E. Britt

Centrilobular emphysema combined with pulmonary fibrosis results in improved survival

BackgroundWe hypothesized that, in patients with pulmonary fibrosis combined with emphysema, clinical characteristics and outcomes may differ from patients with pulmonary fibrosis without emphysema. We identified 102 patients who met established criteria for pulmonary fibrosis. The amount of emphysema (numerical score) and type of emphysema (centrilobular, paraseptal, or mixed) were characterized in each patient. Clinical characteristics, pulmonary function tests and patient survival were analysed.ResultsBased on the numerical emphysema score, patients were classified into those having no emphysema (n = 48), trivial emphysema (n = 26) or advanced emphysema (n = 28). Patients with advanced emphysema had a significantly higher amount of smoking in pack/years than patients with no emphysema or trivial emphysema (P < 0.0001). Median survival [1st, 3rd quartiles] of patients with advanced emphysema was 63 [36, 82] months compared to 29 [18, 49] months in patients without emphysema and 32 [19, 48] months in patients with trivial emphysema (P < 0.001). Median forced vital capacity (FVC) and total lung capacity (TLC) were higher in the advanced emphysema group compared to patients with no emphysema (P < 0.01 and P < 0.001, respectively), whereas median DLCO did not differ among groups and was overall low. Within the advanced emphysema group (n = 28), further characterization of the type of emphysema was performed and, within these subgroups of patients, survival was 75 [58, 85] months for patients with centrilobular emphysema, 75 [48, 85] months for patients with mixed centrilobular/paraseptal emphysema, and 24 [22, 35] months for patients with paraseptal emphysema (P < 0.01). Patients with advanced paraseptal emphysema had similar survival times to patients without emphysema.ConclusionsPatients with pulmonary fibrosis combined with advanced centrilobular or mixed emphysema have an improved survival compared with patients with pulmonary fibrosis without emphysema, with trivial emphysema or with advanced paraseptal emphysema.

Inhaled Cyclosporine and Pulmonary Function in Lung Transplant Recipients

BACKGROUND Chronic rejection, manifesting as bronchiolitis obliterans, is the leading cause of death in lung transplant recipients. In our previously reported double-blinded, placebo-controlled trial comparing inhaled cyclosporine (ACsA) to aerosol placebo, the rate of bronchiolitis-free survival improved. However, an independent analysis of pulmonary function, a secondary endpoint of the trial, was not performed. We sought to determine the effect of ACsA, in addition to systemic immunosuppression, on pulmonary function. METHODS From 1998-2001, 58 patients were randomly assigned to inhale either 300 mg of ACsA (28 patients) or placebo aerosol (30 patients) 3 days a week for the first 2 years after transplantation. Longitudinal changes in pulmonary function of ACsA patients were compared to aerosol placebo patients. In another analysis, the rate of decline from 6-month maximum FEV(1) in randomized patients was compared to the rate of decline in patients receiving conventional immunosuppression from the Novartis transplant database (644 patients, 12 centers worldwide, transplanted from 1990-1995). RESULTS The average duration of ACsA and aerosol placebo was 400 days +/- 306 and 433 +/- 256, respectively. The change in FEV(1) of ACsA patients (adjusted for Cytomegalovirus (CMV) mismatch and transplant type, followed for a maximum duration of 4.6 years) was superior to the aerosol placebo controls (9.0 +/- 71.4 mL/year vs. -107.9 +/- 55.3, p = 0.007). The FEF(25-75) decreased by -220.3 +/- 117.7 L/(second x year) vs. -412.2 +/- 139.2, p = 0.07, respectively. Similarly, percent FEV(1) decline from maximal values was improved in ACsA patients compared to aerosol placebo and Novartis controls (ACsA -0.43 +/- 1.12%/year vs. aerosol placebo -4.08 +/- 1.4, p = 0.04; ACsA vs. Novartis -4.7 +/- 0.31, p = 0.007). Single-lung recipients receiving ACsA showed improvement in FEV(1) compared to Novartis controls (FEV(1) -0.8 +/- 1.8%/year vs. -4.94 +/- 0.4, p = 0.03) but double-lung recipients showed improvement compared to aerosol placebo controls only (FEV(1) -0.28 +/- 1.22%/year vs. -8.53 +/- 5.95, p = 0.048). CONCLUSIONS In this single center trial, ACsA appears to ameliorate important pulmonary function parameters in lung transplant recipients compared to aerosol placebo and historical control patients. Single- and double-lung transplant recipients may not respond uniformly to treatment, and ongoing randomized trials in lung transplant recipients using ACsA may help elucidate our findings.

Early outcomes using alemtuzumab induction in lung transplantation.

Immunosuppressive regimens for lung transplantation frequently fail to prevent rejection and are toxic. Alemtuzumab was used as induction to investigate whether oral immunosuppression could be reduced. From November 2006 to March 2008, 20 consecutive lung transplant patients received alemtuzumab induction, with reduced maintenance immunosuppression; tacrolimus (target level 10 ng/ml), mycophenolate mofetil (MMF) 250 mg bid and prednisone 7.5 mg. Twenty control cases transplanted before 2006 were treated with standard immunosuppression; tacrolimus (target level 10 ng/ml), MMF 750 mg bid and prednisone 15 mg qd. End-points included patient and graft survival, acute rejection (AR) and infection rate. There were no significant differences in six-month and 12-month survival (alemtuzumab 90% vs. controls 95%, P=0.52 and 76% vs. 95%, respectively, P=0.19). AR events were similar (alemtuzumab 2/16 vs. controls 5/20, P=0.43) - as were - bacteria positive bronchoalveolar lavage (BAL) cultures (alemtuzumab 4.9+/-7.3 per patient per year vs. controls 2.7+/-3.3, P=0.26) and viral or fungal infections (alemtuzumab 0.4+/-1.4 per patient per year vs. controls 0.1+/-0.3, P=0.87; alemtuzumab 3.9+/-6.6 vs. controls 2.3+/-1.9, P=0.57, respectively). Alemtuzumab induction and reduced immunosuppression appears to offer comparable early survival, rejection and infection rates to high-dose standard immunosuppression.

Variable prevalence of pulmonary hypertension in patients with advanced interstitial pneumonia

BACKGROUND Pulmonary hypertension may occur in patients with interstitial pneumonia and is associated with increased mortality. We sought to determine the prevalence of pulmonary hypertension in sub-groups of patients with interstitial pneumonia and to investigate possible associations between pulmonary vascular hemodynamics and pulmonary function. METHODS The presence or absence of pulmonary hypertension was assessed in 70 patients with advanced interstitial pneumonia who underwent right heart catheterization. The associations of pulmonary hypertension with clinical characteristics and pulmonary function tests were analyzed. RESULTS The prevalence of pulmonary hypertension in patients with idiopathic interstitial pneumonia was 29% vs 64% in patients with connective tissue disease-interstitial pneumonia (p = 0.013). African American patients had a significantly higher prevalence of pulmonary hypertension in the entire study population (81% vs 22%, p < 0.001) and in the idiopathic interstitial pneumonia group (70% vs 19%, p < 0.01). Regression analyses revealed no association between mean pulmonary artery pressure (mPAP) and forced vital capacity or mPAP and diffusion capacity of the lung for carbon monoxide in the entire cohort or in sub-groups of patients. CONCLUSIONS African American patients and patients with connective tissue disease-interstitial pneumonia had a high prevalence of pulmonary hypertension. Non-African American patients with advanced idiopathic interstitial pneumonia (including idiopathic pulmonary fibrosis) had a low prevalence of pulmonary hypertension.

Belatacept for renal rescue in lung transplant patients.

Renal failure causes morbidity and mortality after lung transplantation and is aggravated by exposure to nephrotoxic immunosuppressant (IS) drugs. We report an off‐label experience using belatacept for lung transplant recipients with severe renal insufficiency to reduce nephrotoxic IS exposure. We analyzed data retrospectively from a consecutive series of lung transplant patients with renal insufficiency in whom belatacept treatment was initiated between June 2012 and June 2014 at the University of Maryland Medical Center. Eight patients received belatacept because of acute or chronic renal insufficiency (median) GFR 24 (IQR 18–26). Glomerular filtration rate (GFR) remained stable in two patients and increased in five. One patient with established renal and respiratory failure received only the induction dose of belatacept and died 4 months later of respiratory and multisystem organ failure. Calcineurin inhibitor or sirolimus exposure was safely withheld or reduced without moderate or severe acute rejection during ongoing belatacept in the other seven patients. FEV1 remained stable over the 6‐month study interval. Belatacept use appears to permit safe transient reduction in conventional immunosuppressive therapy and was associated with stable or improved renal function in a small retrospective series of lung transplant recipients with acute or chronic renal insufficiency.

Pulmonary mycobacterial spindle cell pseudotumor in a lung transplant patient: progression without therapy and response to therapy.

Mycobacterial spindle cell pseudotumor (MSP) represents a rare, non‐malignant, mass‐forming reaction to various mycobacterial infections, typically occurring in immunocompromised patients. It is characterized by the proliferation of spindle‐shaped fibrohistiocytic cells without the formation of epithelioid granulomas. Without staining for acid‐fast bacilli, histological distinction from other spindle cell lesions, including malignancy, can be difficult. Most of the MSP cases reported in the literature have involved lymph nodes, skin, spleen, or bone marrow, but rarely involve the lung. MSP predominately occurs in patients who are immunosuppressed. We present a patient with MSP of the transplanted lung caused by non‐tuberculous mycobacteria, in whom both the natural course of the untreated pseudotumor as well as the response to antimycobacterial treatments were observed.

Transcriptomic evidence of immune activation in macroscopically normal-appearing and scarred lung tissues in idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease manifested by overtly scarred peripheral and basilar regions and more normal-appearing central lung areas. Lung tissues from macroscopically normal-appearing (IPFn) and scarred (IPFs) areas of explanted IPF lungs were analyzed by RNASeq and compared with healthy control (HC) lung tissues. There were profound transcriptomic changes in IPFn compared with HC tissues, which included elevated expression of numerous immune-, inflammation-, and extracellular matrix-related mRNAs, and these changes were similar to those observed with IPFs compared to HC. Comparing IPFn directly to IPFs, elevated expression of epithelial mucociliary mRNAs was observed in the IPFs tissues. Thus, despite the known geographic tissue heterogeneity in IPF, the entire lung is actively involved in the disease process, and demonstrates pronounced elevated expression of numerous immune-related genes. Differences between normal-appearing and scarred tissues may thus be driven by deranged epithelial homeostasis or possibly non-transcriptomic factors.