Endothelial cell chimerism associated with graft rejection after human lung transplantation.

Endotheliitis is a major sign of graft rejection. Recipient-derived endothelial cells found in two series of liver and kidney transplants were related to graft rejection. Here, we assessed the presence and the number of chimeric endothelial cells in lung transplants, and their relation with graft rejection. In six males grafted with female lungs out of 193 lung transplantations, endothelial chimerism was studied by combined XY-fluorescent in situ hybridization with CD31 and CD45 immunostainings and blood group antigens. On samples graded according to the revised working formulation for lung allograft rejection, we found chimeric macrophages (73.1 to 87.2%) in all cases and chimeric endothelial cells (1.3 to 2.1%) in four patients. Another method using ABO blood group also showed endothelial cells positive for recipient-type blood group antigens in three patients. By both methods, presence of chimeric endothelial cells was related to pathological signs of acute rejection (P<0.05).

Pulmonary vascular lesions in end-stage idiopathic pulmonary fibrosis: Histopathologic study on lung explant specimens and correlations with pulmonary hemodynamics.

In patients presenting with idiopathic pulmonary fibrosis (IPF), modifications of pulmonary vessels are well defined in fibrotic areas but have not been accurately assessed in the intervening patches of preserved lung. Moreover, the relation between pulmonary vessel lesions and pulmonary hemodynamics is not well known. We therefore designed a retrospective study on lung explant specimens from 26 patients with a firm diagnosis of IPF who had undergone lung transplantation. Our aim was to (1) describe the vascular lesions, especially in preserved lung areas, and (2) correlate them with pulmonary hemodynamics. In dense fibrotic zones, thickening of the arterial and venous wall with severe luminal narrowing was present in each patient. In architecturally preserved lung zones, occlusion of venules and small pulmonary veins was observed in 65% of the patients, although there were only mild changes of muscular pulmonary arteries. We found a significant positive correlation between the macroscopic extent of lung fibrosis and mean pulmonary artery pressure, but we failed to find a relation between mean pulmonary artery pressure and venous/venular lesions in nonfibrotic areas. Our study points out that in many patients with IPF, nonfibrotic lung areas demonstrate an occlusive venopathy, the signification of which remains undetermined.

Primary intrathoracic synovial sarcoma: a clinicopathologic study of 40 t(X;18)-positive cases from the French Sarcoma Group and the Mesopath Group.

Synovial sarcoma (SS), an aggressive neoplasm accounting for up to 14% of soft tissue sarcomas, was recently recognized as a primary tumor in the lung and pleura. SS is characterized by the chromosomal translocation t(X;18)(SYT-SSX) found in more than 95% of the tumors. We report a cooperative study from the French Sarcoma Group and the Mesopath Group on 40 t(X;18)(SYT-SSX)-positive primary intrathoracic SS. There were 22 males and 18 females, whose age ranged from 16 to 79 years (median, 47 years). Neoplasms were mostly circumscribed and of large size (median, 7.5 cm; range, 2-16 cm). Thirty-nine tumors were monophasic SS, including 24 (60%) monophasic fibrous and 15 (37.5%) poorly differentiated cases, and one lesion was a biphasic SS. A larger proportion of poorly differentiated tumors were observed among intrathoracic SS as compared with soft tissue SS. Immunohistochemically, 90% of the cases reacted with at least one epithelial marker. CD34 was focally expressed in 3 cases. SYT-SSX1 fusion transcripts were detected in 22 cases (56.4%) and SYT-SSX2 fusion transcripts in 17 cases. Median and 5-year disease-specific survival in 33 patients was 50 months and 31.6%. Median and 5-year disease-free survival was 24 months and 20.9%. Patient sex, age, tumor size, histologic subtype, grade, and SYS-SSX fusion type had no significant impact on outcome. In conclusion, intrathoracic SS are rare but aggressive tumors with poor prognosis. In this unusual location, the detection of SYT-SSX fusion transcripts is a valuable diagnostic adjunct.

Analysis of the different histologic lesions observed in transbronchial biopsy for the diagnosis of acute rejection. Clinicopathologic correlations during the first 6 months after lung transplantation.

Acute rejection is an extremely common complication of lung transplantation. (1) To appreciate the interobserver variation in the interpretation of histologic findings and (2) to assess the efficacy of transbronchial biopsy (TBB) for acute rejection diagnosis and associated diseases, particularly infection, we performed a retrospective study including 53 consecutive patients who underwent at least one clinically indicated TBB during the first 6 months after lung transplantation. A total of 94 TBB was obtained. The following histologic features observed in TBB specimens-perivascular mononuclear infiltrates, lymphocytic bronchitis/bronchiolitis, and alveolar lesions, were reliably reproduced by 2 pathologists from the same transplant center, with kappa values ranging from 0.79 to 0.82. For identifying perivascular mononuclear infiltrates, discordance between the 2 observers was significantly associated with moderate/severe alveolar lesions. For the diagnosis of acute rejection, perivascular mononuclear infiltrates had a specificity of 96.5%, a positive predictive value of 97.5%, and a sensitivity of 67.7%, whereas lymphocytic bronchitis/bronchiolitis had a specificity of 56.3% and a sensitivity of 19.4%. Interestingly, there was a positive independent correlation between infection and moderate/severe alveolar histologic lesions ( P < .01). In conclusion, the interobserver agreement between experienced pathologists in TBB interpretation is good. Perivascular mononuclear infiltrates remain the cornerstone for acute rejection diagnosis. The presence of moderate/severe alveolar lesions should prompt to search for infection.

[Lung transplantation in patients with pulmonary fibrosis]. / Transplantation pulmonaire chez les patients atteints de fibrose pulmonaire.

Lung transplantation has been developed over the last fifteen years as a therapeutic option for different forms of advanced-stage lung disease. Idiopathic pulmonary fibrosis is a good indication. For these patients, single lung transplantation is usually preferred, bilateral lung transplantation to a lesser extent. Survival is similar for these two types of transplantation. The post-transplantation survival in patients with pulmonary fibrosis is about 65-70% at one year and 40% at five years. This rate is lower than observed for COPD or cystic fibrosis. If there are no complications, the patient can recover nearly normal lifestyle. Among the different complications, reimplantation edema, infection, rejection, and bronchial complications predominate. Chronic rejection, also called obliterative bronchiolitis syndrome, is a later complication which can be observed in about half of the patients. Improvement in graft survival depends greatly in improvement in prevention and management of complications. Despite such complications, graft survival in fibrosis patients is greater than spontaneous survival on the waiting list; idiopathic fibrosis is associated with the highest mortality on the waiting list. Patients should be referred early for the pre-transplantation work-up because individual prognosis is very difficult to predict.

Survival benefit of lung transplantation for patients with idiopathic pulmonary fibrosis.

OBJECTIVE: Although lung transplantation is viewed as an acceptable option for patients with end-stage idiopathic pulmonary fibrosis, the survival benefit of this approach is still debated. This study examined whether there was a survival benefit of lung transplantation in a cohort of patients referred to our transplant center with a diagnosis of idiopathic pulmonary fibrosis according to American Thoracic Society criteria. METHODS: Forty-six patients accepted for lung transplantation during a 12-year period with a diagnosis of idiopathic pulmonary fibrosis form the basis of this study. Survival benefit offered by lung transplantation was assessed using Cox proportional-hazards modeling, with patients on a waiting list as the control group. RESULTS: Twenty-eight patients underwent lung transplantation (27 single and 1 double), 16 patients died while waiting, and 2 patients remained on the active waiting list. Diagnosis of idiopathic pulmonary fibrosis was made on histologic examination of the explanted lung or lung biopsy before lung transplantation. There was a pattern of usual interstitial pneumonia in 31 cases (67%). The 15 remaining patients fulfilled all American Thoracic Society criteria for idiopathic pulmonary fibrosis. The median waiting time for organs was 51 days. Survival after lung transplantation was 79.4% at 1 year, 63.5% at 2 years, and 39% at 5 years. The multivariable analysis showed that lung transplantation reduced the risk of death by 75% (95% confidence interval, 8%-86%; P =.03) after adjustment on potential confounding variables. CONCLUSIONS: Lung transplantation is effective in improving the survival of selected patients affected by idiopathic pulmonary fibrosis.

Early expression of adhesion molecules after lung transplantation: evidence for a role of aggregated P-selectin-positive platelets in human primary graft failure.

BACKGROUND: Primary graft failure (PGF) secondary to ischemia-reperfusion injury is the main cause of death in the first month after lung transplantation. The aim of this study was to identify early cellular and immunologic events associated with PGF in human lung transplants. METHODS: Induction of P-selectin, E-selectin and intercellular adhesion molecule-1 (ICAM-1) and evaluation of leukocytes and platelets accumulation were investigated in 18 post-reperfusion surgical specimens of lung allografts by an immunohistochemical technique. RESULTS: Selectins were restricted to the venular plexus after reperfusion as in the normal lung, whereas ICAM-1 was induced in all cases on alveolar capillaries. Numerous polymorphonuclear cells (18 of 18 cases) and aggregated platelets (7 of 18 cases) were identified along the venular plexus after reperfusion. Compared with the other patients, those with aggregated P-selectin-positive platelets were characterized by a longer duration of mechanical ventilation (p < 0.01), a lower PaO2/FiO2 ratio (p < 0.01) and the presence of radiologic edema (p < 0.05) within the first 3 post-operative days. CONCLUSIONS: We showed in the reperfused lung a distinct expression of adhesion molecules on venous and capillary pulmonary endothelia that may influence the role of leukocytes and platelets during the early course of transplantation. Furthermore, the knowledge of an association between the presence of P-selectin-positive platelet aggregates and PGF criteria might have implications for graft management and therapeutic strategies.

Non-traumatic pulmonary haematoma complicating oral anticoagulation therapy.

Several cases of non-traumatic pulmonary haematoma have been reported in the literature. However, very few of them are related to anticoagulation therapy. The authors report two cases of pulmonary haematoma caused by oral anticoagulant therapy without any underlying pathological lesion. The evolution was fatal in the first case, whereas a slow spontaneous resolution of the haematoma was noted in the second. Non-traumatic pulmonary haematoma can be a complication of oral anticoagulation and should be considered in the differential diagnosis of pulmonary densities in this setting.

Pulmonary cystic disorder related to light chain deposition disease.

Light chain deposition disease (LCDD) is a rare disorder that very uncommonly affects the lung. We report three cases of severe cystic pulmonary LCDD leading to lung transplantation. Such a presentation has never been previously reported. The three patients present with a progressive obstructive pulmonary pattern associated with numerous cysts diffusely distributed in both lungs. The disease was histologically characterized by non-amyloid amorphous deposits in the alveolar walls, the small airways and the vessels. It was associated with emphysematous-like changes and small airway dilation. Monotypic kappa light chain fixation was demonstrated on the abnormal deposits and along the basement membranes. Electron microscopy revealed coarsely granular electron-dense deposits in the same localizations. Mild extrapulmonary deposits were found in salivary glands in one patient. No immunoproliferative disorder was identified. We conclude that LCDD may primarily affect the lung, present as a pulmonary cystic disorder, and lead to severe respiratory insufficiency.

Acute respiratory failure after interferon-gamma therapy of end-stage pulmonary fibrosis.

Interferon (IFN)-gamma was recently proposed as a treatment for idiopathic pulmonary fibrosis. We report on four patients who developed acute respiratory failure with new alveolar opacities after 2 (two patients), 6, and 35 injections of IFN-gamma-1b. All four patients had advanced idiopathic pulmonary fibrosis (total lung capacity less than 45% predicted or carbon monoxide diffusion capacity less than 30% predicted), and two patients had familial pulmonary fibrosis. No other cause of deterioration was found. Refractory hypoxemia led to death in three cases and to lung transplantation in one case. Pathologic studies in two patients showed diffuse alveolar damage lesions with preexisting usual interstitial pneumonia. These cases suggest that IFN-gamma therapy can induce an acute respiratory failure in patients with end-stage idiopathic pulmonary fibrosis.