D-dimer as a predictor of venous thromboembolism in acutely ill, hospitalized patients: a subanalysis of the randomized controlled MAGELLAN trial.

BACKGROUND: D-dimer concentrations have not been evaluated extensively as a predictor of increased venous thromboembolism (VTE) risk in acutely ill, hospitalized medical patients. OBJECTIVES: To analyze the relationships between D-dimer concentration, VTE and bleeding in the MAGELLAN trial (NCT00571649). PATIENTS/METHODS: This was a multicenter, randomized, controlled trial. Patients aged ≥ 40 years, hospitalized for acute medical illnesses with risk factors for VTE received subcutaneous enoxaparin 40 mg once daily for 10 ± 4 days then placebo up to day 35, or oral rivaroxaban 10 mg once daily for 35 ± 4 days. Patients (n = 7581) were grouped by baseline D-dimer ≤ 2 × or > 2 × the upper limit of normal. VTE and major plus non-major clinically relevant bleeding were recorded at day 10, day 35, and between days 11 and 35. RESULTS: The frequency of VTE was 3.5-fold greater in patients with high D-dimer concentrations. Multivariate analysis showed that D-dimer was an independent predictor of the risk of VTE (odds ratio 2.29 [95% confidence interval 1.75-2.98]), and had a similar association to established risk factors for VTE, for example cancer and advanced age. In the high D-dimer group, rivaroxaban was non-inferior to enoxaparin at day 10 and, unlike the low D-dimer group, superior to placebo at day 35 (P < 0.001) and days 11-35 (P < 0.001). In both groups, bleeding outcomes favored enoxaparin/placebo. CONCLUSIONS: Elevated baseline D-dimer concentrations may identify acutely ill, hospitalized medical patients at high risk of VTE for whom extended anticoagulant prophylaxis may provide greater benefit than for those with low D-dimer concentrations.

Prognostic value of serum carcinoembryonic antigen levels in patients who undergo lung transplantation.

BACKGROUND: Potential candidates for lung transplantation undergo a rigorous evaluation before transplant. Serum carcinoembryonic antigen (CEA) levels are used as a screening tool for occult malignancy in many lung transplant centers. We reviewed the pre-transplant CEA levels in lung transplant recipients in our institution to determine their prognostic significance. MATERIALS AND METHODS: We performed a retrospective database review of the first 200 patients that had undergone lung or heart-lung transplant at our institution (dates were 1/20/92-7/25/98). Data extracted included CEA levels (in ng/ml) at the time of lung transplant evaluation, demographic data, and survival. Patients had one of the following diagnoses: alpha-1-anti-trypsin deficiency, cystic fibrosis, chronic obstructive pulmonary disease, Eisenmenger's syndrome, idiopathic pulmonary fibrosis, primary pulmonary hypertension, sarcoidosis, or other. RESULTS: After excluding re-transplants, CEA results were available for 174 of 193 (90.2%) patients. CEA levels were elevated in 85 patients (48.9%) with a mean value of 3.15 +/- 2.55 (normal < 2.5). Solid organ cancers developed in 6 patients, at a median follow-up of 27.5 months after transplant. Their mean pre-transplant CEA level was similar to the rest of the group (3.52 +/- 2.05). Pre-transplant CEA levels did not predict post-transplant survival. Patients with idiopathic pulmonary fibrosis had the highest pre-transplant CEA levels, whereas patients with primary pulmonary hypertension and Eisenmenger's syndrome had the lowest (5.36 +/- 4.59, 0.83 +/- 0.56, and 1.43 +/- 0.81, respectively; p = 0.0001). CONCLUSIONS: CEA levels are high in patients with end-stage lung disease, especially IPF. Their levels appear to be a marker of the underlying disease and do not predict the post-transplant survival or development of malignancy.

Results of a randomized, prospective, multicenter trial of mycophenolate mofetil versus azathioprine in the prevention of acute lung allograft rejection.

BACKGROUND: Although the use of mycophenolate mofetil (MMF) has reduced the incidence of acute rejection in heart and kidney allograft recipients, its role in lung transplantation remains controversial. Therefore, we conducted a randomized, prospective, open-label, multicenter study in lung transplant recipients to determine whether MMF decreases episodes of acute allograft rejection when compared with azathioprine (AZA). METHODS: Between March of 1997 and January of 1999, 81 consecutive lung transplant recipients from two centers were prospectively randomized to receive cyclosporine, corticosteroids, and either 2 mg/kg per day of AZA or 1 g twice daily of MMF. The primary study endpoint was biopsy-proven acute allograft rejection over the first 6 months posttransplant. Secondary endpoints included clinical rejection, cytomegalovirus (CMV) infection, adverse events, and survival. Surveillance bronchoscopies were performed at 1, 3, and 6 months, or if clinically indicated. Pathologists interpreting the biopsy results were blinded to the randomization. Results were analyzed according to intention-to-treat. Between group comparisons of means and proportions were made by using two sample t tests and Fisher's exact tests, respectively. Six-month survival was calculated by the Kaplan-Meier method and compared by the log rank test. RESULTS: Thirty-eight patients were prospectively randomized to receive AZA, and 43 MMF. The incidence of biopsy proven grade II or greater acute allograft rejection at 6 months was 58% in the AZA group and 63% in the MMF group (P=0.82). The 6-month survival rates in the MMF and AZA groups were 86% and 82%, respectively (P=0.57). Rates of CMV infection and adverse events were not significantly different between the two groups. CONCLUSIONS: Acute rejection rates and overall survival at 6 months are similar in lung transplant recipients treated with either MMF- or AZA-based immunosuppression.

Vena caval filters in pulmonary embolism.

Since the early 1900s, surgical interruption of the inferior vena cava (IVC) has been utilized in the management of venous thromboembolism (VTE). With the advent of newer-generation percutaneous devices in the late 1970s, their use and indications have expanded. The literature to support their efficacy, however, is limited to several case series and a single randomized controlled trial. Despite this, some have advocated the use of IVC filters as primary treatment of VTE in certain patient populations. In addition, there has been a large amount of interest in their use as prophylaxis against pulmonary embolism (PE) in high-risk patients. In the past 10 years, we have also seen the development and initial use of temporary devices, although their role in the management of this disease is even less certain. This article will review the recent literature on efficacy, complications, and indications for the use of IVC filters in the prevention and treatment of PE.

Gastroesophageal reflux as a reversible cause of allograft dysfunction after lung transplantation.

Gastroesophageal reflux (GER) is increasingly recognized as contributing to a number of pulmonary disorders. The relationship of GER to pulmonary allograft dysfunction after lung transplantation is unknown. In this report, we describe a lung transplant recipient who developed an acute decline in pulmonary function several months after a retransplantation for chronic rejection. A pulmonary workup at that time, including bronchoscopy with biopsy, revealed bronchial inflammation with no allograft rejection or infection. Because of increasing GI symptoms after retransplantation, the patient also underwent additional testing, which revealed severe acid reflux. The treatment of this patient's acid reflux with Nissen fundoplication surgery resulted in a prompt and sustained improvement in his pulmonary function. We suggest that GER should be considered among the potential causes of allograft dysfunction after lung transplantation.

Influence of panel-reactive antibodies on posttransplant outcomes in lung transplant recipients.

BACKGROUND: Panel-reactive antibody (PRA) is used to estimate the degree of humoral sensitization in the recipient before transplantation. Although pretransplant sensitization is associated with increased complications in other solid organ transplant recipients, less is known about the outcome of sensitized lung transplant recipients. Therefore, we sought to determine the impact of elevated pretransplant PRA on clinical outcomes after lung transplantation. METHODS: The records of the first 200 lung transplant operations performed at Duke University Medical Center were reviewed. The outcomes of sensitized patients, PRA greater than 10% before transplantation (n = 18), were compared with the outcomes of nonsensitized patients. RESULTS: Sensitized patients experienced a significantly greater number of median ventilator days posttransplant (9 +/- 8) as compared with nonsensitized recipients (1 +/- 11; p = 0.0008). There were no significant differences between the number of episodes of acute rejection; however, there was a significantly increased incidence of bronchiolitis obliterans syndrome occurring in untreated sensitized recipients (56%) versus nonsensitized (23%; p = 0.044). In addition, there was a trend towards decreased survival in the sensitized recipients, with a 2-year survival of 58% in sensitized recipients as compared with 73% in the nonsensitized patients (p = 0.31). CONCLUSIONS: Sensitized lung transplant recipients experience more acute and chronic complications after transplantation. These patients probably warrant alternative management strategies.

Significance of blood stream infection after lung transplantation: analysis in 176 consecutive patients.

BACKGROUND: Although infection is a leading cause of death after lung transplantation, very little is known about the incidence, epidemiology, and clinical significance of bloodstream infections in lung transplant recipients. METHODS: All blood cultures were reviewed in 176 consecutive lung transplant recipients over a 6-year period. Data were obtained from a prospectively collected microbiological database. RESULTS: Bloodstream infection (BSI) occurred in 25% (44/176) of all lung transplant recipients over the 6-year study period. Staphylococcus aureus, Pseudomonas aeruginosa, and Candida species were the most common bloodstream isolates after lung transplantation. The epidemiology of posttransplant BSI, however, varied considerably between early and late posttransplant time periods and also differed between cystic fibrosis (CF) and non-CF patients. BSI infection after transplantation was associated with significantly worse survival by Kaplan-Meir analysis (P value log rank test=0.0001). In a multivariable logistic regression model, posttransplant BSI was a significant predictor of posttransplant death (odds ratio 5.62, CI 2.41-13.11, P=0.001), independent of other pre- and posttransplant factors. CONCLUSIONS: Bloodstream infection represents a serious complication after lung transplantation, occurring more frequently than previously recognized, and independently contributing to posttransplant mortality.

Respiratory viral infections in lung transplant recipients: radiologic findings with clinical correlation.

PURPOSE: To evaluate radiologic finding of respiratory viral infection in lung transplant recipients with clinical correlation. MATERIALS AND METHODS: Over 5 years, 21 episodes of respiratory viral infection (parainfluenza [n = 9], respiratory syncytial virus [n = 8], adenovirus [n = 5], influenza [n = 2]) were diagnosed 6-727 days (mean, 270 days) after lung transplantation in 20 recipients. Chest radiographs, computed tomographic (CT) images, and clinical records were reviewed. RESULTS: Sixteen episodes of respiratory viral infection were diagnosed in patients with symptoms of lower respiratory tract infection or acute allograft dysfunction; five were diagnosed in asymptomatic patients. Chest radiographs were abnormal in 11 (52%) episodes; findings included heterogeneous or homogeneous opacities and masslike consolidation. All patients with radiographic abnormalities were symptomatic. Chest radiographs were unchanged from baseline in 10 (48%) episodes; in one, CT revealed findings not depicted at radiography. Adenoviral infection (n = 5) was typically symptomatic, was associated with new radiographic abnormalities, and was rapidly lethal (n = 4). Infection with parainfluenza and/or respiratory syncytial virus was commonly asymptomatic and was not associated with radiographic abnormalities; affected patients had good outcomes. CONCLUSION: Respiratory viral infections are important causes of morbidity and mortality in lung transplant recipients. Radiographic abnormalities in patients with respiratory viral infections were usually accompanied by symptoms of lower respiratory tract infection. Adenoviral infection was frequently accompanied by progressive pulmonary opacity and fatal outcome.

Cystic fibrosis: usefulness of thoracic CT in the examination of patients before lung transplantation.

PURPOSE: To evaluate the usefulness of thoracic computed tomography (CT) in the pre-lung transplantation examination of patients with cystic fibrosis (CF). MATERIALS AND METHODS: Fifty-six patients (age range, 12-42 years) with CF were evaluated for possible lung transplantation from 1991 to 1997. Twenty-six of these patients underwent bilateral lung transplantation, 19 were awaiting transplantation at the time of the study, seven died before transplantation, and four were excluded for psychosocial concerns. Preoperative chest radiographic and CT findings were reviewed and correlated with clinical, operative, and pathology records. RESULTS: In seven patients, discrete, 1-2-cm pulmonary nodules were detected at CT. Five of these patients underwent transplantation; the nodules were found to be mucous impactions. No malignancy was found in any of the patients who underwent transplantation. Pretransplantation sputum cultures grew Aspergillus fumigatus in seven patients, none of whom had radiologic findings suggestive of Aspergillus infection. Radiographic or CT findings were suggestive of mycetoma in five cases, but no such tumors were found at transplantation. The accuracies of chest radiography and CT for the detection of pleural disease in 48 hemithoraces were 81% (n = 39) and 69% (n = 33), respectively. The radiologic findings of pleural thickening did not influence the surgical approach in any patient. CONCLUSION: Thoracic CT has little utility in the routine pre-lung transplantation examination of patients with CF.

Hyperpolarized 3He-enhanced MR imaging of lung transplant recipients: preliminary results.

OBJECTIVE: Bronchiolitis obliterans syndrome is the major cause of long-term graft failure in lung transplant recipients and may be partially reversible if diagnosed early and treated. Diagnosis is difficult because findings of transbronchial biopsy are often negative in patients with early disease. We are investigating a novel MR ventilation agent, hyperpolarized 3He, for evaluating ventilatory abnormalities in lung transplant recipients with suspected bronchiolitis obliterans syndrome. CONCLUSION: In this preliminary study, the extent of ventilatory defects revealed on 3He-enhanced MR images correlated with severity of bronchiolitis obliterans syndrome using an established clinical grading system. This new technique may hold potential for diagnosing bronchiolitis obliterans syndrome in lung transplant recipients.

Rabbit antithymocyte globulin decreases acute rejection after lung transplantation: results of a randomized, prospective study.

STUDY OBJECTIVES: The efficacy of antithymocyte induction therapy in lung transplantation is controversial, and its use varies from center to center. We hypothesized that rabbit antithymocyte globulin (RATG) induction therapy would decrease acute rejection after lung transplantation, and we designed a single-center, randomized, prospective study to test this hypothesis. DESIGN: A total of 44 single or bilateral adult lung transplant recipients were randomly assigned to receive either RATG induction therapy (dosage, 1.5 mg/kg/d for 3 days) at the time of transplantation, along with conventional immunosuppression (cyclosporine, azathioprine, and prednisone), or conventional immunosuppression alone with no induction therapy. RESULTS: Although a similar number of biopsies were performed in each group, the number of patients experiencing biopsy-proven grade II or greater acute rejection was significantly reduced in the group receiving RATG induction therapy (23% incidence), as compared to the patients treated with conventional immunosuppression alone (55% incidence; p = 0.03). In addition, there was a nonsignificant reduction in the incidence of bronchiolitis obliterans syndrome at the conclusion of the study in patients who received RATG induction (20%), as compared to patients in the control group (38%). The incidence of posttransplant infections and malignancies were similar between the two groups. CONCLUSION: Induction therapy with RATG significantly reduces the incidence of acute allograft rejection after lung transplantation.

Pulmonary cholesterol granulomas in patients with pulmonary artery hypertension: chest radiographic and CT findings.

OBJECTIVE: We describe the chest radiographic and CT findings of pulmonary cholesterol granulomas in patients with pulmonary artery hypertension. CONCLUSION: Histopathologic evidence of cholesterol granulomas was found in five (25%) of 20 patients with severe pulmonary hypertension. In three of these five patients, the granulomas manifested on chest radiographs and CT as small centrilobular nodules mimicking the appearance of sarcoidosis, bronchiolitis, hypersensitivity pneumonitis, or aspiration.

Bronchial anastomotic complications in lung transplant recipients: virtual bronchoscopy for noninvasive assessment.

PURPOSE: To compare the accuracy of virtual bronchoscopy (VB) with that of axial computed tomography (CT) in the assessment of bronchial anastomotic complications in lung transplant recipients. MATERIALS AND METHODS: Twenty-seven bronchial anastomoses in 17 patients were evaluated with helical CT. Axial CT and VB images were evaluated for surface irregularity and the presence, length, and severity of stenosis. Findings were correlated with the results of fiberoptic bronchoscopy (FOB). RESULTS: There were 12 anastomotic stenoses at FOB. Pooled accuracy (among all four readers) of VB and axial CT for diagnosis of clinically relevant stenosis was 97% and 80%, respectively, at the right bronchial anastomoses and 92% and 75%, respectively, at the left bronchial anastomoses. Pooled accuracy of VB and Axial CT for stenosis length was 72% and 62%, respectively, at the right anastomoses and 81% and 69%, respectively, at the left anastomoses. These differences were not statistically significant. Both the VB and axial CT images showed surface irregularities when anastomotic infection (n = 2) or dehiscence (n = 1) was present but resulted in an overdiagnosis of mucosal abnormalities when anastomoses were normal. CONCLUSION: VB was slightly more accurate than axial CT for diagnosis of clinically relevant stenoses at bronchial anastomoses in lung transplant recipients. However, because VB is not 100% accurate and has no role in the diagnosis of infection or dehiscence, it probably will not replace FOB for assessment of bronchial anastomotic complications in this population.

Candidal anastomotic infection in lung transplant recipients: successful treatment with a combination of systemic and inhaled antifungal agents.

Anastomotic infection is an uncommon but potentially life-threatening complication after lung transplantation. We recently encountered three lung transplant recipients with invasive candidal anastomotic infection. Two patients were admitted with dyspnea and fever, and one asymptomatic infection was detected on surveillance bronchoscopy. All three patients were treated similarly with a combination of intravenous amphotericin B, inhaled amphotericin B, and oral fluconazole. The combination of systemic and inhaled antifungal agents successfully treated all three cases of anastomotic infection.

Does hyperexpansion of the native lung adversely affect outcome after single lung transplantation for emphysema? Preliminary findings.

RATIONALE AND OBJECTIVES: The authors evaluated the effect of the native emphysematous lung on graft function after single lung transplantation. MATERIALS AND METHODS: Thirty-two patients who underwent single lung transplantation were examined with radiography preoperatively for degree of emphysema and postoperatively for hyperexpansion of the native lung. All patients underwent ventilation-perfusion scanning before transplantation and ventilation scanning after transplantation. Pulmonary function tests and measurement of arterial partial pressure of oxygen were also measured before and after surgery. The postoperative course was graded on a subjective scale. RESULTS: Hyperexpansion of the native lung was seen in 16 of the 32 patients in the postoperative period. On the basis of serial measurements of forced expiratory volume in 1 minute, these patients fared poorly in the postoperative period compared with patients without hyperexpansion. Pulmonary blood flow to the native lung, as measured with perfusion scintigraphy, paradoxically increased in 11 patients after transplantation. Nine of these 11 patients demonstrated hyperinflation of the native lung, suggesting that graft compression adversely affects blood flow to the transplanted lung. CONCLUSION: Hyperexpansion of the native lung after single lung transplantation for emphysema may have a deleterious effect on graft function and possibly on clinical outcome.

Pulmonary rehabilitation in the surgical patient. Lung transplantation and lung volume reduction surgery.

Prior to lung transplantation or lung volume reduction surgery, patients complete a comprehensive pulmonary rehabilitation program. The program aids physicians in the selection of appropriate surgical candidates and prepares patients physically and psychologically for the stress of surgery. Because lung transplantation often involves relocation and prolonged waiting, stress levels can be particularly high. Rehabilitation continues through the perioperative and postoperative period to facilitate recovery and bring patients to the highest possible level of function. Studies of lung transplant recipients suggest that most patients who survive to hospital discharge enjoy a significant improvement in pulmonary function and many resume work and household responsibilities. Initial experiences with lung volume reduction surgery also suggest that many patients experience improved dyspnea symptoms and functional status after the procedure. As lung transplantation and lung volume reduction surgery emerge as viable therapeutic options for many patients with end-stage lung disease, comprehensive pulmonary rehabilitation programs are essential to address the complex medical, surgical, and psychological issues that surround these procedures and to produce optimal therapeutic outcomes.

Community respiratory viral infection in adult lung transplant recipients.

STUDY OBJECTIVE: To define the epidemiology, clinical manifestations, and long-term complications of respiratory viral infections in adult lung transplant recipients. DESIGN: Retrospective review of the records of 122 adult lung transplant recipients over a 5-year period at one institution. RESULTS: Ten episodes of infection with respiratory syncytial virus, parainfluenza, influenza, or adenovirus were identified. All patients presented with symptoms of respiratory tract infection. Two patients died acutely and four patients subsequently had development of obliterative bronchiolitis (OB). CONCLUSIONS: These data suggest community respiratory viral infections cause significant morbidity and mortality in lung transplant recipients. Further prospective studies are warranted to clarify the relationship between respiratory viral infection and OB and to define the optimal therapy for these viral infections.

Lung transplantation for Williams-Campbell syndrome.

Williams-Campbell syndrome is a rare disorder characterized by a deficiency of cartilage in subsegmental bronchi leading to distal airway collapse and bronchiectasis. We report the first case of lung transplantation in a patient with end-stage lung disease secondary to Williams-Campbell syndrome. Although the patient did not have proximal airway collapse prior to transplantation, his posttransplant course was complicated by the development of bronchomalacia of the right and left mainstem bronchi. The patient experienced recurrent pulmonary infections and died of bacterial pneumonia 1 year after transplantation. Autopsy revealed cartilage deficiency in both right and left mainstem bronchi. A hypothesis may be made that a combination of proximal cartilage deficiency and posttransplant airway ischemia led to the development of bronchomalacia after lung transplantation. Thus, in contrast to previous reports, the cartilage deficiency in Williams-Campbell syndrome can involve both proximal and distal airways. Consequently, bilateral sequential lung transplantation may not be an effective therapeutic option in patients with this syndrome.

Iron accumulation in lung allografts after transplantation.

Lung transplantation has become a therapeutic option for end-stage pulmonary diseases, but after transplantation, infections and obliterative bronchiolitis (OB) are major causes of long-term morbidity and mortality. OB is a fibroproliferative disease, of poorly understood etiology, characterized by an irreversible decline in allograft function. Because diseases with tissue iron overload are characterized by fibrosis and end-organ failure, we studied the iron concentrations in BAL fluid and lung tissue in 10 lung allograft patients. BAL fluid revealed significantly elevated iron concentrations in allograft patients compared with five normal volunteers (135+/-16.54 micromol/L vs 33.65+/-7.48 micromol/L, respectively). Prussian blue staining of biopsy specimens of lung allograft tissue revealed an accumulation of iron primarily in alveolar macrophages. Immunohistochemical stains for ferritin revealed accumulation of the protein in macrophages, interstitium, vascular walls, and bronchiolar epithelium. Iron studies of the blood (serum ferritin and iron concentrations) revealed no evidence for systemic iron overload. In conclusion, patients with pulmonary allografts appear to have elevated concentrations of iron in lung tissue. This iron overload may place the allografts at increased risk of metal-mediated injury and fibrosis.

Radiologic issues in lung transplantation for end-stage pulmonary disease.

Lung transplantation has evolved into an effective therapy for end-stage pulmonary disease. The radiologist has an important role in the management of these patients before and after transplantation. Unfortunately, the radiologic findings of the major complications (i.e., reperfusion edema, infection, rejection) that occur after transplantation overlap and are often nonspecific. Clinical correlation, bronchoalveolar lavage, and transbronchial biopsy are usually required for accurate differentiation. The following rules of thumb may be helpful: Radiographic opacities seen during the first week are usually due to reperfusion edema: persistent or progressive opacities beyond the first week suggest infection or acute rejection: infection in the first month is usually bacterial, and opportunistic pneumonia is more common thereafter, nodular opacities are usually due to infection or posttransplantation lymphoproliferative disorders but can also be due to transbronchial lung biopsy; and progressive bronchial dilatation and air trapping seen on expiratory CT are useful signs of BOS.