Successful treatment of donor-derived hepatitis C infection in a lung transplant recipient.

Data are limited regarding the use of direct-acting antivirals for treatment of hepatitis C infection post lung transplant, especially in a donor-derived infection. We present a case of a lung transplant recipient with donor-derived hepatitis C that was successfully treated with a 12-week regimen of simeprevir and sofosbuvir. This case reiterates the importance of screening recipients of increased-risk donor organs for disease transmission and the value of early therapy.

Induction Therapy for Lung Transplantation in COPD: Analysis of the UNOS Registry.

Although studies demonstrate that induction therapy improves outcomes after lung transplantation, its influence on survival in patients with chronic obstructive pulmonary disease (COPD) is not clear. The United Network for Organ Sharing database was queried to obtain data regarding adult patients with COPD receiving lung transplant between May 2005 and June 2014. Therapies evaluated include anti-thymocyte globulin, anti-lymphocyte globulin, thymoglobulin, basiliximab, and alemtuzumab. Data were categorized based on receiving induction (INDUCED) and no induction (NONE). Kaplan-Meier plots, Cox proportional hazards models of patient survival, and competing-risks regression models for secondary endpoints were utilized. A total of 3,405 patients who underwent lung transplantation for COPD were enrolled with 1,761 (52%) receiving induction therapy. Of INDUCED, 1,146 (65%) received basiliximab, 380 (22%) received alemtuzumab, and 235 (13%) received a polyclonal preparation. The hazard ratio for INDUCED vs. NONE was 0.793 (95% CI = 0.693, 0.909; p = 0.001) in the fully adjusted Cox model. A multivariable competing-risks model also found a protective influence of induction therapy with respect to delayed onset of bronchiolitis obliterans syndrome after transplantation (SHR = 0.801; 95% CI = 0.694, 0.925; p = 0.003). In a cohort of recently transplanted patients with COPD, there appears to be a benefit from contemporary induction agents with no concurrent increase in the risk of death due to infection.

Cigarette smoking following lung transplantation: effects on allograft function and recipient functional performance.

PURPOSE: Despite mandatory tobacco abstinence following lung transplantation (LTX), some recipients resume smoking cigarettes. The effect of smoking on allograft function, exercise performance, and symptomatology is unknown. METHODS: A retrospective review was conducted of LTX recipients who received allografts over an 8-year interval and who were subjected to sequential posttransplant pulmonary function testing (PFT), 6-minute walk (6MW) testing, and assessments of exertional dyspnea (Borg score). Using post-LTX PFT results, recipients were determined to have either bronchiolitis obliterans syndrome (BOS), a manifestation of chronic allograft rejection, or normal pulmonary function (non-BOS). With respect to post-LTX pulmonary function, 6MW distances, and Borg scores, comparisons were made between these recipient groups and those who resumed smoking. RESULTS: Of 34 LTX recipients identified, 13 maintained normal lung function (non-BOS), while 16 demonstrated a decline in their PFT values consistent with BOS. Five recipients began smoking at median postoperative day 365 and smoked 1 pack per day for a mean of 485.6 days. Smokers developed a deterioration of their PFT values that was similar to those with BOS (P = .47) and tended to be worse than those in the non-BOS group (P = .09). All smokers experienced a decline in 6MW distances similar to those with BOS and non-BOS but reported less exertional dyspnea (lower Borg scores) than those with BOS. CONCLUSION: Recipients of LTX who resume cigarette smoking demonstrate a decline in pulmonary function similar to those afflicted with chronic allograft rejection but do not experience a decrement in their functional performance or increased dyspnea.

Changes in pulmonary artery pressure affect survival differently in lung transplant recipients who have pulmonary hypertension or chronic obstructive pulmonary disease.

OBJECTIVES: Pulmonary hypertension and right ventricular dysfunction can complicate lung transplant. Pulmonary artery pressures affect outcome are uncertain during wait list. We evaluated changes in wait list pulmonary artery pressures on survival after lung transplant. MATERIALS AND METHODS: We queried the United Network for Organ Sharing/Standard Transplant Analysis and Research registry from 1987 to 2012 for all lung transplants. Recipients with unique pulmonary artery pressure measurements upon listing and transplant were included. Mean pulmonary artery pressure was rated as increased (increase > 5 mm Hg), decreased (decrease > 5 mm Hg), or unchanged (variation < 5 mm Hg). RESULTS: There were 23 951 lung transplants and 1677 recipients were included. Diagnoses demonstrated significant changes in mean pulmonary artery pressure during the listing period (P ≤ .0001). In recipients with chronic obstructive pulmonary disease, survival was poorer when mean pulmonary artery pressure was increased than decreased (P ≤ .03). In recipients with primary pulmonary hypertension, survival was poorer when mean pulmonary artery pressure was decreased than increased (P ≤ .02). Proportional hazards analysis showed that increases in mean pulmonary artery pressure independently affected survival (hazard ratio, 0.78; 95% confidence interval, 0.62-0.96). CONCLUSIONS: Although the mechanism is unknown, an increase in mean pulmonary artery pressure in patients with chronic obstructive pulmonary disease is associated with poorer survival after lung transplant. In contrast, patients with primary pulmonary hypertension with decreased mean pulmonary artery pressure have poorer survival after lung transplant. In patients with primary pulmonary hypertension, changes in pulmonary artery pressure may be a surrogate for a failing right ventricular function. In chronic obstructive pulmonary disease, the change in pressure suggests an undetermined progressive process. Further study of right ventricular function is warranted to determine the effects of changes in pulmonary artery pressure on lung transplant recipients.

Extracorporeal membrane oxygenation and retransplantation in lung transplantation: an analysis of the UNOS registry.

BACKGROUND: Despite limited organ availability, extracorporeal membrane oxygenation (ECMO) and retransplantation are becoming more commonplace. METHODS: Using the United Network for Organ Sharing (UNOS) database, we evaluated survival of patients treated with ECMO before lung transplantation and undergoing retransplantation. A query identified cadaveric recipients from 2001 to 2012 over the age of 6 years. RESULTS: Of 15,772 lung recipients, 15 583 never received ECMO, whereas 189 did. Mean age was 52.1 ± 14.4 versus 46.8 ± 16.5 years for non-ECMO and ECMO groups, respectively (p < 0.0001). Using Kaplan-Meier method, there were survival differences between ECMO and non-ECMO groups (p < 0.0001) and first-time transplants with and without ECMO to retransplants with and without ECMO (p < 0.0001). The proportional hazards model identified higher risk with ECMO use in idiopathic pulmonary fibrosis (hazard ratio [HR] 1.09; 95 % confidence interval (CI), 1.02-1.17; p = 0.014) and retransplants (HR 1.77; 95 % CI, 1.55-2.03; p < 0.0001). CONCLUSIONS: Survival for retransplantation was similar to ECMO as a primary option with significant mortality associated with ECMO use in patients with idiopathic pulmonary fibrosis and retransplants.

To induce or not to induce: a 21st century evaluation of lung transplant immunosuppression's effect on survival.

INTRODUCTION: The impact of induction immunosuppression on long-term survival in lung transplant recipients remains unclear. We sought to evaluate the effect of contemporary induction immunosuppression agents in lung transplant recipients' survival, utilizing national registry data. METHODS: We queried the United Network for Organ Sharing registry from 2001 to 2012 for adult, deceased donor lung transplants who received no antibody-based induction (NONE) or the contemporary agents of basiliximab, alemtuzumab, thymoglobulin, antilymphocyte globulin, or antithymocyte globulin (INDUCED). Kaplan-Meier estimates of the survival and Cox proportional hazards models assessed differences in overall survival between the INDUCED and NONE groups; logistic regression models assessed differences in survival and rejection (TR1Y). RESULTS: There were 23 951 lung transplants performed with 12 858 meeting the inclusion criteria; 5713 (44%) were INDUCED. Of INDUCED agents, 62% were basiliximab and 14% alemtuzumab. Being INDUCED significantly increased overall survival (p < 0.0001). Median INDUCED survival was 71.3 months (confidence interval [CI]: 65.7-75.5) as compared with 63.2 months (CI: 60.1-65.9). Of INDUCED, both basiliximab and alemtuzumab had higher median survival times at 75.1 months (CI: 68.6-81.3) and 75.5 months (CI: 63.5-∞), respectively. There was less TR1Y in INDUCED patients (37%), as compared to NONE (42%; p < 0.0001). CONCLUSION: In a contemporary analysis of lung transplant recipients, induction immunosuppression has a significantly positive effect on survival.

Histological spectrum of pulmonary manifestations in kidney transplant recipients on sirolimus inclusive immunosuppressive regimens.

BACKGROUND: After the introduction of novel effective immunosuppressive therapies, kidney transplantation became the treatment of choice for end stage renal disease. While these new therapies lead to better graft survival, they can also cause a variety of complications. Only small series or case reports describe pulmonary pathology in renal allograft recipients on mTOR inhibitor inclusive therapies. The goal of this study was to provide a systematic review of thoracic biopsies in kidney transplant recipients for possible association between a type of immunosuppressive regimen and pulmonary complications. METHODS: A laboratory database search revealed 28 of 2140 renal allograft recipients (18 males and 10 females, 25 to 77 years old, mean age 53 years) who required a biopsy for respiratory symptoms. The histological features were correlated with clinical findings including immunosuppressive medications. RESULTS: The incidence of neoplasia on lung biopsy was 0.4% (9 cases), which included 3 squamous cell carcinomas, 2 adenocarcinomas, 1 diffuse large B-cell lymphoma, 1 lymphomatoid granulomatosis, and 2 post transplant B-cell lymphoproliferative disorders. Diffuse parenchymal lung disease was identified in 0.4% (9 cases), and included 5 cases of pulmonary hemorrhage, 3 cases of organizing pneumonia and 1 case of pulmonary alveolar proteinosis. Five (0.2%) cases showed histological features indicative of a localized infectious process. Patients on sirolimus had neoplasia less frequently than patients on other immunosuppressive combinations (12.5% vs. 58.3%, p = 0.03). Lung biopsies in 4 of 5 patients with clinically suspected sirolimus toxicity revealed pulmonary hemorrhage as the sole histological finding or in combination with other patterns. CONCLUSIONS: Our study documents a spectrum of neoplastic and non-neoplastic lesions in renal allograft recipients on current immunosuppressive therapies. Sirolimus inclusive regimens are associated with increased risk of pulmonary toxicity but may be beneficial in cases of posttransplant neoplasia. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/3320012126569395.

The role of heat shock protein 27 in bronchiolitis obliterans syndrome after lung transplantation.

BACKGROUND: Heat shock proteins (Hsps) are a family of evolutionary conserved proteins classified according to their size as small and large Hsps. They have a cytoprotective role and have been shown to be immunogenic molecules. In addition, self-reactivity to Hsps has been implicated in various autoimmune diseases and in the development of alloimmunity. This study examined the relationship of large and small Hsps and anti-Hsp antibodies in lung transplant (LTx) recipients who have bronchiolitis obliterans syndrome (BOS). METHODS: Anti-Hsp27 and Hsp70 antibodies, and Hsp27, Hsp60, and Hsp70 protein expression levels were evaluated in serum and bronchoalveolar lavage samples collected from 8 LTx recipients with established BOS and 8 recipients without BOS (controls). Serum from 8 healthy individuals was examined for Hsp levels as a comparison. RESULTS: Elevated serum Hsp27 levels were observed in recipients with BOS compared with controls or healthy individuals, whereas Hsp70 and Hsp60 expression showed no difference. Anti-Hsp27 antibody levels were significantly higher in the BAL of recipients with BOS than in those without BOS. In contrast, anti-Hsp70 antibodies levels in serum or BAL showed no difference between groups. CONCLUSIONS: These results support the novel concept that Hsp27, but not the classic Hsp60 and Hsp70, may be associated with the development BOS. The expression of anti-Hsp27 antibodies found only in the BAL fluid suggests a local response occurring at the level of the alveoli and terminal airways.

The lung allocation score and survival in lung transplant candidates with chronic obstructive pulmonary disease.

The Lung Allocation Score (LAS), devised to prioritize candidates awaiting lung transplantation (LTX), is calculated using the predicted duration of survival on the wait list while also considering the recipient's likelihood of post-transplant survival. This score is generated based, in part, on the severity of the candidate's comorbid illnesses. The actual relationship between the LAS and survival is unknown. The current study was performed to evaluate the relationship between the LAS and both wait-list survival and post-transplant survival in candidates with COPD. The study was a retrospective analysis of 41 LTX candidates with chronic obstructive pulmonary disease (COPD) as well as a cohort of 17 candidates who survived to receive a graft. The study was conducted at a university hospital transplant center. Thirty-six of 41 candidates survived to transplant. The LAS of these survivors was 32.62 +/- 1.06 and was significantly lower than the score of 34.45 +/- 1.19 of the nonsurvivors (P < 0.01). The LAS also exhibited a negative association with survival to transplant (P < 0.05, beta = -1.39). A cohort of 17 LTX recipients was chosen for post-transplant analysis in which 13 survived at least 1 year. In this cohort the LAS did not exhibit significant association with 1-year post-transplant survival (P = 0.58, beta = -0.25). As might be anticipated by virtue of its calculation being based in part on the existence and severity of comorbid conditions, a lower LAS was associated with improved survival to transplantation in LTX candidates with COPD. However, the pretransplant calculation of the LAS was not associated with actual post-transplant survival.

Successful management of immunosuppression in a patient with severe hyperammonemia after lung transplantation.

Hyperammonemia after lung transplantation is a rare complication of unknown etiology. Its management is largely supportive and outcomes have been variable. More disconcerting is its immunosuppressive management because the precipitating factors leading to this potentially lethal entity are unknown, but are suspected to be drug-related. We describe the successful management of a lung transplant recipient with severe hyperammonemia.

Multidrug-resistant Acinetobacter baumannii pneumonia in lung transplant recipients.

We present 6 cases of multidrug-resistant (MDR) Acinetobacter baumannii pneumonia in lung transplant recipients. All cases were treated with imipenem and/or non-traditional antibiotics, such as tigecycline and colistimethate, and had different microbiologic and clinical outcomes. Prior treatment with broad-spectrum anti-microbial therapy was the single most likely risk factor for the development of infection due to MDR Acinetobacter baumannii. Ideal preventive and therapeutic strategies for this pathogen in lung transplant recipients require further study.

Biomedical nanotechnology for cancer.

Nanotechnology may hold the key to controlling many devastating diseases. In the fight against the pain, suffering, and death due to cancer, nanotechnology will allow earlier diagnosis and even prevention of malignancy at premalignant stages, in addition to providing multimodality treatment not possible with current conventional techniques. This review discusses nanotechnology already used in diagnostic and therapeutic applications for cancer. Also addressed are theoretic and evolving uses of nanotechnology, including multifunctional nanoparticles for imaging and therapy, nanochannel implants for controlled release of drugs, nanoscale devices for evaluation of proteomics and genomics, and diagnostic techniques that take advantage of physical changes in diseased tissue.

C3d and the septal microvasculature as a predictor of chronic lung allograft dysfunction.

Studies have shown a potential role for humoral rejection in the evolution of lung graft dysfunction, apparently based on antibodies without human leukocyte antigen specificity. The correlation between extent of C4d deposition with clinical status further illustrates the importance of humoral immunity. Our study examines the potential value of C3d as a further diagnostic adjunct. C3d deposition was examined in lung allograft specimens using frozen tissue indirect direct immunofluorescence (IIF) and avidin biotin immunohistochemical applied to paraffin embedded tissue. Intermediate/extensive amounts of C3d using IIF and immunohistochemical (IH) methodologies correlated with chronic graft dysfunction; IIF C3d deposition was associated with septal and bronchial wall fibrosis (p < 0.0001). Weak/absent amounts of IIF and IH C3d correlated with clinical stability (p < 0.0001). Higher levels of C3d by IH were more sensitive than by IIF as a bronchiolitis obliterans syndrome determinant. C3d and C4d deposition using immunofluorescence and IH were correlated (p < 0.00001). C3d deposition appears prognostically significant. Higher tissue expression of C3d mark chronic graft dysfunction/persistent graft failure following transplantation. The close correlation between C3d and C4d lends credence to the role of humoral allograft rejection as a pulmonary graft dysfunction contributing factor. C3d by IH manifests higher sensitivity but similar specificity compared to C3d by IIF.

Ultrastructure as a diagnostic adjunct in the evaluation of lung allograft biopsies.

Humoral immunity contributes significantly to lung graft dysfunction. Recognizing a role of ultrastructural studies in the evaluation and diagnosis of chronic humoral allograft rejection in the kidney, the authors sought to explore its utility as a diagnostic adjunct in lung allograft biopsies. Ultrastructural studies were conducted on 44 biopsies from 26 lung transplant recipients. Endothelial cell activation and necrosis were seen in the setting of acute humoral allograft rejection. Septal chronic vasculopathic changes of thickening and lamellation of the basement membrane zone (BMZ) and BMZ collagen deposition were correlated with greater numbers of humoral allograft rejection episodes and with the development of chronic graft dysfunction/bronchiolitis obliterans syndrome. There was a positive correlation between the extent of septal fibrosis and certain chronic vasculopathic changes, namely collagen deposition in the BMZ and BMZ wrinkling. Patients with chronic graft dysfunction and multiple rejection episodes manifested low diffusion capacities (less than 50% predicted). The results indicate that ultrastructural analysis is useful in identification of septal fibrosis and chronic vasculopathy of the septal microvasculature, correlating with chronic graft dysfunction, encompassing not only fibrotic sequelae of the bronchial wall but also irreversible terminal lung parenchymal changes, the latter associated with repeated episodes of humoral rejection.

Alpha-1 anti-trypsin deficiency and Henoch-Schönlein purpura associated with anti-neutrophil cytoplasmic and anti-endothelial cell antibodies of immunoglobulin-A isotype.

Alpha-1 anti-trypsin (A1AT) deficiency is an inherited enzyme deficiency that manifests with fatal lung and liver complications. In addition to pulmonary and hepatic involvement, the disease has also been linked to an increased incidence of vasculitic syndromes and autoimmune diseases, including Wegener's granulomatosis, microscopic polyarteritis nodosa and Henoch-Schonlein purpura (HSP). HSP, a systemic, small-vessel vasculitis syndrome, is characterized by a non-thrombocytopaenic purpuric rash, arthralgia, abdominal pain and nephritis. Both A1AT deficiency and HSP have been associated with anti-neutrophil cytoplasmic antibodies (ANCA) and anti-endothelial cell antibodies (AECA). We report a case of a 40-year-old man with severe A1AT deficiency, who developed HSP associated with AECA, ANCA and anti-phospholipid antibodies of the immunoglobulin-A isotype.

Evidence that humoral allograft rejection in lung transplant patients is not histocompatibility antigen-related.

We have recently recognized humoral rejection (HR) in lung allograft recipients and its association with acute and chronic graft dysfunction. We have shown that C4d, a stable marker of classic complement activation, is deposited in lung allografts, correlating with clinical rejection and parenchymal injury. The antigenic target may be endothelium in the setting of recurrent acute rejection while varying components of the bronchial wall may be important in chronic graft dysfunction. We sought to establish whether there is a role for antibodies with histocompatibility antigen specificity in the lung humoral allograft phenomenon. Flow cytometric and ELISA assays to assess donor-specific antigens were conducted on sera from 25 lung transplant recipients who had experienced one or more episodes of clinical rejection; in addition, the serum samples were tested for evidence of antiendothelial cell antibody activity. Morphologically, each case had biopsies showing septal capillary injury with significant deposits of immunoreactants with microvascular localization and positive indirect immunofluorescent antiendothelial cell antibody assay. Panel-reactive antibody testing showed absence of MHC Class I/II alloantibodies; ELISA based crossmatch detecting donor-specific MHC Class I/II specific antibodies was negative. HR can occur in the absence of antibodies with HLA specificity; antigenic targets may be of endothelial cell origin.

Use of C4d as a diagnostic adjunct in lung allograft biopsies.

PURPOSE: Humoral allograft rejection is a defined mechanism for cardiac and renal graft dysfunction; C4d deposition, a stable component of complement activation, inversely correlates with graft survival. With the recent recognition of humoral rejection in lung grafts, we examined C4d's role as a prognostic adjunct in lung allografts. MATERIAL AND METHODS: Twenty-three lung recipients underwent biopsies for deterioration in clinical status or routine surveillance. Clinically unwell patients possessed acute rejection or bronchiolitis obliterans syndrome (BOS). Biopsies attributable to infection were excluded from the study. In addition to routine light microscopy, an attempt was made to correlate the clinical status and morphologic findings with the pattern of C4d deposition and also to compare these clinical and morphologic parameters with the other assessed immunoreactants. Panel reactive antibody testing was also carried out at various points in their post transplantation course whereby in 6 of the cases the samples were procured at exactly the same time as the tissue samples. RESULTS: The patients were segregated into two groups: those patients with recurrent acute rejection and those with BOS. In those patients with symptomatic acute rejection, all biopsies showed light microscopic and immunofluorescent evidence of humoral allograft rejection. The level of C4d was positively correlated with the degree of parenchymal injury, the hallmark being one of septal capillary necrosis. In addition, high and intermediate levels of C4d correlated with a clinical diagnosis of acute rejection. C4d was the strongest predictor of parenchymal injury and of the clinical status (p <.0001) compared to other the immunoreactants C1q, C5b-9 and immunoglobulin. There was no specific correlation between C4d deposition and the presence of acute cellular rejection. In those patients fulfilling clinical criteria of BOS, deposits of C4d as well as other immunoreactants were found in the bronchial wall as opposed to the rarity of this finding in bon-BOS patients. However the only statistically significant predictor of BOS was bronchial wall deposition of C1q. In no case were panel reactive antibodies at significant levels discovered post transplantation. CONCLUSIONS: In the context of acute rejection, C4d deposition correlates with clinical evidence of rejection and the degree of humoral rejection assessed pathologically; there is no association with the presence of histocompatibility related antibodies. It is a more specific predictor of allograft status compared to other immunoreactants. C4d deposition within the bronchial wall is a feature of BOS and hence may be used as a marker of chronic graft dysfunction. The antigenic target resulting in C4d deposition may not be histocompatibility related.