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Background: The incidence of posttransplant lymphoproliferative disorders (PTLD) has recently declined, but late cases are increasingly reported in lung transplant recipients., Objectives: We present our experience with PTLD after lung transplantation, attempting to examine the distinguishing characteristics of early versus late cases., Methods: We have reviewed clinical and pathological data of all cases occurring in our institution between 2001 and 2014., Results: Patients, aged 15-63 years, were mostly (12/16) Epstein-Barr virus (EBV) seropositive at the time of transplantation. Eleven early cases, occurring 9.4 ± 5.2 months after transplantation and mostly (9/11) prior to 2010, had EBV+ diffuse large B-cell lymphomas. Lungs and/or thoracic lymph nodes were often involved (n = 8). Treatments included reduction of immune suppression (n = 11), rituximab (n = 8) and chemotherapy (n = 7). Two patients are in complete remission at 26 and 216 months. Nine patients died 8.0 ± 6.5 months after PTLD diagnosis. Of the 5 cases with late PTLD occurring 4-23 years (mean ± SD: 10.4 ± 7.7) after transplantation (and 3/5 after 2009), 1 had pulmonary lymphomatoid granulomatosis (only endothoracic case), 1 cutaneous large T-cell lymphoma, 2 had anaplastic large cell lymphomas, and 1 Hodgkin's disease. Two of the 5 cases were EBV-, including one followed by a second EBV+ PTLD after 8 years of complete remission. Two patients were alive and well (follow-up: 44 and 151 months), one having suffered from EBV-related cholestatic hepatitis 6 years after the PTLD., Conclusion: Our small experience shows a trend toward (very) late occurrence, associated with more unusual clinicopathologic features, but not with a worse prognosis., (© 2015 S. Karger AG, Basel.)

The most accurate treatment of obstructive pulmonary arterial hypertension (PAH) is the obstruction relief by surgery. Pulmonary endarterectomy is the treatment of choice of chronic thromboembolic pulmonary disease, the major cause of obstructive PAH. This procedure is associated with a low mortality rate in experienced centres and results in a dramatic improvement of hemodynamic parameters, functional status and survival rate. This surgery must be performed as early as possible in the history of this disease, preferentially before arteriolitis development in the non obstructed territories. The other obstructive PAH such as angiosarcomas, echinococcosis, arteritis, fibrosing mediastinitis can also be surgically treated by endarterectomy, tumorectomy or by pass according to their aetiology. By contrast lung transplantation is a palliative treatment indicated only after failure of medical treatment in an end-stage disease. Lung and heart-lung transplantation for PAH are associated with a 5 and 10 year actuarial survival rate of 50% and 35% respectively related to a higher postoperative mortality rate than for other organ transplantation and frequent development of graft obliterans bronchiolitis.

Introduction: The diagnosis of chronic obstruction of the pulmonary artery is difficult. We present the case of a woman with an invasive, undifferentiated carcinoma of the pulmonary artery., Case Report: A 61 year old woman complained of increasing dyspnoea. This was evaluated by computed tomography which showed a defect in the main pulmonary artery. There was no clinical or radiological improvement following anticoagulant treatment for two months. A repeat CT scan showed a persisting intravascular defect and the diagnoses considered included post-embolic pulmonary arterial hypertension and angiosarcoma. A surgical biopsy was performed and pericardial and aortic tumour nodules were found during the operation. The pathological examination revealed undifferentiated carcinoma. Further investigations failed to reveal the primary site., Conclusion: Invasion of the pulmonary artery by angiosarcoma or other tumour is part of the differential diagnosis of chronic thromboembolic disease. The diagnosis rests on histology obtained by an intravascular or surgical procedure. Complete surgical excision may be possible in angiosarcoma but it was impossible in our patient. The patient died despite two courses of chemotherapy and targeted therapy with erlotinib.

When treated with invasive endotracheal mechanical ventilation (ETMV), acute respiratory insufficiency after lung resection is fatal in up to 80% of cases. Noninvasive positive-pressure ventilation (NPPV) may reduce the need for ETMV, thereby improving survival. We conducted a randomized prospective trial to compare standard therapy with and without nasal-mask NPPV in patients with acute hypoxemic respiratory insufficiency after lung resection. The primary outcome variable was the need for ETMV and the secondary outcome variables were in-hospital and 120-d mortality rates, duration of stay in the intensive care unit, and duration of in-hospital stay. Twelve of the 24 patients (50%) randomly assigned to the no-NPPV group required ETMV, versus only five of the 24 patients (20.8%) in the NPPV group (p = 0.035). Nine patients in the no-NPPV group died (37.5%), and three (12.5 %) patients in the NPPV group died (p = 0.045). The other secondary outcomes were similar in the two groups. NPPV is safe and effective in reducing the need for ETMV and improving survival after lung resection.

Alveolar macrophages (AMs) play a central role in pulmonary inflammation in response to local stimuli. As a model for investigating anti-inflammatory drugs, we studied the effects of the cyclohexadepsipeptide antibiotic, fusafungine, and that of the glucocorticoid dexamethasone on the expression of ICAM-1, TNF-alpha and RANTES, induced in vitro by rIFN-gamma in human AMs freshly isolated from bronchoalveolar lavage fluid (BAL) obtained in lung-transplanted patients. ICAM-1 antigen expression, induced on AMs after 24 h of culture, was significantly inhibited by fusafungine in a concentration-dependent manner, as measured by flow cytometry analysis using an anti-CD54 monoclonal antibody. TNF-alpha production, but not RANTES release (measured by ELISA), was significantly inhibited. mRNA studies, by means of polymerase chain reaction amplification of complementary deoxyribonucleic acids (RT-PCR), showed no significant modification of mRNA levels, suggesting that fusafungine acts mainly at a post-transcriptional level. In the same conditions, dexamethasone significantly inhibited the release both of TNF-alpha and RANTES by AMs, mainly acting at the mRNA level, but had no effect on ICAM-1 expression. Assessment of the cellular and molecular targets of anti-inflammatory drugs in this model of human AM activation should lead to more appropriate treatment of inflammatory process of the respiratory tract. By virtue of its anti-inflammatory effects on alveolar macrophages, combined with its antibacterial properties, fusafungine should prove particularly suitable for local treatment of bacterial infections of the respiratory tract.

Aspergillus osteomyelitis is a severe complication of invasive aspergillosis. Fewer than 15 cases have been observed after solid organ transplantation. We describe a case of Aspergillus osteomyelitis of the ilium after heart-lung transplantation with favorable outcome after medical treatment.

Local activation of macrophages may play an important role in the immune process of pulmonary infections and in the inflammatory response of lung allograft rejection. To document macrophage activation within human lung allografts displaying various complications, we have investigated ICAM-1 expression in freshly isolated alveolar macrophages (AM) from lung-transplant recipients by immunocytofluorimetric analysis, and rIFN gamma induced in vitro by ELISA. A total of 21 bronchoalveolar lavage fluids (BAL) from 13 transplanted patients displaying no complication, acute rejection, bacterial/fungal infection, or CMV infection entered the study. ICAM-1 was expressed at a higher level in rejecting patients. Surprisingly, TNF alpha release from AM upon in vitro activation was significantly decreased during rejection. Furthermore, we have studied the effects of the glucocorticoid dexamethasone, the key drug for the treatment of allograft rejection, on the expression of ICAM-1 and TNF alpha induced in vitro in AM, at the levels of protein production and of transcription. Whereas dexamethasone did not influence ICAM-1 expression in AM, it downregulated TNF alpha production at least in part at the transcriptional level. Our results suggest strongly that the anti-inflammatory effects of corticosteroids are not related to ICAM-1 modulation on human AM but to the downregulation of the proinflammatory cytokine TNF alpha that is produced early in the inflammatory process. Moreover, our model of human AM activation induced in vitro by rIFN gamma appears a useful tool for in vitro investigation of the cellular and molecular targets of anti-inflammatory drugs for a more appropriate use.

Pentoxifylline (PTX) attenuates neutrophil-mediated lung injury in several models of acute lung inflammation. Because pulmonary neutrophil sequestration is the main determinant of ischemia-reperfusion (IR) injury in lung transplantation, we sought to determine whether or not PTX prevented IR injury in isolated perfused rat and rabbit lungs submitted to IR, and in pigs after left lung allotransplantation. In rat lungs after IR, the coefficient of lung endothelial permeability (Kfc) increased by 112 +/- 12% in controls and by 27 +/- 8% (p < 0.001) in PTX-treated lungs. After IR, lung myeloperoxidase and blood neutrophil count decrease were lower with PTX than in controls, and the changes in Kfc were correlated with the percentage decrease in blood neutrophils during reperfusion. In rabbit lungs, endothelium-dependent relaxation in isolated pulmonary arterial rings was decreased in the control group and normal in the PTX group. In pigs ventilated with pure oxygen, the PaO2 was greater in the PTX group than in the control group (423 +/- 49 vs. 265 +/- 43 mm Hg; p < 0.05), whereas the total pulmonary vascular resistance was lower (15 +/- 1 vs. 30 +/- 9 mm Hg/L/min; p < 0.02). After reperfusion, the decrease in circulating leukocyte count fell by 35 +/- 3% in the control group and remained unchanged in the PTX group, and the leukocyte count per microscopic field in the transplanted lung was lower in the PTX group than in the control group (p < 0.02). In conclusion, PTX prevented IR lung endothelium injury and improved post-IR lung function by decreasing neutrophil lung sequestration, and this agent might be useful in clinical lung transplantation.

Modulation of intercellular adhesion molecule 1 (ICAM-1) expression on alveolar macrophages (AM) may be one of the the basic mechanisms by which AM regulate the course of inflammatory response during pulmonary allograft rejection and infectious processes by mediating macrophage-lymphocyte interactions. As a model for studying anti-inflammatory activity of drugs on AM, we have investigated the effect of fusafungine, a local antibiotic which displays also anti-inflammatory properties, on the regulation of ICAM-1 membrane expression induced in vitro by stimulating AM from lung-transplant recipients. We have studied ICAM-1 membrane expression by immunocytofluorometric analysis using the anti-CD54 monoclonal antibody. The ICAM-1 molecule was expressed on 10 to 47% of freshly isolated AM, depending on the clinical status of the patients. After 24 hr cultivation with 250 U/ml gamma-IFN, the percentage of ICAM-1+ AM s increased to more than 90%. When added with the stimulating agent, fusafungine could inhibit the induction of ICAM-1 membrane expression, up to 90% of inhibition at 8 microgram/ml. However, once ICAM-1 was induced after 24 hr cultivation upon stimulation, fusafungine could not afford any reversion. On going investigations on mRNA for ICAM-1 should indicate whether fusafungine acts at the transcriptional level. These results clearly demonstrate the capacity of fusafungine to down-regulate ICAM-1 expression on AM upon activation. This approach could represent a useful tool for in vitro study of drug efficacy upon inflammatory processes of the respiratory mucasa.

Local activation of macrophages may play an important role in immune complications following lung transplantation. To document such a phenomenon, we have investigated the possible changes of alveolar macrophage surface antigen expression after lung transplantation. Using immunocytofluorometry, we have analyzed the phenotype of alveolar macrophages from 41 bronchoalveolar lavage fluids obtained from 19 lung transplant recipients displaying various complications. The strong expression of HLA-DR observed on almost all alveolar macrophages was similar among groups I (no complication), II (minimal acute rejection), and III (mild to severe acute rejection), but was enhanced in group IV (bronchial infection) (P < 0.03). We observed no significant variation in the monocyte lineage CD14 antigen expression among the 4 groups, and about 83% of alveolar macrophages expressed this marker strongly. Membrane expression of the 27E10 antigen that characterizes infiltrating macrophages in acute inflammatory lesions was significantly higher during mild to severe rejection episodes than in controls (P < 0.02) and during bronchial infections (P < 0.05) but not during minimal rejection. Double staining experiments confirmed that 27E10-positive cells in groups III and IV belonged to the macrophage lineage. In addition, the expression of the 27E10 antigen on cultured alveolar macrophages was found to be increased after stimulation by bacterial lipopolysaccharide or IFN-gamma. These results indicate that a particular alveolar macrophage subpopulation is activated during immune events after lung transplantation. This population, recognized by the 27E10 mAb, might be involved in cytokine production during severe acute rejection and infection episodes.

Despite the development of several lung transplantation procedures, the most advantageous for pulmonary hypertension remains controversial. Between 1986 and February 1992, 30 patients with end-stage primary pulmonary hypertension (n = 24), chronic pulmonary embolism (n = 4), and hystiocytosis X (n = 2) underwent heart-lung (n = 21), double lung (n = 8), or single lung (n = 1) transplantation. Indications for double lung transplantation were similar to those for heart-lung transplantation, and the preoperative clinical and hemodynamic parameters were not significantly different between the two groups. There were no intraoperative deaths, but two reoperations were needed for pleural hematoma. Five early deaths were related to graft failure (two heart-lung transplantations), mediastinitis (one heart-lung transplantation), multiorgan failure (one double lung transplantation), and aspergillosis (one double lung transplantation). There was a similar improvement in early (days 0 and 2) and late (6 months postoperatively) right-sided hemodynamic function in patients undergoing heart-lung and double lung transplantation. Three double lung transplant recipients had early and reversible left ventricular-failure. The early postoperative course of the one patient who had single lung transplantation was characterized by severe pulmonary edema, left ventricular failure, and persistent desaturation and later on by moderate pulmonary hypertension and an important ventilation/perfusion mismatch. The pulmonary function results were also similar in the heart-lung and double lung transplantation groups. The overall projected 2- and 4-year survivals were 49% and 41%, respectively, and were not significantly different between the heart-lung and double lung recipients. Results demonstrate that heart-lung and double lung transplantation are equally effective in obtaining early and durable right-sided hemodynamic and respiratory improvement and similar respiratory function. In patients with pulmonary hypertension, double lung transplantation should be preferred to single lung transplantation because of the critical postoperative course and the uncertain long-term results of single lung transplantation.

To investigate whether survivors of heart/lung and double-lung transplantations have normal or increased nonspecific bronchial responsiveness, nine heart/lung and four double-lung transplant recipients with normal lung histology underwent methacholine challenge and voluntary isocapnic dry air hyperventilation (VIH) in a randomized order at a mean time of 14.8 +/- 12.1 months after surgery. Transplant recipients were compared with 10 normal subjects and 11 patients with mild asthma. Asthmatic patients had a mean provocative concentration of methacholine inducing a 20% fall (PC20) in FEV1 of 3.4 +/- 3.6 mg/ml (SD). Seventy seven percent of the transplant recipients and 70% of the normal subjects had PC20 superior to 32 mg/ml. The percentage fall from baseline FEV1 after VIH was 12.6 +/- 10.4% in asthmatic patients as compared with 1.9 +/- 2.9% in transplant recipients (p = 0.002) and 0.45 +/- 1.2% in normal subjects (p = 0.001). The decrease in FEV1 after VIH was similar in transplant recipients and normal subjects (p = 0.14). These results show that heart/lung or double-lung transplant recipients with normal lung histology have a normal response to nonspecific bronchial stimulation.

Between June 1986 and October 1989, 29 heart lung transplantations and 4 double lung transplantations were performed at the Marie Lannelongue Hospital, Paris. The early and later course of these patients was studied. The actuarial survival rates at one and two years were 65 percent and 55 percent respectively. Bacterial infection was the main cause of early death. Late morbidity was predominantly due to cytomegalovirus infection and episodes of rejection. Respiratory function, evaluated in 19 long-term survivors, was usually normal. Only 3 patients developed a functional pattern of severe obliterative bronchiolitis probably related to uncontrolled rejections. The indications of the different types of lung transplantation are discussed: in cases of primary pulmonary hypertension or Eisenmenger's complex, heart lung transplantation is the only possible procedure. In patients with respiratory failure without cardiac dysfunction, double lung transplantation gives good functional results and makes an extra heart available for transplantation in another patient. Single lung transplantation, which gives worse functional results with a similar mortality rate, must be reserved for patients who are unable to undergo double lung transplantation.

The aim of the present study was to investigate the effects of a three months' treatment with beclomethasone dipropionate on the bronchial mucosa of asthmatic patients. Eleven patients suffering from a mild chronic asthma treated with inhaled salbutamol and theophylline were randomly assigned to receive either 1000 mu g of beclomethasone dipropionate (6 patients) or an aerosolized placebo (5 patients) in a double-blind manner. Bronchial biopsies and bronchial secretions were obtained through a fiberoptic procedure at the beginning and the end of the study. Repeated clinical and spirometric investigations were performed each month. Inter- and intra-group mean changes of clinical symptoms and of spirometric values were not significantly different. Pathogens were rarely found in bronchial aspirates and their occurrence did not seem to be influenced by the beclomethasone therapy. Sixty percent of the bronchial biopsies displayed pathological changes of the mucosa that observed at the beginning and at the end of the study; however, no sign of mucosal atrophy was noted.

We studied some morphologic, histochemical and functional characteristics of rat tracheal granulated cells. These cells are present within the epithelium (globule, leukocytes) and in the subepithelial area (subepithelial mast cells). In the latter, they are mostly concentrated in the membranous part of the mucosa. Both cell types present the main characteristics of mast cells (metachromasia and ability to bind IgE). However, they are distinct from each other in morphological and histochemical criteria and in their response to intensive corticosteroid administration. Marked differences exist between subepithelial mast cells and mast cells from the connective tissue. This raises the hypothesis of the existence of a respiratory counter part to the intestinal mucosal mast cells.

Lymphocyte infiltration of central airway epithelium was evaluated in 13 normal nonsmoking subjects (Group 1), in 11 smokers without clinical signs of chronic bronchitis (Group 2), and in 34 patients who were smokers with chronic bronchitis and mild airflow limitation (Group 3). Bronchial samples were obtained through fiberoptic bronchoscopy. Murine monoclonal antibodies directed against cell-surface antigens and an immunoperoxidase technique were used on cryostat sections to label in situ the following lymphocyte populations: T-lymphocytes (CD3+), helper/inducer T-cells (CD4+), suppressor/cytotoxic T-cells (CD8+) and B-lymphocytes (leu 12+). Virtually no B-cells were found in central airway epithelium from subjects of any group. Conversely, consistent infiltration of epithelial layers with T-lymphocytes of both subsets was observed in all subjects, with a constant predominance of CD8+ over CD4+ cells. For any T-cell marker, differences between mean scores from Group 1 and Group 2 subjects were not statistically significant. On the other hand, mean lymphocyte numbers of both subsets were found increased in patients from Group 3 compared with subjects from the two other groups: statistically significant differences were observed for CD3+, CD4+, and CD8+ cells (p less than 0.001). Furthermore, lymphocyte scores at two different airway generation were compared in some patients from Groups 2 and 3, and a significant positive correlation was observed. These results suggest that T-lymphocyte infiltration of central airway epithelium (1) may be a naturally occurring phenomenon that is amplified in the airways of smokers with chronic bronchitis, and (2) may represent the counterpart to the intraepithelial population of the intestine.(ABSTRACT TRUNCATED AT 250 WORDS)