animal models to address some of the relevant unsolved questions in VCA rejection and vasculopathy. Several model designs involving a variety of species are described in the literature. Here we present a reproducible model of VCA heterotopic hindlimb osteomyocutaneous flap in the rat that can be utilized for translational VCA research. This model allows for the serial evaluation of the graft, including biopsies and different imaging modalities, while maintaining a low level of morbidity.

Prophylactic epinephrine for the prevention of transbronchial lung biopsy-related bleeding in lung transplant recipients (PROPHET) study: a protocol for a multicentre randomised, double-blind, placebo-controlled trial.

INTRODUCTION: Transbronchial lung biopsy (TBLB) is frequently performed in single-lung and double-lung transplant recipients for evaluation of clinical and radiological findings as well as routine surveillance for acute cellular rejection. While rates of clinically significant TBLB-related haemorrhage are <1% for all comers, the incidence in lung transplant recipients is reported to be higher, presumably due to persistent allograft inflammation and alterations in allograft blood flow. While routinely performed by some bronchoscopists, the efficacy and safety profile of prophylactic administration of topical intrabronchial diluted epinephrine for the prevention of TBLB-related haemorrhage has not been explored in a prospective manner. METHODS AND ANALYSIS: In this randomised, double-blind, placebo-controlled multicentre trial (PROPHET Study), single-lung and double-lung transplant adult recipients from participating institutions who are scheduled for bronchoscopy with TBLB for clinical indications will be identified. Potential participants who meet inclusion and exclusion criteria and sign an informed consent will be randomised to receive either diluted epinephrine or placebo prior to performance of TBLB. The degree of TBLB-related haemorrhage will be graded by the performing bronchoscopist as well as independent observers. The primary analysis will compare the rates of severe and very severe bleeding in participants treated with epinephrine or placebo. The study will also evaluate the safety profile of prophylactic topical epinephrine including the occurrence of serious cardiovascular and haemodynamic adverse events. Additional secondary outcomes to be explored include rates of non-severe TBLB-related haemorrhage, overall yield of the bronchoscopic procedure and non-serious cardiovascular and haemodynamic adverse effects. ETHICS AND DISSEMINATION: The study procedures were reviewed and approved by institutional review boards in participating institutions. This study is being externally monitored, and a data and safety monitoring committee has been assembled to monitor patient safety and to evaluate the efficacy of the intervention. The results of this study will be published in peer-reviewed scientific journals and presented at relevant academic conferences. TRIAL REGISTRATION NUMBER: NCT03126968; Pre-results.

Seasonal and Regional Variations in Chronic Obstructive Pulmonary Disease Exacerbation Rates in Adults without Cardiovascular Risk Factors.

RATIONALE: Colder temperatures have been shown to increase hospitalization and mortality rates in adults with chronic obstructive pulmonary disease (COPD) and cardiac disease. Seasonal influences on exacerbation rates in adults with severe COPD but without significant cardiovascular disease are unclear. In addition, regional variations in COPD exacerbations in North America have not yet been explored. OBJECTIVES: In this study, we sought to determine the seasonal and regional variability in exacerbation rates in those with COPD but without significant cardiovascular risk factors. METHODS: We studied adults without cardiovascular risk factors from STATCOPE (Simvastatin in the Prevention of COPD Exacerbations) and placebo arm of MACRO (Azithromycin for the Prevention of Exacerbations of COPD) studies. Forty-five study sites were divided into climate regions in Canada and the United States; seasons were defined as winter, spring, summer, and fall. The primary outcome was the rate of COPD exacerbation. Secondary outcomes included time to first exacerbation, severity of exacerbations, all-cause mortality, and antibiotic and steroid use. RESULTS: We analyzed 1,175 subjects with a mean age of 63.3 ± 8.6 years, forced expiratory volume in 1 second of 41.5 ± 17.1% predicted, and 53.6 ± 29.4 pack-years of smoking history. The COPD exacerbation rate was higher in winter (0.13 exacerbations/person-month) than in spring, summer, and fall (0.11, 0.079, and 0.10 exacerbations/person-month, respectively) (P < 0.001). Summer had the highest proportion of severe exacerbations (40.5%) compared with spring, fall, and winter (32.6%, 34.7%, and 33.1%, respectively) (P = 0.004). Mortality was highest in spring and winter (34% and 30%, respectively). There was significant regional variability in the time to first exacerbation, with the Southeast and West having longer median times to first exacerbation (350 and 342 d, respectively, compared with 184 d in other regions) (P < 0.001). CONCLUSIONS: Significant seasonal and regional variability exist in the rate and severity of exacerbations and overall mortality in adults with COPD without cardiovascular disease.

Azithromycin and risk of COPD exacerbations in patients with and without Helicobacter pylori.

BACKGROUND: Helicobacter pylori (HP) infection is associated with reduced lung function and systemic inflammation in chronic obstructive pulmonary disease (COPD) patients. Azithromycin (AZ) is active against HP and reduces the risk of COPD exacerbation. We determined whether HP infection status modifies the effects of AZ in COPD patients. METHODS: Plasma samples from 1018 subjects with COPD who participated in the Macrolide Azithromycin (MACRO) in COPD Study were used to determine the HP infection status at baseline and 12 months of follow-up using a serologic assay. Based on HP infection status and randomization to either AZ or placebo (PL), the subjects were divided into 4 groups: HP+/AZ, HP-/AZ, HP+/PL, and HP-/PL. Time to first exacerbation was compared across the 4 groups using Kaplan-Meier survival analysis and a Cox proportional hazards model. The rates of exacerbation were compared using both the Kruskal-Wallis test and negative binomial analysis. Blood biomarkers at enrolment and at follow-up visits 3, 12, and 13 (1 month after treatment was stopped) months were measured. RESULTS: One hundred eighty one (17.8%) patients were seropositive to HP. Non-Caucasian participants were nearly three times more likely to be HP seropositive than Caucasian participants (37.4% vs 13.6%; p < 0.001). The median time to first exacerbation was significantly different across the four groups (p = 0.001) with the longest time in the HP+/AZ group (11.2 months, 95% CI; 8.4-12.5+) followed by the HP-/AZ group (8.0 months, 95% CI; 6.7-9.7). Hazard ratio (HR) for exacerbations was lowest in the HP+/AZ group after adjustment for age, sex, smoking status, ethnicity, history of peptic ulcer, dyspnea, previous hospital admission, GOLD grade of severity, and forced vital capacity (HR, 0.612; 95% CI, 0.442-0.846 vs HR, 0.789; 95% CI, 0.663-0.938 in the HP-/AZ group). Circulating levels of soluble tumor necrosis factor receptor-75 were reduced only in the HP+/AZ group after 3 months of AZ treatment (-0.87 ± 0.31 µg/L; p = 0.002); levels returned to baseline after discontinuing AZ. CONCLUSIONS: AZ is effective in preventing COPD exacerbations in patients with HP seropositivity, possibly by modulating TNF pathways related to HP infection.

Tobacco Smoke Exposure Reduces Paraoxonase Activity in a Murine Model.

AIM: To demonstrate a direct inhibitory effect of cigarette smoke exposure on paraoxonase 1 activity in a murine in vivo model. METHODS: At 8 weeks old, we randomized 10 C57/bl6 mice to an environment consisting of either filtered air or cigarette smoke for 6 months. Smoke exposure (7 hours per day, 5 days per week) was standardized using a model TE-10 smoking machine and adjusted to maintain constant sidestream and mainstream smoke. After 6 months of exposure, we assessed differences in lung air space, cholesterol, lipid, and lipoprotein profiles, as well as paraoxonase activity in mice exposed to cigarette smoke extract compared to unexposed control mice. RESULTS: Cigarette smoke exposure by the protocol used was sufficient to result in pathologic changes in lung architecture consistent with emphysema. Specifically, we observed that mice exposed to cigarette smoke had a significantly higher mean linear chord length compared to animals that were exposed to filtered air (p<0.02). Despite this exposure, no differences in total HDL-cholesterol levels or HDL-cholesterol sub-fractions (i.e. HDL2 and HDL3 fractions) were noted between smoke-exposed and unexposed animals (p=1.00, 0.6, and 0.4, respectively). Notably, mean HDL-cholesterol levels were identical between groups (92.8 vs 92.8 mg/dL, p=1.0). Paraoxonase activity, however, was markedly reduced in mice exposed to cigarette smoke compared to those who were not exposed (102, SD=9.6 vs 144, SD=4.1 units of activity, respectively, p=0.002). CONCLUSION: In this murine model, tobacco smoke exposure directly inhibits paraoxonase activity independently of HDL-cholesterol levels rather than indirectly via reduction in HDL-cholesterol levels.

Gender differences in first and secondhand smoke exposure, spirometric lung function and cardiometabolic health in the old order Amish: A novel population without female smoking.

Due to their relatively homogeneous lifestyle and living environment, the Amish offer a novel opportunity to study the health associations of tobacco smoke exposure, particularly secondhand smoke. We hypothesized that secondhand smoke exposure is associated with worse pulmonary and cardiometabolic health. We examined cross-sectional data on 3568 Amish study participants, including tobacco use and secondhand smoke exposure from family members included in the study. Thirty-four percent of Amish men reported ever smoking. Of this proportion, 64% used cigars, 46% cigarettes, and 21% pipes. Less than 1% of women reported ever smoking. Smoking was associated with lower spirometric lung function, higher body mass index, lower HDL cholesterol, higher heart rate, lower ankle-brachial index, and larger aortic diameter in men. A greater number of sources of secondhand smoke exposure (defined from the total of spouses, parents, and siblings who smoke) was associated with higher body mass index (p = 0.03) and with higher fasting glucose in men (p = 0.01), but not in women (p = 0.007 for sex*secondhand smoke interaction). Secondhand smoke exposure was also associated with reduced HDL cholesterol only in women (p = 0.002) and a lower heart rate only in men (p = 0.006). Smoking habits among the Old Order Amish are notable for the absence of female participation and a high proportion of cigar and pipe use. Smoking is associated with decreased spirometric indices of lung function and increased cardiovascular risk in this population and secondhand smoke exposure is associated with a greater burden of risk factors for cardiovascular disease. Sex differences in correlations could reflect differences in exposure patterns, mechanisms, or susceptibilities.

Restrictive versus liberal red blood cell transfusion strategy after hip surgery: a decision model analysis of healthcare costs.

BACKGROUND: Red blood cell transfusion related to select surgical procedures accounts for approximately 2.8 million transfusions in the United States yearly and occurs commonly after hip fracture surgeries. Randomized controlled trials have demonstrated lack of clinical benefit with higher versus lower transfusion thresholds in postoperative hip fracture repair patients with cardiac disease or risk factors for cardiac disease. The economic implications of a higher versus lower hemoglobin (Hb) threshold have not yet been investigated. STUDY DESIGN AND METHODS: A decision tree analysis was constructed to estimate differences in healthcare costs and charges between a Hb transfusion threshold strategy of 8 g/dL versus 10 g/dL from the perspective of both Centers for Medicare and Medicaid Services (CMS) as well as hospitals. Secondary outcome measures included differences in transfusion-related adverse events. RESULTS: Among the 133,697 Medicare beneficiaries undergoing hip fracture repair in 2012, we estimated that 45,457 patients would be anemic and at risk for transfusion. CMS would save an estimated $11.3 million to $24.3 million in payments, while hospitals would reduce charges by an estimated $52.7 million to $93.6 million if the restrictive transfusion strategy were to be implemented nationally. Additionally, rates of transfusion-associated circulatory overload, transfusion-related acute lung injury, acute transfusion reactions, length of stay, and mortality would be reduced. CONCLUSIONS: This model suggests that the uniform adoption of a restrictive transfusion strategy among patients with cardiac disease and risk factors for cardiac disease undergoing hip fracture repair would result in significant reductions in clinically important outcomes with significant cost savings.

Systemically delivered adipose stromal vascular fraction cells disseminate to peripheral artery walls and reduce vasomotor tone through a CD11b+ cell-dependent mechanism.

Vasoactivity, an important aspect of tissue healing, is often compromised in disease and tissue injury. Dysfunction in the smaller vasoactive arteries is most impactful, given the role of these vessels in controlling downstream tissue perfusion. The adipose stromal vascular fraction (SVF) is a mix of homeostatic cells shown to promote tissue healing. Our objective was to test the hypothesis that autologous SVF cells therapeutically modulate peripheral artery vasoactivity in syngeneic mouse models of small artery function. Analysis of vasoactivity of saphenous arteries isolated from normal mice 1 week after intravenous injection of freshly isolated SVF cells revealed that pressure-dependent artery vasomotor tone was decreased by the SVF cell isolate, but not one depleted of CD11b(+) cells. Scavenging hydrogen peroxide in the vessel wall abrogated the artery relaxation promoted by the SVF cell isolate. Consistent with a CD11b(+) cell being the relevant cell type, SVF-derived F4/80-positive macrophages were present within the adventitia of the artery wall coincident with vasorelaxation. In a model of artery inflammation mimicking a common disease condition inducing vasoactive dysfunction, the SVF cells potentiated relaxation of saphenous arteries without structurally remodeling the artery via a CD11b(+) cell-dependent manner. Our findings demonstrate that freshly isolated, adipose SVF cells promote vasomotor relaxation in vasoactive arteries via a hydrogen peroxide-dependent mechanism that required CD11b(+) cells (most likely macrophages). Given the significant impact of small artery dysfunction in disease, we predict that the intravenous delivery of this therapeutic cell preparation would significantly improve tissue perfusion, particularly in diseases with diffuse vascular involvement.

Calcified granulomatous disease: occupational associations and lack of familial aggregation.

PURPOSE: The acute host response to histoplasma capsulatum infection varies according to exposure and susceptibility. Late sequelae include calcifications in the lung, thoracic lymphatics, and spleen. Determinants of calcified granuloma formation are poorly studied and may differ from those affecting acute response. We examined the occupational associations and familial aggregation of radiographic calcified granulomatous disease to characterize the determinants of calcified granuloma formation. METHODS: We analyzed prospectively collected cross-sectional data including computed tomograms from 872 adult members of the Old Order Amish of Lancaster County. RESULTS: Granulomas were present in 71 % of participants. Granulomas were present in the lung of 57 % of participants, in the hilar or mediastinal lymph nodes of 55 % of participants, and in the spleen of 29 % of participants. No significant differences were observed in the presence of granulomas between men and women. Each year of age was associated with 4 % higher odds of splenic calcifications, and a primary occupation of farming was associated with an 84 % higher odds of splenic calcifications. A compelling pattern of familial aggregation was not observed. CONCLUSIONS: Calcified granulomatous disease does not appear to aggregate in families. Determinants influencing patterns of granulomatous disease include occupation, age, and geographic location.