Control of early Aspergillus mortality after lung transplantation: outcome and risk factors.

Historic treatment strategies in our institute had resulted in 10% Aspergillus mortality within the first posttransplant year. Despite nebulized amphotericin B (nAmB) prophylaxis, a significant incidence of Aspergillus infection, usually with poor outcome, is still reported. The aim of this single-center retrospective study was to evaluate the outcomes of patients receiving either standard nAmB or additional systemic caspofungin prophylaxis for selected high-risk patients. We also tried to define independent risk factors for either fungal infection or death. We followed 76 consecutive lung transplant patients performed at our center between 2002 and 2010 from the day of transplantation. The median follow-up duration was 953 days (2.6 years; range, 16-2,751 days). The endpoints were postoperative Aspergillus colonization or disease or death due to any cause. All patients received either nAmB deoxycholate (nAmBd, 15 patients) or nAmB lipid complex (nAmBLC, 61 patients). In addition, 33 patients also received short-term caspofungin prophylaxis. The overall cumulative mortality during the entire follow up was 14.5%. No clinically confirmed invasive Aspergillus infections (IPA) occurred during the first 2 postoperative years; however, there was 1 possible and 1 probable IPA. One patient died of bronchiolitis obliterans and IPA at 2 years 3 months. Twelve patients showed transient Aspergillus colonization. The antifungal prophylactic regimens were well tolerated. The risk factors for death were age >55 years and postoperative Aspergillus detection (P = .011 and P = .015, respectively). Preoperative Aspergillus colonization/disease was not a risk factor for death (P = 1.000). The strongest predictor of death was age >55 years, due to the elder probably being more susceptible to the adverse effects of immunosuppressants. Postoperative detection of Aspergillus still seems to be an indicator of a poorer outcome. Preoperative Aspergillus colonization is not necessarily a threat with prompt institution of antifungal prophylaxis.

Whole blood hypercoagulability despite anticoagulation during mechanical cardiac assist.

We report hypercoagulability despite activated partial thromboplastin time (APTT)-guided heparin treatment during Berlin Heart-supported circulation in a 38-year-old man with heart failure for 19 days. The patient was anticoagulated using unfractionated heparin, acetylsalicylic acid and dipyridamole. Contact and tissue factor-activated thromboelastometry revealed increased clot firmness, although anticoagulation assessed by APTT was in accordance with the treatment protocol. Strength of polymerized fibrin was also increased. We saw no clinical signs of thrombosis. Thromboelastometry normalized after heart transplantation. Our results suggest that hypercoagulability is due to excess fibrin formation. Monitoring anticoagulation using APTT may, therefore, be misleading during mechanical cardiac assist.

Postoperative necrotizing chest-wall infection. Case report of a rare complication after elective lung surgery.

Necrotizing fasciitis, an uncommon, often fulminant bacterial infection, rarely originates in the chest wall. In a 67-year-old woman, elective lower lobectomy of the right lung was followed by fatal necrotizing fasciitis of the chest wall. Tissue necrosis and overwhelming sepsis were due to synergistic infection by Staphylococcus aureus and Streptococcus microaerophilica. As the early appearance of necrotizing fasciitis is deceptively benign, the diagnosis is extremely difficult and is reliant on a high index of suspicion. Prompt surgical intervention is essential.

Experimental piglet lung transplantation: histological bioptic changes and autopsy findings.

To investigate difficulties in diagnosing pulmonary rejection and to create a new model to observe long-term histological consequences, 21 piglets were subjected to left single lung transplantation. Five of these transplants served as targets for unmodified rejection in piglets without immunosuppression (Group I), 13 recipients were treated with cyclosporin A, azathioprine and methylprednisolone (Group II), and in 3 cases reimplantation of an autograft was performed (Group III). In the course of postoperative graft monitoring, transthoracic/bronchial biopsies were obtained on days 3, 5, 7, 10, 14, and 20, and thereafter less frequently up to 134 days. In the unmodified rejection group, grafts consolidated in one week and histologically presented perivascular mononuclear cell infiltrates, except for one case which showed vasculitis. Lymphocytic bronchiolitis and or peribronchiolar infiltrate was present in three of the four autopsied grafts. In Group II acute rejection was detected six times in three piglets, and all except one of these specimens had a peribronchiolar component. Although no incontestable bronchiolitis obliterans developed, mild to moderate chronic obliterative vascular lesions were detected in all immunosuppressed piglets (n = 3) surviving more than 80 days. Contralateral lungs and Group III autografts showed mild changes related to the operation itself and interstitial swine endemic pneumonia (SEP). Chronic changes related to rejection were limited to the vascular wall. The mainly inflammatory bronchiolar changes are thought to present an incipient phase leading to obliterative lesions.

Endothelin content of bronchoalveolar lavage fluid from allotransplanted pigs is increased during unmodified rejection.

To find a new method for detection of rejection of allotransplanted lungs, we studied the endothelin content of bronchoalveolar lavage fluid by radioimmunoassay. Left-sided lung allotransplantation was performed in pigs. One group of animals received no treatment with immunosuppressive drugs (rejection group), the other group of animals (treated group) was treated with a triple-drug immunosuppressive regimen (cyclosporine, azathioprine, and methylprednisone), and nontransplanted lungs were controls. The endothelin content in bronchoalveolar lavage fluid was significantly elevated in the group of pigs with unmodified rejection (29.20 +/- 1.96 pg/ml) compared with that in the immunosuppressed group (15.3 +/- 2.4 pg/ml) and control group (4.27 +/- 1.23 pg/ml). The measurements were made from 5, 33, and 11 samples of bronchoalveolar lavage fluid from the rejection, treated, and control groups, respectively. These results suggest that endothelin content of bronchoalveolar lavage fluid could be a marker of lung allograft rejection.

Single lung transplantation in piglets. Technique and follow-up.

Single lung transplantation was performed in 21 piglets in order to develop a new experimental model for study of chronic rejection phenomena. In group I (unmodified rejection), acute rejection occurred in recipients which survived transplant and mean survival was 7 days. In Group II (triple immunodepression) the mean follow-up was 32 (0-134) days. Acute rejection was histologically detected in five of the 13 allografts and moderate to strong chronic vascular rejection in four. In group III (untreated autografts) the postoperative course was uneventful. The 60-day weight gain was 113% in group II, and 167% in group III. Computed tomography in group II showed 95% increase in allograft volume and 145% increase in contralateral lung volume (mean follow-up 102 days, n = 3). The corresponding gains in bronchial diameter were 39% and 40%. The piglet model allowed versatile monitoring of lung transplants, with manifestations of acute and chronic rejection providing valuable material for further studies. The significant recipient and allograft growth indicate that also children may be accepted as candidates for lung transplantation.

Sequential CT in monitoring experimental lung transplant.

The criteria for diagnosis of lung rejection remain controversial. In this study early changes in lung rejection were characterized using sequential CT with the aim of developing a sensitive and safe monitoring method, which would also provide specific information on graft status. Twenty-one experimental single lung transplants (SLTs) in piglets, including unmodified rejections, immunosuppressed recipients, and autogenic reimplants, were scanned using CT on days 3, 5, 7, 10, 14, 22 up to 134 days after operation. In addition to morphological analysis, bilateral densitometric CT measurements of the peripheral lung parenchyma were used to evaluate the intensity of interstitial infiltration of lung grafts. Altogether 67 postoperative CT studies were carried out. Simultaneous transbronchial/thoracic biopsies were undertaken. The mean follow-up time was 28 days (range 0-134 days). The experience obtained was then used in relation to SLT in a male patient for chronic obstructive pulmonary disease. All piglets had a typical hilar reimplantation response, which disappeared in 10-20 days. Two distinct patterns of radiological acute rejection were found. Increasing peripheral alveolar infiltrates reflected early massive rejection in untreated animals. In immunosuppressed animals, after the initial reimplantation response, acute rejection was detected as densitometrically measured diffuse interstitial infiltration over the whole graft. Local findings, like focal infections, were seen later in the lingula and basal portions of the graft. In the SLT patient, density changes preceded clinical rejection episodes, which responded to steroid therapy. In the experimental study, the lung graft was compared to normal contralateral lung. In the SLT patient, however, this was not possible, and, therefore, the subsequent repeated CT studies formed the basis of clinical follow-up. Sequential imaging and densitometric measurements allowed objective estimation of diffuse interstitial infiltration relating to rejection.

Single-lung allotransplantation in pigs: effects of two preservation methods on pulmonary gas exchange.

Single left lung allotransplantation was performed in 16 pigs to determine an optimal solution for lung preservation. Modified Euro-Collins and oxygenated fluorocarbon solutions (FC-43) were used as the lung preservative. Donors in both groups were pretreated with intravenous prostaglandin E1 infusions. The effects of the two different preservatives on ventilation and oxygenation were noninvasively monitored with capnometry and pulse oximetry. The functional results were further compared with morphologic findings. After implantation the right pulmonary artery was clamped, and the transplanted lung supported pulmonary circulation and ventilation. Arterial carbon dioxide tension (PaCO2) and arterial oxygen tension (PaO2) were measured from the arterial blood samples. The Euro-Collins group experienced hypercarbia (PaCO2, 54 to 72 mm Hg) and low end-tidal carbon dioxide (EtCO2) values (3.3% to 3.9%) when the donor lung was reimplanted and reperfused. The pigs in the Euro-Collins group were also hypoxemic after reimplantation of the left lung. The saturation (SpO2) values were 85% to 89%, and the PaO2 values were between 61 and 66 mm Hg. The oxygenated fluorocarbon group had normal ventilatory parameters and arterial oxygen saturation after reimplantation of the left lung; no significant gradient between EtCO2 and PaCO2 was detected. Scanning and transmission electron-microscopic studies of the transplanted lungs showed good to moderate preservation after reperfusion in the oxygenated fluorocarbon group, whereas preservation was judged to be moderate in the Euro-Collins group. Oxygenated fluorocarbon (FC-43) donor lung preservation thus resulted in superior functional recovery in pulmonary gas exchange during reperfusion compared with Euro-Collins solution. Electron-microscopic findings supported functional results obtained.

Single lung allotransplantation in pigs. A morphologic study of tissue preservation with modified Euro-Collins and fluorocarbon solutions.

In the present study the functional and morphologic effects of two pulmoplegic solutions are evaluated. Single left-lung allotransplantation with ligation of the right pulmonary artery was performed in 15 piglets (13-20 kg). The lungs were preserved after donor prostaglandin E-1 treatment with single pulmonary artery flush with either modified Euro-Collins solution (mECS) (9 pigs) or oxygenated fluorocarbon emulsion (FC-43) (6 pigs) and transplanted after 6-hr storage in cold Physiosol solution. Tidal volumes of 15 ml/kg x fr (18) with 40% inspired oxygen were used for ventilation during reperfusion. Function of the transplanted lung was monitored for 4 hr postoperatively by determining pa CO2 and pa O2 levels from arterial samples and by noninvasive monitoring of end-tidal CO2 values and arterial oxygen saturations. Sequential morphologic changes in pulmonary artery flow surface and lung tissue were studied after 6-hr storage and 4-hr reperfusion, using light, scanning, and transmission electron microscopy (LM, SEM, TEM). There was no mortality. After transplantation the mECS group experienced significant hypoxia and hypercarbia and had low end-tidal CO2 values as signs of defective oxygenation and gas exchange, whereas the FC-43 group was normoxic and normoventilated without disturbed elimination of carbon dioxide. After storage and reperfusion, LM showed signs of increased vascular permeability and reperfusion damage--more evident in the mECS group compared with the FC-43 group--while the lymphoid cell population was more intensely activated in the latter group. Electron microscopy after storage showed good overall preservation of structures in both groups. After reperfusion preservation of pulmonary artery flow surface and lung tissue was estimated to be moderate in the mECS group, whereas it was good-to-moderate in the FC-43 group by SEM (NS). TEM of lung tissue, however, showed significantly better-preserved alveolar epithelial lining in the FC-43 group compared with the mECS group. In conclusion, oxygenated fluorocarbon (FC-43) pulmoplegia gave better functional and morphologic preservation of lung grafts compared with modified Euro-Collins solution.

Single-lung allotransplantation in pigs following donor pretreatment with intravenous prostaglandin E-1. Morphologic changes after preservation and reperfusion.

Single left lung allotransplantation with ligation of the right pulmonary artery was performed on 11 pigs after donor pretreatment with prostaglandin E-1 and pulmonary artery flush with modified Euro-Collins solution. Sequential morphologic changes in pulmonary artery flow surface and lung structure were studied after 6-hour storage and after 4-hour reperfusion, using light microscopy and scanning and transmission electron microscopy. Morphologic observations were compared with functional changes. After 6-hour preservation slight degenerative changes were found in the pulmonary artery flow surface and changes in lung tissue suggestive of increased vascular permeability and edema. During 4-hour reperfusion the changes progressed. Preservation was in general moderate. Lung tissue showed vascular congestion and slight inflammation. Localized areas of reperfusion damage could adjoin near-normal looking alveoli. Oxygenation and gas exchange, though low in the beginning of reperfusion, tended to improve during the reperfusion period. The method was concluded to afford good morphologic preservation of the graft after 6-hour storage, and moderately good morphologic and functional preservation after 4-hour reperfusion.