Utility of a Molecular Classifier as a Complement to High-Resolution Computed Tomography to Identify Usual Interstitial Pneumonia.

Rationale: Usual interstitial pneumonia (UIP) is the defining morphology of idiopathic pulmonary fibrosis (IPF). Guidelines for IPF diagnosis conditionally recommend surgical lung biopsy for histopathology diagnosis of UIP when radiology and clinical context are not definitive. A "molecular diagnosis of UIP" in transbronchial lung biopsy, the Envisia Genomic Classifier, accurately predicted histopathologic UIP.Objectives: We evaluated the combined accuracy of the Envisia Genomic Classifier and local radiology in the detection of UIP pattern.Methods: Ninety-six patients who had diagnostic lung pathology as well as a transbronchial lung biopsy for molecular testing with Envisia Genomic Classifier were included in this analysis. The classifier results were scored against reference pathology. UIP identified on high-resolution computed tomography (HRCT) as documented by features in local radiologists' reports was compared with histopathology.Measurements and Main Results: In 96 patients, the Envisia Classifier achieved a specificity of 92.1% (confidence interval [CI],78.6-98.3%) and a sensitivity of 60.3% (CI, 46.6-73.0%) for histology-proven UIP pattern. Local radiologists identified UIP in 18 of 53 patients with UIP histopathology, with a sensitivity of 34.0% (CI, 21.5-48.3%) and a specificity of 96.9% (CI, 83.8-100%). In conjunction with HRCT patterns of UIP, the Envisia Classifier results identified 24 additional patients with UIP (sensitivity 79.2%; specificity 90.6%).Conclusions: In 96 patients with suspected interstitial lung disease, the Envisia Genomic Classifier identified UIP regardless of HRCT pattern. These results suggest that recognition of a UIP pattern by the Envisia Genomic Classifier combined with HRCT and clinical factors in a multidisciplinary discussion may assist clinicians in making an interstitial lung disease (especially IPF) diagnosis without the need for a surgical lung biopsy.

Single-Cell Transcriptomic Analysis of Human Lung Provides Insights into the Pathobiology of Pulmonary Fibrosis.

Rationale: The contributions of diverse cell populations in the human lung to pulmonary fibrosis pathogenesis are poorly understood. Single-cell RNA sequencing can reveal changes within individual cell populations during pulmonary fibrosis that are important for disease pathogenesis. Objectives: To determine whether single-cell RNA sequencing can reveal disease-related heterogeneity within alveolar macrophages, epithelial cells, or other cell types in lung tissue from subjects with pulmonary fibrosis compared with control subjects. Methods: We performed single-cell RNA sequencing on lung tissue obtained from eight transplant donors and eight recipients with pulmonary fibrosis and on one bronchoscopic cryobiospy sample from a patient with idiopathic pulmonary fibrosis. We validated these data using in situ RNA hybridization, immunohistochemistry, and bulk RNA-sequencing on flow-sorted cells from 22 additional subjects. Measurements and Main Results: We identified a distinct, novel population of profibrotic alveolar macrophages exclusively in patients with fibrosis. Within epithelial cells, the expression of genes involved in Wnt secretion and response was restricted to nonoverlapping cells. We identified rare cell populations including airway stem cells and senescent cells emerging during pulmonary fibrosis. We developed a web-based tool to explore these data. Conclusions: We generated a single-cell atlas of pulmonary fibrosis. Using this atlas, we demonstrated heterogeneity within alveolar macrophages and epithelial cells from subjects with pulmonary fibrosis. These results support the feasibility of discovery-based approaches using next-generation sequencing technologies to identify signaling pathways for targeting in the development of personalized therapies for patients with pulmonary fibrosis.

Clinical risk factors for primary graft dysfunction after lung transplantation.

RATIONALE: Primary graft dysfunction (PGD) is the main cause of early morbidity and mortality after lung transplantation. Previous studies have yielded conflicting results for PGD risk factors. OBJECTIVES: We sought to identify donor, recipient, and perioperative risk factors for PGD. METHODS: We performed a 10-center prospective cohort study enrolled between March 2002 and December 2010 (the Lung Transplant Outcomes Group). The primary outcome was International Society for Heart and Lung Transplantation grade 3 PGD at 48 or 72 hours post-transplant. The association of potential risk factors with PGD was analyzed using multivariable conditional logistic regression. MEASUREMENTS AND MAIN RESULTS: A total of 1,255 patients from 10 centers were enrolled; 211 subjects (16.8%) developed grade 3 PGD. In multivariable models, independent risk factors for PGD were any history of donor smoking (odds ratio [OR], 1.8; 95% confidence interval [CI], 1.2-2.6; P = 0.002); FiO2 during allograft reperfusion (OR, 1.1 per 10% increase in FiO2; 95% CI, 1.0-1.2; P = 0.01); single lung transplant (OR, 2; 95% CI, 1.2-3.3; P = 0.008); use of cardiopulmonary bypass (OR, 3.4; 95% CI, 2.2-5.3; P < 0.001); overweight (OR, 1.8; 95% CI, 1.2-2.7; P = 0.01) and obese (OR, 2.3; 95% CI, 1.3-3.9; P = 0.004) recipient body mass index; preoperative sarcoidosis (OR, 2.5; 95% CI, 1.1-5.6; P = 0.03) or pulmonary arterial hypertension (OR, 3.5; 95% CI, 1.6-7.7; P = 0.002); and mean pulmonary artery pressure (OR, 1.3 per 10 mm Hg increase; 95% CI, 1.1-1.5; P < 0.001). PGD was significantly associated with 90-day (relative risk, 4.8; absolute risk increase, 18%; P < 0.001) and 1-year (relative risk, 3; absolute risk increase, 23%; P < 0.001) mortality. CONCLUSIONS: We identified grade 3 PGD risk factors, several of which are potentially modifiable and should be prioritized for future research aimed at preventative strategies. Clinical trial registered with www.clinicaltrials.gov (NCT 00552357).

The Impact of the Envisia Genomic Classifier in the Diagnosis and Management of Patients with Idiopathic Pulmonary Fibrosis.

Rationale: The diagnosis of idiopathic pulmonary fibrosis (IPF) remains challenging and can result in delayed or misdiagnosis. IPF diagnosis is based on the presence of either a radiographic or histologic usual interstitial pneumonia (UIP) pattern in the absence of an identifiable etiology. The Envisia Genomic Classifier is a clinically validated molecular diagnostic test that identifies UIP in transbronchial biopsies. Objectives: To determine the impact of the Envisia Genomic Classifier on physicians' clinical decision-making in the diagnosis and management of IPF. Methods: This prospective randomized decision impact survey was designed to test the hypothesis that including an Envisia UIP-positive result will increase IPF diagnoses, diagnostic confidence, and the recommendation for antifibrotic therapy. The survey included patients from the BRAVE (Bronchial Sample Collection for a Novel Genomic Test) study who had a high-resolution computed tomographic scan without a typical UIP pattern, an Envisia UIP-positive result, and a final diagnosis of IPF by multidisciplinary team discussion. Each case was presented in three different formats: a pre-post cohort, where each case is presented initially without and then with Envisia, and two independent cohorts, where each case is presented without and with Envisia, respectively. Results: U.S.-based pulmonologists from community and academic centers in geographically diverse practices were approached for inclusion in this study. 103 (65%) U.S.-based pulmonologists met the inclusion criteria and provided 605 case reviews of 11 patient cases. The number of IPF diagnoses increased with Envisia by an absolute difference of 39% from 47 (30%) before Envisia to 107 (69%) after Envisia in the pre-post cohort and by 13% in the independent cohorts. High confidence (⩾90%) of interstitial lung disease diagnoses was more commonly seen with Envisia in both the pre-post cohort and in the independent cohorts. Recommendation for antifibrotic treatment increased with Envisia by an absolute difference of 36% from 15 (10%) before Envisia to 72 (46.4%) after Envisia in the pre-post cohort and by 11% in the independent cohorts. Conclusions: This decision impact survey suggests the clinical utility of the Envisia Classifier by demonstrating a significant increase in IPF diagnoses, diagnostic confidence, and recommendation for antifibrotic therapies to assist physicians in effectively managing patients to improve outcomes of patients with IPF.

Clinical validation and utility of Percepta GSC for the evaluation of lung cancer.

The Percepta Genomic Sequencing Classifier (GSC) was developed to up-classify as well as down-classify the risk of malignancy for lung lesions when bronchoscopy is non-diagnostic. We evaluated the performance of Percepta GSC in risk re-classification of indeterminate lung lesions. This multicenter study included individuals who currently or formerly smoked undergoing bronchoscopy for suspected lung cancer from the AEGIS I/ II cohorts and the Percepta Registry. The classifier was measured in normal-appearing bronchial epithelium from bronchial brushings. The sensitivity, specificity, and predictive values were calculated using predefined thresholds. The ability of the classifier to decrease unnecessary invasive procedures was estimated. A set of 412 patients were included in the validation (prevalence of malignancy was 39.6%). Overall, 29% of intermediate-risk lung lesions were down-classified to low-risk with a 91.0% negative predictive value (NPV) and 12.2% of intermediate-risk lesions were up-classified to high-risk with a 65.4% positive predictive value (PPV). In addition, 54.5% of low-risk lesions were down-classified to very low risk with >99% NPV and 27.3% of high-risk lesions were up-classified to very high risk with a 91.5% PPV. If the classifier results were used in nodule management, 50% of patients with benign lesions and 29% of patients with malignant lesions undergoing additional invasive procedures could have avoided these procedures. The Percepta GSC is highly accurate as both a rule-out and rule-in test. This high accuracy of risk re-classification may lead to improved management of lung lesions.

Differentiated transplant derived airway epithelial cell cytokine secretion is not regulated by cyclosporine.

BACKGROUND: While lung transplantation is an increasingly utilized therapy for advanced lung diseases, chronic rejection in the form of bronchiolitis obliterans syndrome (BOS) continues to result in significant allograft dysfunction and patient mortality. Despite correlation of clinical events with eventual development of BOS, the causative pathophysiology remains unknown. Airway epithelial cells within the region of inflammation and fibrosis associated with BOS may have a participatory role. METHODS: Transplant derived airway epithelial cells differentiated in air liquid interface culture were treated with IL-1ß and/or cyclosporine, after which secretion of cytokines and growth factor and gene expression for markers of epithelial to mesenchymal transition were analyzed. RESULTS: Secretion of IL-6, IL-8, and TNF-α, but not TGF-ß1, was increased by IL-1ß stimulation. In contrast to previous studies using epithelial cells grown in submersion culture, treatment of differentiated cells in ALI culture with cyclosporine did not elicit cytokine or growth factor secretion, and did not alter IL-6, IL-8, or TNF-α production in response to IL-1ß treatment. Neither IL-1ß nor cyclosporine elicited expression of markers of the epithelial to mesenchymal transition E-cadherin, EDN-fibronectin, and α-smooth muscle actin. CONCLUSION: Transplant derived differentiated airway epithelial cell IL-6, IL-8, and TNF-α secretion is not regulated by cyclosporine in vitro; these cells thus may participate in local inflammatory responses in the setting of immunosuppression. Further, treatment with IL-1ß did not elicit gene expression of markers of epithelial to mesenchymal transition. These data present a model of differentiated airway epithelial cells that may be useful in understanding epithelial participation in airway inflammation and allograft rejection in lung transplantation.

Current trends in immunosuppression for lung transplantation.

Lung transplant has become an established therapy in the treatment of end-stage lung disease. Many of the advances in the modern immunosuppression regimen have provided more quality and quantity of life to transplant patients. Immunosuppression agents target various aspects of the immune system to maximize graft tolerance while minimizing medication toxicities and side effects. Lung transplant regimens follow typical protocols but are always tailored to the individual patient based upon previous and current medical problems. Despite the various advances, acute and chronic rejections still occur in the majority of all lung transplants. For these reasons, long-term lung transplantation success remains a challenge. Further improvement in immunosuppression will be geared toward minimizing rejection and infection as well as being tailored to the individual patient. This review details the current armamentarium of immunosuppression medications and the current body of evidence supporting the current trends of usage.

Early readmission is a predictor of overall survival following isolated lung transplantation.

Causes of early readmissions following lung transplantation are not well understood, and the impact is poorly reported. We reviewed 221 consecutive lung transplantations and identified patients readmitted within 90 days. A case control analysis was performed to determine the characteristics that predict readmission and the impact of readmission on survival. Ninety (44%) of the 205 operative survivors required a total of 125 readmissions during the 90 days after transplantation. Twenty-eight patients (13.7%) required multiple readmissions. Causes for readmissions were pulmonary complication (59%), gastrointestinal (18%), cardiac (5%), metabolic (2.5%), neurological (2.5%), hematological (2%), and miscellaneous (11%). The sex, native disease, or type of transplant did not predict readmission. Requirement of cardiopulmonary bypass for transplantation showed a trend toward significance (P = 0.08). The 90-day conditional survival at 1, 3, and 5 years for those patients readmitted within 90 days were 76%, 59%, and 52%, respectively, compared to 93%, 80%, and 76% for patients not readmitted (P = 0.01). Requirement for readmission within 90 days following transplantation is associated with increased mortality. Sex, native disease, and type of transplant are not predictors of readmission or survival.