Elizabeth N. Pavlisko

Pathogenic triad in COPD: oxidative stress, protease–antiprotease imbalance, and inflammation

Patients with chronic obstructive pulmonary disease (COPD) exhibit dominant features of chronic bronchitis, emphysema, and/or asthma, with a common phenotype of airflow obstruction. COPD pulmonary physiology reflects the sum of pathological changes in COPD, which can occur in large central airways, small peripheral airways, and the lung parenchyma. Quantitative or high-resolution computed tomography is used as a surrogate measure for assessment of disease progression. Different biological or molecular markers have been reported that reflect the mechanistic or pathogenic triad of inflammation, proteases, and oxidants and correspond to the different aspects of COPD histopathology. Similar to the pathogenic triad markers, genetic variations or polymorphisms have also been linked to COPD-associated inflammation, protease–antiprotease imbalance, and oxidative stress. Furthermore, in recent years, there have been reports identifying aging-associated mechanistic markers as downstream consequences of the pathogenic triad in the lungs from COPD patients. For this review, the authors have limited their discussion to a review of mechanistic markers and genetic variations and their association with COPD histopathology and disease status.

Impact of Forced Vital Capacity Loss on Survival after the Onset of Chronic Lung Allograft Dysfunction

RATIONALE Emerging evidence suggests a restrictive phenotype of chronic lung allograft dysfunction (CLAD) exists; however, the optimal approach to its diagnosis and clinical significance is uncertain. OBJECTIVES To evaluate the hypothesis that spirometric indices more suggestive of a restrictive ventilatory defect, such as loss of FVC, identify patients with distinct clinical, radiographic, and pathologic features, including worse survival. METHODS Retrospective, single-center analysis of 566 consecutive first bilateral lung recipients transplanted over a 12-year period. A total of 216 patients developed CLAD during follow-up. CLAD was categorized at its onset into discrete physiologic groups based on spirometric criteria. Imaging and histologic studies were reviewed when available. Survival after CLAD diagnosis was assessed using Kaplan-Meier and Cox proportional hazards models. MEASUREMENTS AND MAIN RESULTS Among patients with CLAD, 30% demonstrated an FVC decrement at its onset. These patients were more likely to be female, have radiographic alveolar or interstitial changes, and histologic findings of interstitial fibrosis. Patients with FVC decline at CLAD onset had significantly worse survival after CLAD when compared with those with preserved FVC (P < 0.0001; 3-yr survival estimates 9% vs. 48%, respectively). The deleterious impact of CLAD accompanied by FVC loss on post-CLAD survival persisted in a multivariable model including baseline demographic and clinical factors (P < 0.0001; adjusted hazard ratio, 2.73; 95% confidence interval, 1.86-4.04). CONCLUSIONS At CLAD onset, a subset of patients demonstrating physiology more suggestive of restriction experience worse clinical outcomes. Further study of the biologic mechanisms underlying CLAD phenotypes is critical to improving long-term survival after lung transplantation.

Hyaluronan Contributes to Bronchiolitis Obliterans Syndrome and Stimulates Lung Allograft Rejection through Activation of Innate Immunity

RATIONALE Although innate immunity is increasingly recognized to contribute to lung allograft rejection, the significance of endogenous innate ligands, such as hyaluronan (HA) fragments, in clinical or experimental lung transplantation is uncertain. OBJECTIVES To determine if HA is associated with clinical bronchiolitis obliterans syndrome (BOS) in lung transplant recipients, and evaluate the effect of low- or high-molecular-weight HA on experimental lung allograft rejection, including dependence on innate signaling pathways or effector cells. METHODS HA concentrations were measured in bronchoalveolar lavage and plasma samples from lung recipients with or without established BOS. BOS and normal lung tissues were assessed for HA localization and expression of HA synthases. Murine orthotopic lung recipients with established tolerance were treated with low- or high-molecular-weight HA under varied experimental conditions, including Toll-like receptor (TLR) 2/4 and myeloid differentiation protein 88 deficiency and neutrophil depletion. MEASUREMENTS AND MAIN RESULTS HA localized within areas of intraluminal small airways fibrosis in BOS lung tissue. Moreover, transcripts for HA synthase enzymes were significantly elevated in BOS versus normal lung tissues and both lavage fluid and plasma HA concentrations were increased in recipients with BOS. Treatment with low-molecular-weight HA abrogated tolerance in murine orthotopic lung recipients in a TLR2/4- and myeloid differentiation protein 88-dependent fashion and drove expansion of alloantigen-specific T lymphocytes. Additionally, TLR-dependent signals stimulated neutrophilia that promoted rejection. In contrast, high-molecular-weight HA attenuated basal allograft inflammation. CONCLUSIONS These data suggest that accumulation of HA could contribute to BOS by directly activating innate immune signaling pathways that promote allograft rejection and neutrophilia.

Impact of CLAD Phenotype on Survival After Lung Retransplantation: A Multicenter Study

Chronic lung allograft dysfunction (CLAD) remains a major problem after lung transplantation with no definitive treatment except redo lung transplantation (re‐LTx) in selected candidates. However, CLAD is not a homogeneous entity and different phenotypes exist. Therefore, we aimed to evaluate the effect of CLAD phenotypes on survival after re‐LTx for CLAD. Patients who underwent re‐LTx for respiratory failure secondary to CLAD in four LTx centers between 2003 and 2013 were included in this retrospective analysis. Bronchiolitis obliterans syndrome (BOS) and restrictive CLAD (rCLAD) were distinguished using pulmonary function, radiology and explant lung histopathology. Patient variables pre‐ and post‐re‐LTx were collected and analyzed. A total of 143 patients underwent re‐LTx for CLAD resulting in 94 BOS (66%) and 49 rCLAD (34%) patients. Unadjusted and adjusted survival after re‐LTx for rCLAD was worse compared to BOS (HR = 2.60, 1.59–4.24; p < 0.0001 and HR = 2.61, 1.51–4.51; p = 0.0006, respectively). Patients waiting at home prior to re‐LTx experienced better survival compared to hospitalized patients (HR 0.40; 0.23–0.72; p = 0.0022). Patients with rCLAD redeveloped CLAD earlier and were more likely to redevelop rCLAD. Survival after re‐LTx for rCLAD is worse compared to BOS. Consequently, re‐LTx for rCLAD should be critically discussed, particularly when additional peri‐operative risk factors are present.

Acute allograft rejection: cellular and humoral processes.

Acute cellular rejection affects greater than one-third of lung transplant recipients. Alloreactive T-lymphocytes constitute the basis of lung allograft rejection. Recent evidence supports a more complex immune response to the allograft. Interaction between recipient genetics, immunosuppression therapies, and allograft environmental exposures likely contribute to high rejection rates after lung transplantation. A greater understanding of the heterogeneous mechanisms of lung rejection is critical to developing effective therapies that target the precise pathophysiology of the disease and ultimately improve long-term lung transplant outcomes.

Acute Cellular and Antibody-Mediated Allograft Rejection

Survival post-lung transplantation remains limited to ∼ 50% at 5 years, far below survival after other solid organ transplants. Allograft rejection is a major cause of this limited survival. At least a third of lung transplant recipients experience acute rejection within 1 year posttransplantation. Acute rejection, though rarely a direct cause of death, represents the principal risk factor for chronic rejection, which is the greatest obstacle to long-term post-lung transplant survival. This article reviews in detail the two major subtypes of acute rejection: acute cellular rejection (ACR) and antibody-mediated rejection (AMR). ACR is diagnosed primarily by bronchoscopic transbronchial biopsies and is defined as perivascular or peribronchiolar lymphocytic infiltrates in the absence of infection. AMR remains poorly defined but is thought to involve anti-donor antibodies, allograft dysfunction, and pathological evidence of lung tissue injury or deposition of complement. Pathophysiological mechanisms, clinical presentation, clinical significance, known risk factors, and treatment strategies are discussed. Additionally, the limitations of current diagnostic modalities for both ACR and AMR are explained. Emerging data on the importance of donor-specific and non-donor-specific anti-human leukocyte antigen (anti-HLA) antibodies as well as non-HLA antibodies are presented. Larger cohorts have improved statistical analyses in recent years, leading to a clearer understanding of important topics related to ACR and AMR. Further collaborative studies and multicenter trials will be key in further advancing lung transplantation knowledge and improving outcomes in years to come.

Epithelial Clara Cell Injury Occurs in Bronchiolitis Obliterans Syndrome After Human Lung Transplantation

Bronchiolitis obliterans syndrome (BOS) is a condition of progressive airflow obstruction that affects a majority of lung transplant recipients and limits long‐term posttransplant survival. Although epithelial injury appears central to the development of BOS, little is known regarding the specific epithelial cell types that are affected in this condition. We hypothesized that BOS would involve preferential injury to the secretory Clara cells that function in innate defense and epithelial repair. To test this hypothesis, we assessed tissue transcript, tissue protein and lung fluid protein expression of Clara cell secretory protein (CCSP), a marker for Clara cells, in lung transplant recipients with BOS, BOS‐free patients and in donor controls. Our results demonstrate that CCSP tissue transcript and protein expression are significantly reduced in lung transplant recipients with BOS compared to BOS‐free or donor controls. In addition, we demonstrate that CCSP protein levels are significantly reduced in the lung fluid of patients with BOS compared to BOS‐free controls, in cross‐sectional and longitudinal analysis. Collectively, these complementary results illustrate that BOS involves a selective alteration in the distribution and function of bronchiolar Clara cells.

Pseudoaneurysm Formation After Medtronic Freestyle Porcine Aortic Bioprosthesis Implantation: A Word of Caution

BACKGROUND A growing literature describes aneurysmal deterioration after implantation of the stentless porcine aortic Medtronic Freestyle bioprosthesis (MFB; Medtronic Inc, Minneapolis, MN), with some suggesting inadequate tissue fixation with immune response as a cause. However, disjointed reports make the significance of these findings difficult to interpret. We address this concern by aggregating available data. METHODS We reviewed institutional data, the Food and Drug Administrations Manufacturer and User Facility Device Experience registry, and the medical literature for mention of aneurysm or pseudoaneurysm after MFB. Case details were aggregated, and the rate of aneurysmal deterioration was estimated. Immunohistopathologic examination of institutional explanted specimens was performed to elucidate a cause. RESULTS We found 42 cases of aneurysmal deterioration with adequate detail for analysis; all occurred with full root replacement and valve sizes ranging from 23 to 29 mm. The rate of aneurysmal deterioration considering all data sources was 1.1% (9 of 851; 95% confidence interval, 0.5% to 2.0%) vs 4.7% (4 of 86; 95% confidence interval, 1.3% to 11.5%) at our institution, where yearly surveillance imaging is performed. Rate of aneurysmal deterioration appeared constant until 5 years after the operation; however, events are reported out to 10 years. Consistent with previous reports, histopathology demonstrated an immune cell infiltrate in areas of MFB wall breakdown. CONCLUSIONS Aneurysmal deterioration is an increasingly described complication of MFB implantation as a full root, with an incidence as high as 4.7%. Given the observed immune reaction and lack of occurrence in smaller (19-mm and 21-mm) valve sizes, inadequate pressure fixation of larger valves is a potential etiology. Patients with MFB require annual surveillance imaging, and consideration of this complication should factor into preoperative decision making because treatment mandates redo root replacement, which may not be feasible in high-risk patients.

Validation and Refinement of Chronic Lung Allograft Dysfunction Phenotypes in Bilateral and Single Lung Recipients.

RATIONALE The clinical course of chronic lung allograft dysfunction (CLAD) is heterogeneous. Forced vital capacity (FVC) loss at onset, which may suggest a restrictive phenotype, was associated with worse survival for bilateral lung transplant recipients in one previously published single-center study. OBJECTIVES We sought to replicate the significance of FVC loss in an independent, retrospectively identified cohort of bilateral lung transplant recipients and to investigate extended application of this approach to single lung recipients. METHODS FVC loss and other potential predictors of survival after the onset of CLAD were assessed using Kaplan-Meier and Cox proportional hazards models. MEASUREMENTS AND MAIN RESULTS FVC loss at the onset of CLAD was associated with higher mortality in an independent cohort of bilateral lung transplant recipients (hazard ratio [HR], 2.75; 95% confidence interval [CI], 2.02-3.73; P < 0.0001) and in a multicenter cohort of single lung recipients (HR, 1.80; 95% CI, 1.09-2.98; P = 0.02). Including all subjects, the deleterious impact of FVC loss on survival persisted after adjustment for other relevant clinical variables (HR, 2.36; 95% CI, 1.77-3.15; P < 0.0001). In patients who develop CLAD without FVC loss, chest computed tomography features suggestive of pleural or parenchymal fibrosis also predicted worse survival in both bilateral (HR, 2.01; 95% CI, 1.16-5.20; P = 0.02) and single recipients (HR, 2.47; 95% CI, 1.24-10.57; P = 0.02). CONCLUSIONS We independently validated the prognostic significance of FVC loss for bilateral lung recipients and demonstrated that this approach to CLAD classification also confers prognostic information for single lung transplant recipients. Improved understanding of these discrete phenotypes is critical to the development of effective therapies.

Banff study of pathologic changes in lung allograft biopsy specimens with donor-specific antibodies

BACKGROUND The diagnosis of antibody-mediated rejection (AMR) in the lung transplant is still an area under investigation. We performed a blinded multicenter study to determine if any statistically significant histologic findings in transbronchial biopsy specimens from lung transplant patients correlate with the presence of donor-specific antibodies (DSAs). METHODS We asked 9 pathologists with experience in lung transplantation to evaluate 161 lung transplant biopsy specimens for various histologic parameters. The findings were correlated with antibody status positive for DSAs, positive for non-DSAs, and no antibodies (NABs) present. The significance of each histologic variable was reviewed. RESULTS We found no statistically significant association with acute cellular rejection, airway inflammation, or bronchiolitis obliterans and the presence or absence of antibodies. However, biopsy specimens with DSAs had a statistically significant difference vs NABs in the setting of acute lung injury, with or without diffuse alveolar damage (p = 0.0008), in the presence of capillary neutrophilic inflammation (p = 0.0014), and in samples with endotheliitis (p = 0.0155). In samples with complement 4d staining, there was a trend but no statistically significant difference between specimens associated with DSAs and specimens with NABs. CONCLUSIONS Capillary inflammation, acute lung injury, and endotheliitis significantly correlated with DSAs. The infrequently observed diffuse staining for complement 4d limits the usefulness of this stain.