Remzi Bag

An Immune Basis for Lung Parenchymal Destruction in Chronic Obstructive Pulmonary Disease and Emphysema

ABSTRACT Background Chronic obstructive pulmonary disease and emphysema are a frequent result of long-term smoking, but the exact mechanisms, specifically which types of cells are associated with the lung destruction, are unclear. Methods and Findings We studied different subsets of lymphocytes taken from portions of human lungs removed surgically to find out which lymphocytes were the most frequent, which cell-surface markers these lymphocytes expressed, and whether the lymphocytes secreted any specific factors that could be associated with disease. We found that loss of lung function in patients with chronic obstructive pulmonary disease and emphysema was associated with a high percentage of CD4+ and CD8+ T lymphocytes that expressed chemokine receptors CCR5 and CXCR3 (both markers of T helper 1 cells), but not CCR3 or CCR4 (markers of T helper 2 cells). Lung lymphocytes in patients with chronic obstructive pulmonary disease and emphysema secrete more interferon gamma—often associated with T helper 1 cells—and interferon-inducible protein 10 and monokine induced by interferon, both of which bind to CXCR3 and are involved in attracting T helper 1 cells. In response to interferon-inducible protein 10 and monokine induced by interferon, but not interferon gamma, lung macrophages secreted macrophage metalloelastase (matrix metalloproteinase-12), a potent elastin-degrading enzyme that causes tissue destruction and which has been linked to emphysema. Conclusions These data suggest that Th1 lymphoctytes in the lungs of people with smoking-related damage drive progression of emphysema through CXCR3 ligands, interferon-inducible protein 10, and monokine induced by interferon.

Comparison of Sirolimus with Azathioprine in a Tacrolimus-based Immunosuppressive Regimen in Lung Transplantation

RATIONALE Lung transplantation has evolved into a life-saving therapy for select patients with end-stage lung diseases. However, long-term survival remains limited because of chronic rejection. Sirolimus is beneficial in preventing cardiac rejection and may decrease rejection after lung transplantation. OBJECTIVES To determine the potential benefit versus risk of sirolimus in lung transplantation. METHODS We conducted a multicenter randomized, open label controlled trial comparing sirolimus (SIR) with azathioprine (AZA) in a tacrolimus-based immunosuppressive regimen in lung transplantation. The primary end point was the incidence of acute rejection at 1 year after transplantation between the two study groups. MEASUREMENTS AND MAIN RESULTS One hundred eighty-one patients were randomized to be included in this study. At 1 year after transplantation, there was no significant difference in the incidence of grade A acute rejection between the two study groups. Similarly, the incidence of chronic rejection and graft survival was no different between the two study groups. Cytomegalovirus infection was decreased in the SIR arm compared with the AZA arm (relative risk, 0.67 [95% confidence interval, 0.55, 0.82]; P < 0.01). There was a higher rate of adverse events leading to early discontinuation of SIR (64%) compared with AZA (49%) during the course of this study. CONCLUSIONS Sirolimus, an mTOR inhibitor, did not decrease the incidence of acute rejection at 1 year compared with azathioprine in lung transplantation. These results differ from previous results in cardiac and renal transplantation and emphasize the need for multicenter randomized controlled trials in lung transplantation. Clinical trial registered with www.clinicaltrials.gov (NCT 00321906).

Increased risk of venous thromboembolism with a sirolimus-based immunosuppression regimen in lung transplantation

BACKGROUND Sirolimus (rapamycin) is a potent anti-proliferative agent with immunosuppressive properties that is increasingly being used in solid-organ and hematopoietic stem cell transplantation. In addition, this drug is being investigated for treatment of a broad range of disorders, including cardiovascular disease, malignancies, tuberous sclerosis, and lymphangeioleiomyomatosis. In this study, we found an increased risk of venous thromboembolism (VTE) in lung transplant recipients treated with a sirolimus (SIR)-based immunosuppressive regimen. METHODS One hundred eighty-one lung transplant recipients were enrolled in a prospective, multicenter, randomized, open-label trial comparing a tacrolimus (TAC)/SIR/prednisone immunosuppression regimen with a TAC/azathioprine (AZA)/prednisone immunosuppressive regimen. The differences in rates of VTE were examined. RESULTS There was a significantly higher occurrence of VTE in the SIR cohort [15 of 87 (17.2%)] compared with the AZA cohort [3 of 94 (3.2%)] (stratified log-rank statistic = 7.44, p < 0.01). When adjusted for pre-transplant diagnosis and stratified by transplant center, this difference remained essentially unchanged (hazard ratio for SIR vs AZA = 5.2, 95% confidence interval 1.4 to 19.5, p = 0.01). CONCLUSION Clinicians prescribing SIR should maintain a high level of vigilance for VTE, particularly among patients with other risk factors for this complication.

The Effect of Heliox-Driven Bronchodilator Aerosol Therapy on Pulmonary Function Tests in Patients with Asthma

To compare the effects of heliox-driven (He 80:O2 20) to air-driven (N 79:O2 21) β2-agonist aerosol therapy on pulmonary function tests (PFTs) in patients with asthma, a prospective randomized crossover study was undertaken in the asthma clinic of the university-affiliated county hospital in Houston, TX. Thirty-one patients (22 female, age range 18–44) with clinically stable asthma consented. All patients were studied on two different days with both heliox and air as driving gas, therefore serving as their own controls. The PFTs including forced expiratory volume in 1 sec (FEV1), forced vital capacity (FVC), maximal mid-expiratory flow rate (FEF25–75), and maximal expiratory flow rate (FEFmax) were obtained while breathing ambient air at baseline and 30 min after the bronchodilator treatment. Albuterol sulfate 2.5 mg was nebulized with either heliox or compressed air at 8 L/min for 8 min. When heliox was used as driving agent, additional heliox was delivered via a closed system and no entrainment of external air was allowed. Primary outcome measure was absolute change in FEV1 (ΔFEV1). There were no statistically significant differences in baseline PFTs on the two days of the study. All patients had good bronchodilator response (≥12% improvement in FEV1) with either driving gas. The ΔFEV1 after heliox-driven bronchodilator (HDBD) and air-driven bronchodilator (ADBD) were 0.68±0.38 L/sec (CI: 0.54–0.82) vs. 0.51±0.26 L/sec (CI: 0.42–0.60), respectively (p=0.004). The ΔFEV1 with HDBD was 49±90% (range −36% to 433%) more than ADBD. A subgroup analysis showed this was largely due to better response rates in patients with moderate to severe obstruction. There was more improvement in both FVC and FEFmax with HDBD than ADBD (p<0.05). The changes in FEF25–75 were similar. We conclude that HDBD therapy improves FEV1, FVC, and FEFmax significantly more than ADBD in patients with asthma. Further large randomized studies are needed to better characterize responders and the impact on clinical outcomes.

Interobserver Variability in Grading Transbronchial Lung Biopsy Specimens After Lung Transplantation

BACKGROUND Acute rejection remains a major source of morbidity after lung transplantation. Given the importance of this diagnosis, an international grading system was developed to standardize the diagnosis of acute lung-allograft rejection. The reliability of this grading system has not been adequately assessed by previous studies. METHODS We examined the level of agreement in grading transbronchial biopsy specimens obtained from a large multicenter study (AIRSAC [Comparison of a Tacrolimus/Sirolimus/Prednisone Regimen vs Tacrolimus/Azathioprine/Prednisone Immunosuppressive Regimen in Lung Transplantation] trial). Biopsy specimens were initially graded for acute rejection and lymphocytic bronchiolitis by the site pathologist and subsequently graded by a central pathologist. Reliability of interobserver grading was evaluated using Cohen κ coefficients. RESULTS A total of 481 transbronchial biopsy specimens were graded by both the site and central pathologists. The overall concordance rates were 74% and 89% for grade A and grade B biopsy specimens, respectively. When samples from biopsies performed at different time points after transplantation were assessed, there was a higher level of agreement early (≤ 6 weeks) after transplant compared with later time points for acute rejection. However, there was still only moderate agreement for both grade A (κ score 0.479; 95% CI, 0.29-0.67) and grade B (κ score 0.465; 95% CI, 0.08-0.85) rejection. CONCLUSIONS These results expand upon previous reports of interobserver variability in grading transbronchial biopsy specimens after lung transplantation. Given the variability in grading these specimens, we advocate further education of the histopathologic findings in lung transplant biopsy specimens, as well as revisiting the current criteria for grading transbronchial biopsy specimens to improve concordance among lung transplant pathologists. TRIAL REGISTRY ClinicalTrials.gov; No. NCT00321906; URL: www.clinicaltrials.gov.

Decreased incidence of cytomegalovirus infection with sirolimus in a post hoc randomized, multicenter study in lung transplantation

BACKGROUND Cytomegalovirus (CMV) is the most common opportunistic infection in lung transplantation. A recent multicenter, randomized trial (the AIRSAC study) comparing sirolimus to azathioprine in lung transplant recipients showed a decreased incidence of CMV events in the sirolimus cohort. To better characterize this relationship of decreased incidence of CMV events with sirolimus, we examined known risk factors and characteristics of CMV events from the AIRSAC database. METHODS The AIRSAC database included 181 lung transplant patients from 8 U.S.-based lung transplant centers that were randomized to sirolimus or azathioprine at 3 months post-transplantation. CMV incidence, prophylaxis, diagnosis and treatment data were all prospectively collected. Prophylaxis and treatment of CMV were at the discretion of each institution. RESULTS The overall incidence of any CMV event was decreased in the sirolimus arm when compared with the azathioprine arm at 1 year after lung transplantation (relative risk [RR] = 0.67, confidence interval [CI] 0.55 to 0.82, p < 0.01). This decreased incidence of CMV events with sirolimus remained significant after adjusting for confounding factors of CMV serostatus and CMV prophylaxis. CONCLUSIONS These data support results from other solid-organ transplantation studies and suggest further investigation of this agent in the treatment of lung transplant recipients at high risk for CMV events.

Bile Acid Aspiration Associated With Lung Chemical Profile Linked to Other Biomarkers of Injury After Lung Transplantation

Aspiration of gastrointestinal contents has been linked to worse outcomes following lung transplantation but uncertainty exists about underlying mechanisms. We applied high‐resolution metabolomics of bronchoalveolar lavage fluid (BALF) in patients with episodic aspiration (defined by bile acids in the BALF) to identify potential metabolic changes associated with aspiration. Paired samples, one with bile acids and another without, from 29 stable lung transplant patients were studied. Liquid chromatography coupled to high‐resolution mass spectroscopy was used to interrogate metabolomic contents of these samples. Data were obtained for 7068 ions representing intermediary metabolites, environmental agents and chemicals associated with microbial colonization. A substantial number (2302) differed between bile acid positive and negative samples when analyzed by false discovery rate at q = 0.01. These included pathways associated with microbial metabolism. Hierarchical cluster analysis defined clusters of chemicals associated with bile acid aspiration that were correlated to previously reported biomarkers of lung injury including T cell granzyme B level and the chemoattractants CXCL9 and CXCL10. These data specifically link bile acids presence in lung allografts to inflammatory pathways known to segregate with worsening allograft outcome, and provide additional mechanistic insight into the association between reflux and lung allograft injury.

Fungal pneumonias in transplant recipients.

Fungi are ubiquitous in the environment. Opportunistic fungal pneumonias in the immunocompromised host continue to increase most commonly due to Aspergillus sp. Affected patients are usually hematopoietic stem cell and lung transplant recipients. Clinical presentation is protean, and the diagnosis is challenging. Culture of respiratory specimens has limited utility. The detection of circulating fungal antigens and DNA seems promising, but more studies are needed. Value of prophylactic strategies or preemptive therapy remains contentious. New antifungal drugs for managing invasive pulmonary aspergillosis continue to emerge, with better safety, efficacy, and pharmacologic profiles.

Respiratory failure in interstitial lung disease

Purpose of review Respiratory failure associated with interstitial lung disease (ILD) occurs commonly, often as a terminal event after a prolonged course of illness. Diagnosis and management of the underlying ILD and respiratory failure pose great challenges. Recent findings Respiratory failure in the absence of a clearly identifiable cause has a high mortality and frequent complications. Patients with idiopathic pulmonary fibrosis who are admitted with respiratory failure have a grim prognosis and may not benefit from prolonged aggressive therapy including mechanical ventilation. Presence of diffuse alveolar damage or usual interstitial pneumonia on lung biopsy specimens from patients with respiratory failure may be a marker of poor prognosis. Recently, the importance of the clinical-radiologic-pathologic diagnosis has been emphasized. Summary The prognosis and treatment may vary according to the type of ILD and the cause of the respiratory failure, which must therefore be established before treatment is initiated. Prevention of iatrogenesis and timely application of palliation are as important as specific treatment of underlying ILD.

ISHLT Consensus ReportsPrimary Lung Graft DysfunctionReport of the ISHLT Working Group on Primary Lung Graft Dysfunction, part I: Definition and grading—A 2016 Consensus Group statement of the International Society for Heart and Lung Transplantation

From the Allergy, Immunology and Respiratory Medicine, Alfred Hospital, Melbourne, Victoria, Australia; Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine in St. Louis, St. Louis, Missouri; Institute for Advanced Organ Disease and Transplantation, Tampa General Hospital/University of South Florida, Tampa, Florida; Department of Surgery, Michigan State University, Ada, Michigan; Lung Transplant Program, University of Chicago, Chicago, Illinois; Lung Transplant Program, Harefield Hospital, Harefield, United Kingdom; Division of Pulmonary, Critical Care, and Sleep Medicine, University of Florida, Gainesville, Florida; Division of Pulmonary Medicine, Medical University of South Carolina, Charleston, South Carolina; Section of Lung Transplantation, Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; Section of Pulmonary and Critical Care, Department of Medicine, and Lung Transplant Program, University of Chicago, Chicago, Illinois; Department of Pulmonary, Allergy and Critical Care Medicine, Respiratory Institute, Cleveland Clinic, Cleveland, Ohio; National Pulmonary Hypertension Service (Newcastle), The Newcastle upon Tyne Hospitals NHS Foundation Trust, and Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom; Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; and the Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania.